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PubMed2004

[Nuclear auto-antibodies: a useful tool for the diagnosis, the classification and the prognosis of systemic sclerosis].

PURPOSE: Systemic sclerosis (SSc) like other connective tissue diseases is characterized by the occurrence of antinuclear auto-antibodies (ANA). We reviewed the diagnostic value and prognostic value of ANA in SSc. CURRENT KNOWLEDGE AND KEY POINTS: LeRoy proposed new criteria of limited forms of SSc which take into account the immunological profile of the patients. Anticentromere, antitopoisomerase I, antifibrillarin, anti-PM-Scl, antifibrillin or anti-RNA-polymerase I or III are considered as specific anti-autobodies. Whereas anticentromere antibodies are more associated with limited SSc and antitopoisomerase I with diffuse SSc, other auto-antibodies were associated with other organ involvement : anti-RNA-polymerase I or III and renal crisis, anti-U1-RNP and pulmonary hypertension and pulmonary fibrosis, etc. Patient with persistent antitopoisomerase I antibodies have a poor survival, those with antitopoisomerase antibodies that disappear with time have a better prognosis. FUTURE PROSPECTS AND PROJECTS: A better identification of the patients with SSc, an individual biological profile and organ involvement may help better management of the disease and better access to clinical trials. The development of new immunological tests and their clinical application should help us in that way.

Antibodies, Antinuclear↗
PubMed2004

Human leukocyte antigen class II associations with systemic sclerosis in South Africans.

Human leukocyte antigen class II typing, using polymerase chain reaction-sequence-specific primers, was performed in 52 Black South Africans with systemic sclerosis (SSc) and 112 controls. Increased frequencies of DR2 in the overall SSc group (OR = 2.4), DRB1*0301 in the limited cutaneous SSc (lcSSc) subset (OR = 9.0), and DQB1*0301/4 in the diffuse cutaneous SSc (dcSSc) subset (OR = 9.0) were observed. Pulmonary fibrosis was associated with DRB1*11 and anti-topoisomerase I antibodies were associated with DPB1*1301 and DRB1*15. Patients with anti-fibrillarin antibodies (AFAs) had increased the frequencies of DRB1*1101 allele group (OR = 16) and DQB1*0603/14 (OR = 13.6). These findings provide new serological and immunogenetic data on a previously unreported population. The association of AFAs with class II alleles merits further investigation.

Africa, Southern↗
PubMed2004

Mapping of the immunodominant T cell epitopes of the protein topoisomerase I.

OBJECTIVES: To identify the immunodominant T cell epitopes of the topoisomerase I protein in patients with systemic sclerosis (SSc) and control subjects, using computational analysis software (TEPITOPE) and T cell proliferation assays. METHODS: Six oligopeptides, predicted by TEPITOPE software as potential topoisomerase protein epitopes, were used to perform T cell proliferation assays in 21 patients with SSc and 15 healthy controls. RESULTS: A positive response to at least one of the peptides was seen in 10/21 patients and 7/15 healthy controls. Among responders, the proliferative response was limited to a single peptide in 6/7 healthy controls, whereas 5/10 patients responded to more than one peptide. In responding patients a significant correlation was found between disease duration and number of peptides inducing a response (p = 0.007). CONCLUSIONS: Several T cell epitopes of the topoisomerase I protein have been identified and evidence has been found to suggest epitope spreading in patients with SSc.

Adult↗
PubMed1996

The relationship of thoracic lymphadenopathy to pulmonary interstitial disease in diffuse and limited systemic sclerosis: CT findings.

OBJECTIVE: Mediastinal lymphadenopathy is frequently associated with interstitial lung disease (ILD) in patients with systemic sclerosis (SSc). This study compared the extent of lymphadenopathy in diffuse and limited SSc with the presence and type of ILD found on CT scans. SUBJECTS AND METHODS: Seventy-three patients with diffuse and limited SSc underwent thoracic CT. The presence of lymphadenopathy was correlated with the frequency and type of ILD. RESULTS: Fifty-eight percent (18/31) of patients with diffuse cutaneous SSc and 40% (17/42) of patients with limited cutaneous SSc had lymphadenopathy. A significant relationship was found between lymphadenopathy and the presence of interstitial disease (p = .0002). Seventy-two percent (18/25) of patients with a ground-glass parenchymal pattern of interstitial disease and 74% (14/19) of patients with a honeycomb pattern had lymphadenopathy. CONCLUSION: Lymphadenopathy is prevalent in patients with SSc and ILD regardless of clinical subtype or interstitial pattern. Lymphadenopathy appears to increase as a function of the profusion rather than the morphology of ILD.

Female↗
PubMed2006

Increased expression of basic fibroblast growth factor in skin of patients with systemic sclerosis.

Increased collagen deposition is a hallmark of systemic sclerosis (SSc). Several fibrogenic cytokines play a role in this sclerosis. The role of basic fibroblast growth factor (bFGF), the most potent fibrogenic cytokine, is poorly understood in SSc. Skin biopsies from forearm of 13 patients with SSc and 3 normal individuals were analyzed by immunohistochemistry using avidin biotin-system to amplify the signal. In addition serum levels of bFGF were also measured in 30 patients including these 13 and 23 healthy controls. Thirteen patients with SSc were all females and had a median age of 26.5 years, median disease duration of 2.25 years. Of these thirteen, seven had diffuse and six had limited disease. The skin biopsies from patients showed increased expression of bFGF in the basal layer of epidermis, dermis (periappendageal, perivascular, matrix tissue) as compared to normal tissues. The expression of bFGF did not correlate with duration of disease or skin score. In contrast, only low levels of bFGF were detectable in 4/30 sera from SSc patients as compared to 3/23 from healthy controls (p = ns). Overexpression of bFGF in skin of patients with SSc along with normal serum levels suggests that bFGF probably acts in an autocrine or paracrine manner in fibrogenesis.

Adolescent↗
PubMed2000

Gynaecologic history in systemic sclerosis.

The aim of the study was to analyse the gynaecologic history of 150 Brazilian patients with systemic sclerosis (SSc) by comparing the outcome of the pregnancies before and after disease onset and in the two clinical variants of SSc, as well as to assess the effects of the pregnancy on the progress of the disease. A retrospective analysis was carried out of 150 female SSc patients, more than 18 years old, who attended the outpatient clinic of the Unit of Rheumatology of the State University of Campinas. The patients were questioned about the number of pregnancies, deliveries (full-term infants, premature births and twins) and fetal deaths (spontaneous abortions and perinatal deaths). These data were subdivided into pregnancies before and after SSc onset. In those gestations started after disease onset the patients were questioned about the evolution of SSc during the pregnancy. The patients were also asked about dyspareunia and the age at menopause. Thirty-two patients (21 %) had never been pregnant, and only five of them were considered infertile. One hundred and eighteen patients (79%) had a total of 406 pregnancies, with an average of 3.4 per patient; there were 364 pregnancies before and 42 after SSc onset. There were 58 fetal deaths (14% of the pregnancies), 50 of these occurring before and eight after disease onset; 55 were spontaneous abortions and the other three were perinatal deaths. The fertility rate was higher in the limited SSc (3.6) than in the diffuse SSc patients (3.1), although the percentage of fetal deaths and the evolution of SSc during the pregnancy were similar in the two clinical variants. In the pregnancies that occurred after the onset of SSc, the clinical course remained stable in 72% of the cases, worsened in 14% and improved in 14%. Dyspareunia was mentioned by 49 patients (37% of those with an active sexual life). Menopause was reported by 72 patients, predominantly with limited SSc (61 patients). The fertility rate in the postmenopausal SSc patients was 3.9, similar to that observed in general postmenopausal population in Brazil. The analysis of the gynaecologic history in this series of SSc patients showed no increased risk in infertility or spontaneous abortions. The fertility rate in the two SSc clinical variants was higher than that observed in the local global population. Most of the patients who became pregnant after the onset of SSc showed no signs of worsening during the course of the disease.

Adult↗
PubMed1997

Circulating intercellular adhesion molecule-1 in the sera of patients with systemic sclerosis: enhancement by inflammatory cytokines.

We measured serum levels of circulating intercellular adhesion molecule-1 (cICAM-1) in patients with systemic sclerosis (SSc) and normal controls. The levels of cICAM-1 were determined by sandwich enzyme-linked immunosorbent assay in sera from 88 patients with SSc and in 20 healthy controls. In addition, these levels were examined in the supernatants of cultured peripheral blood mononuclear cells (PBMC) and dermal fibroblasts from 10 patients with SSc and 10 healthy control subjects. Serum levels of cICAM-1 were significantly higher in patients with SSc than in healthy controls. Serum cICAM-1 levels were significantly higher in patients with diffuse cutaneous SSc (dcSSc) than in patients with limited cutaneous SSc (lcSSc). These serum levels were correlated with the presence of contracture of phalanges, pulmonary fibrosis, joint involvement and increased erythrocyte sedimentation rate. The release of cICAM-1 was significantly increased in the supernatants of cultured PBMC from patients with SSc. Moreover, inflammatory cytokines (interferon-gamma, interleukin-1 and tumor necrosis factor-alpha) enhanced the release of cICAM-1 in vitro in SSc cells. These findings suggest that cICAM-1 may be involved in immune reactions in this disease.

Cells, Cultured↗
PubMed2001

Anti-fibrillarin antibodies in systemic sclerosis.

OBJECTIVES: To investigate the nature and extent of organ involvement in anti-fibrillarin antibody (AFA)-positive patients within a UK systemic sclerosis (SSc) population. METHODS: We investigated 1026 consecutive patients with SSc. AFA was identified by the characteristic clumpy nucleolar and coilin body pattern of staining in interphase cells and staining of fibrillarin in metaphase cells by indirect immunofluorescence using HEp-2 cells. Identity of the 34-kDa fibrillarin protein was confirmed by immunoprecipitation from [(35)S]methionine-labelled HeLa cell extract. RESULTS: AFA was detected in 42 patients (4.1%) with early disease onset (mean age 36 yr). Sixteen (38%) patients had limited cutaneous (lcSSc) and 26 (62%) diffuse cutaneous SSc (dcSSc). All eight Afro-Caribbean patients with AFA had dcSSc whereas the Caucasians were equally divided between dcSSc and lcSSc. Within the dcSSc subgroup, 54% had myositis, 35% had pulmonary hypertension, 15% had cardiac involvement and 23% had renal involvement. CONCLUSIONS: AFA identifies young SSc patients with frequent internal organ involvement, especially pulmonary hypertension, myositis and renal disease. In contrast to previous reports, AFA was not restricted to dcSSc patients in Caucasians.

Adult↗
PubMed2000

[Progressive hemifacial atrophy in the young patient: physiopathologic hypotheses, diagnosis and therapy].

Parry-Romberg syndrome is characterized by a limited progressive hemifacial atrophy. Since its first description in 1825, this syndrome has aroused interrogation and reflection about is pathophysiology, its variable clinical expression and its progression. The first part of this focuses on the different hypotheses advanced to date to explain this type of atrophy. We then recall the different steps for clinical diagnosis and treatment. Management of such an unpredictable disorder is particularly difficult. Because of the uncertain pathophysiology, medical therapy has not been very successful. Palliative reconstruction surgery remains the only possibility. We present three cases illustrating this review of progressive hemifacial atrophy.

Adolescent↗
PubMed2004

Appropriate utilization of semi-quantitative analysis in salivary scintigraphy.

AIM: The purpose of this case-control study was to determine whether semi-quantitative indices derived from salivary time-activity curves (TACs) are useful in the diagnosis and management of xerostomia. METHODS: Twenty-six healthy volunteers and 83 consecutive patients with xerostomia, including a subset of 40 patients with Sjogren's syndrome, underwent sequential salivary scintigraphy (SSS). Semi-quantitative analysis of the TACs was performed, deriving six different indices, previously cited in the literature, for each patient. These reflected trapping and uptake, stimulated excretion, or stimulated and unstimulated oral radioactivity. The indices were the percentage uptake, uptake ratios, maximum accumulation, pre-stimulatory oral radioactivity index, post-stimulatory oral radioactivity index and ejection fraction. RESULTS: Reduced parotid activity relative to submandibular activity, expressed as the P : S ratio, was able to distinguish abnormal from normal salivary function, and a parotid ejection fraction of greater than 50% also indicated normal parotid function. The other parameters showed no statistically significant difference between controls and patients. Individual variation in all indices served to widen the reference limits obtained from controls to the extent that they overlapped with those from the xerostomic population. CONCLUSIONS: This finding, together with previous work indicating that uptake parameters are only sensitive to differences exceeding 25% of the gland mass, the possibility that xerostomia may result from qualitative as well as quantitative changes in saliva and the probability that immune factors decrease neurosecretory circuits without affecting acinar mass, suggest that those indices derived from salivary TACs that directly reflect trapping and uptake are not useful in the detection of salivary gland disease.

Case-Control Studies↗
PubMedDate not supplied

Elevated whole blood chemiluminescence in patients with systemic sclerosis.

OBJECTIVE: Systemic sclerosis (SSc) is accompanied by oxidative stress that in turn may accelerate endothelium degeneration and thus disease progression. We tested whether phagocytes from SSc patients release more reactive oxygen species (ROS) and whether this release correlates with some clinical parameters. METHODS: ROS production by blood phagocytes was measured with the luminol enhanced whole blood chemiluminescence (CL). Resting and N-formyl-methionyl-leucyl-phenylalanine -induced CL (fMLP-induced CL) was measured in 30 patients with SSc and 30 healthy controls matched as to age, sex, and level of cigarette smoking. RESULTS: Resting CL and fMLP-induced CL calculated per 10(4) phagocytes present in the assayed blood sample were higher in patients with systemic sclerosis than in healthy controls (median; range, 0.88; 0.47-1.39 vs. 0.73; 0.13-1.07 aU/10(4)p and 621; 293-3522 vs. 411; 289-810 aUxs/10(4)p, p<0.02). Patients treated with cyclophosphamide and/or prednisone for 11; 3-168 months did not differ in respect to CL from those that never received the medications. Similarly, no significant differences were found between patients with limited and diffuse SSc. Resting CL correlated (p<0.05) with clinically manifested interstitial lung disease (r=0.59), single breath carbon monoxide diffusing capacity (r= -0.56) and serum autoantibodies titre (r= 0.43). CONCLUSIONS: Blood phagocytes from patients with systemic sclerosis, especially from those with interstitial lung disease, generate elevated amounts of ROS as assessed with CL. This confirms the presence of systemic oxidative stress in SSc patients.

Adolescent↗
PubMed2000

HLA-DQA1*0501 is associated with diffuse systemic sclerosis in Caucasian men.

OBJECTIVE: Systemic sclerosis (SSc) is uncommon in men, and relatively little is known about factors contributing to its pathogenesis in this population. In the current study, we investigated HLA class II alleles in men with SSc. We also investigated the hypothesis that HLA compatibility of the mother could be a risk factor for SSc in men. METHODS: Sequence-specific oligonucleotide probe typing was used to determine DQA1, DQB1, and DRB1 alleles of SSc patients (50 men and 36 parous women), healthy controls (59 men and 80 parous women), 26 mothers of men with SSc, and 44 mothers of healthy men. All study subjects were Caucasian, and allele frequencies were compared with those of Caucasian controls from the Eleventh International Histocompatibility Workshop as well as those of local controls. RESULTS: The DQA1*0501 allele was significantly increased among men with SSc compared with healthy men (odds ratio [OR] 2.3, P = 0.006, Pcorr = 0.04). DQA1*0501 was associated with diffuse SSc in men (OR 3.0, P = 0.004, Pcorr = 0.03), but not with limited SSc in men. Maternal HLA compatibility was not a risk factor for SSc in men. CONCLUSION: Previous studies have shown associations of DRB1 alleles with SSc, but have rarely determined DQA1 allele frequencies. Our findings indicate that a specific DQA1 allele is associated with SSc, and that DRB1 associations may be due to linkage disequilibrium with DQA1. Moreover, by analyzing genetic susceptibility according to sex, we found that the contribution of HLA genes to the risk of SSc was substantially greater in men than in parous women.

Alleles↗
PubMed1995

T cell repertoire in systemic sclerosis.

An increase of certain T cell subsets in systemic sclerosis patients, particularly of V delta 1+ gamma delta T cells in the blood and lungs and CD8+ alpha beta T cells in the lungs, has been shown. The diversity of T cell antigen receptor (TCR) V delta 1, V alpha, and V beta gene repertoires was examined using reverse transcriptase-polymerase chain reaction to amplify rearranged TCR transcripts across the junctional region. This was followed by two methods of analysis. First, the relative expression of V alpha and V beta genes was determined in the blood and bronchoalveolar lavage fluid of the patients. Second, we looked for evidence of restricted diversity of the junctional regions in TCR V delta 1 transcripts and in different V alpha and V beta gene families. Limited V delta 1-C delta junctional region lengths were observed in the patients compared to controls. This was confirmed by sequence analysis of V delta 1-C delta junctional regions after subcloning amplified products in a bacterial vector. A restricted diversity of the junctional region lengths was also detected in a number of V alpha and V beta gene families, particularly within bronchoalveolar CD8+ T cell subset. These data suggest that the oligoclonal expansion of the corresponding alpha beta and gamma delta T cells is antigen-driven and may be important in the pathogenesis of systemic sclerosis.

Blood↗
PubMed2003

Analysis of lymphocyte subpopulations in systemic sclerosis.

Systemic sclerosis (SSc) is a chronic inflammatory connective-tissue disease of unknown etiology, characterized by fibrosis and microvascular injury in affected organs. It has become clear that the activated cellular-immune system plays a central role in the pathogenesis of SSc. This study analyzes the numbers of lymphocyte subpopulations and their relations with clinical and laboratory manifestations. We studied a group of 42 patients with SSc and a group of 28 matched normal controls by flow cytometry using the lymphocyte cell-surface markers CD2, CD3, CD4, CD8, CD19, CD25, CD45RA, CD56, CD71, HLA-DR, TCR alpha/beta, and TCR gamma/delta. Patients with SSc had similar percentages of CD2+, CD3+, CD3+ CD4+, CD3+, CD8+, CD25+, CD4+ CD45RA+, CD8+ CD45RA+, CD71+ cells, and CD4+/CD8+ cell ratio when compared to normal controls. In contrast, the percentages of TCR gamma/delta cells were significantly lower in SSc patients with diffuse and late-stage disease with pulmonary involvement, muscle involvement, and the presence of anti-Scl-70 antibodies. Patients with diffuse SSc in early- and late-stage disease had significantly increased percentages of HLA-DR in CD4+ and CD8+ cells. Patients with late-stage disease had increased percentages of CD4+ CD45RA+ T-cells. Patients with limited and early-stage disease had smaller percentages of B-cells (CD19+). Patients with diffuse and late-stage disease had smaller percentages of NK-cells (CD56+). These results suggest that T-, B-, and NK-cell alterations may be involved in the onset of the disease, and/or in the perpetuation of disease, and may eventually be useful as a prognostic indicator in selected patient subgroups.

Adult↗
PubMed1994

[Expression of p53 in the skin in systemic sclerosis. Immunohistochemical study of 8 cases].

P53 gene belongs to the family of "Tumor suppressor gene". It encodes a nuclear phosphoprotein involved in cell proliferation control; mutations of p53 gene are the most common genetic alterations found in human tumors. These mutations may cause the production of an altered protein that usually loses its physiological function. The mutant p53 protein is more stable than the wild type form and it is immunohistochemically detectable. Systemic Sclerosis is characterized by activation of fibroblasts, endotheliocytes and lymphocytes; furthermore, in this disease, a proto-oncogenic activation has already been shown in fibroblasts and lymphocytes. The aim of this study was to verify p53 expression in the skin of SSc patients. Eight patients, all classified in the limited cutaneous subset of SSc, after informed consent, underwent skin biopsies of the affected and apparently unaffected skin. P53 was investigated by immunohistochemistry, using a monoclonal anti-p53 antibody (DO-7), on formalin fixed, paraffin embedded tissue. P53 immunoreactive cells were found in 4 out of 8 biopsies; in all cases the positivity was confined to cells of the basal layer of the epidermis, histologically identified as keratinocytes. A large case series and a molecular biology approach are needed to support these preliminary observations.

Adult↗
PubMed1989

Congenital fascial dystrophy: stiff skin syndrome--a human counterpart of the tight-skin mouse.

Four patients are described with stony-hard induration of the skin and deeper tissues, most pronounced on the buttocks, thighs, and legs, and with limitation of joint mobility and contractures of the lower limbs. Two patients were siblings and one was the product of a consanguineous marriage. The disorder appears to be genetically determined, but the mode of inheritance has not been established. The disease was noticed in the patients' early infancy and was not progressive. Except for functional impairment of the lungs caused by an underdeveloped thorax that resulted from pressure of the thickened thoracic fascia, there was no involvement of the viscera or muscles and no immunologic abnormalities. The most important finding was markedly thickened fascia. This hereditary connective tissue disorder has all the characteristics of the tight-skin mouse.

Adult↗
PubMed2004

Detection of circulating soluble CD28 in patients with systemic lupus erythematosus, primary Sjögren's syndrome and systemic sclerosis.

The aim of this study was to evaluate the presence and the role of the serum soluble costimulatory molecule CD28 in patients with systemic lupus erythematosus (SLE), primary Sjögren's syndrome (SS), and systemic sclerosis (SSc). Soluble CD28 concentration was determined by ELISA in 45 patients with SLE, 45 patients with primary SS, 30 patients with SSc, and 45 healthy subjects. We also evaluated CD28 mRNA expression by semiquantitative RT-PCR, and the biological activity of recombinant soluble CD28 on T lymphocyte activity. Concentrations of soluble CD28 were significantly higher in patients with SLE, primary SS and SSc than in healthy subjects. Soluble CD28 concentrations were higher in patients with systemic primary SS than in patients with glandular-limited primary SS. PCR analysis suggested that soluble CD28 resulted from the shedding of the membrane form. In vitro assay revealed that soluble CD28 inhibits the anti-CD3 mAb induced T cell proliferation. Soluble CD28, which modulates the proliferation of T lymphocytes, could be associated with disease severity in patients with autoimmune disease, especially primary SS. These results suggest that soluble CD28 could play an important role in the regulation of autoimmune diseases.

Adolescent↗
PubMed1993

Autoantibody reactive with RNA polymerase III in systemic sclerosis.

OBJECTIVE: To determine the clinical significance of anti-RNA polymerase III antibody in systemic sclerosis (SSc). DESIGN: A point prevalence study of autoantibody to RNA polymerase III and longitudinal examination of its clinical significance in patients with SSc and in controls. SETTING: University medical center rheumatology practice. PATIENTS: Two hundred fifty-two consecutive new patients with SSc and 170 controls (150 patients with other connective tissue diseases and 20 normal volunteers). MEASUREMENTS: The presence of anti-RNA polymerase III antibody was determined by immunoprecipitation, immunoblotting, and immunodepletion studies. MAIN RESULTS: Serum specimens from 57 of the 252 patients with SSc (23%; 95% CI, 18% to 28%) reacted with RNA polymerase III, compared with none of the specimens from 170 controls (0%; 95% CI, 0% to 2%). In 40 of these 57 specimens, immunoprecipitation studies also showed the presence of RNA polymerase I or II, or both. Anti-RNA polymerase III antibody was detected in sera from 50 of the 111 patients (45%) who had SSc with diffuse cutaneous involvement (dcSSc), 7 of 114 patients (6%) who had SSc with limited cutaneous involvement, and none of 27 patients with an SSc overlap syndrome (P < 0.001). Among patients with dcSSc, anti-RNA polymerase III antibody was more common than antitopoisomerase I antibody (45% compared with 27%; P = 0.008). Patients with anti-RNA polymerase III antibody had a statistically significant higher mean maximum skin thickness score but statistically significant lower frequencies of telangiectasias, inflammatory myopathy, restrictive lung disease, and serious cardiac abnormalities than did patients with antitopoisomerase I antibody. CONCLUSION: Anti-RNA polymerase III antibody is a new marker autoantibody for many patients who have SSc with diffuse or extensive cutaneous involvement.

Antibodies, Antinuclear↗