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PubMed1993

Gastrointestinal regulatory peptides in systemic sclerosis.

OBJECTIVE: Gastrointestinal involvement commonly occurs in systemic sclerosis (SSc), but its pathogenesis is not well understood. Since there is evidence of a defect in neurotransmitter release, we were interested in examining the relationship between gastrointestinal dysfunction and plasma concentrations of gastrointestinal regulatory peptides in patients with SSc. We studied 43 consecutive patients, 18 with diffuse and 25 with limited cutaneous disease. METHODS: Levels of corticotropin-releasing hormone (CRH), gastrin, motilin, neuropeptide Y (NPY), and peptide YY (PYY) were determined by radioimmunoassay and high-performance liquid chromatography (HPLC). RESULTS: Plasma concentrations of CRH, motilin, NPY, and PYY were significantly increased among SSc patients compared with healthy control subjects, and HPLC-characterization of motilin, NPY, and PYY showed a different pattern of fragments. No correlation was found between esophageal hypomotility and the concentration of peptide. Acid output did not correlate with gastrin levels, but was more often increased in patients with increased CRH and NPY values. Fat malabsorption, assessed by the triolein breath test, was more common among patients with increased motilin and PYY. CONCLUSION: This study shows that elevated peptide concentrations commonly occur in patients with SSc. Since regulatory peptides are involved in gastrointestinal motility, secretion, and absorption, further characterization of this neuroendocrine system may help in understanding the complex regulation of gastrointestinal dysfunction in SSc.

Adult↗
PubMed1988

Progressive systemic sclerosis: mode of presentation, rapidly progressive disease course, and mortality based on an analysis of 91 patients.

The overwhelming majority of patients with PSS present with combinations of Raynaud's phenomenon, sclerodactyly, polyarthralgias, or swelling of an extremity. However, the clinical presentation of PSS may be atypical; 14% of patients in the present series initially sought medical attention for symptoms other than Raynaud's phenomenon, tight skin, or joint pain. In the present series, only 31% of patients fulfilled the ARA criteria for PSS at the time of initial medical evaluation. Most patients manifested advanced disease by the time the criteria were fulfilled. The ARA criteria for the classification of PSS appear to have limited value with regard to making the diagnosis in an individual patient. Rapidly progressive PSS occurred in 17.6% of patients in this series and represents a particularly fulminant form of the disease whose course may not be predictable on clinical grounds at the time of initial medical evaluation or diagnosis. Patients destined to develop renal or cardiorespiratory failure usually do so in the first 3 years of disease. Close observation of PSS patients during the first 12 to 18 months may serve to identify those individuals who will undergo an accelerated disease course. Prognosis for patients with rapidly progressive PSS is poor and is associated with significantly higher mortality compared with patients with a more protracted disease course. Future therapeutic trials in PSS should be designed with the recognition that a subgroup of patients with this disorder will have a rapidly progressive disease course.

Adolescent↗
PubMed2003

Elevated vascular endothelial growth factor in systemic sclerosis.

OBJECTIVE: To determine the serum levels of vascular endothelial growth factor (VEGF) in patients with systemic sclerosis (SSc) and to search for relationships between its serum levels and the clinical manifestations. METHODS: Serum levels of VEGF in patients with SSc and healthy controls were determined by ELISA. At the time of blood sampling, individual organ involvement was assessed, and a video microscope and PC based image processing were used to visualize nailfold capillaries and to quantify capillary density. RESULTS: Serum levels of VEGF in 48 patients with SSc were significantly higher than in 30 controls (432 +/- 356 vs 91 +/- 64 pg/ml; p < 0.001). Patients with diffuse cutaneous SSc (n = 21) had higher levels of serum VEGF than those with limited cutaneous SSc (n = 27) (432 +/- 356 vs 135 +/- 127 pg/ml; p < 0.001). Serum VEGF levels correlated well with the extent of skin sclerosis, as determined by modified Rodnan skin score (r = 0.656, p < 0.001) and serum TGF-beta levels (r = 0.530, p < 0.001). In particular, serum VEGF levels were inversely correlated with the capillary density of nailfold (r = -0.649, p < 0.001). However, no significant differences were found in the serum levels of VEGF between patients with systemic organ involvement and those without. CONCLUSION: The extent of skin sclerosis may contribute to the elevation of serum VEGF and high VEGF levels may serve as a surrogate indicator of capillary damage in SSc.

Adult↗
PubMed1999

[Pulmonary hypertension in rheumatic diseases].

In rheumatic diseases (RD) pulmonary hypertension (PH) may result by either direct damage of the pulmonary arteries (isolated PH) or pulmonary interstitial fibrosis and other causes. PH is an important cause of morbidity and mortality in systemic sclerosis in which it is more frequently isolated in the limited cutaneous variant and secondary to interstitial fibrosis in the diffuse type. In isolated PH the main histopathological finding is an occlusive arteriopathy. The role of recurrent vasospasm ("lung Raynaud's phenomenon") is still being debated. In systemic lupus erythematosus, although uncommon, PH is being increasingly reported and may recognize multiple etiological factors including vasoconstriction, vasculitis, in-situ pulmonary thrombosis or chronic recurrent thromboembolism. PH may be a severe and often fatal complication of mixed connective tissue disease and dermato/polymyositis. PH may also be diagnosed in patients with rheumatoid arthritis, primary Sjögren's syndrome and primary antiphospholipid syndrome. Doppler echocardiography is the technique of choice for the evaluation of PH because it is nonivasive and allows serial determinations of the arterial pulmonary pressure. The therapy of PH associated with RD includes corticosteroids, immunosuppressive drugs, calcium-antagonists, ACE-inhibitors, anticoagulants, O2, prostacyclin or its stable analogue, iloprost. Carefully selected patients may benefit from single lung or heart-lung transplantation.

Algorithms↗
PubMed1995

Oligoclonal expansion of V delta 1+ gamma/delta T-cells in systemic sclerosis patients.

Systemic sclerosis (SSc) is a multisystem disease characterized by T-cell infiltration of involved tissues, fibrosis, and small vessel vasculopathy. Using flow cytometric analyses, we found an increased percentage of gamma/delta T-cells expressing the T-cell antigen receptor variable (V) delta 1 gene segment in the peripheral blood and bronchoalveolar lavage fluid of patients with SSc. To estimate clonality of these V delta 1+ T-cells, the diversity of V delta 1 junctional regions (V-Diversity-Joining gene segments) was examined using a reverse transcriptase-polymerase chain reaction to amplify T-cell antigen receptor delta chain transcripts isolated from peripheral blood mononuclear cells, lung, esophagus, stomach, or skin of patients and controls. Limited diversity of V delta 1-J delta junctional regions in SSc patients was demonstrated by the finding of greater restriction in the nucleotide lengths of junctional region cDNAs in individual SSc patients than in controls. Sequence analyses confirmed that V delta 1-J delta junctional regions from the blood of SSc patients had less diversity than those from controls, in that a significantly higher proportion of sequences were repeated in patients (54.4% vs. 19.4% in controls). Evidence for selection of the V delta 1+ T-cells in tissues of individual SSc patients came from the findings that the same V delta 1-J delta junctional sequences could be isolated from the same tissue over time and that identical V delta 1-J delta junctional sequences could be isolated from multiple tissues. These data suggest that expansion of V delta 1+ gamma/delta T cells may be antigen driven in SSc patients.

Base Sequence↗
PubMed2002

Influence of prior pregnancies on disease course and cause of death in systemic sclerosis.

BACKGROUND: Microchimerism from fetal or maternal cells transferred during pregnancy has been implicated in the pathogenesis of systemic sclerosis (SSc). OBJECTIVE: To determine whether a prior pregnancy influenced disease progression and cause of death in patients with SSc. PATIENTS AND METHODS: The patients comprised a retrospective study cohort of 111 women with SSc: 78 patients with prior pregnancies (PP) and 33 who were never pregnant (NP), followed up at Thomas Jefferson University. Differences in age at onset, disease subset, organ involvement, cause of death, and type of antinuclear autoantibodies were evaluated statistically, including regression analysis. RESULTS: The age at onset of SSc in NP patients was 32.0 years compared with 45.7 years in patients with one or two prior pregnancies (p<0.0001), 46.6 years in patients with three or four pregnancies (p<0.0001), and 51.3 years in patients with five to seven pregnancies (p<0.0005). In the 16 patients who had an elective pregnancy termination, 14/16 (87.5%) had diffuse SSc v 2/16 (12.5%) with limited SSc (p<0.0001; odds ratio (OR)=49.0). Of the NP women, 7/30 (23%) died from SSc related causes v 3/78 (4%) women who had pregnancies (p=0.0058; OR=7.6). A carbon monoxide transfer factor (TLCO) of <60% and disease duration >10 years was found in 10/13 (77%) NP patients v 10/23 (43%) patients who had pregnancies (p=0.05; OR=4.7), and a TLCO <50% and disease duration >10 years was identified in 7/13 (54%) NP patients v 6/23 (26%) of the patients who had pregnancies (p=0.09; OR=3.2). CONCLUSIONS: There are differences in the age at onset, clinical course, severity of lung involvement, and cause of death in women who develop SSc before pregnancy compared with those who develop it after pregnancies. The NP patients with SSc had onset of disease at an earlier age, more severe lung involvement, and higher rate of death due to SSc.

Adult↗
PubMed2004

Elevated matrix metalloproteinase-9 in patients with systemic sclerosis.

Matrix metalloproteinase-9 (MMP-9) has been implicated in the pathogenesis of cancer, autoimmune disease, and various pathologic conditions characterized by excessive fibrosis. In this study, we investigated the expression of MMP-9 and its clinical significance in systemic sclerosis (SSc). The patients (n = 42) with SSc had higher concentrations of MMP-9 and of tissue inhibitor of metalloproteinase-1 (TIMP-1) and a higher ratio of MMP-9 to TIMP-1 in sera than healthy controls (n = 32). Serum MMP-9 concentrations were significantly higher in the diffuse type (n = 23) than the limited type of SSc (n = 19). Serum concentrations of MMP-9 correlated well with the degree of skin involvement, as determined by the Rodnan score and with serum concentrations of transforming growth factor beta. Moreover, dermal fibroblasts from patients with SSc produced more MMP-9 than those from healthy controls when they were stimulated with IL-1beta, tumor necrosis factor alpha, or transforming growth factor beta. Such an increase in MMP-9 production was partially blocked by treatment with cyclosporin A. In summary, the serum MMP-9 concentrations were elevated in SSc patients and correlated well with skin scores. The increased MMP-9 concentrations may be attributable to overproduction by dermal fibroblasts in SSc. These findings suggest that the enhanced production of MMP-9 may contribute to fibrogenic remodeling during the progression of skin sclerosis in SSc.

Adult↗
PubMed1999

Seasonal variation of Raynaud's phenomenon secondary to systemic sclerosis.

OBJECTIVE: Patients with systemic sclerosis (SSc) were assessed for 12 months to quantify the seasonal variation in Raynaud's phenomenon (RP) in patients with an underlying connective tissue disease. METHODS: Eighteen patients with SSc (17 limited, 1 diffuse type) were studied. Raynaud's attacks were recorded in a daily diary for four 2-week periods at 3 month intervals. Daily number and duration of attacks and overall severity of RP were calculated for each 2-week period. Mean daily temperatures, measured and perceived, were obtained for each period. RESULTS: In winter, patients had a mean of 2.9 attacks/day (SD +/-1.1), daily duration 70 minutes (SD +/-48) and a severity of score of 4.1 (SD +/-2.0) out of 10. All 3 variables correlated with ambient outdoor temperature and varied significantly over the 12 months (p<0.001) with mean reductions of 48, 50, and 56% respectively from winter to summer. Only 3 of 18 patients reported no attacks during the summer period. The mean measured and perceived outdoor temperatures increased from winter to summer by 10.6 and 14.3 degrees C, respectively. CONCLUSION: For patients with SSc, RP is a problem throughout the year. Symptoms may be reduced by about 50% in the summer months, but few patients experience complete relief.

Female↗
PubMed1997

Epidemiology and estimated population burden of selected autoimmune diseases in the United States.

Autoimmune diseases cause significant and chronic morbidity and disability. The actual number of persons in the United States that are affected by autoimmune diseases and the resultant magnitude of their impact on the public's health are limited to a few specific diseases. In order to understand the clinical, public health and economic importance of these diseases it is necessary to have estimates of incidence and prevalence rates in the population. In this analysis, we estimate the number of persons affected by 24 autoimmune diseases in the United States by applying mean weighted prevalence and incidence rates obtained from published articles to U. S. Census data. The study was restricted to 24 autoimmune predefined diseases for which there was direct or indirect evidence for autoimmune pathogenesis. Subsequently, we used computerized search software and ancestry searching (bibliographies) to conduct a comprehensive search of articles published from 1965 to the present. Eligible studies included those which adhered to standard disease definitions and which included population-based estimates of incidence or prevalence rates. Mean weighted incidence and prevalence rates were calculated from eligible published studies with greater weight proportionately given to larger studies. The mean rates were then applied to the U.S. Census population figures to estimate the number of persons currently afflicted with each disease and the number of new cases occurring each year in the United States. Only U.S. and European studies were used to estimate prevalence and incidence rates when there were at least six eligible studies available for a disease. When there were fewer than six studies, all available studies were included, regardless of country of origin. The number of eligible incidence and prevalence studies found in the literature varied considerably between the 24 autoimmune diseases selected. The largest number of eligible prevalence studies were conducted on multiple sclerosis (MS), rheumatoid arthritis, and systemic lupus erythematosus (SLE) (>/=23), followed by insulin-dependent diabetes (IDDM), myasthenia gravis, primary biliary cirrhosis, and scleroderma (>/=7). There were only one to four eligible studies done on 11 other diseases, and no prevalence studies on 6 diseases. Incidence studies were less frequent but the largest number of studies were conducted on IDDM (n = 37) and MS (n = 28), followed by Graves' disease/hyperthyroidism, glomerulonephritis, primary biliary cirrhosis, rheumatic fever, rheumatoid arthritis, scleroderma, and SLE (>/=9). On the other 11 diseases, there were one to six eligible studies, and no studies on 5 diseases. There were no eligible incidence or prevalence studies on Goodpasture's syndrome, idiopathic thrombocytopenia purpura, or relapsing polychondritis. Overall we estimate that 8,511,845 persons in the United States or approximately 1 in 31 Americans are currently afflicted with one of these autoimmune diseases. The diseases with the highest prevalence rates were Graves'/hyperthyroidism, IDDM, pernicious anemia, rheumatoid arthritis, thyroiditis, and vitiligo, comprising an estimated 7,939, 280 people or 93% of the total number estimated. Glomerulonephritis, MS, and SLE added an estimated 323,232 people. The prevalence of the other diseases reviewed were rare, less than 5.14/100,000. Most diseases were more common in women. From the incidence data we estimate that 237,203 Americans will develop an autoimmune disease in 1996 and that approximately 1,186,015 new cases of these autoimmune diseases occur in the United States every 5 years. Women were at 2.7 times greater risk than men to acquire an autoimmune disease. After reviewing the medical literature for incidence and prevalence rates of 24 autoimmune diseases, we conclude that many autoimmune diseases are infrequently studied by epidemiologists. As a result the total burden of disease may be an underestimate. (ABSTRACT TRUNCATED)

Autoimmune Diseases↗
PubMed2004

Digital iontophoresis of vasoactive substances as measured by laser Doppler imaging--a non-invasive technique by which to measure microvascular dysfunction in Raynaud's phenomenon.

OBJECTIVE: To test the hypothesis that microvascular vasodilation is impaired in patients with systemic sclerosis (SSc) compared with patients with primary Raynaud's phenomenon (PRP) and healthy controls, using the technique of laser Doppler imaging to quantify blood flow responses to iontophoresis of vasoactive agents. METHODS: Microvascular blood flow was measured by laser Doppler imaging before, during and after 120 s iontophoresis (30 microA) of 1% acetylcholine chloride (ACh, endothelium-dependent) and 1% sodium nitroprusside (NaNP, endothelium-independent). Two adjacent fingers of the left hand were studied, and the procedure then repeated on the right. Ten patients with limited cutaneous SSc (LCSSc), 10 patients with PRP and 11 healthy control subjects were studied. RESULTS: Vasodilation in response to both ACh and NaNP iontophoresis, as measured by 'area under the blood flow.time curve' (AUC), normalized for baseline flux, was similar in the control and PRP groups, but was diminished in the LCSSc group compared with both control and PRP groups (ACh results: control vs LCSSc P = 0.028, PRP vs LCSSc P = 0.005; NaNP results: control vs LCSSc P = 0.004, PRP vs LCSSc P = 0.005). There were no differences between groups in baseline flux values nor in voltages required to drive the 30 microA current. CONCLUSIONS: Both endothelium-dependent and endothelium-independent vasodilation are impaired in patients with LCSSc. Vasodilatory responses in patients with PRP are similar to those in controls. If reproducibility is confirmed to be satisfactory, then these techniques could be used to examine disease progression over time and responsiveness to vasoactive treatment, thus facilitating clinical trials.

Acetylcholine↗
PubMed1990

Immunological abnormalities in a group of patients with limited cutaneous systemic sclerosis and prominent vascular disease.

Antinuclear antibodies, circulating immune complexes, rheumatoid factors and anticardiolipin antibodies were detected in the sera of 17 patients affected by the limited cutaneous subset of systemic sclerosis and marked clinical evidence of ischaemic cutaneous lesions (fingertip ulcerations). This study was designed to evaluate the possible role of anticardiolipin (aCL) antibodies and other immunological disorders in the endothelial damage characteristic of the disease. ACL antibodies were found in 41% of the patients. With the exception of a significant connection with positive rheumatoid factor tests (RIA), no notable associations between anticardiolipin antibodies and antinuclear antibodies, circulating immune complexes (CIC), and other serological abnormalities were found. ACL antibodies did not significantly correlate with the presence of vascular lesions in our patients. However, a role of these antibodies in endothelial damage cannot be excluded, possibly in association with other serum factors such as immune complexes and antinuclear antibodies. A positive connection between the incidence of CIC and the severity of lung perfusion impairment was observed, and the previously reported relationship between anticentromere antibodies and calcinosis was indirectly confirmed.

Adolescent↗
PubMed2004

Angiotensin II in the lesional skin of systemic sclerosis patients contributes to tissue fibrosis via angiotensin II type 1 receptors.

OBJECTIVE: Tissue fibrosis in systemic sclerosis (SSc) is attributed to excessive deposition of extracellular matrix components produced by fibroblasts in skin lesions. Angiotensin II (Ang II), a vasoconstrictive peptide, is reported to have profibrotic activity as a result of induction of the extracellular matrix. The aim of the present study was to examine the expression of Ang II and its type 1 (AT(1)) and type 2 (AT(2)) receptors in affected skin and dermal fibroblasts from patients with SSc and to study the role of Ang II in collagen production by SSc dermal fibroblasts. METHODS: Levels of Ang II in sera from SSc patients and normal subjects were measured by a solid-phase immobilized-epitope immunoassay. Expression of angiotensinogen (Angt) in the skin was evaluated by immunohistochemistry. Expression of Angt, AT(1), and AT(2) in cultured dermal fibroblasts was analyzed by reverse transcription-polymerase chain reaction and immunohistochemistry. Levels of type I procollagen produced by cultured dermal fibroblasts were measured by enzyme-linked immunosorbent assay. RESULTS: Serum Ang II levels in patients with diffuse cutaneous SSc were significantly higher than those in patients with limited cutaneous SSc and in healthy donors. Immunohistochemical and immunoblotting analyses showed that Angt was present in skin from SSc patients, but not in normal skin. Angt messenger RNA (mRNA) was expressed in fibroblasts from patients with diffuse cutaneous SSc who had high levels of serum Ang II, but not in normal fibroblasts. AT(1) mRNA expression was found in both SSc and normal fibroblasts, whereas AT(2) mRNA was found only in SSc fibroblasts. Exogenous Ang II augmented the production of type I procollagen and transforming growth factor beta1 by cultured fibroblasts via activation of AT(1). CONCLUSION: Aberrant Ang II production may be involved in tissue fibrosis through excessive production of the extracellular matrix components in SSc dermal fibroblasts. This suggests that the use of AT(1) receptor antagonists may be a novel strategy for the treatment of tissue fibrosis in SSc patients.

Adult↗
PubMed2006

[Pulmonary arterial hypertension in connective tissue disease].

INTRODUCTION: Pulmonary arterial hypertension (PAH) is one of the most severe complications of connective tissue diseases. PAH is defined by mean arterial pulmonary pressure > 25 mmHg at rest (or 30 mmHg during exercise) during right heart catheterisation. STATE OF THE ART: About 10% of cases of PAH are related to connective tissue diseases. PAH may be observed in any of the connective tissue diseases; it is mostly encountered in systemic sclerosis (prevalence estimated to 8%), and is more frequent in the limited form of the disease with anticentromeres antibodies, in the presence of Raynaud's phenomenon, of antinuclear antibodies, decreased CO diffusion capacity, and during the perimenopausal period. Histopathological lesions are similar to that of idiopathic PAH (with plexogenic lesions being more rare); mutations have not been described. Venous thromboembolic disease (especially in lupus) and hypoxemia related to pulmonary fibrosis should be investigated. Screening for PAH is recommended in systemic sclerosis (by echocardiography every year and in case of dyspnea). Few clinical trials have been conducted specifically in PAH related to connective tissue diseases, therefore the treatment approach is similar to that of idiopathic PAH, with a poorer prognosis, including treatment with bosentan, epoprostenol and other prostacyclin analogs, and sildenafil. Immunosuppressive therapy may occasionally improve PAH in patients with systemic erythematosus lupus or mixed connective tissue disease. PERSPECTIVES: Respective indications of drugs and treatment associations need to be precised. CONCLUSION: The availability of efficacious treatments of PAH justifies its screening and early diagnosis in connective tissue diseases.

Antihypertensive Agents↗
PubMedDate not supplied

Glucocorticoid effects on myocardial performance in patients with systemic sclerosis.

OBJECTIVE: Myocardial inflammation andfibrosis are common autopsyfindings in systemic sclerosis (SSc) and, although symptomatic cardiac involvement occurs less often, current therapies remain empiric and do not prevent or modify its course. In this open, uncontrolled study we assessed the short-term effects of glucocorticoid administration on myocardial performance in patients with SSc in the absence of clinically overt cardiac disease. METHODS: Resting radionuclide ventriculography with 99mTc was performed before and 20 days after the administration of prednisolone, 20 mg daily, in 32 patients with SSc without clinically evident myocardial dysfunction at rest; 13 and 19 patients with systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA), respectively, were studied in parallel as controls. RESULTS: The mean left ventricular ejection fraction (LVEF) value at baseline was 59% in the SSc group; similar values were found for the SLE (61%) and RA (59%) groups. An impaired LVEF (i.e., <50%) was found in 6 patients with SSc and in 1 patient with SLE. Prednisolone administration resulted in a significant percent improvement in the baseline LVEF (mean 18%, p = 0.0001) in the SSc group; this improvement was greater in the patients with diffuse SSc than in those with limited skin disease (27% vs 10%, p = 0.02). The improvement was most prominent in the 6 patients with an initial impaired LVEF No significant improvement was observed in the SLE or RA control groups. The linear trend betveen the individual baseline LVEF values in patients with SSc and their percent changes after treatment (r2 = 0.55, p: 0.00001) showed that the lower the initial LVEF the greater the improvement caused by prednisolone. The degree of LVEF improvement was also associated with the individual erythrocvte sedimentation rate values and serum IgG concentrations at baseline. Prednisolone-induced changes in LVEF were not associated with any changes in blood pressure, heart rate, blood, plasma, or red cell volumes. CONCLUSION: Glucocorticoid administration may improve myocardial performance in some patients with SSc. Although further double-blind controlled studies of the long-term effects are warranted, such treatment may be useful in those patients with SSc and documented low LVEF if they are kept under careful observation for objective improvement.

Adolescent↗
PubMed2003

Distinct immune profiles characterize patients with diffuse or limited systemic sclerosis.

Mitogen-stimulated IL-2, IFN-gamma, TNF-alpha (type 1 cytokines), and IL-10 (type 2 cytokine) production by peripheral blood mononuclear cells, as well as expression of surface markers on immune cells, was evaluated in systemic sclerosis (SSc) patients. Fifty-four SSc patients with either diffuse (dSSc) or limited (lSSc) disease and 20 age- and sex-matched healthy controls (HCs) were examined. Fourteen patients were treated with prednisone and 9 patients with prednisone and cyclophosphamide pulses. Results showed that (1) IL-2 production is significantly decreased, whereas IL-10 is higher in untreated patients compared to HCs; IL-10, IFN-gamma, and TNF-alpha production is higher in lSSc compared to dSSc patients; (2) CD4+25+ (IL-2R), CD8+, and CD8+45RA-28+57- (memory) lymphocytes are reduced in patients compared to HCs; (3) CD95-expressing CD4+ and CD8+ cells are significantly higher in dSSc patients; and (4) steroids are more effective alone than in combination with cyclophosphamide in reducing IL-10 and IFN-gamma production in these patients. These results confirm that a complex imbalance in cytokine production is present in SSc patients and suggest that peculiar phenotypic populations are underrepresented in these patients. Overexpression of Fas in dSSc could results from the attempt of the immune system to induce apoptosis of autoreactive T-cell clones.

Aged↗
PubMed2001

[Treatments of progressive systemic sclerosis].

Progressive Systemic Sclerosis (PSS) is still an incurable disease but there are treatments for it, and the list of proposed treatments is long. The methodology of trials concerning PSS is complex, due to the low prevalence of the disease and therefore its financial interest for pharmaceutical companies, the lack of simple end points for efficacy, and the large number of clinical expressions with various prognoses. These causes explain why most open studies are fiercely positive, and why controlled studies are so rare. The progress made during the last 10 years concern 1) the diagnosis, which is now made earlier due to capillaroscopy and antibody assays, especially of anticentromere antibodies, 2) better knowledge of the prognosis, due to the classification of PSS into limited and the diffuse forms which have different prognoses, and 3) the recognition of a serious complication of the disease, ie. pulmonary hypertension, which can now be detected by non-invasive methods. All these improvements will also improve the methodology of future trials of drugs for treating PSS. In this ocean of uncertainties, some treatments have a valid background, and 3 visceral locations of PSS can be efficiently treated: renal involvement, with angiotensin-converting enzyme inhibitors, respiratory involvement, with D-penicillamine, and pulmonary hypertension, with prostacyclin derivatives. Corticosteroids are suspected to increase the risk of renal complications. Calcium blockers are considered a useful symptomatic treatment of the associated Raynaud's phenomenon and of the risk of digital necrosis, and may also constitute a treatment of PSS itself. A recent trial conducted by the French Microcirculation Society and its acrosyndrome Study Group considered the effects of an oral derivative of prostacyclin. Beneficial effects were: a reduction of the risk of digital necroses, improved overall wellbeing, less necessity for hospitalizations, fewer giant capillaries, and a dramatic fall in the level of von-Willebrand factor.

Humans↗
PubMedDate not supplied

Type III procollagen N-terminal propeptide, soluble interleukin-2 receptor, and von Willebrand factor in systemic sclerosis.

OBJECTIVE: To evaluate the blood concentration of type III procollagen N-terminal propeptide (PIIINP), soluble interleukin-2 receptor (sIL-2R), and von Willebrand factor (vWF) in systemic sclerosis (SSc) patients. METHODS: PIIINP, sIL-2R, and vWF were measured in the sera and plasma of 29 SSc patients and 29 sex- and age-matched healthy controls. Serum PIIINP was determined by radioimmunoassay. Both serum sIL-2R and plasma vWF were measured by enzyme-linked immunosorbent assay (ELISA). Associations between concentrations and clinical and laboratory features were evaluated. RESULTS: Serum levels of PIIINP and sIL-2R were significantly higher in the SSc group than in the control group (p < 0.01 for both). No differences in serum PIIINP and sIL-2R levels were found between the limited and diffuse cutaneous subsets. However, PIIINP concentrations were significantly higher in anti-Scl-70 positive SSc patients compared with those of anti-Scl-70 negative patients (p = 0.01). Serum PIIINP levels were significantly higher in SSc patients with restrictive pulmonary function (FVC < 80%) than in patients with normal pulmonary function (p < 0.05). The correlation between PIIINP levels and FVC (p < 0.05) was negative, but the correlation between PIIINP levels and modified Rodnan skin scores (p < 0.05) was positive. sIL-2R levels were not correlated with skin and pulmonary involvement of SSc. There was no difference in vWF levels between those of the SSc patients and those of the control groups. CONCLUSION: These results suggest that serum PIIINP serves as a biologic marker for the extent of skin and pulmonary involvement in systemic sclerosis. Increased serum levels of sIL-2R in SSc patients support a role for T lymphocyte activation in the pathogenesis of systemic sclerosis.

Adult↗
PubMed1996

Identification of autoantibodies to the I protein of the heterogeneous nuclear ribonucleoprotein complex in patients with systemic sclerosis.

OBJECTIVE: To assess the presence of autoantibodies to the 1 protein (polypyrimidine-tract binding protein) of the heterogeneous nuclear RNPs (hnRNP) in different connective tissue diseases. Antibodies to other hnRNP proteins (A1, A2, and B) have been previously found in patients with rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), and mixed connective tissue disease (MCTD). METHODS: Sera from 101 patients with various connective tissue diseases and 25 normal controls were investigated by enzyme-linked immunosorbent assay and immunoblotting, for their reactivity to highly purified recombinant hnRNP I. Moreover, reactivity to cellular hnRNP I protein was investigated by immunoblotting using a partially purified preparation of hnRNP proteins (including A1, A2, B, and I), and by indirect immunofluorescence. For the analysis of the fluorescence pattern, affinity-purified antibodies to hnRNP I; obtained from a selected patient, were tested on HEp-2 cells. RESULTS: By immunoblotting, antibodies reacting to recombinant hnRNP I were found in 22 of 40 patients with systemic sclerosis (SSc), 3 of 32 with RA, 0 of 23 with SLE, and 0 of 6 with MCTD. Antibodies to recombinant hnRNP I were more frequently found in patients with pre-SSc or limited SSc (15 of 24) than in those with intermediate or diffuse SSc (7 of 16). In indirect immunofluorescence studies, affinity-purified anti-hnRNP I autoantibodies gave a diffuse nucleoplasmic staining. Using an hnRNP preparation from nuclear extracts, anti-hnRNP I reactivity was detectable in SSc sera, while it was not detectable in RA, SLE, and MCTD sera reacting with hnRNP A/B proteins. CONCLUSIONS: Human autoimmune sera show distinct patterns of anti-hnRNP reactivity, i.e., anti-A/B in SLE and RA sera, and anti-I in SSc sera. This suggests that A/B proteins and the I protein may be involved in different dynamic hnRNP complexes that elicit different autoimmune responses. From a clinical perspective, anti-hnRNP I antibodies are frequently associated with pre-SSc features, suggesting an early appearance of these antibodies during the course of the disease.

Autoantibodies↗