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PubMed2005

Evaluation of topoisomerase-1-specific CD8+ T-cell response in systemic sclerosis.

Measurement of disease activity in systemic autoimmune disorders is often unreliable, and immunosuppressive therapy is often titrated to crude clinical response and/or onset of complications. Systemic sclerosis (SSc) presents a distinct clinical phenotype associated with specific autoantibodies. Anti-topoisomerase-1 (SCL-70) is selectively detected in 30-60% of subjects with diffuse skin and interstitial lung involvement. Such patients offer an ideal clinical model to characterize and quantify the autoantigen-specific T-cell response and its correlation with disease phenotype and activity. Human leukocyte antigen A2 (HLA-A2)-restricted topo-1 peptides were selected based on an epitope prediction algorithm. For initial studies, the best binder topo-1(262-270) KMLDHEYTT (#262) was used alone or loaded onto an artificial antigen-presenting platform generated by coupling a dimeric major histocompatibility complex-immunoglobulin G fusion protein (HLA-A2-Ig) and anti-CD28 antibodies onto magnetic beads (artificial antigen-presenting cells). Blood samples (100 microL) from HLA-A2+ SSc patients and cytomegalovirus (CMV) seropositive healthy control subjects were tested in an intracellular cytokine staining assay. Gamma interferon production by CD8+ T cells was measured after stimulation with peptide #262, CMVpp65, or MART-1 (irrelevant peptide). In two of five SCL-70+ patients, peptide #262-loaded aAPCs induced a specific CD8+ T-cell response (0.45% +/- 0.23% of total CD8+ cells). This response was not observed in the seven SCL-70- (five SSc and two CMV+) control subjects studied (0.03% +/- 0.02%). Interestingly, bronchoalveolar lavage fluid obtained from one topo-1-responsive SSc patient who had worsening respiratory function and active alveolitis showed striking enrichment of topo-1-specific CD8+ T cells (3.94%). This small-volume ex vivo assay may prove to be a sensitive and specific tool to assess disease activity and to monitor response to therapy in patients with scleroderma.

Autoimmune Diseases↗
PubMed2002

High prevalence of polymorphisms of angiotensin-converting enzyme (I/D) and endothelial nitric oxide synthase (Glu298Asp) in patients with systemic sclerosis.

PURPOSE: Systemic sclerosis is characterized by progressive microvascular occlusion and fibrosis and by an imbalance in the fibrinolytic system. In vivo and in vitro studies suggest that the renin-angiotensin system partly regulates vascular fibrinolytic balance. Angiotensin II increases the production and secretion of plasminogen activator inhibitor-1, while angiotensin-converting enzyme (ACE) contributes to reduced production of tissue plasminogen activator and endothelial nitric oxide synthesis by bradykinin degradation. The aim of our study was to investigate the effects of ACE insertion/deletion (I/D) and endothelial nitric oxide synthase (eNOS) Glu298Asp (G894-->T) and T-786-->C polymorphisms in patients with systemic sclerosis. SUBJECTS AND METHODS: We studied 73 consecutive patients (47 with limited and 26 with diffuse cutaneous systemic sclerosis) and 112 control subjects. ACE I/D and eNOS polymorphisms were genotyped by polymerase chain reaction-restriction fragment length polymorphism analysis. RESULTS: The ACE I/D and the eNOS G894-->T polymorphisms were more common in patients than in controls (for the ACE D allele: odds ratio [OR] = 3.4; 95% confidence interval [CI]: 1.5 to 7.9; P = 0.003; for the eNOS T allele: OR = 1.9; 95% CI: 1.0 to 3.4; P = 0.04). There was no association between the eNOS T-786-->C polymorphism and systemic sclerosis. CONCLUSIONS: Our findings of an increased risk of systemic sclerosis in ACE D and eNOS 894T allele carriers suggest that these polymorphisms may contribute to the pathogenesis of the disease.

Adult↗
PubMed2004

Quantification of fetal microchimeric cells in clinically affected and unaffected skin of patients with systemic sclerosis.

OBJECTIVE: Fetal microchimerism has been hypothesized as a potential pathogenic mechanism for systemic sclerosis (SSc). This hypothesis was based on the clinical similarities between SSc and graft-vs-host disease and the identification of microchimeric cells in affected SSc tissues. The aim of this study was to compare the quantity of microchimeric cells in clinically affected and non-affected skin of female patients with SSc. METHODS: Fluorescence in situ hybridization (FISH) and real-time PCR were employed in paired skin biopsies obtained from clinically affected and unaffected areas from five female SSc patients with diffuse cutaneous SSc (dcSSC) and 10 healthy women. All women in the study had delivered a male fetus. RESULTS: FISH analysis revealed the presence of male fetal cells in 1/5 SSc patients (20.0%) compared with 0/10 healthy women (P = 0.0037), whereas quantification by real-time PCR revealed that all SSc samples were positive for male DNA compared with none of the controls. In the five patients with dcSSc, there were similar numbers of microchimeric cells in both affected and unaffected skin (P = 0.4) CONCLUSION: The presence of higher numbers of microchimeric cells in clinically unaffected SSc skin, before any clinically detectable evidence of sclerotic changes, suggests that an influx of microchimeric cells may precede the development of tissue fibrosis. This provides additional support to the hypothesis that fetal microchimerism may play a role in the pathogenesis of SSc.

Aged↗
PubMed2004

Serum concentrations of soluble P-selectin glycoprotein ligand-1 are increased in patients with systemic sclerosis: association with lower frequency of pulmonary fibrosis.

OBJECTIVE: To determine serum concentrations of soluble P-selectin glycoprotein ligand-1 (sPSGL-1) and its clinical associations in patients with systemic sclerosis. METHODS: Serum sPSGL-1 concentrations from 65 patients with systemic sclerosis were examined by enzyme linked immunosorbent assay. In a retrospective longitudinal study, 177 sera from 35 patients with systemic sclerosis were analysed (follow up 0.3 to 6.3 years) RESULTS: Serum sPSGL-1 was raised in patients with limited cutaneous systemic sclerosis (lSSc) (n = 34) and diffuse cutaneous systemic sclerosis (dSSc) (n = 31) compared with healthy controls (n = 22) and patients with systemic lupus erythematosus (n = 20) or dermatomyositis (n = 20). Patients with systemic sclerosis who had raised sPSGL-1 concentrations less often had pulmonary fibrosis and decreased vital capacity (%VC) than those with normal sPSGL-1 levels. sPSGL-1 concentrations were positively correlated with %VC in patients with systemic sclerosis. In the longitudinal study, patients with systemic sclerosis but without pulmonary fibrosis had consistently increased sPSGL-1 concentrations in the early phase, while those with pulmonary fibrosis had decreased sPSGL-1 throughout the follow up period. CONCLUSIONS: A raised serum sPSGL-1 is associated with a lower frequency and severity of pulmonary fibrosis in systemic sclerosis. sPSGL-1 could be a protective factor against the development of pulmonary fibrosis in this disease and as such would be a possible therapeutic target.

Adolescent↗
PubMedDate not supplied

Anti-endothelial cell antibodies in systemic sclerosis: significant association with vascular involvement and alveolo-capillary impairment.

OBJECTIVE: To assess the frequency of antiendothelial cell autoantibodies (AECAs) in a group of patients with systemic sclerosis (SSc) and possible associations with clinical and serologic features of the disease. METHODS: Sera from 50 patients with SSc (38 with the limited and 12 with the diffuse form) were screened for AECA (ELISA). The reference limits were were 56.6% for the IgM isotype and 3.3.5% for the IgG isotype. AECA results were analyzed in relation to lung involvement (chest x-ray, high resolution computed tomography (HRCT), ventilation scintiscan with radioaereosol (DTPA), pulmonary pressure (echodoppler technique): heart involvement (EKG, 24 hr ambulatory EKG, echocardiography), cutaneous involvement (skin score), capillaroscopic characteristics and digital ulcers. AECA were also correlated with the erythrocyte sedimentation rate (ESR), anticentromere (ACA) and antitopoisomerase I (ATA) autoantibodies, and angiotensin converting enzyme plasma levels (ACE). RESULTS: The AECA IgG prevalence was 40% (22/50) for the SSc group as a whole, without significant differences between subsets. A significant negative correlation was shown between the AECA and ACE plasma levels in both subsets. In the diffuse form, a significant positive correlation was found between AECA and ESR and significant associations were found between AECA and the parameters reflecting alveolo-capillary involvement (DLco, DTPA), the pulmonary artery pressures, digital ulcers and capillaroscopic abnormalities. No statistically significant correlations were found between AECA and heart involvement, the skin score or pulmonary interstitial fibrosis. CONCLUSIONS: These data suggest that in SSc the anti-endothelial cell antibodies are directly linked to vascular injury and could reflect endothelial damage. Further studies are needed to verify whether AECA might identify a subgroup of patients at higher risk for the development of vascular crises and whether they might therefore be considered a predictor of outcome in SSc patients.

Autoantibodies↗
PubMed2002

Correlation between plasma concentrations of calcitonin gene related peptide and pulmonary pressure in patients with systemic sclerosis.

OBJECTIVE: To examine plasma levels of calcitonin gene related peptide (p-CGRP) in patients with systemic sclerosis (SSc) and pulmonary hypertension (PH). MATERIAL AND METHODS: Twenty nine patients with SSc, 10 with diffuse form, 18 with limited form and one with overlapping systemic lupus erythematosus were examined. Twelve patients displayed normal systolic pulmonary artery pressure (PAPsyst) < or =30 mm Hg and 17 increased PAPsyst >30 mm Hg. Eight patients had isolated PH without interstitial lung disease (ILD) and nine had PH and ILD (secondary PH). PAPsyst was measured non-invasively by Doppler cardiography. CGRP was determined by radioimmunoassay. RESULTS: Patients with PH had higher p-CGRP than patients with normal pressure. A positive relation was found between p-CGRP and PAPsyst and between p-CGRP and erythrocyte sedimentation rate (ESR), particularly in patients with isolated PH. CONCLUSION: In patients with SSc p-CGRP correlates with pulmonary pressure and with ESR. Whether CGRP reflects disease activity or is released secondary to pulmonary vasoconstriction needs to be investigated further.

Adult↗
PubMed2003

Hemodynamics and survival in patients with pulmonary arterial hypertension related to systemic sclerosis.

STUDY OBJECTIVES: The goal of this study was to determine whether the survival of patients with pulmonary hypertension related to systemic sclerosis (SScPH) was different from that of patients with other forms of pulmonary arterial hypertension. DESIGN: Retrospective cohort study. SETTING: Tertiary care medical center. PATIENTS: Our cohort was composed of 33 patients with pulmonary hypertension that is sporadic, familial, or related to anorexigen use (PPH) and 22 patients with SScPH who underwent initial pulmonary artery catheterization and vasodilator study at our center between January 1997 and June 2001. MEASUREMENTS AND RESULTS: Patients with SScPH had somewhat lower percentage of predicted lung volumes than patients with PPH (total lung capacity, 80% vs 92%; p = 0.06) and had lower percentage of predicted diffusion capacity of the lung for carbon monoxide (42% vs 68%; p = 0.0002). Right atrial pressure, pulmonary artery pressure, and cardiac index were similar between the groups. Patients with SScPH and PPH were treated with usual medical therapies, such as digoxin, warfarin, and continuous IV epoprostenol. Despite these similarities, the risk of death in patients with SScPH was higher than in patients with PPH (unadjusted hazard ratio, 2.9; 95% confidence interval, 1.1 to 7.8; p = 0.03). This increased risk appeared to persist after adjustment for a variety of demographic, hemodynamic, or treatment variables. CONCLUSIONS: Despite having similar hemodynamics, patients with SScPH have a higher risk of death than patients with PPH. Future studies of the mechanism and therapy of pulmonary arterial hypertension should focus on the distinctions between the different forms of this disease.

Adult↗
PubMed2005

Increased cutaneous T-cell-attracting chemokine levels in sera from patients with systemic sclerosis.

OBJECTIVE: We sought to assess serum cutaneous T-cell-attracting chemokine (CTACK) levels and CTACK expression levels in skin from patients with systemic sclerosis (SSc), and determine whether serum CTACK levels correlate with clinical features in SSc patients. METHODS: Serum samples were obtained from 73 SSc patients, 32 patients with systemic lupus erythematosus and 26 patients with dermatomyositis. Serum CTACK levels were determined by enzyme-linked immunoabsorbent assay. CTACK mRNA expression in sclerotic skin was assessed by real-time reverse transcription-polymerase chain reaction. RESULTS: Serum CTACK levels were significantly increased in patients with diffuse cutaneous SSc (dSSc; n=32) and those with limited cutaneous SSc (lSSc; n=41) compared with normal controls (n=31; P<0.05 and P<0.0005, respectively). The presence of calcinosis and muscle involvement was more frequently detected in SSc patients with elevated CTACK levels (P<0.05 and P<0.05, respectively). Elevated C-reactive protein levels were also observed more frequently in SSc patients with increased CTACK levels (P<0.05). CTACK mRNA expression levels in the sclerotic skin of SSc patients were augmented. In a longitudinal study, serum CTACK levels were generally decreased during the follow-up. CONCLUSIONS: The increased serum CTACK levels and enhanced skin CTACK expression in SSc patients suggest that CTACK is related to the inflammation associated with SSc.

Adult↗
PubMed2006

Differential expression of stromal cell-derived factor 1 and its receptor CXCR4 in the skin and endothelial cells of systemic sclerosis patients: Pathogenetic implications.

OBJECTIVE: Systemic sclerosis (SSc) is characterized by early endothelial damage evolving to vascular desertification. Stromal cell-derived factor 1 (SDF-1) and its receptor CXCR4 regulate specific steps in new vessel formation. We undertook this study to determine whether an alteration of the SDF-1/CXCR4 axis might be involved in the pathogenetic mechanisms following ischemic damage during SSc. METHODS: We enrolled 36 SSc patients and 15 controls. Skin biopsy samples were obtained from each subject, and the expression of SDF-1 and CXCR4 was assessed by immunohistochemistry, reverse transcription-polymerase chain reaction (RT-PCR), and Western blot analyses. Furthermore, isolated microvascular endothelial cells (MVECs) from 4 patients with diffuse cutaneous SSc (dcSSc) and 3 controls were analyzed for SDF-1 and CXCR4 by confocal laser scanning microscopy, RT-PCR, and Western blotting. RESULTS: SDF-1 and CXCR4 were up-regulated in the skin of patients with early (edematous) SSc, both in the diffuse and limited cutaneous forms, and progressively decreased, with the lowest expression in the latest phases of both SSc subsets. MVECs from patients with dcSSc expressed significantly higher amounts of both isoforms of SDF-1 in the early stage of disease, with a progressive reduction of SDF-1 and CXCR4 in later stages. On the surface of cultured MVECs from patients with dcSSc, SDF-1 and CXCR4 colocalized in polarized areas, suggesting that they are activated in vivo and that they are under strict genetic control to retain capping function. CONCLUSION: Due to its transient expression, SDF-1 could be considered a future therapeutic target to induce new vessel formation 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↗
PubMed2002

Open-label compassionate use one year-treatment with pirfenidone to patients with chronic pulmonary fibrosis.

OBJECTIVE: We attempted to evaluate the feasibility (therapeutic efficacy, tolerance, and clinical courses after treatment) of pirfenidone, an anti-fibrotic drug for patients with chronic pulmonary fibroses such as idiopathic pulmonary fibrosis (IPF). METHODS: Open-label one-year treatment for compassionate-use. PATIENTS OR MATERIALS: Oral pirfenidone (40 mg/kg body weight) was administered to 8 patients with advanced IPF and 2 with interstitial pneumonia associated with diffuse systemic sclerosis. The plasma concentration of the drug was serially followed. Radiographic scores, pulmonary functions, and arterial blood oxygen pressure were compared at three time points: at one-year before treatment, at the time of entry, and at one-year after entry. RESULTS: While pirfenidone did not show a definite therapeutic effect on overall survival (2 years after entry). During one-year treatment, there was no significant deterioration in terms of chest radiographic scores and arterial oxygen pressure, and the drug was well tolerated with minimal adverse effects within the ranges observed in this study, plasma pirfenidone concentrations did not seem to relate to the appearance of adverse effects or differences in therapeutic effects. CONCLUSION: The feasibility of Pirfenidone as a therapeutic drug was confirmed for patients with advanced pulmonary fibrosis.

Aged↗
PubMed2000

Pulmonary hypertension is associated with impaired exercise performance in patients with systemic sclerosis.

OBJECTIVE: The aim of this study was to evaluate the exercise tolerance by expired gas analysis during stress test in patients with Systemic Sclerosis (SSc). METHODS: Eighteen women (mean age 48.56+/-12.48 years) affected by SSc were studied. A complete echocardiographic examination including pulmonary artery systolic pressure estimation, pulmonary function tests, diffusion lung capacity for carbon monoxide (DLCO), and exercise test were performed. During exercise, breath-by-breath expired gas analysis was performed. RESULTS: Seven patients (39%) had baseline pulmonary systolic hypertension (group A) and 11 patients (61%) did not (group B). Six patients had reduced DLCO values. Both maximal oxygen consumption (VO2max) and anaerobic threshold (VO2AT) values were markedly decreased compared to the predicted values. Seven of 18 patients were unable to complete a maximal exercise (5 of whom affected by pulmonary systolic hypertension). Group A patients showed reduced VO2max, VO2AT, and O2 pulse compared with patients with group B patients (p=0.004, 0.017, and 0.013, respectively); VO2max, VO2AT and O2 pulse were significantly correlated to baseline pulmonary artery systolic pressure. CONCLUSIONS: An exercise intolerance in patients affected by SSc is present. Impairment of exercise performance is associated with pulmonary hypertension.

Adult↗
PubMed1999

Association of human leukocyte antigen class II genes with autoantibody profiles, but not with disease susceptibility in Japanese patients with systemic sclerosis.

OBJECT: To examine the role of human leukocyte antigen (HLA) class II genes in the development of systemic sclerosis (SSc) as well as in the clinical and serologic expression of SSc in patients. METHODS: HLA-DRB1, DRB3, DRB4, DQB1, and DPB1 alleles were determined by genotyping; and serum antinuclear antibodies were identified using indirect immunofluorescence, double immunodiffusion and immunoprecipitation. PATIENTS: One hundred and five Japanese patients with SSc and 104 race-matched healthy controls. RESULTS: Frequencies of DRB1 and DQB1 alleles were not different between SSc patients and healthy controls, while DPB1*0901 was marginally increased in SSc patients. In contrast, SSc-related autoantibodies were closely associated with the clinical features. HLA class II genes were detected as follows: anti-DNA topoisomerase I antibody with diffuse cutaneous involvement, pulmonary fibrosis, and DRB1*1502-DQB1*0601-DPB1*0901; anti-U1RNP antibody with overlapping features of lupus and/or myositis and DRB1*0401/*0802-DQB1*0302; and anticentromere antibody with limited cutaneous involvement and DRB1*0101-DQB1*0501-DPB1*0402. In the analysis of the association of HLA class II and the clinical features in SSc patients significant differences were obtained only for the increased frequencies of arthritis and rheumatoid factor in patients with DRB1*0405 compared to those without. CONCLUSION: HLA class II genes strongly influence the production of SSc-related autoantibodies rather than the development of SSc. In addition, SSc is a composite disease of distinctive subsets defined by serum autoantibodies, which have specific clinical and HLA class II associations.

Adolescent↗
PubMed2006

Impact of pain in health related quality of life of patients with systemic sclerosis.

OBJECTIVES: Systemic sclerosis (SSc) has an heterogenous clinical pattern, with variable organ involvement and degrees of severity. Like in other rheumatic diseases, the self-questionnaires have been used to evaluate SSc globally. The aim of the study is as to evaluate the quality of life (QoL) in patients with either diffuse or limited SSc, and to examine the impact of pain on the QoL scores. METHODS: Patients with SSc, either diffuse or limited SSc, were included in a cross-sectional study. The QoL was evaluated with the short-form 36 (SF-36) and the functional repercussion with the SSc-modified Health Assessment Questionnaire (S-HAQ). RESULTS: A total of 89 patients (67 with diffuse and 22 with limited SSc) were included. The SF-36 score values were lower in SSc patients than those reported in the general population. The physical component scores (PCS) of the SF-36 was significantly worse in diffuse compared with limited SSc (P < 0.05). The PCS was significantly negatively related to the number of clinical manifestations (ANOVA, P < 0.0001). The mental component score (MCS) was not influenced by the type of SSc or the number of clinical manifestations presented by the patient. The QoL of SSc patients was highly correlated with pain (R = 0.69) and disability (R = 0.70). Interestingly, the QoL of SSc patients was only slightly correlated with cutaneous (R = 0.42) and pulmonary involvement (R = 0.57). CONCLUSION: The QoL of patients with SSc is strongly influenced by the type of SSc, the burden of clinical manifestations, the functional disability and by the pain, whatever its cause. The treatment of pain should be considered as priority to improve the QoL of SSc patients.

Adolescent↗
PubMed2005

Abnormal natural killer cell function in systemic sclerosis: altered cytokine production and defective killing activity.

Natural killer (NK) cells are innate immune effectors that produce various immunoregulatory cytokines. Recent studies have shown that NK cells are involved in the initiation of autoimmunity. In this study, we determined abnormalities of NK cells in systemic sclerosis (SSc), an autoimmune connective tissue disease, by assessing the frequency and absolute number, activation marker expression, cytokine production, and killing activity. The frequency and absolute number of NK cells increased in diffuse cutaneous SSc (dcSSc), whereas they were normal in limited cutaneous SSc (lcSSc). NK cells from both dcSSc and lcSSc patients exhibited activated phenotypes characterized by up-regulated CD16 and CD69 expression and downregulated CD62L expression. Interferon (IFN)-gamma production by non-stimulated NK cells from both dcSSc and lcSSc patients was increased compared to the normal control, whereas on stimulation, a reduced amount of IFN-gamma was produced. Interleukin (IL)-5 and IL-10 production by non-stimulated NK cells and IL-6 production by stimulated NK cells were augmented in dcSSc patients, but not in lcSSc patients. Despite the augmented cytokine production by non-stimulated NK cells, natural cytotoxicity activity and granzyme B secretion was reduced in NK cells from dcSSc and lcSSc patients. These results suggested that altered NK cell function contributes to immunological abnormalities in SSc.

Adult↗
PubMed2003

Correlation of serum collagen I carboxyterminal telopeptide concentrations with cutaneous and pulmonary involvement in systemic sclerosis.

OBJECTIVE: Systemic sclerosis (SSc) is characterized by fibrosis involving the skin and various internal organs. Type I collagen (Col I) is the most abundant extracellular matrix protein deposited in cutaneous involvement. We investigated Col I biochemical markers in patients with SSc. METHODS: All consecutive patients admitted for SSc over a 9 month period and a healthy control group were investigated. Serum concentrations of the C-terminal telopeptide of Col I (s-CTX-I), C-terminal type I procollagen propeptide (PICP), osteocalcin, and bone alkaline phosphatases (ALP), and urinary concentrations of deoxypyridinoline (u-DPD) and u-CTX-I were determined by ELISA. RESULTS: A total of 33 patients with SSc were included: mean age +/- SD was 54 +/- 12 yrs, with a mean disease duration of 5.4 +/- 3.9 years. Sixteen of 33 patients with SSc had s-CTX-I values exceeding the upper limit of normal values of the test and the mean +/- SEM was significantly higher (7388 +/- 1422 pmol/l) than in healthy controls (2800 +/- 1120 pmol/l; p < 0.001). s-CTX-I correlated with the Rodnan skin score (p = 0.003); it was higher in patients with diffuse disease (8459 +/- 3125; n = 14) than in patients with the limited form (6453 +/- 1235; n = 19; p < 0.02). This marker also correlated with acute phase reactants (C-reactive protein, p = 0.004; erythrocyte sedimentation rate, p = 0.02). s-CTX-I was high in patients with positive antitopoisomerase I autoantibodies (p = 0.04) and in patients with a decrease in forced vital capacity to less than 75% (p = 0.02). u-DPD concentration was high in patients with SSc (10.6 +/- 1.4 nmol/mmol creatinine vs 6.3 +/- 2.1 in controls; p < 0.01). No difference between patients and controls or correlations with the disease were found for PICP, u-CTX-I, osteocalcin, and bone ALP concentrations. CONCLUSION: s-CTX-I, a marker of Col I degradation, is correlated with cutaneous and pulmonary involvement and with acute phase reactants in patients with SSc. This marker is a good candidate for further evaluation for disease activity and treatment purposes.

Aged↗
PubMed1985

[How to explore the microangiopathy of collagen diseases].

Numerous methods for the exploration of the microangiopathy of collagen disease exist, but their perspective differs as a function of their use to assist early diagnosis, to establish a prognosis, to provide follow-up data or to attempt better understanding of the mechanism of these affections. Progressive systemic sclerosis is a very suitable collagen disease with which to illustrate these methods, since in this affection the microangiopathy is frequent, diffuse, of early onset and also formally implicated in the pathogenic rank. Biopsy specimens provide details of morphologic anomalies of the microcirculation. Capillary changes have been demonstrated in muscle and the choroid but in clinical practice histology samples involve mainly the digital pulp, subungual fold and accessory salivary glands. Isotopic and fluorescent angiography are, on the contrary, in vivo methods for dynamic exploration of skin microcirculation, but the invasive nature of these methods is an obstacle to their repetition in a same patient and to follow-up of the microangiopathy. Non-invasive vascular explorations avoid this pitfall. Thermometry, thermography, digital plethysmography under hot and cold conditions, videomicroscopy of the nailbed, percutaneous PO2 and laser-doppler tests measure functional parameters, the hemodynamic significance of which require discussion. Capillaroscopy, mainly oriented towards the study of capillary morphologic changes, also allows, together with plethysmography, measurement of digital systolic pressure. Exploration of the microangiopathy of collagen disease requires a judicious combination of currently available morphologic and functional techniques which, far from being superimposable are on the contrary complementary.

Capillaries↗
PubMed1995

Systemic sclerosis and impotence: a clinicopathological correlation.

A hypothesis of the mechanism of systemic sclerosis associated impotence was developed by making a clinicopathological correlation between the results of preoperative erectile function testing and those of pathological examination of excised erectile tissue in an impotent man with systemic sclerosis. Preoperative examination revealed firm corporeal tissue with diminished penile stretch capability. Pharmacocavernosometry/pharmacocavernosography under conditions consistent with trabecular smooth muscle relaxation revealed severe diffuse corporeal veno-occlusive dysfunction. During penile implantation surgery the compact erectile tissue was unable to be dilated and required sharp corporeal tissue excision under direct vision to achieve cylinder insertion. Histological investigation of the excised corporeal tissue demonstrated severe corporeal fibrosis. Computer assisted color histomorphometry revealed that the mean percentage of trabecular smooth muscle area to total erectile tissue area was 18.2 +/- 13.9% (normal 40 to 52). Immunohistochemical staining with desmin, a protein found in smooth muscle, verified prolific corporeal fibrosis. In situ hybridization of the corporeal tissue demonstrated messenger ribonucleic acid collagen and fibronectin messenger ribonucleic acid expression. Strong hybridization signals were found in mesenchymal cell types, including trabecular smooth muscle cells. In summary, clinicopathological correlation revealed that veno-occlusive dysfunction and loss of penile length were secondary to the excessive accumulation of extracellular matrix, partially due to trabecular smooth muscle cells undergoing synthetic as opposed to contractile phenotypic activity.

Adult↗