Serum prolidase activity in systemic sclerosis

Systemic sclerosis, also known as scleroderma, is a complex systemic inflammatory autoimmune disease that targets the vasculature and connective tissue-producing cells and components of the innate and adaptive immune systems. The disease is characterized by a hardening of the skin and an increased synthesis of collagen. Prolidase is a specific imidodipeptidase involved in collagen degradation. The aim of this study was to search the serum prolidase activity (SPA) in the two subtypes of systemic sclerosis: diffuse and limited cutaneous systemic sclerosis. For this purpose, 35 patients diagnosed with systemic sclerosis (24 diffuse and 11 limited) and 41 healthy control subjects were included in the study. SPA was determined using Myara’s method, which is a modification of Chinard’s method. SPA did not differ between the scleroderma patients and controls (p = 0.467). However, SPA was significantly lower in diffuse form than in both limited form and control subjects (p = 0.021 and p = 0.024, respectively). SPA also did not differ between the limited form and control subjects (p = 0.145). Scleroderma is characterized by excessive deposition of collagen and tissue fibrosis due to the reduced collagen degradation. SPA is reduced in scleroderma patients, especially in diffuse form. Circulating autoantibodies, oxidative stress, and decreased physical activity may contribute to this process.     

Suppressor cell activity in progressive systemic sclerosis

Prostaglandin-producing suppressor cell activity was significantly increased in patients with progressive systemic sclerosis (p less than .01). No significant differences were found in concanavalin-A induced suppressor T cell activity. Although these results indicate an alteration in immunoregulatory function they may represent a compensatory reaction to a defect in the regulation of fibrogenesis.     

Pupillocynetic activity of substance P in systemic sclerosis

OBJECTIVE: In systemic sclerosis (SSc), dysfunctions of peripheral nervous system (PNS) have been observed. Substance P (SP) instillation in human eye induces a cholinergic-independent pupil myosis. Pupil basal diameters (PBD) and pupil responsiveness to SP, expressed as area under the curve (AUC), were studied by pupillometry to assess SP-ergic fiber state and function in SSc. METHODS: Forty SSc patients [24 with limited (lSSc), 16 with diffuse (dSSc) disease] and 40 controls underwent pupillometric evaluation. After evaluation of PBD, SP 10-3 M was instilled in one eye and placebo in the contralateral eye. Antinuclear (ANA), anticentromere (ACA), and anti-Scl-70 autoantibodies were correlated with PBD and AUC. RESULTS: PBD was significantly lower in SSc patients versus controls (p < 0.001). PBD was minor in lSSc versus both dSSc and controls (p < 0.05), but no difference was found between dSSc and controls. In SSc, SP 10-3 M induced greater myosis compared to controls (p < 0.001). SP 10-3 M-induced myosis was higher in lSSc versus both dSSc and controls (p < 0.05). ACA significantly correlated with decreased values of PBD and AUC (p < 0.001). CONCLUSION: Our results show that PBD is reduced in patients with SSc and that SP induces a more intense myosis in SSc than controls. Moreover, in lSSc PBD is lower and SP increases the myosis in lSSc compared to dSSc and controls. This suggests a peculiar dysfunction of PNS in patients with the limited subset of SSc.     

Assessment of damage and activity in systemic sclerosis

The determination of damage and activity in the course of a disease are important matters. Monitoring damage activity is critical in the evaluation of individual patients and in evaluating treatment efficacy in clinical trials. A disease damage (severity) scale has been published for systemic sclerosis. A number of potential cytokine and other soluble protein markers of disease activity for this disease have been proposed in recent publications, reviewed here.     

Interdigestive motor activity in patients with systemic sclerosis

Fasting antral, duodenal, and jejunal motor activity and plasma motilin and pancreatic polypeptide were studied in 14 patients with systemic sclerosis, 6 and 9 without clinical evidence of small bowel involvement, and 8 healthy control subjects. Normal interdigestive motor activity was present in control subjects and patients without intestinal involvement. However, cyclic motor activity was absent in 3 of the patients with intestinal disease and the motility index per interdigestive cycle (or per 6-h recording period in those without cyclic activity) was significantly less in the antrum (181 +/- 103 mm2 compared with 760 +/- 86 and 1116 +/- 96 mm2 for patients without involvement and healthy control subjects, respectively), duodenum (153 +/- 101 mm2 compared with 1425 +2- 186 nd 1055 +/- 241 mm2), and jejunum (268 +/- 131 mm2 compared with 1166 +/- 97 and 1105 +/- 128 mm2). Metoclopramide and bethanechol significantly increased motor activity at the three sites in all subjects but the magnitude of the metoclopramide response was less in patients with intestinal involvement. Fasting concentrations of motilin and pancreatic polypeptide exhibited cyclic variation with peak values occurring during phase 3 of the interdigestive cycle. Plasma motilin during each phase of motor activity was significantly higher in patients with scleroderma, with or without intestinal involvement, than in control subjects. The abnormal motor activity demonstrated here indicates a possible mechanism by which intestinal stasis and bacterial overgrowth could occur and by which clinical disturbances of intestinal transit might arise.     

Antiangiogenic plasma activity in patients with systemic sclerosis

OBJECTIVE: Systemic sclerosis (SSc; scleroderma) is a systemic connective tissue disease with an extensive vascular component that includes aberrant microvasculature and impaired wound healing. The aim of this study was to investigate the presence of antiangiogenic factors in patients with SSc. METHODS: Plasma samples were obtained from 30 patients with SSc and from 10 control patients without SSc. The samples were analyzed for the ability of plasma to affect endothelial cell migration and vascular structure formation and for the presence of antiangiogenic activity. RESULTS: Exposure of normal human microvascular dermal endothelial cells to plasma from patients with SSc resulted in decreased cell migration (mean +/- SEM 52 +/- 5%) and tube formation (34 +/- 6%) compared with that in plasma from control patients (P < 0.001 for both). SSc plasma contained 2.9-fold more plasminogen kringle 1-3 fragments (angiostatin) than that in control plasma. The addition of angiostatin to control plasma resulted in inhibition of endothelial cell migration and proliferation similar to that observed in SSc plasma. In vitro studies demonstrated that granzyme B and other proteases contained in T cell granule content cleave plasminogen and plasmin into angiostatin fragments. CONCLUSION: Plasminogen conformation in patients with SSc enables granzyme B and granule content protease to limit the proangiogenic effects of plasmin and increase the levels of antiangiogenic angiostatin. This increase in angiostatin production may account for some of the vascular defects observed in patients with SSc.     

Update on indices of disease activity in systemic sclerosis

OBJECTIVE: An important barrier in the study of systemic sclerosis (SSc) is the difficulty in measuring disease activity. We reviewed the literature on currently available global measures of disease activity in SSc. METHODS: The PubMed database (1950-2006) was searched for the key words "scleroderma" in conjunction with "disease activity" and then "disease severity." All relevant original and review articles in English and French were reviewed. Textbooks in rheumatology and pertinent secondary references were also reviewed. RESULTS: There are currently 3 tools that are used to measure disease activity globally in SSc. Physician global assessments have been commonly used but have not been formally evaluated. The Valentini Disease Activity Index is a new measure that consists of 10 variables and a resulting score ranging from 0 to 10. It appears easy to use but lacks some face and content validity and responsiveness to change has yet to be demonstrated. The Medsger Disease Severity Scale measures disease severity in 9 organ systems. However, it assesses mostly damage and is difficult to score. CONCLUSIONS: There is currently no gold standard measure of disease activity in SSc. Given the need to measure disease activity in SSc and the limitations of the currently available instruments, efforts are ongoing to develop new ones. This represents a major challenge but one that remains particularly important to undertake.     

Reduced natural killer cell activity in patients with systemic sclerosis

Natural killer (NK) cell number and function were determined in 69 systemic sclerosis (SSc) patients (41 with diffuse cutaneous SSc, 24 with limited cutaneous SSc, and 4 with scleroderma in an overlap syndrome). The results were compared with those obtained from 5 patients with Raynaud's disease and from 27 normal controls. Natural and antibody-dependent killing was reduced in the total group of SSc patients compared with controls, but these differences were primarily attributable to patients with the diffuse form of the disease who were seen early in their illness (<5 years after onset). NK cell numbers were not significantly reduced in patients compared with controls, although lower numbers were observed in individuals with early diffuse disease. Other clinical parameters, such as treatment with D-penicillamine or the presence of scleroderma-specific autoantibodies, did not exert an independent effect on NK cell function. These findings suggest a possible central role for NK cells in the pathogenesis of SSc.     

Autoantibodies in systemic sclerosis

OBJECTIVES: To describe the clinical, laboratory, and prognostic features associated with the scleroderma-specific autoantibodies. METHODS: Using the Pittsburgh Scleroderma Databank, all consecutive patients seen between 1980 and 1995 who had autoantibody studies performed were studied. Anticentromere antibodies (ACA), antitopoisomerase (TOPO), anti-U1-RNP (U1-RNP), anti-RNA Polymerase III (Pol 3), anti-U3-RNP (U3-RNP), anti-Th/To (Th/To), and anti-Pm/Scl (Pm/Scl) were determined according to previously described methods. The frequency of clinical features, organ system outcomes, and survival within the patients with a specific antibody were cumulative over the course of the disease. The frequency of a specific feature was compared across groups to identify significant manifestations and outcomes in patients with a specific antibody. RESULTS: Some demographic, clinical, and organ system findings were associated with the specific antibody, and other features with the scleroderma subtype (limited cutaneous or diffuse cutaneous scleroderma). U3-RNP, U1-RNP, and TOPO were seen more commonly in African-American patients, and ACA was seen in older, female Caucasians. Muscle inflammation was seen in patients with U1-RNP and U3-RNP. Digital tip ulcers and digital tuft resorption were seen more frequently in those with ACA and TOPO. A vasculopathy causing pulmonary hypertension typically occurs with ACA and pulmonary fibrosis with TOPO; however, both types of lung disease were seen in patients with nucleolar antibodies, Th/To and U3-RNP. Importantly, severe interstitial fibrosis was rarely seen in cases with Pol 3. Renal crisis was strongly associated with Pol 3. Survival within limited scleroderma was decreased in the Th/To patients compared with ACA patients. Within the diffuse scleroderma group, patients with Pol 3 had the best survival. CONCLUSIONS: Scleroderma autoantibodies are associated with very specific demographic, clinical, organ system, and survival features. RELEVANCE: The determination of scleroderma autoantibodies may be helpful in assessing the prognosis, monitoring, and treatment of scleroderma patients.     

Seizures in systemic sclerosis

The aim of this study was to evaluate the frequency of seizures in systemic sclerosis (SSc) and to determine the clinical and laboratory features associated with their occurrence. Thirty-four SSc patients (ACR criteria) were analyzed by a standard interview, physical examination, and review of medical charts. Risk factors for seizures, clinical manifestations, associated co-morbidities and current treatment were evaluated. We identified 3 (8.8 %) SSc patients with seizures. A higher median age [61 (35–64) vs. 48 (27–71) years, p = 0.0005] and higher activity score [4.75 (4.5–5.0) vs. 2.5 (0–5–5) years, p = 0.006] were observed in SSc patients with seizures. No other clinical or laboratory feature was associated with the occurrence of seizure in this cohort. This study demonstrated a higher prevalence of seizures in SSc when compared to general population. Seizures were associated with older age and higher activity score in this cohort.     

Pregnancy in systemic sclerosis

While in the past, pregnant SSc patients were thought to be at high risk for poor fetal and maternal outcome, at present, careful planning, close monitoring and appropriate therapy allows these patients to have a successful pregnancy. Retrospective studies clearly show an increased frequency of pre-term births and small full-term infants but the frequency of miscarriage and neonatal survival rate did not differ from healthy controls. The worst life-threatening complication of a pregnancy is scleroderma renal crisis: despite the fact that ACE inhibitors are associated with congenital abnormalities and are relatively contraindicated in pregnancy, in this case their use is recommended. In order to avoid complications, pregnancies in SSc should be planned when the disease is stable, and should be avoided in rapidly progressing diffuse SSc as such patients are at a greater risk for developing serious cardiopulmonary and renal problems early in the disease. HCQ, intravenous immunoglobulins (if blood pressure is not high and renal function is normal) and low doses of steroids may be safely used. In case of rapid worsening of disease activity, elective termination in the first trimester and an induced pre-term birth in the last trimester may be suggested. In order to minimize risks, a multidisciplinary team should assist scleroderma patients to suggest the best timing for a pregnancy and to tailor adequate supportive treatment during the pregnancy.     

Fibrosis in systemic sclerosis

This article reviews current understanding of the pathophysiology of fibrosis in systemic sclerosis. It highlights recent discoveries, insights, and emerging research, and potential opportunities for the development of targeted antifibrotic therapies.     

Antifibrotics in systemic sclerosis

Systemic sclerosis (SSc) is a rare and complex disease, involving multiple organs, with high morbidity and mortality. Fibrosis is the hallmark of SSc, although vascular and inflammatory mechanisms are also implicated in its pathogenesis. Disease management is challenging, due to its heterogeneous presentation, and to the limited number of controlled clinical trials to guide treating clinicians. Immunosuppressive agents have been used to prevent progression, especially in the lung, before irreversible injury occurs, with some, although modest, benefit. Nintedanib, a tyrosine kinase inhibitor, has recently demonstrated safety and efficacy in interstitial lung disease (ILD) associated with SSc, and many other antifibrotics are being assessed as possible beneficial therapies, with promising results. An important unmet need remains, to clarify to which patients, when, and with which agent therapy should be initiated, to achieve optimal outcomes. This review summarizes available evidence for current and emerging antifibrotic therapies in SSc patients.     

Free radical activity and antioxidative systems in patients with systemic sclerosis

Background: Free radicals have been said to contribute to vascular damage in patients with systemic sclerosis. The aim of the study was to determine the level of lipid peroxidation products and antioxidative enzyme activity in patients with systemic sclerosis and in healthy controls. Methods: 10 women with definite systemic sclerosis and 10 age-matched healthy women were studied. Results: A significant increase in serum lipid peroxidation product levels (i.e. diene conjugates and thiobarbituric acid-reactive substances) was found in patients with systemic sclerosis. These changes were accompanied by a decrease in superoxide dismutase, catalase, and glutathione peroxidase activity in erythrocyte lysate. Furthermore, there was diminished activity of glutathione reductase and a depressed total serum level of antioxidants compared to the controls. Blood thiol group concentration in patients with systemic sclerosis was also found to be decreased. Conclusions: The results obtained indicate increased oxidative stress in patients with systemic sclerosis.     

Nailfold capillary microscopy can suggest pulmonary disease activity in systemic sclerosis

OBJECTIVE: To evaluate the association of capillaroscopic alterations with pulmonary disease activity in systemic sclerosis (SSc). METHODS: Ninety-one patients with SSc were studied by means of interview, physical examination, nailfold capillary microscopy (NCM), serology, pulmonary function tests, esophageal transit scintigraphy, Doppler echocardiography, and pulmonary high resolution computed tomography (HRCT). Pulmonary disease activity was diagnosed by the observation of ground-glass opacities on pulmonary HRCT. Capillary loss on NCM was evaluated using the avascular score: patients with mean score > or = 1 or mean number of megacapillaries per finger > or = 1 were considered to have severe capillaroscopic alterations. RESULTS: Patients with higher skin scores, longer disease duration, signs of peripheral ischemia, esophageal dysfunction, antitopoisomerase I antibodies, and ground-glass opacities had higher mean avascular scores (p < or = 0.05 in all tests). The association between ground-glass opacities and higher avascular scores was particularly strong in patients with disease duration < or = 5 years. Among these patients, ground-glass opacities were present in 14 of 19 patients with severe NCM alterations, but were absent in all patients (n = 8) with mild or no NCM alterations (p < 0.001). ROC curves confirmed the ability of NCM to discriminate between patients with and without ground-glass opacities among those with disease duration < or = 5 years. However, NCM could not predict the presence of reduced pulmonary diffusing capacity. CONCLUSION: The severity of NCM abnormalities is associated with lung disease activity in SSc, particularly when the disease duration is relatively short.