Home Page - About the Arthritis Center -Hopkins Rheumatology - Myositis Center - Vasculitis Center - Scleroderma Center
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| Laura Hummers, M.D.
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Abstract 1137 Improvements in the Net Ulcer Burden and Hand Functionality in Patients with Digital Ulcers Related to Systemic Sclerosis Endothelin-1 may be involved in the pathogenesis of not only pulmonary hypertension in patients with scleroderma, but may also have a role in fibrosis and the obliterative vasculopathy that occurs as well. Bosentan (Tracleer) is a dual endothelin-1 receptor blocker (receptor type A and B) that is approved for the treatment of pulmonary hypertension. The authors here present a new analysis of the data available from the RAPIDS-1 trial to examine the impact of bosentan on digital ischemia and hand function. The RAPIDS-1 trial (Randomized, Placebo-Controlled Study on the Prevention of Ischemic Ulcers secondary to Systemic Sclerosis) was a 16 week double-blind, placebo-controlled treatment trial of bosentan to prevent digital ischemic ulcerations. The initial trial results were presented at the 2002 ACR meeting (Arthritis Rheum 46; 3414-5, 2002) which showed a reduction in new ulcerations compared to placebo (1.4 new ulcerations vs. 2.7 in the placebo group). Patients in this trial were randomized 2:1 to receive bosentan or placebo. The dose was initially 62.5 mg BID then increased to 125 mg BID after 4 weeks. The primary outcome for this analysis was net ulcer burden (NUB) (the change in total number of digital ulcers from baseline to week 16). The other outcome was the components of the Scleroderma-Health Assessment Questionnaire that relate to hand function. Patients treated with bosentan had a decrease in NUB of 0.5 compared to the placebo group, which had an increase of 0.4 (p=0.03). Patients with the largest number of ulcers at baseline seemed to have the greatest improvement. The treated group also had significant benefit in all of the components of the hand functionality component of the Scleroderma-HAQ compared to placebo. Editorial Comment: This is the second study showing bosentan improves digital ulcerations in patients with scleroderma. This affect may be multi-factorial as endothelin-inhibitors may have effects in addition to the vasodilatory properties. This study was of relatively short duration. As ulcer healing in scleroderma patients is a long process, a longer trial will be necessary to determine effectiveness. There is a second study, RAPIDS-2 which has a longer duration of treatment (24 weeks) that should be available in the next year which looks at new ulcer formation, cardinal ulcer healing, total ulcer number and hand functionality. | |||||||||||||||||||
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Abstract 1140 Bosentan for Scleroderma Associated Pulmonary Arterial Hypertension - A Subgroup Analysis of Two Placebo Controlled Trials The dual endothelin receptor inhibitor, bosentan (Tracleer) has been shown in several randomized, placebo-controlled clinical trials to be effective in the treatment of pulmonary hypertension. These trials have both included patients with scleroderma-associated pulmonary hypertension. It has been shown, however, that patients with scleroderma-associated pulmonary hypertension have a worse survival than those with primary pulmonary hypertension overall. This study examines the outcome of the scleroderma patients in these two trials (12 and 16 week trials) and the two-year, open-label extension. In total, 52 of the 246 patients in these two clinical trials had scleroderma-associated pulmonary hypertension (85 % were female and the mean age was 60 years). Thirty seven received active treatment and 15 were on placebo. These patients were WHO functional class III or IV and had pulmonary hypertension documented by right heart catheterization. Patients with significant interstitial lung disease were excluded (TLC <70% predicted). The primary outcome of the study was exercise capacity (measured by 6 minute walk test). Secondary endpoints were dyspnea (as measured by Borg index), WHO functional status and evidence of clinical worsening (death, hospitalization, switch to prostacyclin, withdrawal from the study treatment). There was a significant improvement in the 6 minute walk test during the study (+ 36.8 meters) which was significantly better than placebo. The magnitude of improvement, however, seems to be smaller than the overall group (primary + scleroderma). There was no difference in the WHO functional status or dyspnea index between bosentan and placebo treated scleroderma patients. There was a trend toward improvement in time to clinical worsening favoring bosentan, but this was not statistically significant. In the open label extension, there was evidence of stability of the six minute walk time in the scleroderma patients at 2 years. Twenty-five percent of patients, however, required switch to prostacyclin therapy. Editorial Comment: This subgroup analysis of the patients with scleroderma-associated pulmonary hypertension shows that although there is a symptomatic improvement in scleroderma patients, the magnitude of effect appears to be less than in the overall study results. The number of patients available for comparison, however, was relatively small (particularly in the open label extension) and therefore firm conclusions are difficult to make at this time. This group of patients have moderate to severe disease, and it is interesting to speculate that initiation of treatment at an earlier stage (< WHO class III symptoms) may improve outcomes. Endothelin inhibitors may impact other pathways in scleroderma patients (angiogenesis, fibrosis) and this is currently under investigation. | |||||||||||||||||||
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Abstract 1104 Impaired Function of Circulating Endothelial Precursors in Patients with Systemic Sclerosis: Implication for Pathogenesis of Microvascular Damage It has been postulated that defects in angiogenesis may be involved in many vascular diseases such as myocardial infarction, systemic lupus and sickle cell disease. Circulating endothelial precursors (CEP) are likely derived from the bone marrow and involved in repair of damaged vessels. The authors evaluated CEPs in a group of scleroderma patients to determine the functional properties of these cells. Eleven patients with scleroderma were compared to 11 patients with rheumatoid arthritis (RA) and 11 normal controls. The patients were gender matched and matched for the presence of smoking and hypertension. The mean age in the 3 groups were 57 in the scleroderma group, 58 in the RA group and 52 in normal controls. CEPs were identified from peripheral blood samples using flow cytometry as CD34+VEGFR2+CD133+ cells. ELISA was used to determine the levels of several angiogenesis factors, VEGF (vascular endothelial growth factor), bFGF (basic fibroblast growth factor) and HGF (hepatocyte growth factor) from peripheral blood samples. The ability of the CD 133+ cells to differentiate into mature endothelial cells was determined by culturing the cells in a ""bath" of angiogenic factors and performing immunohistochemistry to determine the percentage of cells expressing von Willebrand factor (vWF) or VEGFR2. The number of CEPs was significantly decreased in scleroderma patients compared to RA patients and controls (274 156 versus 1,318 834 and 1,015 347, P < 0.001 in both comparisons). The number of CEPs did not seem to correlate with age, disease duration or skin score among the scleroderma patients. Those patients with vascular disease, however, had a lower number of CEPs. The number of circulating endothelial cells (not precursors) was similar in scleroderma and RA but higher than in the normal controls. Scleroderma patients had a significant elevation in pro-angiogenic factors (VEGF, bFGF, HGF) vs. normal controls (although similar to RA) and a significantly lower proportion of CD133+ cells that underwent maturation (as defined by +vWF) (19 7.5 vs. 88.6 8.1 in normal controls, p <0.0001). The authors postulate that defective vascular repair mechanisms may be responsible for the microvascular damage that occurs in scleroderma. Editorial Comment: Microvascular damage is ubiquitous among scleroderma patients. There is clinical evidence of avascularity (nailfold capillary dropout) which makes the idea of disordered angiogenesis appealing. This study involves a very limited number of patients, but the findings were striking and suggest several possible steps in the angiogenesis pathways that may be altered. Further study is needed in this area with larger numbers of patients. | |||||||||||||||||||
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Abstact 1139 NT-pro-B-type Brain Natriuretic Peptide as a Diagnostic Marker of Early Pulmonary Arterial Hypertension and Effects of Calcium Channel Blockers in Systemic Sclerosis B-type brain natriuretic peptide (BNP) is a neurohormone synthesized in the cardiac ventricles. It is released as N-terminal pro-BNP (NT-proBNP) and cleaved enzymatically to the NT fragment and the immunoreactive BNP. BNP has diuretic and natriuretic properties. Measurement of BNP is now a widely available assay and is helpful and diagnosing and monitoring patients with heart failure. In this study, the investigators evaluated NT-pro-BNP levels in a group of scleroderma patients with and without pulmonary hypertension. 40 consecutive patients with scleroderma were studied. Twenty seven had limited skin involvement and 13 were diffuse and the average disease duration was 9 years. Ten of the 40 patients had evidence of pulmonary hypertension defined as a systolic pulmonary artery pressure of >40 mmHg by 2D echocardiogram. No patients had WHO class III or IV symptoms and no patient had any evidence of left ventricular dysfunction. NT-pro-BNP levels were determined at baseline (after discontinuation of calcium channel blockers (CCB) for 72 hours), after 3 doses of CCB and after 6-9 months of CCB therapy (only 20 patients evaluated, 10 with and without pulmonary hypertension). 4/30 patients without pulmonary hypertension and 9/10 patients with pulmonary hypertension had elevated NT-pro-BNP levels at baseline (defined as >97th percentile) and a positive correlation was noted (r=0.44). This test has a sensitivity of 90%, specificity of 90.3%, positive predictive value of 69.2% and negative predictive value of 96%. After reinitiation of CCB therapy, elevated NT-pro-BNP levels were present in only 2/10 patients with pulmonary hypertension and in 4/10 of these patients at 6-9 months. Four patients with pulmonary hypertension became symptomatic during the follow-up period. In those patients, the decrease in the NT-pro-BNP levels was less than in those without symptoms (-27% vs. -71%, p=0.01). Editorial Comments: NT-pro-BNP levels are likely a useful diagnostic marker for pulmonary hypertension in scleroderma. It is important to note that it is likely not specific to scleroderma and any right or left heart strain will likely elevate these levels. This may, however, be an important marker for progression of disease in these patients. Many patients with scleroderma have mild elevations in pulmonary artery pressures and we often do not know which group of patients will have progressive disease. The echocardiogram is not an ideal diagnostic study and right heart catheterizations are the gold standard but are invasive. A prospective study of a large number of scleroderma patients would be needed to determine the validity of this marker as a predictor of progression. | |||||||||||||||||||
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Abstract 1141 Survival Following Lung Transplantation in Systemic Sclerosis Compared With Other Transplant Indications This study examines the outcomes of patients with scleroderma that have undergone lung transplantation and the University of Pittsburgh and Johns Hopkins University from 1989 to 2002. 689 patients were transplanted at the two centers during that time period and 29 of those patients had scleroderma (15 secondary to interstitial lung disease, 11 for pulmonary hypertension and 3 for both). Outcome in these patients were compared to 70 patients with idiopathic pulmonary fibrosis (IPF) and 38 patients with primary pulmonary hypertension (PAH). Roughly 2/3 of the scleroderma patients underwent a single lung transplant and 1/3 a double lung transplant. Two patients had a combined heart-lung transplant. Multiple potential predictors of transplant survival were collected and examined: age, sex, BMI, smoking status, creatinine clearance, CMV antibody status and type of allograft. At 6 months, cumulative survival was 69% for the scleroderma patients, 80% for the IPF patients and 79% for the PAH patients (not statistically significant). During 24 months of follow-up, 11 patients with scleroderma, 23 patients with IPF and 14 patients with PAH had died (61%, 64% and 62.7% respectively). The relative risk of death in scleroderma compared to the other groups in a univariate analysis was 1.70 (0.74-3.93) and 1.52 (0.59-3.96) respectively at 6 months. Of the 14 deaths in the scleroderma group, 7 died in the first month after transplant and of those patients, 4 died of primary graft failure and 3 of pneumonia. Patients with early graft failure all had undergone transplantation for pulmonary hypertension and had a single lung transplant. Factors that were significantly predictive of increased mortality in a multiple regression model included increased duration of scleroderma (HR= 1.63 for each increase in 5 years duration), decreased creatinine clearance (HR= 1.22 for each decrease in 10 ml/min). Editorial Comment: This study demonstrates that patients with scleroderma have a similar outcome to those with other indications for transplant. There appears to have been an early difference in mortality between the groups that converged beyond 6 months. The 4 patients with early graft failure all had scleroderma-associated pulmonary hypertension and had undergone a single lung transplantation, which may suggest that double lung transplants may be required in these patients, although the numbers are small and this is speculative. This study examined a relatively small number of patients (although this is likely the largest experience worldwide as many transplant centers will not transplant patients with scleroderma), which makes multiple comparisons difficult. Overall this study is reassuring that transplant should be considered a treatment option in scleroderma patients with significant lung disease. | |||||||||||||||||||
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Abstract 1142 Hematopoietic Stem Cell Transplantation for Severe Systemic Sclerosis: European Results 1996-2003 Several European centers have been performing hematopoietic stem cell transplantation for severe systemic sclerosis over the last 7 years. This study examines the collective outcome of all of these centers. All of these studies were open label and records are kept in a multinational database (EBMT/EULAR). Follow-up was at least 6 months was kept and as long as 3 years. Each center had a unique protocol for mobilization of stem cells and conditioning or preparative regimens, although all included cyclophosphamide. Outcomes were categorized into complete response (CR), partial response (PR), or non-response (NR) and were based on skin scores and organ function testing and survival. Fifty-seven patients were included in the analysis. The majority of the patients were diffuse, the median age was 40 years, and 47 were female. The median disease duration was 36 months and the median follow up was 20 months (range 0.3-81.1 months). All patients had some evidence of internal organ dysfunction (either reduced FVC, elevated PA pressure or decreased left ventricular systolic function). Significant decreases in total skin scores (>25%) were documented in 70% of patients at 6 months, 67% of patients at 12 months, 79% of patients at 24 months and 60% of patients at 36 months (only 10 patients with data to 36 months). A partial response was noted in 32/50 (64%) patients, complete response in 14/50 (38%) patients, and non-response in 4/50 (8%) patients. Relapses occurred in 16/46 (35%) of patients with an initial either partial or complete response after 10 months. There was a 72% overall survival at 5 years with 13 deaths that occurred during follow-up. Five deaths were related to the treatment and 8 due to disease progression. Editorial Comment: The role of myeloablative chemotherapy and stem cell transplant in the treatment of severe autoimmune diseases is still unclear. Conceptually this strategy makes sense as an attempt to "reset the immunostat" to quell a dysfunctional and self-sustaining immune response. There is still much to be learned about whom the ideal candidates for this treatment may be and what the ideal treatment regimen entails. The high mortality rate seen in this group suggests that we need to be highly selective for patients who have significant risk of disease progression and poor outcome. The heterogeneity of the inclusion/exclusion criteria, the preparative regimens and outcome assessment make interpretation of this data difficult. All of these protocols were also single arm, open label studies. There is now an ongoing trial in Europe, the ASTIS trial, which is a randomized trial comparing stem cell transplant to 12 months of IV cyclophosphamide. This trial is likely to improve our understanding of the role of this intensive treatment strategy. | |||||||||||||||||||
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Abstract 843 Anti-Fibrillin-1 Autoantibodies Induce Activation of Normal Skin Fibroblasts which Resembles the Scleroderma Phenotype There is increasing evidence that fibrillin-1 (Fib-1), a component of microfibrils in the extracellular matrix (ECM), may be involved in the pathogenesis of scleroderma. Polymorphisms in the gene encoding Fib-1 have been associated with a susceptibility to scleroderma (in Japanese and Choctaw native-Americans) and many patients with scleroderma produce anti-fibrillin autoantibodies. This study examines the effect of these anti-fibrillin antibodies on normal fibroblasts in culture. The investigators purified anti-fibrillin-1 autoantibodies from scleroderma patients using a recombinant Fib-1 peptide. Normal skin fibroblasts were cultured in the presence of either this purified antibody, normal human IgG or normal culture media for 24 hours. Gene and protein expression of the fibroblasts were examined by multiple methods (microarray, quantitative PCR (Q-PCR), immunoblotting and immunohistochemistry). The Fib-1 Ab co-cultured fibroblasts showed a distinctive gene array pattern compared to the other 2 groups. Q-PCR verified an increased expression of collagen type Ia2, collagen type IIa1, MMP-1 and tissue inhibitor of MMP-3 which is characteristic of the "scleroderma fibroblast" phenotype. Genes involved in immune regulation, such as MHC genes, IL-10, insulin-like growth factor-2 (IGF-2), IGF binding-protein-7, PDGF receptor a and were also up-regulated by microarray analysis. Fibroblasts treated with the Fib-1 Ab increased the Fib-1 containing microfibril formation as determined by immunostaining. Editorial Comment: Prior studies have shown that the Fib-1 containing microfibrils in scleroderma ECM may be "unstable" (increased degradation, and altered ultrastructure) and it was hypothesized that this may lead to the revelation of cryptic epitopes leading to autoantibody production. This study suggests that antibodies to Fib-1 may be directly pathogenic and contribute to tissue fibrosis in scleroderma. This may be interpreted that there is a self-sustaining cycle of autoimmunity and fibrosis. | |||||||||||||||||||
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Abstract SY-4 The Immunoglobulin Fraction of Scleroderma Sera Activates Pathways of Inflammation, Fibrosis, and Apoptosis in Adult Human Dermal Endothelial Cells This study examined the effect of scleroderma immunoglobulins on cultured human dermal endothelial cells (EC). Human dermal endothelial cells were cultured in the presence of either 1) 10% normal human sera, 2) pooled sera from scleroderma patients with anti-Scl-70 (topoisomerase-1) autoantibodies, including both Ig and non-Ig fractions, 3) sera from scleroderma patients with anti-centromere (ACA) autoantibodies, including both Ig and non-Ig fractions. After incubation for 18 hours microarrays were performed on the extracted RNA from these endothelial cells. Cluster analysis revealed similar expression patterns between the whole sera and Ig fractions from scleroderma patients (both ACA and Scl-70). GenMAPP analysis revealed numerous genes that were either up or down-regulated in scleroderma patients vs. controls. There was also differential expression of many genes in scleroderma sera-treated ECs and some overlap was noted between the ACA and Scl-70 groups (See figure below).
Some of the genes with increased expression included those in the NFkB inflammation pathway, increased Fas CD-95, connective tissue growth factor (CTGF), thrombospondin-1 collagen 1a-1 and collagen 4a-1, IL-6, IL-8, COX-2, ICAM-1, VCAM-1 and endothelial leukocyte adhesion molecule-1. These gene-products are involved in apoptosis, extracellular matrix regulation, inflammation and adhesion. Editorial Comment: This data suggests there are unique expression profiles of endothelial cells exposed to scleroderma sera in vitro. Other studies have demonstrated that anti-endothelial cell antibodies are produced in a number of patients with scleroderma and have been shown to induce apoptosis of endothelial cells. This suggests a possible direct pathogenic role of autoantibodies in the pathogenesis of scleroderma. This study, like all gene microarray studies, examines a large number of genes, making interpretation of each individual gene expression difficult. This study needs to be followed-up with conformational studies. | |||||||||||||||||||
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