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| Fredrick Wigley, M.D.
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Abstract 250 Distinct Patterns of Autoantibodies to Cnetromere Proteins in Sjogren's Syndrome and Scleroderma Traditionally, the presence of anti-centromere antibodies is considered to be associated with the limited form of scleroderma or the CREST syndrome. This study found that 12 of 47 (26%) of patients with primary Sjogrens are positive for anti-centromere antibody. These investigators also characterized the specific centromere proteins (CENP-B or CENP-C) that are targeted by the anti-centromere antibodies in primary Sjogrens versus scleroderma. They report that Sjogrens patients target CENP-C alone, while scleroderma patients target both CENP-B and CENP-C. Editorial Comment: This study demonstrates very specific autoantibodies associate with unique clinical phenotypes and suggest a different molecular disease process exist in each disease. Abstract 251 Fine Specificity Mapping of Scleroderma Autoantigens Targeted by Anti-Centromere Autoantibodies It is now clear that auto-antigens have several epitopes or binding sites for auto-anti-bodies. Some parts of the auto-antigen are dominant or more likely to be the target site for binding of auto-antibodies. These investigators found that scleroderma patients with anti-centromere bind the CENP-A and CENP-B proteins of the centromere complex. They further characterized the specific binding sites and fond that 50-80% of patients with anti-centromere binds sequential regions on the protein. Editorial Comment: These studies give insight in to the potential mechanism of why a protein is an auto-antigen. Abstract 374 Increased Incidence of Normal Tension Glaucoma in Systemic Sclerosis Abnormal micro-vascular disease is known to occur in scleroderma resulting in failed angiogenesis and bizarre capillary enlargement. This abstract reports a new finding of an increase in the prevalence of normal tension glaucoma among patients with scleroderma. Editorial Comment: This case-controlled study suggests that patients with scleroderma should be screened for glaucoma and that neo-vascularization may be the cause of this problem. Abstract 375 Clinical Features Associated with Breast and Lung Cancer in Systemic Sclerosis Radiation therapy is often part of the treatment of breast and lung cancer. An increased prevalence of breast and lung cancer is thought to occur among scleroderma patients and radiation therapy is reported to cause exaggerated fibrosis in these cases. This abstract is a survey of the experience of breast and lung cancer in University Centers specializing in scleroderma. The authors report that only 2 of 9 patients with breast cancer that were treated with radiation therapy had problems: one was intense burning and the other generalized thickening of the chest wall. Editorial Comment: This experience suggests that severe radiation reactions do not always occur in scleroderma and radiation therapy may be used as an alternative to mastectomy. Abstract 377 Comparison of Reproductive Factors in 365 Limited Scleroderma (SSc) and 240 Rheumatoid Arthritis (RA) Pregnancies Abstract 380 Male Microchimerism in Women with Scleroderma and Healthy Women who Only Gave Birth to Daughters or who Have Never Been Pregnant Abstract 381 Fetal and Maternal Microchimerism are Simulatenously Present in Multiple Organs in Systemic Sclerosis: A Quantitative Study Abstract 382 Quantitative Analysis of Fetal Microchimerism in Clinically Affected and Unaffected Skin of Patients with Systemic Sclerosis Abstract 458 Microchimeric Cells Identified by Immunophenotyping and Fluorescence in situ Hybridization in Active Lesions from Patients with Systemic Sclerosis are Activated T Cells Abstract 1664 Parity and the Risk of Scleroderma The pathogenesis of scleroderma is not understood but there is some similarity between systemic sclerosis (scleroderma) and graft versus host disease. This finding lead to the finding that fetal microchimerism (i.e., the retention of fetal cells in the blood and tissue by the mother) occurs more frequently in scleroderma compared to normal controls. These abstracts present further information about microchimerism as a potential mechanism to trigger scleroderma. The first study (abstract 377) found no increase number of pregnancies or number of children among scleroderma patients compared to rheumatoid arthritis patients. One would think that more exposure would increase the chances of fetal microchimerism. The second study (abstract 380) found evidence for fetal DNA in women who had no pregnancy and male DNA in women with older brothers who had no history of pregnancy. These findings suggest that these cells can be transferred from mother to daughter. The third study (abstract 381) reported that both fetal and maternal microchimerism is found in the tissues of patients with scleroderma; thus supporting that these cells might contribute to the disease. Control tissues were not presented. The fourth study (abstract 382) found fetal microchimerism in both affect and non-affected skin of patients with scleroderma. They argue that this finding supports an early role for fetal microchimerism. However they provide no further data to support this speculation. The next abstract (458) provided evidence that fetal cells in affected scleroderma tissue are activated T cells; supporting that microchimerism is important in scleroderma. The final study (abstract 1664) reports that nulliparity was associated with an increased risk of scleroderma and a decreased risk with increase number of births. While this finding does support fetal microchimerism as measured by parity, it does not account for the fact that fetal cells can be passed from mother to child. Editorial Comment: The role of microchimerism is still not settled in scleroderma and we must await more studies. Abstract 390 Antibody Mediated Gastrointestinal Dysmotility in Scleroderma Scleroderma bowel disease is characterized by smooth muscle dysfunction in the absence of significant fibrosis or vascular disease. The pathogenesis of this finding is unknown. This abstract reported that M3-muscarinic receptor mediated contractions of mouse colon muscle was inhibited by scleroderma serum compared to healthy controls. Editorial Comment: Although this finding is very preliminary and was not specific for scleroderma it is of interest to consider that immunoglobulin or specific anti-bodies might interfere with smooth muscle function in these patients. Abstract 901 Characterization of Inflammatory Cells and Study of TGF beta, Type I, and Type III Collagen Gene Expression in Affected Skin from Nephrogenic Fibrosing Dermopathy, a Newly Recognized Scleroderma-Like Disease Nephrogenic Fibrosing Dermopathy is a newly recognized clinical skin and tissue disorder seen in patients on hemodiaylsis for chronic renal failure. It is characterized by scleroderma-like skin changes and a widespread diffuse fasciitis. This abstract reported increased macrophages and increased transforming growth factor beta (TGF-beta) in the diseased tissues of these patients. Editorial Comment: This is of interest in that TGF-beta is thought to mediate fibrosis in a number of disease states including scleroderma. Abstract 986 Lionel Schachna, Neil A Braunstein, James H Dauber, Fredrick M Wigley, Thomas A Medsger, Jr., Barbara White, Virginia D Steen, John V Conte, Steven C Yang, Kenneth R McCurry, Judith Vensak, Marvin C Borja, Allan C Gelber, Jonathan B Orens Scleroderma and other connective tissue diseases are considered a contraindication for lung transplantation at many transplant centers. This report from two large transplant centers reported their experience with 29 scleroderma patients who underwent lung transplant for pulmonary hypertension (PHT), interstitial lung disease or both. The outcome of the scleroderma patients was compared to patients with idiopathic pulmonary fibrosis (IPF). The overall survival was the same in both groups (63.5% versus 70.6%) at one year but there were was a higher mortality among the scleroderma patients in the first 6 months following transplant. Interestingly, the increased risk for dead was associated with isolated PHT when treated with single lung transplant. Editorial Comment: This study suggests that careful selected patients with scleroderma should be considered for transplant and the one year survival is as good as non-scleroderma patients. Patients with isolated PHT should have two lung transplant and not single lung. Abstract 1210 Race and Risk of Mortality in Scleroderma The likelihood of survival in scleroderma appears to be improving. It is also clear that certain clinical and laboratory features can predict outcome. These investigators conducted a survey of a large cohort (n=1166) followed at a university Scleroderma Center to determine risk factors for mortality in scleroderma. At three years the cumulative survival was 78.6% among blacks compared to 82.2% in the white patients. Black race was associated with a sixty percent increase risk of mortality after adjustment for age, gender, disease subtype, smoking or auto-antibody status. Editorial Comment: While this study suggests that black race increase the mortality risk in scleroderma, the authors did not address the cause of this risk including such as issues as social and environmental factors. | ||
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Abstract 378 Reliability and Utility of Durometer Measurements of Skin Hardness for Scleroderma One of the challenges of caring for scleroderma patients and in conducting clinical trials in this disease is defining the status of the skin disease. The "skin score" is a subjective test that scores the skin by pinching in several areas of the body. This investigation tested a durometer, an instrument that measures the hardness of the skin and found that intra-observer and inter-observer scores were more reliable that the traditional skin score. Editorial Comment: While more testing is needed this type of semi-quantitative testing may provide a more object outcome measure for scoring scleroderma skin disease. Abstract 911 Characterization of Inflammatory Cells and Study of TGF beta, Type I, and Type III Collagen Gene Expression in Affected Skin from Nephrogenic Fibrosing Dermopathy, a Newly Recognized Scleroderma-Like Disease Nephrogenic Fibrosing Dermopathy is a newly recognized clinical skin and tissue disorder seen in patients on hemodiaylsis for chronic renal failure. It is characterized by scleroderma-like skin changes and a widespread diffuse fasciitis. This abstract reported increased macrophages and increased transforming growth factor beta (TGF-beta) in the diseased tissues of these patients. Editorial Comment: This is of interest in that TGF-beta is thought to mediate fibrosis in a number of disease states including scleroderma. | ||
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Abstract 457 The Response of Fibrotic and Non-fibrotic Patients with Scleroderma-associated Pulmonary Hypertension (SScPHT) to Continuous Ambulatory Iloprost Therapy: Is a Similar Therapeutic Approach Justified? Pulmonary hypertension (PHT) is now recognized to be a major cause of mortality and morbidity among scleroderma patients. Pulmonary vascular disease can occur in the absence or presence of interstitial lung disease (ILD). Serious ILD is considered a relative contraindication for new vasodilator therapy (prostacyclin or endothelin inhibitors) because of the increased shunting causing by increased blood flow to unventilated fibro tic lung. These investigators reported that patients with PHT with or without fibrosis tolerated iloprost (a prostacyclin analogue) and suggested that iloprost could be used in patients with ILD and PHT. Editorial Comment: The main problem with this conclusion is that the study did not define the degree of fibrosis and did not relate the outcome in patients with severe ILD. Milder degrees of fibrosis are usually not the problem, but iloprost and other vasodilators should still be used with caution in scleroderma patients with PHT secondary or associated with severe ILD. Abstract 460 Selective T Cell Reduction in Scleroderma Lung Disease, Using LFA-3/IgG1 Human Fusion Protein (Alefacept) Alefacept is a human fusion protein using LFA-3/ IgG1 that binds CD2 on T cells to inhibit T cell activation and proliferation and FcgammaRIII on accessory cells to cause selective apoptosis of memory-effector T cells. T cells, particularly CD8 positive cells, are thought to mediate the inflammatory alveolitis that causes the lung fibrosis in scleroderma lung disease. This abstract presented pilot data on the use of alefacept in scleroderma patients with active alveolitis. The study demonstrated a good safety profile for alefacept and the ability to deplete T cells and reduce alveolar macrophages and neutrophils from bronchoalveolar lavage fluid in 8 patients. Lung function remained stable during the 26 week follow-up period. Editorial Comment: This novel therapy needs further investigations to be done. Abstract 913 Treatment of Subcutaneous Calcinosis in Limited Cutaneous Systemic Sclerosis with Minocycline This abstract reported that minocycline treatment improved subcutaneous calcinosis associated with scleroderma. Unfortunately, the data was quite limited (9 patients) and the examples of success unconvincing. Subcutaneous Calcinosis remains a difficult problem without a definite treatment option except surgical removal. Abstract 914 Multicenter, Open-Label Trial of Minocycline in Early Diffuse SSc An uncontrolled experience in a small number of patients suggested that minocycline successfully treated the skin disease of early diffuse scleroderma. This abstract reports a multicenter, open-label trial of minocylcline in 36 patients with early diffuse scleroderma. They found only a mild reduction in the skin score of -3.9 (12.6%) during the follow-up period. Editorial Comment: Although this study was not placebo controlled and the follow-up varied, the findings suggest little benefit from minocycline in the treatment of scleroderma. Abstract 915 TNFaAntagonists Induce Lupus-Like Syndrome in Patients with Scleroderma and Polyarthritis TNF inhibitors are being used in the treatment of rheumatoid arthritis and other forms of inflammatory arthritis. This abstract reports two cases of patients with MCTD who were treated with etanercept or infliximab for active arthritis. Both cases developed a lupus-like syndrome, associated with new anti-DNAds antibodies and low serum complements. After discontinuation of the TNF inhibitors the syndrome resolved, the anti-DNA antibodies disappeared and complements returned to normal. Editorial Comment: Caution is suggested when using TNF inhibitors for arthritis in patients with MCTD. Abstract 987 Course of Alveolitis in Severe Systemic Sclerosis (SSc) after Autologous Stem Cell Transplantation (ASCT) Autologous stem cell transplantation (ASCT) is now under study for the treatment of severe diffuse scleroderma. This abstract reviewed the pulmonary experience of 17 patients who were treated with ASCT. Alveolitis defined by bronchoalveolar lavage (BAL) was seen in 10 of the 17. Only 1 of 12 had alveolitis three months after ASCT, but 6 of 10 had a relapse of the alveolitis at one year. The authors suggest that ASCT may not resolve scleroderma lung disease, but did not show data on non-scleroderma patients treated by ASCT to define the affect of ASCT on the lung. Editorial Comment: We must await new information of the clinical outcomes of the scleroderma patient treated by ASCT. Abstract LB01 Prevention of Ischemic Digital Ulcers in Systemic Sclerosis by Endothelin Receptor Antagonism A large multicenter placebo controlled trial of bosentan in the treatment of digital ulcers was reported. There was a significant reduction in new ulcer formation in the bosentan treated group compared to placebo. Specific measures of hand function and pain also improved. However, the study did not demonstrate any improvement in healing of active digital ulcers compare to placebo; nor was there any reported improvement in Raynauds phenomenon (RP). The study did not control for activity of the patient or ambient temperature and it was designed to prevent new ulcers and did not define the role of bosentan in managing RP. Bosentan is on the market for the treatment of pulmonary hypertension, but has the potential for liver toxicity and is quite expensive. Editorial Comment: More studies are needed to that evaluate prevention as well as RP and healing of existing digital ulcers.
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