This subproject is one of many research subprojects utilizing theresources provided by a Center grant funded by NIH/NCRR. The subproject andinvestigator (PI) may have received primary funding from another NIH source,and thus could be represented in other CRISP entries. The institution listed isfor the Center, which is not necessarily the institution for the investigator.Severe systemic sclerosis (SSc) is a serious autoimmune disorder in which a person's own immune cells attack organs in the body. SSc affects the skin, joints, lungs, heart, intestinal tract, and kidneys, and half of the patients with the most severe organ involvement die within 5 years. Treatment for SSc usually includes supportive care or immunosuppressive drugs. As the immune cells are believed to be causing the disease, researchers are looking for new therapies that either slow down or stop this process while not being too toxic.The main purpose of this study is to determine the safety and effectiveness of high-dose immunosuppressive therapy followed by transplantation of a subject's autologous (self) peripheral blood stem cells (PBSCs) compared to treatment with monthly (for 12 months) intravenous doses of cyclophosphamide therapy for the treatment of severe systemic sclerosis (SSc). These treatments are being given in order to determine if they will slow down or stop SSc from becoming more severe, and if they can reverse the effects of the disease. We are evaluating the effects of the two treatments on serious organ damage and survival related to SSc, while also looking at the side effects of the two treatments.The first treatment, from here on referred to as the 'Stem Cell Transplant Treatment,' uses high-dose chemotherapy and total body irradiation (TBI) to completely destroy the immune cells thought to be causing SSc. The high-dose chemotherapy consists of cyclophosphamide (Cytoxan, CTX) and antithymocyte globulin (ATGAM, a protein that removes immune cells that cause damage to the body). Subjects will then receive their own blood stem cells back, after they have been treated to remove most of the mature immune cells thought to be causing SSc. These stem cells will have been collected before they begin treatment, through a process called blood cell mobilization. The stem cell infusion restores the bone marrow, blood cells and allowed the body to form new immune cells. The theory is that all or most of the disease-causing immune cells will be destroyed, and the infused stem cells will develop into new immune cells that do not cause SSc. This study is based on experience in over 30 high-risk patients with SSc undergoing transplantation, which has shown significant improvements in skin and quality of life. Some patients experienced fatal side effects from this treatment and modifications in the transplant protocol have been made to improve the safety. This treatment has never been directly compared to other therapies for SSc in a research study, and therefore, is being evaluated in this clinical trial. None of the drugs given with high-dose chemotherapy now the radiation given with the stem cell transplant are FDA-approved for the treatment of scleroderma.The second treatment, from here on referred to as the 'High-Dose Cytoxan Treatment,' uses 12 monthly intravenous (IV) doses of cyclophosphamide (Cytoxan, CTX). This treatment has not been directly compared in a research study to other therapies or to no therapy in SSc, but has been used by physicians to treat autoimmune diseases including SSc. CTX has emerged as the current standard of care in the rheumatology community. The dose being used in this study is about 50% higher than that commonly used by most physicians to treat many other autoimmune diseases. The higher dose is being used because, while lower doses have been somewhat effective, some patients have shown a more positive response to the higher dose. However, this has not been studied in a formal clinical trial. Doses of CTX higher than the dose used in this study have also been used to treat other autoimmune diseases. CTX reduces the numbers of immune cells thought to be causing SSc. It has been reported that this treatment has resulted in stabilization and/or improvement in the disease, particularly at the higher dose being used in this study. It has been reported to be e'ffective in slowing down the damage in the lungs caused by SSc, and may have improved the skin, and therefore, is being evaluated in this clinical trial. The use of CTX is not currently FDA-approved for the treatment of scleroderma.Treatment with CTX was chosen for the study as a control treatment against which to compare the 'Stem Cell Transplant Treatment.' However, because it has not been directly compared to other therapies or to no treatment, it is possible that the 'High-Dose Cytoxan Treatment' is ineffective and could be more harmful than receiving no treatment.The total dose of cyclophosphamide (CTX) in the 12 monthly IV treatments arm is higher than the total dose of cyclophosphamide in the stem cell transplant treatment arm. The delivery of the medication is different for the two treatment groups, which will make a difference in the expected side effects for each. In the stem cell transplant treatment, subjects will receive the full dose of cyclophosphamide at once, along with the ATGAM and radiation. The regimen is powerfully immunosuppressive, and will probably increase the likelihood of infections and may increase the likelihood of death in the period immediately following the treatment. With time, the immune system recovers, although a lesser degree of immunosuppression will last for approximately one year following the transplant.In the monthly High-Dose Cytoxan Treatment, the doses of cyclophosphamide are divided into 12 treatments, each of which is smaller than in the stem cell transplant treatment group, but the total dose of all 12 monthly treatments added together will be higher than with the transplant. The immune system will be suppressed for the entire year, though not as much as for the subjects receiving the stem cell transplantation.
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