Scleroderma: Cyclophosphamide or Transplantation (SCOT)

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 (drugs to suppress the immune system). 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 reinfusion (transplantation) of the participant's own
autologous (self) peripheral blood stem cells (PBSCs) compared to treatment with monthly (for
12 months) intravenous doses of cyclophosphamide (Cytoxan) 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. The researchers 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.

This trial also includes three optional mechanistic sub-studies open to a subset of
participants enrolled in the SCOT trial:

1. Pharmacokinetics of 4-hydroxycyclophosphamide in Patients Receiving Cyclophosphamide for
the SCOT trial (Originally listed separately as DAIT SCSSc-01-01, NCT00848614). The
purpose of this study is to determine the plasma concentration and exposure time
required for cyclophosphamide to produce optimal immunosuppressive activity with minimal
toxicity in participants with severe systemic sclerosis.

2. Vascular Progenitor Cells and the Pathogenesis of Systemic Sclerosis(Originally listed
separately as DAIT SCSSc-01-02, NCT00871221). The purpose of this study is to measure
and characterize the circulating endothelial progenitor cells from the blood of 30
participants and also to determine the extent of vascular cell apoptosis and
proliferation in cutaneous microvasculature in these participants before and after the
receipt of the two SCOT treatment regimens.

3. Molecular Analysis of T Cell Immune Recovery for the SCOT Trial(Originally listed
separately as DAIT SCSSc-01-03, NCT00872508). The purpose of this study is [1] to
describe the condition of peripheral T cell reactivity and repertoire diversity in SSc
patients and evaluate evidence for potential defects prior to randomization, [2] to gain
a better understanding of the impact of cyclophosphamide (Cytoxan) and high-dose
immunosuppressive therapy with autologous stem cell transplantation on thymopoiesis, and
[3] to describe the kinetics and breadth of T cell immune recovery in SSc patients
treated with these interventions.

Inclusion Criteria:

- Severe systemic sclerosis (SSc) as defined by the American College of Rheumatology
(ACR);

- SSc, including extensive skin and internal organ involvement involving either the
lungs or the kidneys, that threatens participant's life; and

- Willingness to use accepted methods of contraception for at least 15 months after
starting study treatment.

Exclusion Criteria:

- Lung, heart, liver, or kidney impairment that would interfere with the study or
compromise participant's survival;

- Active blood vessel dilation in the stomach (Active Gastric Antral Vascular
Ectasia/GAVE, also known as "watermelon stomach"). Patients found to have this
disorder at study screening can receive treatment outside the study and then be
re-screened. For more information about this study criterion, refer to the study
protocol.

- Previous treatment with cyclophosphamide, as defined by: a) prior IV cyclophosphamide
administration for more than 6 months OR a total cumulative IV dose greater than 3
g/m^2; b) prior oral cyclophosphamide administration for more than 4 months,
regardless of dose; or c) combination of prior oral and IV cyclophosphamide
administration for more than 6 months, independent of dose.

- Steroid therapy at doses of greater than 10 mg/day, or more than 2 pulses for
concurrent illnesses within prior 12 months;

- Unwillingness or inability to discontinue certain disease-modifying antirheumatic
drugs (DMARDs) for the treatment of SSc;

- Presence of clinically significant rheumatic diseases other than scleroderma requiring
significant immunosuppression;

- Any active uncontrolled infection that would interfere with high-dose therapy or pulse
cyclophosphamide regimens:

- Hepatitis B virus infected

- Hepatitis C virus infected or

- HIV infected.

- Blood abnormalities;

- Diagnosis of cancer within 2 years prior to study entry. Participants with adequately
treated squamous cell skin cancer, basal cell carcinoma, and carcinoma in situ are not
excluded.

- Other comorbid illnesses with an estimated life expectancy of less than 5 years;

- Defective formation of bone marrow cells (myelodysplasia);

- Uncontrolled hypertension;

- History of hypersensitivity to murine or Escherichia coli (e.g., E. coli) proteins;
History of noncompliance with prior medical care;

- History of substance abuse within 5 years prior to study entry; or

- Pregnancy.