|Exclusion Criteria:||1) i. Severe pulmonary dysfunction with (1) a hemoglobin corrected DLCO < 45% of predicted at the First Phase Screening visit, (2) a hemoglobin-corrected DLCO < 40% of predicted at the Second Phase Screening visit, or (3) FVC < 45% of predicted at the First or Second Phase Screening visit, ii. pO2 < 70mmHg or pCO2 >/= 45 mmHg without supplemental oxygen, or iii. O2 saturation < 92% at rest without supplemental oxygen as measured by forehead pulse oximeter.|
2) Significant pulmonary hypertension defined as: ibi. Peak systolic pulmonary artery pressure >55 mmHg by echocardiogram or pressure > 55 mmHg by echocardiogram, or ibii Mean pulmonary artery pressure by right heart catheterization exceeding 30 mmHg at rest. Peak systolic pulmonary artery pressure 45-55 mmHg by echocardiogram requires a right heart catheterization.
3) If PAP is not evaluable on echocardiogram due to lack of a Tricuspid regurgitant jet, then normal anatomy and function, as evidenced by normal right atrium and ventricle size, shape, and wall thickness, and septum shape must be documented to rule-out PAH. Otherwise, a right heart catheterization is indicated.
4) Uncontrolled clinically significant arrhythmias; clinical evidence of significant CHF (NYHA Class III or IV); LVEF < 50% by echocardiogram; or prior insertion of a pacemaker or cardioverter-defibrillator.
5) Significant renal pathology as defined as: i. Estimated CrCl < 40 mL/min and serum creatinine > 2.0 mg/dL; OR ii. Active, untreated SSc renal crisis at the time of enrollment. Presence of nephrotic range proteinuria (defined as >/ = 3.5 gms/24 hours, or protein:creatinine ratio >/= 3.5), active urinary sediment, urinary RBCs > 25 per hpf, or red cell casts requires further investigation by a nephrologist to rule out glomerulonephritis, overlap syndromes, or other causes of renal disease in all subjects. Subjects with glomerulonephritis or overlap syndromes will be excluded.
6) Active hepatitis (ALT, AST, or bilirubin > 2 times the ULN) or evidence of moderate to severe periportal fibrosis by liver biopsy.
7) Active Gastric Atrial-Venous Ectasia (GAVE, "watermelon stomach"). If found on the screening endoscopy, subjects must receive treatment outside of the study, and may then be re-screened.
8) Previous treatment with cyclophosphamide per the following criteria: a) prior IV cyclophosphamide administration for > 6 months OR a total cumulative IV dose > 3 g/m2; b) prior oral cyclophosphamide administration for > 4 months, regardless of dose; or c) combination of prior oral and IV cyclophosphamide administration for > 6 months independent of dose.
9) 1. Subjects who received > 10 mg/day prednisone or equivalent within 30 days prior to randomization. 2. Subjects who have been treated for concurrent illnesses (e.g., asthma) with the equivalent of prednisone 1 mg/kg/day or its equivalent for > 5 days on > 2 occasions in the previous 12 months or > 1 occasion in the prior 6 months.
10) Unwilling or unable to discontinue disallowed DMARDs for treatment of SSc (MTX for any indication except arthritis, cyclophosphamide, AZA, LEF, MMF, tacrolimus, CSA, TNFblockers,and bosentan except for the treatment of digital ulcers).
11) A history or presence of overlap syndrome. The presence of anti-ds-DNA with a diagnosis of otherwise "pure" SSc must be reviewed by the eligibility review committee.
12) Positive serology for Hepatitis B surface antigen and/or Hepatitis C confirmed by PCR.
13) Positive serology for human immunodeficiency virus (HIV)
14) Hematologic abnormalities as defined below: a. ANC < 1500 cells/mu L b. Platelets < 120,000 cells/mu L c. Hematocrit < 27% d. Hemoglobin <9.0 g/dl
15) Diagnosis of any malignancy within the previous 2 years, excluding adequately treated squamous cell skin cancer, basal cell carcinoma, and carcinoma in situ.
16) Evidence of myelodysplasia.
17) Uncontrolled hypertension.
19) History of hypersensitivity to murine proteins or E. Coli proteins.
20) Inability to give voluntary informed consent.
21) Demonstrated lack of compliance with prior medical care.
22) Unwilling to use contraceptive methods for at least 15 months after starting treatment.
23) History of substance abuse within the last 5 years.
24) was #23 now #24 Active uncontrolled infection that would be a contraindication to safe use of high-dose therapy or pulse cyclophosphamide.
25) was 24 now #25 Presence of other comorbid illnesses with an estimated median life expectancy < 5 years