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Inclusion Criteria Individuals must meet all the following criteria to be eligible for this study. 1. Patient, parent, or legal guardian must have given written informed consent. For patients ≥ 16 years of age who are developmentally able, assent or affirmation will be obtained. 2. Age 16-70, inclusive, at time of consent. 3. Diagnosed with Systemic Sclerosis (SSc), according to the 2013 ACR/EULAR criteria (van den Hoogen et al., 2013). 4. All patients must meet either the following skin or ILD criteria. Disease duration is defined as time from first non-Raynaud symptom. Skin Criteria: Diffuse SSc, defined by presence of proximal skin thickening and: A. If disease duration is of <2 years, patients must have a calculated mortality risk prediction score which places them in the intermediate or high risk category (Domsic et al., 2016). B. If disease duration is of >2 years, patients must have evidence of active cutaneous disease based upon 1) a worsening Modified Rodnan Skin Score (MRSS) in the preceding three months or 2) the presence of palpable tendon friction rubs. ILD Criteria: A. The presence of recognized fibrosis on imaging of <2 years AND either > 10% of lung involvement by CT scan or FVC% pred <80% or B. Fibrosis on imaging of any duration with a decline in FVC% pred of ≥10% over the preceding 12-18 months. 5. Negative for human immunodeficiency virus (HIV), hepatitis B virus and hepatitis C virus, all confirmed by PCR testing. 6. Negative pregnancy test for females. 7. All females of childbearing potential and sexually active males must agree to use an FDA approved method of birth control for up to 24 months after BMT or for as long as they are taking any medication that may harm a pregnancy, an unborn child or may cause a birth defect. Exclusion Criteria Individuals who meet any of these criteria are not eligible for this study. 1. Moderate to severe cardiac involvement defined by any of the following: 1. New York Heart Association classification of heart failure ≥3. 2. Left ventricular ejection fraction (LVEF) ≤40% as determined by cardiac MRI. 3. Significant pulmonary hypertension, for subjects ≥ 18 years of age, defined as mean PASP ≥30 mmHg determined by right heart catheterization, or for subjects ≤ 17 years of age, defined as mean PASP >45 mmHg, determined by echocardiogram. 4. Atrial tachycardia, atrial fibrillation or atrial flutter of ≥1-minute duration, determined by electrocardiogram (EKG) and implanted loop recorder, or on anti-arrhythmic therapy for the arrhythmias listed above. For subjects ≤ 17 years of age, this will be determined by EKG and cardiac event monitor. 5. e. Ventricular tachycardia of ≥6 beats at rate of ≥100 beats per minute, determined by EKG and implanted loop recorder, or on an anti-arrhythmic therapy for any ventricular arrhythmia. For subjects ≤ 17 years of age, this will be determined by EKG and cardiac event monitor. 6. Left bundle branch block, bifascicular heart block, Mobitz 2 heart block, complete heart block or infarction pattern as determined by EKG and implanted loop recorder. For subjects ≤ 17 years of age, this will be determined by EKG and cardiac event monitor. 7. Presence of pacemaker or implantable cardioverter defibrillator. 2. Moderate to severe pulmonary involvement defined by any of the following: 1. Hemoglobin-corrected DLCO <40%, determined by pulmonary function tests. 2. FVC <45%, determined by pulmonary function tests. 3. pO2 <70 mmHg, determined by an arterial blood gas (not applicable for subjects ≤17 years of age). 4. pCO2 ≥45 without supplemental O2 determined by an arterial blood gas (not applicable for subjects ≤17 years of age). 5. O2 sat <92% at rest without supplemental O2, determined by an arterial blood gas (not applicable for subjects ≤17 years of age). 3. Estimated CrCl <40 mL/min,using Cockcroft-Gault formula based on actual body weight. 4. Serum creatinine >2.0 mg/dL. 5. Active, untreated SSc renal crisis at the time of consent. 6. Dependence on nutritional supplementation/hyperalimentation. 7. Active gastric antral vascular ectasia (GAVE), defined by a decrease in hemoglobin greater than 1 g/dL in the preceding 60 days, attributed to GAVE. 8. Active hepatitis, defined by any of the following: 1. AST > 2x upper limit of normal. 2. ALT > 2x upper limit of normal. 3. Bilirubin >2x upper limit of normal. 9. Evidence of moderate to severe periportal fibrosis, determined by liver biopsy, if applicable. 10. Active, uncontrolled infection that would be a contraindication to safe use of high-dose immunosuppressive therapy or cyclophosphamide. 11. Hematologic abnormalities as defined by any of the following peripheral blood counts: 1. ANC < 1500 cell/µL. 2. Platelets < 100,000 cells/ µL. 3. Hemoglobin < 9.0 g/dL. 12. Evidence of myelodysplasia (MDS), confirmed by bone marrow aspirate, if applicable. 13. Malignancy within 2 years prior to enrollment, excluding adequately treated squamous cell cancer, basal cell carcinoma or carcinoma in situ. Treatment should have been completed with cure/remission status documented for at least 2 years, with the exception of hormonal therapy for breast cancer. 14. Females who are pregnant or who are lactating. 15. Tobacco use, by subject admission, within previous 4 weeks of time of consent. 16. History of sensitivity to murine proteins or E. coli proteins. 17. Known history of substance abuse, determined by medical record or subject admission, within 6 months of time of consent. . 18. Past or current medical problems or findings from physical examination or laboratory testing that are not listed above, which, in the opinion of the investigator, may pose additional risks from participation in the study, may interfere with the participant's ability to comply with study requirements or that may impact the quality or interpretation of the data obtained from the study.

This is a single center, phase II trial where after a process of stem cell mobilization and conditioning, adult subjects receive a CD34-selected autologous peripheral blood stem cell rescue. By virtue of positive selection for the stem/progenitor cell marker of CD34, the graft will be at least 3-log depleted for T, B and NK lymphocytes and other immune cells such as monocytes that may be pathogenic. This is an open label study and there will be no randomization or blinding as a part of this study. The proposed regimen of high-dose immunoablative therapy will demonstrate safety that is consistent or improved with other published regimens in SSc patients, while maintaining a treatment effect. We also hypothesize that our mechanistic studies will yield biomarkers that may herald disease recurrence or progression following alterations in the recovery of immune cells in the skin and/or bronchial lavage or blood. The primary objectives of this study are to determine the safety and treatment effect of high-dose immunoablative therapy followed by transplantation of CD34+ positively selected peripheral blood stem cells (PBSC) for systemic scleroderma (SSc) patients using a regimen designed to maximize patient safety while also aiming to eradicate autoreactive clones responsible for the disease. Safety will be determined by monitoring for death of any cause, regimen-related toxicities, and severe or life-threatening infections. Treatment effect will be determined by assessing event-free survival in comparison to a SSc observational cohort control group treated with standard of care medication (mycophenolate mofetil) at 12 and 36 months post hematopoietic stem cell transplant (HSCT). Enrolled subjects will be followed for survival, secondary malignancies, and SSC activity at least yearly up to 36 months post-HSCT. The secondary objectives of this study are to:

• - To assess cutaneous disease response to high dose immunosuppressive therapy (HDIT) by comparing pre- and post-transplant measurements of the modified Rodnan skin score (mRSS).

• - To assess pulmonary disease response by longitudinally tracking FVC (pulmonary function test) and DLCO (diffusing capacity of the lung for carbon monoxide) yearly up to 36 months post-HSCT.

• - To evaluate the treatment effect on disease activity/progression, as indicated by severity measures of cardiac, pulmonary and renal organ involvement, and need for concomitant disease-modifying antirheumatic drugs (DMARD) use.

• - To evaluate quality of life by comparing pre- and post-transplant quality of life measurements.

These measurements will include the Scleroderma Health Assessment Questionnaire (SHAQ), the Medical Outcomes Study Questionnaire Short Form 36 Health Survey (SF-36) and the Scleroderma Skin Patient Reported Outcome (SSPRO) pre- and post-mobilization. The research (mechanistic) objectives are as follows:

• - Understand the effect of the combination of rituximab and alemtuzumab on lymphocyte subsets and myeloid cells in the skin of patients undergoing treatment.

• - Understand the effect of total body irradiation (TBI) and Thiotepa on subsets of lymphocytes and myeloid cells in the skin of patients undergoing treatment.

• - Understand the relationship between the response of patient skin disease to depletion and repopulation of skin leukocyte subpopulations and gene expression.

- Characterize the evolution of humoral and cellular immune markers of autoreactivity in blood and BAL (bronchoalveolar lavage)when feasible

Arms

Experimental: Autologous Stem Cell Transplantation

CD34-selected autologous stem cell being performed on CliniMACS depletion device. Conditioning regimen will not start sooner than 3 weeks, and ideally no more than 90 days, after cyclophosphamide dose in the mobilization regimen.

Interventions

Drug: - Cyclophosphamide

Stem Cell Mobilization

Drug: - Mesna

Stem Cell Mobilization

Drug: - Rituximab

Transplantation Conditioning

Drug: - Alemtuzumab

Transplantation Conditioning

Drug: - Thiotepa

Transplantation Conditioning

Drug: - GM-CSF

Transplantation Conditioning

Drug: - Intravenous immunoglobulin

Transplantation Conditioning

Radiation: - Total Body Irradiation

Transplantation Conditioning