Scleroderma Treatment With Autologous Transplant (STAT) Study

Inclusion Criteria: * Patients with SSc as defined by the American College of Rheumatology with diffuse cutaneous disease (except Group 5) at risk of disease progression * Patients must have failed a prior \>= 4-mponth course of either MMF/Myfortic or cyclophosphamide before being eligible for the study (determined at \>= 1 week before start of mobilization); "failure" is defined as evidence of disease progression or absence of improvement; the response prior to MMF of cyclophosphamide will be assessed by the participating site study rheumatologist * Patients must meet eligibility in at least 1 of the following 6 groups: * GROUP 1: * Patients must have 1) both a and b below; and 2) either c, or d * a) Diffuse cutaneous scleroderma as defined by skin thickening proximal to the elbows and knees and/or involving the torso in addition to distal extremity involvement; a skin score will be obtained but not used to determine eligibility * b) Duration of systemic sclerosis =\< 7 years from the onset of first non-Raynaud's symptom; for those patients with disease activity between 5-7 years from the onset of first non-Raynaud's symptom, recent progression or activity of disease must be documented * c) Presence of SSc-related pulmonary disease with forced vital capacity (FVC) \< 80% or hemoglobin-adjusted diffusing capacity for carbon monoxide (DLCO) \< 70% of predicted AND evidence of alveolitis or SSc-related interstitial lung disease by high-resolution chest computed tomography (CT) scan and/or by bronchoalveolar lavage (BAL) (interstitial lung disease may be nonspecific interstitial pneumonia \[NSIP\] or usual interstitial pneumonia \[UIP\]; a bronchoalveolar lavage \[BAL\] should be done to confirm the findings of alveolitis only if the high resolution CT scan \[HRCT\] fails to show findings typically associated with systemic sclerosis changes \[ground glass NSIP, UIP, SSc related interstitial lung disease\]); alveolitis by BAL cell count will be defined based on a BAL cell differential count (\> 3% neutrophils and/or \> 2% eosinophils) from any lavaged lobe * d) History of SSc-related renal disease that may not be active at the time of screening; stable serum creatinine must be documented for a minimum of 3 months post-renal crisis at the time of the baseline visit; history of scleroderma hypertensive renal crisis is included in this criterion and is defined as follows: * History of new-onset hypertension based on any of the following (measurements must be repeated and confirmed at least 2 hours apart within 3 days of first event-associated observation, with a change from baseline): * Systolic blood pressure (SBP) \>= 140 mmHg * Diastolic blood pressure (DBP) \>= 90 mmHg * Rise in SBP \>= 30 mmHg compared to baseline * Rise in DBP \>= 20 mmHg compared to baseline * AND one of the following 5 laboratory criteria: * Increase of \>= 50 % above baseline in serum creatinine * Proteinuria: \>= 2+ by dipstick confirmed by protein:creatinine ratio \> 2.5 * Hematuria: \>= 2+ by dipstick or \> 10 red blood cell (RBC)s/hematopoietic-promoting factor (HPF) (without menstruation) * Thrombocytopenia: \< 100,000 platelets/mm\^3 * Hemolysis: by blood smear or increased reticulocyte count * The above definition of SSc hypertensive renal crisis is independent of whether concomitant anti-hypertensive medications are used * Subjects who present with solely skin and renal disease in the absence of other organ involvement, except classic SSc renal crisis as described above and including non-hypertensive renal crisis, must see a nephrologist to confirm that their renal disease is secondary to only SSc * Note: Subjects may be re-screened if they fail to meet inclusion criteria on initial evaluation * GROUP 2: * Progressive pulmonary disease as defined by a decrease in the FVC or DLCO-adjusted by 10 or 15 percent or greater, respectively, from a prior FVC or DLCO-adjusted in the previous 18-month period * Patients will have diffuse cutaneous disease and may have both FVC and DLCOcorr \>= 70% at screening for the study * Patients must also have evidence of alveolitis as defined by abnormal chest computed tomography (CT) or bronchoalveolar lavage (BAL) * GROUP 3: Diffuse scleroderma with disease duration =\< 2 years since development of first sign of skin thickening plus modified Rodnan skin score \>= 25 plus either * Erythrocyte sedimentation rate (ESR) \> 25 mm/1st hour and/or hemoglobin (Hb) \< 11 g/dL, not explained by causes other than active scleroderma * Lung involvement (either FVC or DLCO \< 80% and evidence of interstitial lung disease by CT scan or alveolitis by BAL) * GROUP 4: Diffuse scleroderma with disease duration =\< 2 years and skin score \>= 30 * GROUP 5: * Limited cutaneous scleroderma and SSc-related pulmonary disease with FVC \< 80% or hemoglobin-adjusted DLCO \< 70% of predicted * AND evidence of alveolitis/interstitial lung disease by high-resolution chest CT scan and/or by BAL (interstitial lung disease may be nonspecific interstitial pneumonia \[NSIP\] or usual interstitial pneumonia \[UIP\]; A bronchoalveolar lavage \[BAL\] should be done to confirm the findings of alveolitis only if the high resolution CT scan \[HRCT\] fails to show findings typically associated with systemic sclerosis changes \[ground glass, NSIP, UIP, SSc related interstitial lung disease\]) * Alveolitis by BAL cell count will be defined based on a BAL cell differential count (\> 3% neutrophils and/or \> 2% eosinophils) from any lavaged lobe * GROUP 6: Progressive gastrointestinal disease as defined by all of the following items: * Disease duration of scleroderma =\< 2 years. * Documented severe malabsorption syndrome requiring nutritional support; severe malabsorption syndrome is \> 10% weight loss and on total parenteral nutrition (TPN) or enteral feedings * High score on distention/ bloating scale (\>= 1.60 out of 3.00) on gastrointestinal (GI) questionnaire Exclusion Criteria: * Subjects with pulmonary, cardiac, hepatic, or renal impairment that would limit their ability to receive cytoreductive therapy and compromise their survival; this includes, but is not restricted to, subjects with any of the following: * Pulmonary dysfunction defined as: * Severe pulmonary dysfunction with (1) a hemoglobin corrected DLCO \< 40% of predicted at the Baseline Screening visit, or (3) FVC \< 45% of predicted Baseline Screening visit, or * Partial pressure (pO2) \< 70 mmHg or pCO2 \>= 45 mmHg without supplemental oxygen, or * O2 saturation \< 92% at rest without supplemental oxygen as measured by forehead pulse oximeter * Significant pulmonary artery hypertension (PAH) defined as: * Peak systolic pulmonary artery pressure \> 50 mmHg by resting echocardiogram will require right heart catheterization; if pulmonary artery pressure (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, right heart catheterization is indicated; prior history of PAH but controlled with medications will not exclude patients from the protocol; PAH is considered controlled with medications if peak systolic pulmonary artery pressure is \< 45 mmHg or mean pulmonary artery pressure by right heart catheterization is \< 30 mmHg at rest * Mean pulmonary artery pressure by right heart catheterization exceeding 30 mmHg at rest; if mean PAP is elevated and pulmonary vascular resistance and transpulmonary gradient are normal then the patient is eligible for the protocol * New York Heart Association (NYHA)/World Health Organization Class III or IV * Cardiac: Uncontrolled clinically significant arrhythmias; clinical evidence of significant congestive heart failure (CHF) (NYHA Class III or IV); left ventricular ejection fraction (LVEF) \< 50% by echocardiogram * History/presence of arrhythmia (even controlled) on chemical anti-arrhythmic(s) must have cardiac consult to ensure the subject could safely proceed with protocol requirements * Significant renal pathology defined as: * Estimated creatinine clearance (CrCl) \< 40 mL/min (using Cockcroft-Gault formula based on actual body weight) and serum creatinine \> 2.0 mg/dL; OR * 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 require 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 * Hepatic: Active hepatitis (alanine aminotransferase \[ALT\], aspartate aminotransferase \[AST\], or bilirubin \> 2 times the upper limit of normal \[ULN\]) or evidence of moderate to severe periportal fibrosis by liver biopsy * Active or clinically significant Gastric Antral Vascular Ectasia (GAVE, "watermelon stomach") * Unwilling or unable to discontinue disallowed disease-modifying antirheumatic drugs (DMARDs) for treatment of SSc prior to mobilization * History or presence of a 2nd autoimmune disease requiring immunosuppressive therapy that has substantial risk of immunosuppressive treatment beyond transplant with the following exceptions: * History and/or presence of Sjogren's Syndrome is allowed * Stable myositis (A history of myositis that is clinically stable as defined by lack of progressive proximal muscle weakness and a stable or decreasing creatine phosphokinase \[CPK\] \< 3 x ULN) is allowed * The presence of anti-double stranded (ds)-deoxyribonucleic acid (DNA) without clinical systemic lupus erythematosus in a patient with a diagnosis of otherwise "pure" SSc is allowed * Concomitant rheumatoid arthritis without extra-articular disease characteristic of rheumatoid arthritis is allowed * Active uncontrolled infection that would be a contraindication to safe use of high-dose therapy * Positive study for Hepatitis B surface antigen or Hepatitis B or C confirmed by polymerase chain reaction (PCR) * Positive serology for human immunodeficiency virus (HIV) * Absolute neutrophil count (ANC) \< 1500 cells/uL * Platelets \< 100,000 cells/uL * Hematocrit \< 27% * Hemoglobin \< 9.0 g/dL * Malignancy within the 2 years prior to entry in study, excluding adequately treated squamous cell skin cancer, basal cell carcinoma, and carcinoma in situ; treatment must have been completed (with the exception of hormonal therapy for breast cancer) with cure/remission status verified for at least 2 years prior to entry in this study * Presence of other comorbid illnesses with an estimated median life expectancy \< 5 years * Evidence of myelodysplasia (MDS); subjects with history of receiving any prior chemotherapy and/or radiotherapy for the treatment of malignant disease, history of greater than 2 months total prior cyclophosphamide for any condition (regardless of dose and route) and/or subjects presenting with abnormal peripheral blood counts require unilateral bone marrow aspiration for pathology, flow cytometry, cytogenetics, and fluorescence in situ hybridization (FISH) MDS panel (per institutional profile) to rule out MDS * Pregnancy * Inability to give voluntary informed consent * Unwilling to use contraceptive methods for at least 15 months after starting treatment * History of smoking tobacco (or other related/herbal products) in the prior 3 months * History of prior autologous hematopoietic cell transplantation