Treatment With Human Umbilical Cord-derived Mesenchymal Stromal Cells in Systemic Sclerosis

Inclusion Criteria:

1. SSc according to American College of Rheumatology/European League Against Rheumatism (ACR/EULAR) 2103 classification criteria for systemic sclerosis

2. Severe disease defined as: i) disease duration of 2 years or less with an mRss of > 20 and (ESR > 25 mm and/orhemoglobin < 11 g/dL, not explained by other causes than SSc), or ii) mRss >15without any restriction as to disease duration plus at least one major organinvolvement as defined by: a) respiratory involvement consisting of lung diffusioncapacity for carbon monoxide (DLCO) and/or forced vital capacity (FVC) < 80%predicted and evidence of interstitial lung disease (chest X-ray and/or highresolution computed tomography (HRCT) scan); b) renal involvement consisting of pastrenal crisis and/or stage 2 or 3 chronic kidney disease (glomerular filtration ratebetween 30-89 mL/min) not explained by other causes than SSc; c) cardiac involvementconsisting of reversible congestive heart failure, atrial or ventricular rhythmdisturbances such as recurrent episodes of atrial fibrillation or flutter, recurrentatrial paroxysmal tachycardia, conduction abnormalities (2nd or 3rd degreeatrioventricular block), and/or mild to moderate pericardial effusion. All causes oforgan involvement should be attributed to SSc.

3. Inadequate response (determined by patient and physician judgement) or adverseevents necessitating discontinuation of standard therapy (usually consisting ofmethotrexate 25 mg subcutaneous (or as tolerated) per week and/or mycophenolatemofetil 2-3 gm/d (or as tolerated) for at least 3 months

4. Ineligibility or unwillingness to undergo autologous hematopoietic stem celltransplant

Exclusion Criteria:

1. Age < 18 years

2. Pregnancy or unwillingness to use adequate contraception

3. Life-threatening end-organ damage defined as:

• FVC < 45% and/or DLCO (corrected for hemoglobin) < 30% predicted;

• Left ventricular ejection fraction < 40% by cardiac echocardiography;

• Pulmonary hypertension with baseline resting systolic pulmonary arterialpressures > 50 mmHg by cardiac echocardiography, or mean pulmonary arterypressure > 25 mmHg (and pulmonary wedge pressure < 15 mmHg) on right heartcatheterization;

• stage 4 or more chronic kidney disease (glomerular filtration rate < 30 ml/min)

4. Liver failure defined as an abnormal transaminase level (aspartate aminotransferase (ASAT), alanine aminotransaminase (ALAT) > 3 normal) unless related to activity ofthe disease

5. Concurrent neoplasms or myelodysplasia

6. Uncontrolled hypertension

7. Uncontrolled acute or chronic infection (HIV, HTLV-1/2 (Human T-lymphotropic virus),hepatitis B surface Ag positive, hepatitis C positive) or high risk thereof

8. Significant malnutrition with BMI < 18 kg/m2

9. Severe concomitant psychiatric disorder

10. Bone marrow insufficiency defined as neutropenia < 0.5 x 109 cell/L,thrombocytopenia < 30 x 109 cell/L, anemia < 8g/dL, CD4+ T lymphopenia < 200 x 106cell/L due to other diseases than SSc (CD4 - cluster of differentiation 4)

11. History of poor compliance

12. Concurrent enrolment in any other protocol using an investigational drug

13. Inability to provide informed consent