Upfront Autologous HSCT Versus Immunosuppression in Early Diffuse Cutaneous Systemic Sclerosis

Prior treatment

• Previous treatments with immunosuppressants \> 12 months including MMF, methotrexate, azathioprine, rituximab, tocilizumab, glucocorticosteroids.
• Previous treatments with TLI, TBI or alkylating agents including CYC.

Other illness

• eosinophilic myalgia syndrome; eosinophilic fasciitis.

Lab values

• Concomitant severe disease =
  • respiratory: resting mean pulmonary artery pressure (mPAP) \> 25 mmHg (by right heart catheterisation), DLCO \< 40% predicted, respiratory failure as defined by the primary endpoint
  • renal: creatinine clearance \< 40 ml/min (measured or estimated)
  • cardiac: clinical evidence of refractory congestive heart failure; LVEF \< 45% by cardiac echo or cardiac MR; chronic atrial fibrillation necessitating oral anticoagulation; uncontrolled ventricular arrhythmia; pericardial effusion with hemodynamic consequences
  • liver failure as defined by a sustained 3-fold increase in serum transaminase or bilirubin, or a Child-Pugh score C
  • psychiatric disorders including active drug or alcohol abuse
  • concurrent neoplasms or myelodysplasia
  • bone marrow insufficiency defined as leukocytopenia \< 4.0 x 109/L, thrombocytopenia \< 50x 10\^9/L, anaemia \< 8 gr/dL, CD4+ T lymphopenia \< 200 x 106/L
  • uncontrolled hypertension
  • uncontrolled acute or chronic infection, including HIV, HTLV-1,2 positivity
  • ZUBROD-ECOG-WHO Performance Status Scale \> 2

Other

• Pregnancy or unwillingness to use adequate contraception during study
• Significant exposure to bleomycin, tainted rapeseed oil, vinyl chloride, trichlorethylene or silica;
• Poor compliance of the patient as assessed by the referring physicians.

• Age between 18 and 65 years.
• Fulfilling the 2013 ACR-EULAR classification criteria for SSc
  • Either: 3.1 or 3.2 3.1. Disease duration ≤ 3 years (from onset of first non-Raynaud's symptoms) and diffuse cutaneous disease with
  • \- progressive skin involvement with a mRSS ≥ 15 (in a diffuse pattern: involvement of skin on the upper limbs, chest and/or abdomen)
  • and/or
  • \- major organ involvement as defined by either:
  • clinically significant respiratory involvement = i. DLCO and/or (F)VC ≤ 85% (of predicted) and evidence of interstitial lung disease on HR-CT scan with clinically relevant obstructive disease and emphysema excluded. ii. Patients with a DCLO and/or FVC \> 85%, but with a progressive course of lung disease: defined as rela-tive decline of \>10% in FVC predicted and/or TLC predicted, or \>15% in DLCO predicted and evidence of interstitial lung disease on HR-CT scan with clinically relevant obstructive disease and emphysema ex-cluded, within 12 months. Intercurrent infections excluded.
  • clinically significant renal involvement = i. new renal insufficiency (serum creatinine \> upper limit of normal) AND
  • persistent urinalysis abnormalities (proteinuria, haematuria, casts), AND/OR
  • microangiopathic haemolytic anaemia AND/OR
  • hypertension (two successive BP readings of either systolic ≥ 160 mm Hg or diastolic \> 110 mm Hg, at least 12 hours apart), ; non-scleroderma related causes (e.g. medication, infection etc.) must be reasonably excluded.
  • clinically significant cardiac involvement = any of the following criteria: i. reversible congestive heart failure, ii. atrial or ventricular rhythm disturbances such as atrial fibrillation or flutter, atrial paroxysmal tachycar-dia or ventricular tachycardia, 2nd or 3rd degree AV block, iii. pericardial effusion (not leading to hemodynamic problems), myocarditis; non-scleroderma related causes must have been reasonably excluded
  • 3.2. Disease duration ≤ 1 year (from onset of first non-Raynaud's symptoms) and diffuse cutaneous disease with mRSS ≥ 10 and
  • High risk ANA for organ based disease: ATA or ARA positivity and/ or
  • Acute phase response (ESR \> 25 mm/h and/or CRP \> 10.0 mg/L )
  • 4\. Written Informed consent