Infusion of Allogeneic Stromal Mesenchymal Stem Cells From Wharton´s Jelly in Patients With Diffuse Cutaneous Systemic Sclerosis With Refractory Pulmonary Involvement to Treatment

This study aims to evaluate the therapeutic effects of allogeneic mesenchymal stromal cell infusion as a treatment in patients with systemic sclerosis refractory to conventional therapy. The study population will be selected from the database of families affiliated with Stem Regenerative Medicine according to the inclusion and exclusion criteria and verified by the academic committee.

Administration will be performed intravenously, at a concentration of 2 × 10⁶ mesenchymal cells per kilogram of patient body weight. Infusions will be scheduled in conjunction with cyclophosphamide treatment cycles, ten days after each administration within the cyclophosphamide regimen for each patient.

To assess safety and therapeutic effects, the occurrence of any adverse event will be documented from the start of infusion until completion of the trial at six months. To evaluate treatment response, assessments will be conducted pre-infusion and at six months post-infusion, including clinical variables, paraclinical parameters, and hemodynamic tests. Skin involvement will be evaluated using the modified Rodnan score, along with assessment of nailfold capillaroscopy, pulmonary function, and structural involvement by high-resolution chest tomography (HRCT), diffusion capacity for carbon monoxide (DLCO), and the 6-minute walk test.

As part of cardiovascular assessment, brain natriuretic peptide (BNP) levels and transthoracic echocardiography will be performed. The Cambridge Pulmonary Hypertension Outcome Review (CAMPHOR) and SYSQ will be used as assessment tools for pulmonary hypertension. A comparison of these parameters before initiation of therapy and after completion of 24 weeks of the infusion protocol will be conducted.

Inclusion criteria

• Age> 18 years and <65 years.
• Established diagnosis of systemic sclerosis according to the criteria of the American College of Rheumatology
• SSc of poor prognosis, involving life-threatening severe visceral involvement (cardiac or pulmonary hypertension ), lack of response to conventional immunosuppressive therapy used in severe forms of the disease according to the European recommendations of EUSTAR and EBMT, relying on high doses of IV cyclophosphamide (either in monthly bolus for at least six months); or SSc with life-threatening pulmonary hypertension. Patients may or may not have pulmonary fibrosis.
• Signed informed consent.
• Presence of a consenting MSC donor
• Affiliation to social security.

Exclusion criteria

• Pregnancy or absence of appropriate contraception throughout the study.
• Pulmonary artery systolic pressure (PASP) >75mmHg (on echocardiography or after right heart catheterization);

• Theorical DLCO <30%
• Calculated creatinine clearance <30 ml/mn/m2
• Clinical sign of a congestive heart failure refractory ;
• Left ventricular ejection fraction <35% at myocardial scintigraphy or echocardiography;
• Chronic atrial fibrillation requiring oral anticoagulant therapy;
• Uncontrolled ventricular arrhythmia;
• Pericardial effusion with hemodynamic compromise assessed by echocardiography.
• Hepatic impairment defined as a persistent increase in transaminases or bilirubin to 3 times normal.
• Psychiatric disorders, including drug taking and alcohol abuse.
• Active neoplasia or concomitant myelodysplasia, antecedent of neoplasia.
• Bone marrow failure defined by neutropenia <0.5 x 109 / L, thrombocytopenia <50 x 109 / L, anemia <8 g / dL, CD4 lymphopenia <200 x 106 / L.
• Uncontrolled systemic hypertension.
• Uncontrolled acute or chronic infection, HIV1, 2 or HTLV-1, 2seropositivity.
• Chronic hepatitis B or C active.
• Significant exposure to bleomycin, toxic oils, vinyl chloride, trichloroethylene or silica; eosinophilia-myalgia syndrome, eosinophilia fasciitis.
• Risk of poor patient compliance