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J, Henes et al.
tion of the follow-up was 24 (range, 6-57) months after stem cell transplantation using cyclophosphamide plus antithymocyte globulin conditioning for all, with CD34+ selection in 35 patients. At 2 years, the pro- gression-free survival rate was 81.8%, the overall survival rate was 90%, the response rate was 88.7% and the incidence of progression was 11.9%. The 100-day non-relapse mortality rate was 6.25% (n=5) with four deaths from cardiac events, including three due to cyclophosphamide toxicity. Modified Rodnan skin score and forced vital capacity improved with time (P<0.001). By multivariate analysis, baseline skin score >24 and older age at transplantation were associated with lower progression-free sur- vival (hazard ratios 3.32 and 1.77, respectively). CD34+-cell selection was associated with better response (hazard ratio 0.46). This study confirms the efficacy of autologous stem cell transplantation, using non- myeloablative conditioning, in real-life practice for severe systemic sclerosis. Careful cardio-pulmonary assessment to identify organ involvement at the time of the patient’s referral, reduced cyclophosphamide doses and CD34+-cell selection may improve outcomes. The study was registered at ClinicalTrials.gov: NCT02516124.
Introduction
Systemic sclerosis (SSc) is a rare systemic autoimmune connective tissue disease characterized by vasculopathy, immune dysregulation and progressive fibrosis, affecting primarily the skin, gastrointestinal tract, lungs, heart and kidneys.1 It is associated with high disease-related mortali- ty2 and the main causes of death are related to cardiac, pul- monary and renal involvement.2-5 Mortality rates in patients with SSc have remained higher than those in the general population (standardized mortality ratio above 3.5) over the past decades, in contrast to reductions in mortality for other rheumatic diseases or cancer.6 After the diagnosis of non-Raynaud phenomenon, the following risk factors for higher mortality related to progressive disease have been identified:2 diffuse skin fibrosis measured by the modified Rodnan skin score (mRSS, range 0-51),7 elevated C-reactive protein levels, altered left or right ventricular ejection fraction, interstitial lung disease with reduced forced vital capacity (FVC) or diffusion capacity for carbon monoxide (DLCO) on lung function testing, proteinuria and male sex. Earlier studies had found that the presence of anti-topoisomerase II (Scl-70) auto-antibodies, reduced functional status - as measured by the Scleroderma Health Assessment Questionnaire (sHAQ, range from 0 to 3, with lower values indicating a better quality of life)8 - or pul- monary arterial hypertension adversely affect survival.3-5 Treatment with biologic or immunosuppressive drugs did not improve SSc survival.2,9,10
Following early phase I-II trials,11-13 three randomized controlled trials, namely ASSIST (American scleroderma stem cell versus immune suppression trial, phase II),14 ASTIS (Autologous stem cell transplantation international scleroderma trial, phase III)15 and SCOT (Scleroderma: cyclophosphamide or transplantation, phase II)16 demon- strated the superiority of autologous hematopoietic stem cell transplantation (HSCT) compared to the standard cyclophosphamide pulse treatment with regards to overall and event-free survival. In this context, autologous HSCT has become the best treatment option for patients with severe or rapidly progressive SSc, with a grade 1 level of evidence since 2012 according to the Autoimmune Disease Working Party (ADWP) of the European Society for Blood and Marrow Transplantation (EBMT) recom- mendations.17,18 After two decades of progress in HSCT for autoimmune diseases, the use of autologous HSCT for severe or rapidly progressive SSc has also been endorsed by the European League Against Rheumatism (EULAR)10
and the American Society for Blood and Marrow
Transplantation10,17,19 and the demand for this therapeutic
procedure is the fastest growing indication for HSCT in Europe.10,17,19,20
We therefore designed this ADWP-EBMT non-interven- tional study, NISSC1, to further evaluate the efficacy and safety of autologous HSCT for early, severe, progressive SSc, when performed in real-life practice, and to identify risk factors for early adverse events and transplant-related mortality, in order to make this approach safer.
Methods
Study design
This study is a prospective, open, multicenter, non-interven- tional study. Data regarding patients included in this study were prospectively collected using a specific case report form, designed according to EBMT guidelines for HSCT in SSc.17 All EBMT partic- ipating centers agreed to report their consecutive patients aged 18 to 65 years with severe progressive SSc undergoing their first autologous HSCT between December 2012 and February 2016. Inclusion and exclusion criteria are detailed in the Online Supplementary Appendix. Participating centers followed their own local protocols for the transplant procedure as wells as the patients’ evaluation at baseline and during the 2-year follow-up.
The study was approved by the EBMT board in 2012 and by local ethics committees in participating countries and registered at ClinicalTrials.gov (NCT02516124). All patients gave written informed consent to their participation in the study.
Patients’ evaluation
The SSc patients’ characteristics were assessed at baseline (within 3 months before autologous HSCT) and at 3, 6, 12, 18 and 24 months after transplantation (day 0 was defined as the time point of reinfusion of stem cells). Data collected included mRSS, erythrocyte sedimentation rate (in mm/h), creatine kinase levels, presence or absence of autoantibodies, left ventric- ular ejection fraction (LVEF in %) and systolic pulmonary arterial pressure (in mmHg) on echocardiography, resting and 24 h Holter-electrocardiograms, abnormal cardiac magnetic reso- nance imaging (MRI) or pulmonary arterial hypertension on right heart catheterization (RHC), FVC and DLCO (% of pre- dicted values), high resolution computed tomography of the lungs and kidney function as well as immunosuppressive drugs given before transplantation. The sHAQ was used to evaluate patients’ quality of life.
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