Edited by: Giancarlo Castaman, University of Florence, Italy
Reviewed by: Lucia Prezioso, University Hospital of Parma, Italy
Mutlu Arat, Memorial Sisli Hospital, Türkiye
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Autologous hematopoietic cell transplantation (HCT) has been introduced for patients with severe systemic sclerosis (SSc). We aimed to assess the safety and long-term efficacy of HCT modality for severe SSc, refractory to conventional therapy, in 17 patients who were referred to our – The Joint Accreditation Committee of the International Society for Cellular Therapy (ISCT) and the European Group for Blood and Marrow Transplantation (EBMT)-accredited Unit from 2005 to 2024. Peripheral blood stem cells were collected using cyclophosphamide and GCSF. An immunoablative conditioning regimen of cyclophosphamide and anti-thymocyte globulin was administered. Disease assessments were done before and after mobilization treatment and post-transplant, focusing on skin sclerosis, pulmonary function, cardiac involvement, gastrointestinal manifestations, the necessity for additional immunosuppressive therapy, and overall patient well-being. Before transplantation, 13/17 (76%) of the patients had diffuse skin involvement with a mean mRSS of 31 (2–49), 2/17 (12%) had pulmonary hypertension, and 14/17 (82%) had gastrointestinal manifestations. The median follow-up period was 9.1 (0. 5–14. 3) years. Improvement of skin sclerosis was observed, with a decrease in mRSS before transplantation from 31 (2–49) to 7 (2–22) post-HCT. Lung function remained stable in 8/15 (53%) patients, improved in 5/15 (33%), and deteriorated in 2/15 (13%). Gastrointestinal manifestations were improved in 12/14 (86%) patients, while all patients (16/16, 100%) reported a great impact on their quality of life. Ten out of the 16 (63%) patients were free of immunosuppressive drugs after the HCT. Overall survival was 16/17 (94.2%). Concerning TRM, there was one (1/17, 5.8%) death early post-transplant. In this specific cohort of selected patients with severe SSc refractory to immunosuppressive medications, autologous HCT led to improvements in the outcomes assessed.
Systemic sclerosis (SSc) is an immune-mediated rheumatic disease characterized by three main dysfunctions, namely autoimmune responses, vascular damage, and fibrosis of the skin and internal organs, including the lungs, heart, kidney, and gastrointestinal tract (
Data show that mortality rates of SSc have steadily declined in the past two decades, although systemic sclerosis patients still experience a significant burden of disease (
On top of non-HCT therapies, autologous hematopoietic stem cell transplantation is a promising therapeutic approach (
The development of autologous HCT as a therapeutic modality for systemic sclerosis has overcome major barriers in the last 25 years, such as morbidity and treatment-related mortality rates that were too high for an autoimmune disease. Best clinical practice with a very strict and careful patient selection, as well as optimal early timing of the transplant procedure, emerged as a critical value. Many organizations have recommended autologous HCT for early severe diffuse cutaneous SSc patients. The European Group for Blood and Marrow Transplantation in 2012 (
The present study aims to evaluate the safety and long-term efficacy of HCT modality for severe SSc patients at a single expert center, highlighting the strengths and limitations of this approach.
This study is a retrospective, single-center study. The aim of the study was to assess the safety and long-term efficacy of autologous HCT in patients with severe systemic sclerosis. All HCT procedures took place in the JACIE-accredited Hematopoietic Cell Transplantation Unit, in the G. Papanicolaou Hospital, Thessaloniki, Greece, between 2005 and 2024. Patients were eligible for the HCT procedure if they fulfilled the 1980 classification criteria of the American College of Rheumatology for SSc (
The local ethics committee of G. Papanicolaou Hospital approved this study (No. 187/2016), which was conducted according to the Declaration of Helsinki. All patients gave their written informed consent to participate in the study.
Each patient was thoroughly evaluated prior to transplantation (day 0 was defined as the time of infusion of stem cells) to determine baseline status and identify possible exclusionary conditions. Laboratorial assessment included blood and urine samples for complete blood counts, biochemical profile, urine analysis, creatinine clearance, proteinuria, pregnancy tests, infectious serologies, and the presence or absence of autoantibodies. Skin sclerosis (mRSS) evaluation was based on clinical examination, cardiac functionality was assessed by cardiac magnetic resonance imaging (MRI) and echocardiography, and pulmonary arterial hypertension was diagnosed based on the findings of HRCT. Moreover, pulmonary status was evaluated with the use of HRCT and the assessment of FEV1 and DLCO. Lastly, patient-reported outcomes regarding functional ability and quality of life were collected.
The first phase of autologous HCT consists of the mobilization of hematopoietic progenitor cells from the bone marrow into the peripheral blood through the infusion of cyclophosphamide at a dose of 4 gr/m2 and G-CSF. The next step is the apheresis and cryopreservation of the hematopoietic progenitor cells. The second phase of autologous HCT is characterized by intense immunoablation with an immunoablative regimen that consists of cyclophosphamide (50 mg/kg/d for 4 days) and anti-thymocyte-globulin (Rabbit ATG; 2.5 mg/kg/d for 3 days). Lastly, the previously collected cells are infused. The target CD34 + number was 4 × 106, the standard target according to JACIE accreditation.
The main goal of this study was to examine the safety of this procedure. Early treatment-related mortality was defined as any death during the 100 days following transplant for which HCT was the major causal influencing factor.
Secondary endpoints were overall survival, the need for additional immunosuppressive drugs post-transplant, and the response to treatment. The response to treatment was defined as a > 25% improvement in mRSS, a subjective report of improvement in gastrointestinal symptoms, and an improvement in lung function, which was categorized as follows: “no change” for 0–9% change of FEV1 or DLCO, “improvement” for increases of ≥ 10%, or “deterioration” for decreases of ≥ 10%. Descriptive statistical analysis was performed by SPSS version 22. The limited patient population did not allow for further statistical comparison.
A total of 17 patients underwent auto-HCT, 14 women (82%) and 3 men (18%). The median age was 34 (range 21–50) years with median disease onset 3 (2–13) years prior to the transplantation. Before HCT, skin involvement was detectable in 13 (13/17, 76%) patients with a median mRSS of 31 (range 2–49). Two patients (2/17, 12%) were also diagnosed with pulmonary arterial hypertension. Median DLCO was 61.0% (range 42–95) and median FEV1 was 78.0% (range 56–98) of the respective target values. Gastrointestinal manifestations were found in 14 of 17 patients (82%). In
Baseline patient characteristics.
| Baseline patient characteristics | |
|---|---|
| Gender, |
|
| Female | 14 (82) |
| Male | 3 (18) |
| Median age years (range) | 34 (21–50) |
| Median disease duration years (range) | 3 (2–13) |
| Mean number of prior administrations of immunosuppressive therapy in each patient (95% CI) | 4 (2–7) |
| Number of patients who received cyclophosphamide infusions, |
13 (76) |
| Mean overall cyclophosphamide dose for each patient, gr (95% CI) | 6 (2.5–12) |
| Mean modified Rodnan skin score (before transplant) (95% CI) | 31 (2–49) |
| Patients with mRSS < 15 and severe lung disease, |
4 (23) |
| Patients with gastrointestinal involvement, |
14 (82) |
| Lung involvement, | |
| Mean FEV1% | 78 (56–98) |
| Mean DLCO% | 61 (42–95) |
| Patients with pulmonary arterial hypertension, |
2 (12) |
| Mean ejection fraction%, | 70 (60–75) |
| Number of patients with ECOG < 3, |
17 (100) |
DLCO, diffusing capacity of the lungs for carbon monoxide; ECOG, Eastern Cooperative Oncology Group; FEV1, forced expiratory volume in 1 s; mRSS: Mean Modified Skin Score.
After auto-HCT, the mean period for the neutrophil engraftment was 9 (7–14) days, for the platelet engraftment was 9 (5–13) days, and the mean time for discharge from the unit was 14 (13–38) days.
Two (2/17, 12%) patients presented pneumothorax as a complication of central venous catheter insertion. Fever during the neutropenic phase of auto-HCT was noted in 10 (10/17, 58%) patients. Regarding infections, 3 (3/17, 17%) patients presented lower respiratory tract infections and another (1/17, 5.8%) patient exhibited BK polyomavirus–associated hemorrhagic cystitis. After engraftment, cytomegalovirus (CMV) reactivation was detected in two (2/17, 12%) patients, Epstein Barr reactivation in 4 (4/17, 23%) patients, and Herpes Zoster reactivation in one (1/17, 5.8%) patient.
Complications and transplant-related events after transplantation.
| Complications and transplant-related events after transplantation | |
|---|---|
| Pneumothorax during central venous catheter placement procedure | 2 (12) |
| Neutropenic fever | 10 (63) |
| Lower respiratory tract infection | 3 (17) |
| Polyomavirus-induced hemorrhagic cystitis | 1 (5.8) |
| CMV reactivation | 2 (12) |
| EBV reactivation | 4 (23) |
| Herpes Zoster | 1 (5.8) |
| Transplant-related death (total) |
1 (5.8) |
CMV, Cytomegalovirus; EBV, Epstein Barr Virus.
There was one (1/17, 5.8%) death that was considered transplant-related at 87 days after the procedure. This patient was heavily pre-treated with severe pulmonary disease (DLCO 49%). The patient died due to infection, sepsis, and multiorgan failure in the intensive care unit (ICU).
The median mRSS was significantly improved after the HCT, with the median mRSS being 7 at the last follow-up (2–22). Regarding lung function, DLCO and FEV1 percentages stabilized after HCT in 8 (8/15, 53%) SSc patients, two (2/15, 13%) patients presented more than a 10% decline in FEV1 or DLCO, and 5 (5/15, 33%) patients presented improvements in both FEV1 and DLCO. Gastrointestinal manifestations were improved in 12 (12/14, 86%) patients. All patients (16/16, 100%) reported a great impact on their quality of life. Further immunosuppressive treatment was needed in 6 (6/16, 37%) patients who had disease reactivation after HCT.
In the past 30 years, hematopoietic cell transplantation has been investigated as a treatment for many autoimmune diseases, including systemic sclerosis. Despite the high risk of transplant-related mortality and other complications, HCT is supposed to be the only treatment able to induce long-term, symptom-free remission without the necessity for additional pharmacological management in many refractory autoimmune rheumatic diseases (
Interestingly, the first patient reported to be treated with an HCT for an autoimmune disease had systemic sclerosis complicated with pulmonary artery hypertension, who denied lung transplant (
Currently, HCT is geared toward patients with severe SSc, but the selection criteria for these patients can go beyond that (
Recent data suggest that mortality, quality of life, and skin tightness are among the clinical manifestations that are definitely improved, with high levels of evidence, after the HCT procedure. Lung function (Forced vital capacity, FVC) appears to be mildly improved, while the improvement of pain, interstitial lung disease (as far as the inflammation, not the fibrosis), gastrointestinal symptoms, range of motion of joints, hand grip strength, and exercise capacity is supported by a medium level of evidence. HCT also seems to prevent the development of pulmonary arterial hypertension (PAH) and heart failure (HF), but its effect on established PAH and HF remains unclear. Esophageal motility, myositis, and peripheral neuropathy possibly present an improvement but without a strong level of evidence yet. Conversely, renal function and esophageal dilation appear to be negatively affected (
Here, we describe the clinical outcomes of 17 adult SSc patients with a severe form of the disease, refractory to conventional therapy, treated at a single center from 2005 to 2024 under similar transplant protocols. However, our experience in autologous transplantation goes back to 1997 with our pioneering work on multiple sclerosis (
It seems that the positive outcome of the HCT procedure is correlated with a shorter interval from the diagnosis time to the HCT, as less tissue damage and internal organ impairment has been accumulated over time, so these lesions may still be reversible. Thus, many studies have included patients with disease duration of up to 4 years (
HCT is not a “panacea” for patients with severe SSc. The likelihood of nonresponse or relapsing (whether manageable or not) and the lack of justified prognostic factors for the 4–17% of patients who experience transplant-related mortality (
Our study reported one transplant-related death (1/17, 5.8%) of a patient who was refractory to immunosuppressives up to 7 times before the HCT and died of infection, sepsis, and multiple organ dysfunction 87 days after the procedure. HCT-related mortality in our series is remarkably low (5.8%) and we have to consider that the HCT procedure was the only treatment choice left in this patient’s therapeutic options. Interestingly, 6 of our patients (6/16, 37%) initiated immunosuppressive therapy after the HCT procedure, at a median time of 2.1 years (0.6–3.2). It is important to stress that the necessity for immunosuppressive drugs after HCT is not uncommon (
Our study has some methodological limitations. Firstly, this is a single-center open study, so the results may not have the same scientific power as those derived from a multicenter controlled trial. Secondly, there was not a control group treated with conventional immunosuppressive drugs to make the comparison between them or among other studies. Thirdly, our study is retrospective with a small sample size. Lastly, data regarding FVC measurements as well as the autoantibody status, while assessed prior to the auto-HCT, are not available.
High treatment-related mortality, although significantly reduced, remains the Achilles heel of HCT, requiring an assessment of risk versus benefit at an individual level to make an informed decision after appropriate evaluation, investigation, and discussion with each patient. Looking for alternative treatment options with comparable efficacy to HCT, chimeric antigen receptor (CAR) T-cell therapy, as well as new combinations of immunomodulatory drugs (
A cure for the severe form of systemic sclerosis has been desired by physicians for many years. Based on our data, autologous HCT is a safe and effective therapy for SSc patients, with durable long-term outcomes. Although many details are yet to be clarified regarding the timing, patients’ eligibility criteria, prognostic factors for the TRM, and a strict framework of guidelines, it seems that a unique opportunity has emerged for people with severe systemic sclerosis and for autoimmune diseases in general.
The original contributions presented in the study are included in the article/supplementary material, further inquiries can be directed to the corresponding authors.
The studies involving humans were approved by the local ethics committee of G. Papanicolaou Hospital approved this study (No. 187/2016) which conducted according to the Declaration of Helsinki. The studies were conducted in accordance with the local legislation and institutional requirements. The participants provided their written informed consent to participate in this study. Written informed consent was obtained from the individual(s) for the publication of any potentially identifiable images or data included in this article.
EG: Writing – original draft. DM: Writing – original draft. IB: Writing – original draft. ZB: Writing – original draft. AV: Writing – original draft. NS: Writing – original draft. GK: Writing – original draft. AP: Writing – original draft. PD: Writing – original draft. CV: Writing – original draft. VA: Writing – original draft. PA: Writing – original draft. PV: Writing – original draft. DS: Writing – original draft. PS: Writing – review & editing. IS: Supervision, Writing – original draft.
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