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 Table of Contents  
Year : 2017  |  Volume : 12  |  Issue : 6  |  Page : 218-226

Hematopoietic stem cell transplantation in systemic sclerosis

Department of Clinical Immunology, JIPMER, Puducherry, India

Date of Web Publication23-Nov-2017

Correspondence Address:
V S Negi
Department of Clinical Immunology, JIPMER, Puducherry
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/0973-3698.219078

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Systemic sclerosis (SSc) is a disease associated with a significant morbidity and mortality, with relatively small benefits seen with immunosuppression. Of late, hematopoietic stem cell transplantation has emerged as a promising therapy for SSc with a significant reduction in mortality in the longer term. We discuss the principles behind stem cell transplantation in SSc as well as the recent trials which have shown significant promise with this technique.

Keywords: Cytokines, immunosuppression, morbidity, mortality, myeloablation, stem cell

How to cite this article:
Chengappa K G, Negi V S. Hematopoietic stem cell transplantation in systemic sclerosis. Indian J Rheumatol 2017;12, Suppl S1:218-26

How to cite this URL:
Chengappa K G, Negi V S. Hematopoietic stem cell transplantation in systemic sclerosis. Indian J Rheumatol [serial online] 2017 [cited 2022 Jun 27];12, Suppl S1:218-26. Available from:

  Introduction Top

Systemic sclerosis (SSc), also known as scleroderma, is an autoimmune inflammatory rheumatic disease characterized by deposition of excess collagen in the connective tissue matrix. The disease affects not only the skin but also most of the internal organs in varying degrees of severity. The pathophysiology and the progression of SSc have been attributed to a combination of vasculopathy involving small-to-medium-sized blood vessels, immune activation, and low-grade inflammation, ultimately culminating into excessive fibrosis.

SSc can be classified based on the clinical phenotype into two categories: limited cutaneous SSc and diffuse cutaneous SSc (dcSSc) forms. Apart from the skin involvement, the two classes also differ in terms of internal organ involvement, autoantibody profile, and prognosis.

SSc is not only physically disfiguring but also causes significant morbidity and mortality with reduced life expectancy. Standardized mortality ratios (SMRs) in patients with SSc are known to be at least three times higher than that of the normal population. A meta-analysis [1] comprising 2691 patients with SSc followed up over 40 years has shown that the pooled SMR for these patients was 3.5 (95% confidence interval [95%]: 3.0–4.1). dcSSc and female gender had a worse outcome with an SMR of 7.1 along with lung involvement. Various reports on scleroderma (either limited or diffuse) have shown that organ involvement progresses steadily despite a plateau or reversal effect in skin fibrosis.

The 10-year survival rate, which was at a dismal 54%–60% in the 1970s, has steadily improved to 66%–78% in the 1990s and has plateaued since then. The improvement that was observed in the 1980s and 1990s is likely due to earlier disease detection and better management of specific organ disease, which includes successful treatment of scleroderma renal crisis with angiotensin-converting enzyme inhibitors. The introduction of cyclophosphamide (CYC) in the last two decades has provided the initial impetus in some form of cure for SSc. CYC has been synonymous with “the standard of care” for SSc, especially in patients with early aggressive skin disease and concomitant interstitial lung disease. Various studies have demonstrated effective arrest of disease progression with CYC. Evidence supporting benefits of immunosuppressive agents such as azathioprine, methotrexate, rituximab, and mycophenolate in SSc is limited.

Hence, the current modalities of treatment in SSc are targeted at halting the progression of internal organ involvement rather than reversing the disease process. With a better understanding of the disease pathophysiology, it is now believed that the accumulation of extracellular matrix/fibrosis is reversible. This view is further supported by a few of the newer antifibrotic targets such as interleukin 6 (IL-6) blockade, soluble guanylate cyclase agonist, tyrosine kinase inhibitors, and 5-HT2R antagonists.[2] Most of the drugs being experimented for their antifibrotic property are in a nascent experimental stage or early clinical trials and are way too far from being used in clinical practice.

  Stem Cells: Properties and Early Use in Therapeutics Top

Stem cell transplant is a modality of treatment which helps to arrest the aberrant immune process and reset it to a more natural phenotype.

Stem cells are undifferentiated cells which have an ability to differentiate and mature into one or more of the tissue types in vivo. In adults, stem cells have a limited capacity to differentiate and are hence known as “tissue-specific stem cells.” Hematopoietic stem cells (HSCs) are one such group of tissue-specific stem cells which are widely used in various clinical scenarios.

The HSCs have two important properties which make them a desirable therapeutic option:

  1. Self-renewal
  2. Ability to differentiate into all the mature blood cell lineages.

HSCs and hematopoietic stem progenitor cells have a surface expression of CD34. This is a sialomucin-like surface glycoprotein which acts as a cell–cell adhesion factor which is necessary for the attachment of stem cells to bone marrow (BM) extracellular matrix.[3] The HSCs in a quiescent state reside in the osteoblast niche near the trabecular bone and the vascular niche adjacent to blood vessels. The CD 34+ HSCs are activated only on reception of certain signals, modulating their replication and proliferation.

The idea of stem cell transplantation as a possible modality for the treatment of refractory autoimmune diseases (ADs) was conceived serendipitously. Early evidence was gathered from patients receiving myeloablative allogeneic BM transplantation (BMT) for hematologic malignancies. Some of these patients were coincidentally found to also have an AD. These investigators observed that post BMT, these patients had a long-term remission of AD.

By the later part of the 1990s, several case series of HSCT as a treatment modality in autoimmune disorders were published. In 2001, Binks et al.[4] published data of 41 SSc patients with adverse prognostic features who underwent autologous stem cell transplantation (ASCT). They reported a dramatic improvement in skin scores. The number of patients undergoing stem cell transplant for SSc has been on a constant rise since then.

The procedure of hematopoietic stem cell transplantation and the rationale

HSC transplant can either be autologous or allogeneic in origin. Allogeneic transplants theoretically have a better disease-curing effect as they have a potential to replace an auto-aggressive deregulated immune system with a healthy one. This hypothesis has been challenged by various facts and evidence in human and animal studies. The hypothesis of complete cure with allogeneic transplant has been disproved in a few case reports where rheumatoid arthritis [5] patients who received allogeneic HSCT for aplastic anemia had a relapse in joint symptoms after a transient period of remission. Besides this, allogeneic HSCT is associated with the graft-vs-host disease with devastating consequences. Hence, ASCT is the preferred modality in ADs unless a patient has a concomitant hematological malignancy.

Autologous HSCs are harvested from two sources, i.e., peripheral blood or bone marrow. Peripheral blood progenitor cells are mobilized using cytokines for proliferation prior to harvesting and are the preferred choice for HSCT. These cells result in a more rapid reconstitution of the hematopoietic system as they provide a larger number of CD34+ stem cells per harvest and have better engraftment than BM-derived stem cells.

HSCT is a multistep process which involves the following basic steps:

  1. Hematopoietic cell mobilization and cell harvesting
  2. Conditioning and transplantation
  3. Supportive care after transplantation.

Hematopoietic cell mobilization and cell harvesting

HSCs in their natural state are quiescent and nonreplicating. They reside in the osteoblast niche near the trabecular bone and the vascular niche adjacent to blood vessels. These stem cells are activated and mobilized by appropriate cytokine stimuli provided externally.

The European Society for Blood and Marrow Transplantation (EBMT)[6] recommends mobilization with CYC (2–4 g/m2) plus MESNA. CYC is followed by the administration of granulocyte-colony stimulating factor (G-CSF) (5–10 μg/kg). The appropriate dose of CYC is in contention as higher cumulative doses are related with increased infection and malignancy risk. In 2016, Blank et al.[7] published a retrospective analysis in which administration of CYC at 2 × 2 g/m 2 (n = 16) and 1 × 2 g/m 2 (n = 17) was found to be equally effective for peripheral blood stem cell mobilization. Until further studies with a lower dose of CYC are published, CYC at a dose of 2–4 g/m 2 has to be considered for clinical practice.

Inhibiting the binding of CXC-chemokine receptor 4 (CXCR4) to stromal-derived factor 1α19 is an alternative option for stem cell mobilization in cases where the classical regimen fails. Trials on multiple myeloma and malignant lymphomas have successfully combined treatment with plerixafor (a CXCR4 antagonist)[8] and G-CSF. The use of this regimen for SSc should only be limited to research, given the current level of evidence.

Peripheral blood stem cells are collected via leukapheresis after the mobilization process. The target mononuclear cell count of 3–5 × 106 CD34+cells per kg has to be ensured during the apheresis process.


In autologous HSCT, conditioning regimen is a process to eliminate autoreactive T-cells from the host. The conditioning regimens are considered as immunoablative rather than myeloablative, which leads to depletion of selected T- and B-cell clones. This is achieved by infusing high-dose CYC and antithymocyte globulin (ATG) or antiCD52. Based on the extent of myeloablation, the conditioning regimens can be classified as high intensity (total-body irradiation or high-dose busulfan) or low intensity (CYC, melphalan, or fludarabine).

Patients with SSc are subjected to an intermediate conditioning regimen. This regimen consists of a combination of ATG with either high-dose CYC or other chemotherapeutic drugs. The Autoimmune Disease Working Party from the EBMT recommends 200 mg/kg CYC along with polyclonal or monoclonal serotherapy like ATG for adults.[7] The previously harvested and cryopreserved stem cells are then reinfused into the patient at a minimum dose of 2 × 106 CD34+ viable cells per kg bodyweight of the patient.

Need for selective apheresis of CD34+ stem cells has been widely debated. A retrospective analysis by Oliveira et al.[9] was done on 138 patients with SSc. They published clinical and laboratory data at diagnosis, before, and after HSCT. CD34+ stem cell selection was employed in 47% of patients versus 53% who received unmanipulated cells. All the patients in the study had received serotherapy (ATG or Campath-1H). The study failed to identify any significant difference between the two groups in terms of progression-free survival and incidence of relapse.

Overall, the selective harvesting of CD34+ cells increases the costs of autologous HSCT. In the absence of compelling evidence, the ex vivo manipulation of graft has to be made on the basis of individual patients and institutional experience.

Supportive care

Considering a high level of early mortality, optimum supportive care has to be planned for the patient. Adequate antibiotic, antifungal, and antiviral prophylaxes have to be administered to the patients. Psychosocial support and educating the patient about hygiene precautions and danger signs have to be ensured.

  Possible Mechanisms by Which Stem Cells Help in Disease Control Top

HSCT in the case of SSc attempts to reset the immune system and reeducate the newer T- and B-cells. Though the mechanisms of immune reconstitution are not clearly delineated, the basic principles of the stem cell transplant have been deciphered and can be understood under the following headings:

  1. Effect on CD4+ T-cell repertoire
  2. Effect on B-cells
  3. Effect on the innate immune cells
  4. Effects on the cytokines

Effect on T-cell repertoire

The moderately intense conditioning regimen prior to transplant leads to marked depletion of both T- and B-cells. This cytopenic environment triggers the first phase of immune reconstitution. The peripheral Tcell populations which have survived the conditioning regimen begin to proliferate via the action of homeostatic cytokines and antigen stimulation. The proliferation is guided either by self-antigens similar to what happens during T-cell development in the newborn or by foreign antigens leading to T-cell receptor (TCR) oligoclonality.[10]

Following this, thymopoiesis of naïve T-cells occurs leading to establishment of a heterogeneous TCR repertoire. This phase lasts longer than the above-mentioned oligoclonal expansion of T-cells. Hence, it has been proposed that early disease remission after HSCT is associated with increased thymus activation, relaying of polyclonal TCR repertoire, and reduction of central memory Tcells.[11]

Besides the above-mentioned effects on T-cells, an increase in the regulatory T-cell (T reg) subset has also been observed. Baraut et al.[12] studied the number of CD4+CD25 hi FOXP3+ Treg cells in patients with SSc undergoing HSCT. In comparison to the healthy individuals, T Reg cell numbers were low in patients with SSc before transplantation. They observed that the numbers returned to levels seen in healthy controls by 2 years of HSC. Though the above-elaborated mechanisms might be responsible for the early immune reconstitution, late reconstitution is due to increased polyclonality of TCRs as time progresses.

Farge et al.[13] reported the analysis of long-term immune response in SSc patients undergoing HSCT. They investigated the changes in T-cells by combining immunophenotyping and TCR diversity analysis. The data trace patient's TRC diversity up to a mean of 6 years post-HSCT. They compared various parameters in responders (n = 5) versus nonresponders/relapsers (n = 5). They identified distinct differences in the posttransplant TCR repertoire when compared to pretransplant TCR-Vβ profiles. Within the patient groups, two profiles of TCR-Vβ were noted. TCRs displayed either a polyclonal profile which was similar to healthy individuals or a skewed oligoclonally expanded TCR-Vβ family. Overall, T-cell diversity improved in almost all long-term patients compared to baseline, and the percentage of polyclonal TCR-Vβ families increased significantly with time.

Effect on B-cells

SSc patients have increased naıve B-cells which are activated. However, the number of memory B-cells is lesser than that found in healthy controls. Post-HSCT, the naïve B-cell numbers normalize from 3 to 6 months. This is not associated with increase in the memory phenotype.

Anti-Scl-70 antibody is proven to have prognostic implications in SSc patients. Hiroshi Tsukamoto et al.[14] demonstrated that the level of an anti-Scl-70 antibody continuously decreased for 36 months post-HSCT and correlated significantly with the changes in skin score. These changes in anti-Scl-70 levels were independent of the serum immunoglobulin levels which could have been influenced by immunosuppressive therapy like CYC. B-cells thus might have a role in predicting the outcome of HSCT and might help in identifying relapses.

Effect on innate immune cells

Experience from a large number of HSCTs for nonimmune conditions has shown that monocytes are the first subset of cells to engraft. In a less- and moderate-intensive conditioning regimen, neutrophil counts recover by the 5th day posttransplant. These neutrophils might take up to 4 months for complete functional recovery. Farge et al.[12] demonstrated that the NK cells (CD3-, CD16+, and CD56+) post-HSCT in scleroderma returned to pretransplant level within 1 month.

Effect on cytokines

Patients with dcSSc have higher serum levels of monocyte chemoattractant protein (MCP)-1, IL-6, IL-8, IL-10, and interferon gamma compared with healthy controls. Levels of transforming growth factor (TGF)-β1, a key cytokine driving the fibrosis along with platelet-derived growth factor (PDGF), are similar to healthy individuals. Michel et al.[15] demonstrated that, after 6 months of HSCT, there was a significant decrease in IL-2 and IL-8 levels. They reported a significant decrease in TGF-β corresponding to the fall in the skin scores. MCP-1 contributes to enhanced fibroblast proliferation and collagen production. The levels of MCP-1 were demonstrated to reduce up to as late as 4 years' posttransplant. PDGF levels also had a significant decrease at 6 months' posttransplant and may be partly responsible for improved skin scores.

  Existing Evidence: Benefits and Risks Top


Various trials have studied the effects of HSCT in patients with SSc. The results of the trials have been summarized in [Table 1] and [Table 2]. Enough proof has been generated to confirm that HSCT is beneficial both in cutaneous and extracutaneous manifestations of SSc. It was uniformly observed across all studies that the beneficial response on skin and lungs was evident starting from the 1st year posttransplant and was sustained up to as long as 10 years. A small proportion of patients have relapse of disease post HSCT, these patients can be either maintained on conventional disease-modifying anti-rheumatic drugs or a repeat autologous transplant can be attempted.
Table 1: Phase I/II trials of hematopoietic stem cell transplantation in systemic sclerosis

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Table 2: Phase II/III trials of hematopoietic stem cell transplantation in systemic sclerosis

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Risks: Infections, early and late mortality

Overall long-term mortality of HSCT is comparable to the conventional therapy across studies. Treatment-related mortality across various phase I and II studies ranged between 8% and 17%. This figure has shown a positive trend in the later studies with the interim report of SCOT trial reporting an overall mortality of 3% at 52 months. These patients also have a higher incidence of serious adverse effects (15%–20%). Serious adverse effects in the early neutropenic period of HSCT are due to bacterial or fungal infections. Prophylaxis for Pneumocystis Jiroveci pneumonia has to be initiated during this period. A risk of latent viral reactivation is a possibility if there is a period of prolonged lymphopenia postneutrophil engraftment. Thus, it is imperative to administer broad-spectrum antibacterial, anti-fungal, and anti-herpes prophylaxis for at least 100 days posttransplant.

Investigators of ASIST trial have narrowed down to a few factors that may predict adverse prognosis posttransplant. History of ever smoking, presence of pulmonary artery hypertension, and cardiac involvement were identified as predictors of early mortality in ASIST trial. Development of a secondary malignancy is an important long-term complication and has to be screened for at regular intervals posttransplant. Chances of infertility are high given the usage of CYC and irradiation as part of conditioning regimen. Patients have to be provided an opportunity and facility to cryopreserve their sperm or ovum for further use prior to enrolling them into the transplant program.

Risks: Autoimmune side effects

Development of an autoimmune side effect after stem cell transplant is a well-documented phenomenon in transplant literature. The adverse outcomes may vary in severity and repertoire from an insignificant transient appearance of autoantibody to a full blown graft-vs-host disease to a manifestation of an entirely new AD like SLE. Various factors contribute to the development of autoimmunity and are discussed below.

The most important contributing factor for the development of AD is the genetic predisposition. With ASCT, the genetic makeup of an individual is not changed and hence the risk factors for autoimmunity which existed prior to transplant prevail. These genes, as we know, are common for multiple ADs, and in the context of myeloablation, conditioning and stem cell engraftment may have an altered expression resulting in a new AD. Besides this, HSCT fails to ablate the memory cells residing in the immunological niches. Various studies have identified the rapid expansion of such memory cells in the early lymphopenic phase of HSCT. These expanded memory cells may further lead to autoimmune manifestations. Another set of lymphocytes that undergo ablation are the T reg. Hence, in the initial engraftment phase post HSCT, there is an imbalance between pathogenic Th-1 and Th-17 cells to the Treg concentration which may tilt the immune machinery toward autoimmunity. The final theory that has been proposed in the development of autoimmunity post HSCT is the effect of infection. HSCT patients are susceptible to a variety of infections in the early engraftment as well as in the later stages. Infections play a major role in the precipitation of AD in a susceptible individual. Hence, early viral infections may play a role in the development of autoimmunity in these patients.

Although absolute evidence for all the above-mentioned hypothesis is lacking, occurrence of secondary autoimmunity cannot be ignored. Thyroiditis, immune thrombocytopenia, autoimmune hemolytic anemia, and myasthenia gravis are some of the most commonly reported secondary autoimmune manifestations following HSCT. In a large series reported from North America, 155 patients of various ADs requiring HSCT were followed up. Six patients developed some form of secondary autoimmunity.[16] Retrospective EBMT registry data [17] of ADs treated by HSCT reported a cumulative incidence of secondary AD of 7.7% (±1%) after 3 years and 9.8% (±2%) after 5 years of HSCT. The study identified that the patients with SLE undergoing HSCT had the highest risk of developing secondary AD (hazard ratio - 3.21). Other contributing factors that the report identified were duration of illness of <62 months before HSCT and use of ATG for conditioning along with graft manipulation with CD 34+ stem cells.

  Cell-Based Therapies in Systemic Sclerosis Top

Besides stem cell transplantation, several highly selective tissue-specific cell-based treatment modalities are being investigated world over. These modalities can either be administered intravenously or be infiltrated into local lesions [Table 3]. Alternative options also include delivery of specific cytokines and other paracrine factors to the sites of inflammation aiming at alteration of the local cytokine milieu without systemic side effects. All these modalities are in the early stages of development and are not yet a part of standard treatment options available for patients with SSc.
Table 3: Newer cell-based therapies in systemic sclerosis

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  Conclusion Top

Stem cell transplant has now become an important part in the management of SSc. EULAR 2016 update on recommendations for the treatment of SSc proposes HSCT for selected patients with rapidly progressive disease, with risk of organ failure. HSCT causes arrest of fibrotic process and reverses the immune dysfunction. Despite the risk of early mortality, infections, secondary autoimmunity, and malignancy, a careful patient selection backed by an astute risk–benefit calculation augmented with optimal procedural expertise followed up with an adequate posttransplant care can make HSCT a more effective modality for cure in SSc. Several guidelines have been proposed to help select patients for HSCT [Table 4].
Table 4: Existing guidelines for patient selection to undergo HSCT in SSc

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Newer cell-based therapies, though in experimental stages, have shown promise in terms of cure rates and safety. However, given the current level of evidence, these modalities have to be only used as part of experimental therapy in experienced centers[39].

Therapeutics in SSc is making headway in achieving disease reversal and HSCT holds a lot of promise for an otherwise relentless disease.

Financial support and sponsorship


Conflicts of interest

There are no conflicts of interest.

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  [Table 1], [Table 2], [Table 3], [Table 4]

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