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Anaya JM, Shoenfeld Y, Rojas-Villarraga A, et al., editors. Autoimmunity: From Bench to Bedside [Internet]. Bogota (Colombia): El Rosario University Press; 2013 Jul 18.

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Chapter 42Autologous peripheral hematopoietic stem cell transplantation

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Autoimmunity is an inappropriate response of the immune system directed against self-tissues. Autoimmune disease is defined as a clinical syndrome caused by the activation of T cells and/or B cells in the absence of an ongoing infection or other discernible cause (1). The concept of “autoimmune disease” includes a wide spectrum of pathologies that vary in biological and clinical features.

Autoimmune diseases (ADs) are among the most prevalent diseases in the United States, affecting approximately 7% of the population (2). ADs disproportionally occur more in women. In some conditions, 85% or more of the patients are female (3). The knowledge of the etiology of ADs remains limited. Epidemiologic studies have shown that genetic factors are major determinants of susceptibility to ADs (4, 5). However, a trigger like an environmental exposure is needed to initiate frank autoreactivity in a genetically predisposed individual (2, 6).

The majority of patients achieve short-term disease control with immunosuppressive therapy including biological therapies, but long-term remission or a definitive cure remains unattainable (7). There is a group of patients with refractory and life-threatening states for whom the results of conventional therapy have been considered unsatisfactory. In this context, hematopoietic stem cell transplantation (HSCT) has emerged as an alternative therapy for severe and refractory ADs.

Hematopoietic stem cell transplantation

Hematopoietic stem cell transplantation has been the standard therapy for several oncological and hematological disorders since the early 70’s (8). The use of HSCT for ADs evolved in animal models, where experimental investigations showed that inherited and induced autoimmune disease (AD) in laboratory animals could be cured by stem cell transplantation (9, 10). The possibility of HSCT as a treatment for ADs was reinforced by reports of patients with coincident ADs and hematological malignancy who remained in long-term remission after allogeneic transplantation (11). The first hematopoietic stem cell transplants performed specifically for ADs were done in the 90’s. In 1996, the European League Against Rheumatism (EULAR) and the European Group for Blood and Marrow Transplantation (EBMT) supported the utilization of HSCT in patients with ADs as an experimental procedure. In their consensus, it was established that methods had to follow a standardized protocol, and all the patients should be reported to the EBMT–EULAR Autoimmune Disease Data Registry (12). At present, it is estimated that around 3,000 AD patients have been treated by HSTC (7).

Types of HSCT

Hematopoietic stem cell transplantation can be divided into subtypes based on the relationship between the patient and the donor and by the source of the stem cells. The subtype of HSTC influences the short and long-term results of the procedure. Based on the origin of the transplanted cells, HSCT may be:

Autologous transplantation: The progenitor cells are collected from the patient’s own tissues. Then, they are processed, stored, and subsequently transfused into the patient after the conditioning regimen.

Syngeneic transplantation: The couple-donor is an identical twin. The main advantages of this type of HSCT are that it provides a graft free of autoreactive cells and the minimal risk of graft-versus-host disease (GVHD).

Allogeneic transplantation: The progenitor cells are collected from a donor who is not genetically identical. The graft is free of autoreactive cells, but the risk of complications, e.g., GVHD, is significantly increased.

The anatomic source of the progenitor cells may be: 1) peripheral blood – the hematopoietic cells are collected using growth factors, 2) bone marrow – the hematopoietic cells are usually harvested directly from the pelvic bones, 3) umbilical cord blood – unrelated umbilical cord blood is administrated in single or double units. It is associated with a lower risk of GVHD (13). Autologous HSCT (AHSCT) is currently the most frequent transplant procedure worldwide (7).

Autologous peripheral hematopoietic stem cell transplantation (AHSCT)

The transplant procedure consists of: 1) stem cell collection, and 2) transplantation phase: conditioning regimen, aplastic phase, and engraftment. In autologous transplantation, hematopoietic stem cells can be obtained from the patient’s bone marrow or peripheral blood. Peripheral blood stem cells (PBSC) are the main source for AHSCT due to the ease of procurement and the fact that engraftment is faster and more stable (7, 14). The main steps of AHSCT in ADs are shown in Figure 1.

Figure 1. Steps of AHSCT in autoimmune diseases.

Figure 1

Steps of AHSCT in autoimmune diseases. AD: autoimmune disease AHSCT: autologous hematopoietic stem cell transplantation. CYC: cyclophosphamide. G-CSF: granulocyte colony stimulating factors.

Stem cell collection

Peripheral blood stem cells are prepared by administration of growth factors such as granulocyte colony stimulating factors (G-CSF) and chemotherapy. This process is called mobilization. The drug that is used the most as mobilization chemotherapy in AD is cyclophosphamide (CYC). The recommended mobilization regimen is CYC at 2–4 g/m2 with MESNA (2-Mercaptoethanesulfonic Acid Sodium Salt) and cautious hyperhydration followed by G-CSF 5–10 microgram (mcg)/kg (7). Aside from steroid therapy, additional immunosuppressive medications should be discontinued if possible before mobilization (7). Once the mobilization regimen is administrated, PBSC are collected by 1 – 3 leukapheresis for storage and subsequently given to the patient by transfusion.

Currently, the use of lymphocyte depletion of autologous PBSC has been implemented. However, the results are controversial and, for the present, the evidence is insufficient to support the routine use of graft manipulation (15).

Conditioning regimens

Ablation of the immune system is the goal of the conditioning regimen. Immunoablative conditioning regimens are preferred over their myeloablative counterparts, and some form of in vivo and/or ex vivo T-cell depletion is generally adopted (16, 17).

Conditioning regimens are divided into: a) high intensity – includes regimens based on total body irradiation (TBI) or high-doses of busulphan; b) intermediate intensity - includes combinations such as BEAM (bischloroethylnitrosourea (BCNU), etoposide, cytarabine (Ara-C), and melphalan) and the combined use of antithymocyte globulin (ATG) with high-dose CYC or other chemotherapy; and, c) low intensity – consists of CYC alone, melphalan alone, or fludarabine-based regimens (18, 19). Intermediate intensity conditioning regimens have been associated with significantly improved outcomes compared to the other regimen types since they achieve a balance between efficacy and safety (20).

In its most recent guidelines, the EBMT has recommended using an intermediate regimen in patients who are being treated under the category “clinical option (CO)” (See Table 1) (7). The following recommended conditioning regimens have a balance between safety and efficacy:

Table 1
. EBMT indications, grade of recommendations and evidence for HSCT in AD for adults and pediatrics.

Table 1

EBMT indications, grade of recommendations and evidence for HSCT in AD for adults and pediatrics.

Cyclophosphamide 200 mg/kg with polyclonal or monoclonal anti-T-cell serotherapy (ATG or alemtuzumab respectively). In pediatrics, the recommended combination is CYC 120 mg/kg, fludarabine 150 mg/kg, and ATG (or other anti-T-cell serotherapy).

For multiple sclerosis (MS) specifically, BEAM regimen (BCNU 300 mg/m2 on day -6, etoposide 200 mg/m2 on day -5 to -2, Ara-C 200 mg/m2, and melphalan 140 mg/m2 on day -1) and ATG (or other anti-T cell serotherapy) are recommended. BEAM conditioning has been found to be attractive due to (a) the positive lympholytic effect and (b) the possibility of BCNU and Ara-C exerting their effect across the blood–brain barrier (21).

The use of TBI in AD has been done less frequently in the recent years but has shown good results in the treatment of juvenile idiopathic arthritis (JIA) (22).

Aplastic phase and engraftment

The aplastic phase lasts approximately 10 – 15 days. Transplantation of more than 2.5 x 10⁶ CD34+ cells per kilogram leads to rapid and sustained engraftment. Three consecutive days with a neutrophil count of over 500 cell/mm3 and platelets over 20,000/mm3 are required to define the engraftment (23). A rapid recovery diminishes the morbidity rate of HSCT.

Candidate selection

Autologous hematopoietic stem cell transplantation has become an emerging therapy for patients with severe or rapidly progressive AD refractory to conventional therapy (20). The selection criteria should be individualized based on the type of AD and the medical status of the patient. A balance between the risks of toxicity and the clinical benefits should be pursued (Table 1). The decision should be made by an appropriate inter-disciplinary team that includes a hematologist and AD specialist or a rheumatologist.

Pre-transplant evaluation includes a detailed history, physical examination, laboratory studies, imaging tests, and disease-specific studies (24). The detailed history should emphasize the presence of co-morbidities, prior therapies, infections, and drug allergies. Physical examination should give special attention to evaluation of heart, lung, kidney, and gastrointestinal function. Laboratory studies and imaging tests complement the evaluation of the mentioned organs. Tests in addition to screening for the presence of infections and pregnancy at the moment of transplantation should also be done (24). Table 2 summarizes the pre-transplant work-up.

Table 2
. Pre-transplant work-up.

Table 2

Pre-transplant work-up.

The most updated guidelines of the European Group for Blood and Marrow Transplantation recommend the following exclusion criteria when considering HSCT (7):

Organ dysfunction: 1) Advanced cardiac disease, defined as left ventricular ejection fraction < 50% in patients with systemic sclerosis (SSc), < 40% in other indications, ventricular arrhythmias or pericardial effusions > 1 cm; 2) renal insufficiency with a creatinine clearance < 40 ml/m2 in SSc or < 30 ml/m2 in other indications; 3) respiratory disease – diffusing ability of the lung for carbon monoxide (DLCO) < 40% predicted, mean pulmonary artery pressure > 50 mmHg or ventilator impairment due to respiratory muscle involvement in multiple sclerosis; and, 4) gastrointestinal bleeding.

Uncontrolled infection: any uncontrolled acute or chronic infection is considered a contraindication.

Pregnancy: it should be evaluated 7 days prior to mobilization regimen administration.

Post-Transplant care

After the procedure, the patient should be placed in an isolation facility under the Joint Accreditation Committee-ISCT (International Stem Cell Therapy) & EBMT (JACIE) accreditation standards (25, 26). Patients with AD and HSCT have a significant risk of developing infections due to profound immunosuppression (20). Therefore, antimicrobial prophylaxis is mandatory in all the patients.

Antimicrobial prophylaxis consists of broad-spectrum antibiotics and antifungal and antiviral prophylaxis. The patients should also receive trimethoprim/sulfamethoxazole 3 times per week for prophylaxis against Pneumocystis jiroveci and Toxoplasma gondii. Antimicrobial therapy is administered for at least 100 days post-transplant. Cytomegalovirus (CMV) disease and Epstein - Barr Virus (EBV) –associated post-transplant lymphoproliferative disorder have been commonly associated with HSCT (27, 28).

Recipients should attend follow-up clinical sessions frequently during the first 3 - 4 months post-transplant or until the recipient is clinically stable. The development of autoimmunity after transplantation is a recognized phenomenon that has to be differentiated from relapse, toxicity, infection, and GVHD (29). Subsequently, the long-term management remains under the supervision of the transplant specialist and AD specialist/rheumatologist. An annual follow-up appointment is recommended as a minimum (7).

Rational use and therapeutic mechanisms of HSCT in AD

The rationale for HSCT in ADs is the ablation ability of the self-reactive immune system by using chemotherapy and then, regeneration of a new self-tolerant immune system from hematopoietic stem cells (HSCs).

Hematopoietic stem cells have the potential to stop ADs by resetting the immune system, establishing a new immune repertoire, replacing the existing one, and achieving a re-instatement of immune regulation (30).

With respect to the concept of resetting the immune balance, 3 main mechanisms for immune resetting have been identified: 1) influx of naïve cells from the thymus; 2) debulking the mature memory lymphocyte repertoire; and, 3) boosting the number of regulatory cells.

Hematopoietic stem cells represent the best characterized type of adult stem cells. They reside in the bone marrow and generate progenitors that become progressively restricted to different lineages (31). HSCs are a group of cells with several developmental potentials based on intrinsic networks driven by transcription factors and input from the local microenvironment in which they reside. HSCs have two defining properties: 1) capacity for self-renewal, and 2) ability to differentiate into mature blood cell lineages (see Table 3).

Table 3
. Objectives of HSCT in autoimmune diseases.

Table 3

Objectives of HSCT in autoimmune diseases.

Hematopoietic stem cells are defined functionally by their ability to reconstitute the entire blood system of a recipient. HSCs and hematopoietic stem progenitor cells (HSPCs) in humans are enriched within the subset of CD34+ cells. CD34 is a type 1 transmembrane protein expressed on HSPCs with the ability to repopulate bone marrow for all lineages. In the bone marrow, HSPCs preferentially reside in two microenvironments: in association with osteoblasts near the trabecular bone and adjacent to blood vessels (32). HSPCs exist in a relatively quiescent state in the bone marrow microenvironment but can be activated to enter the cell cycle and thus drive hematopoiesis as physiological demands dictate (33). Autologous hematopoietic cell transplantation has been evaluated as a treatment for severe forms of immune-mediated disorders including multiple sclerosis (MS), systemic lupus erythematosus (SLE), systemic sclerosis (SSc), and rheumatoid arthritis (RA) or juvenile idiopathic arthritis (JIA). Current concepts of the pathogenesis of autoimmune disorders attribute a crucial role to T and B cells inappropriately recognizing self-antigens and initiating a cell-mediated or humoral reaction, or both, resulting in inflammatory tissue and vascular damage. Autoimmune diseases represent a failure of normal immune regulatory processes as they are characterized by activation and expansion of immune cell subsets in response to non-pathogenic stimuli. Autoimmune diseases result from a failure of normal mechanisms to suppress proliferation in the presence of innocuous or self-antigens (34).

Studies on immune reconstitution following autologous transplant for both ADs and cancer showed a profound lymphopenia in the first year after transplantation. The cytopenia was observed to affect the lymphocyte subsets differently. It is likely that the kinetics of reconstitution depended on different timing of recovery for each cell type. B cells, natural killer (NK) cells, and CD8+ T cells display a rapid and complete reconstitution to pretransplantation levels, whereas the recovery of CD4+ T cells has consistently been observed to be delayed and often incomplete. By extending longitudinal follow-up of patients, recent studies have shown a recovery of the number of CD4+ T cells after a 2-year follow-up in young adults treated for MS (35) and RA (36) and after 12 months in children with JIA (37).

The observation that quantitative recovery of lymphocytes was not correlated to inflammatory activity or disease relapse revealed that numeric immune deficit is an insufficient explanation for a prolonged absence of autoimmune disease activity after AHSCT. A detailed analysis of the T cell receptor (TCR) repertoire showed the regeneration of a different and more diverse TCR repertoire posttransplant. Thymic reactivation, expansion of naïve T cells following autografting, and improved repertoire diversity were subsequently demonstrated in individuals with SLE (30).

It is reasonable to postulate that the normalization of immune regulatory mechanisms could play a role in the suppression of autoimmunity following AHSCT. The CD4+ CD25+ expressing forkhead transcription factor 3 (FoxP3) cells are potent suppressors of immune responses, which are generated in the thymus in both rodents (38) and humans (39). CD25+ FoxP3+ CD4+ T cells were reported to be more resistant to irradiation than effector cells and mediated the amelioration of experimental graft-versus-host disease (GVHD) (40). In experimental autoimmune encephalomyelitis (EAE) rats, there was an increase of CD4+ CD25+ T cells after syngeneic BMT and this was seen in connection with attenuation of active disease and protection from induction of relapses. Longitudinal enumeration of CD4+ CD25+ T cells in children with JIA, was studied following AHSCT, showing recovery of the pretreatment frequency at 6 months post-transplant and a continued increase for the remaining 12-month follow-up. Their frequency were correlated directly with clinical remission (41).

Therefore, re-instatement of immune regulation could be involved in long-term post-transplant tolerance.

In post-transplant patients, both CD4+ CD25+ FoxP3+ and an unusual CD8+ FoxP3+ Treg subset return to levels seen in normal subjects. This is accompanied by almost complete inhibition of pathogenic T cell response to critical peptide autoepitopes from histones in nucleosomes, the major lupus autoantigen from apoptotic cells. Therefore, unlike conventional drug therapy, HSCT generates a newly differentiated population of LAP+ CD103+ CD8TGF-b Treg cells, which repairs the Treg deficiency in human lupus to keep patients in true immunological remission (42). Likewise, responders exhibited normalization of the previously disturbed B-cell homeostasis with numeric recovery of the naïve B-cell compartment within 1 year after AHSCT. These data are the first to demonstrate that both depletion of the autoreactive immunologic memory and a profound resetting of the adaptive immune system are required to reestablish self-tolerance in SLE (30).

Preclinical data

Preclinical data in HSCT are derived from animal models of ADs. Transplant studies in animals with ADs are divided in genetically determined and inducible models. While mice or rats with lupus-like syndrome, transgenic HLA-B27 expression, nonobese diabetes (NOD), and interleukin-1 receptor antagonist (IL-1Ra) deficiency belong to the first category, those with collagen-induced arthritis or EAE as models of RA and MS respectively belong to the second category. Different results were obtained in these models (34). Conditioning followed by syngeneic HSCT resulted in the cure of induced AD, but not of genetically determined AD. In autologous HSCT, and to a lesser extent in allogeneic HSCT, the outcome depended on the stage of the disease at the time of transplant. In inducible disease models, protective as well as therapeutic effects of HSCT were observed: both syngeneic and allogeneic HSCTs in EAE-susceptible mice protected animals from disease when carried out close to immunization, but only allogeneic HSCT with high-grade chimerism was effective in protecting from EAE when the time lag was longer. In another EAE study, HSCT prevented glial scarring and ameliorated disease severity after immunization but was ineffective as a treatment of established disease (43). In established genetic AD such as in lupus-prone mice, allogeneic, but not syngeneic, HSCT reversed both acute and chronic symptoms (44). In the early animal HSCT studies, myeloablative conditioning was employed prior to allogeneic HSCT to achieve full donor chimerism and eradicate autoreactive lymphocytes. More recent studies, however, have shown that nonmyeloablative conditioning is equally effective in inducing stable chimerism while maintaining efficacy (45). It is of note that no GVHD was observed and thus indicates that the putative graft-versus-autoimmunity effect and GVHD are dissociated. Whereas full donor chimerism was needed in the SLE and EAE models, the induction of mixed chimerism was sufficient to ameliorate chronic inflammatory arthritis in IL-1Ra-deficient mice (44, 46). In the latter, no significant relationship between the arthritis score and the ratio of donor to recipient cell populations in mice with mixed chimerism could be found after allogeneic HSCT.

In collagen-induced arthritis, nonmyeloablative conditioning followed by both syngeneic and allogeneic HSCT (the latter yielding a stable donor chimerism over 95%) had a significant therapeutic effect compared with conditioning alone (47). In this study, allogeneic HSCT was more effective than syngeneic HSCT in suppressing pathogenic autoantibodies. In HLA-B27 transgenic rats, TBI followed by HSCT from nontransgenic mice led to a prompt and sustained remission of symptoms. In contrast, all rats who received a syngeneic transplant died from exacerbation of colitis (48).

The heterogeneity of results obtained in different transplant settings and disease models implies that extrapolation to the clinical setting in human AD is difficult. Nevertheless, the data suggest that HSCT may be more effective (and probably less toxic) in patients with active progressive disease than end-stage advanced disease (49).

Clinical data

Autologous HSCT is the most widely used form of HSCT. In hemato-oncological conditions, it is a relatively safe procedure with a transplant-related mortality (TRM) that is typically below 3%. Toxicities and transplant-related causes of death include sepsis, cytomegalovirus infection, and hemorrhage. The overall TRM for autologous HSCT in AD now is approximately 7% although it was as high as 23% in one of the first pilot studies (50). In AD, diagnosis, extent of organ involvement, age, and comorbidity are patient-related determinants of toxicity and TRM. TRM and toxicity also depend on the conditioning regimen and whether or not TBI is done. With adaptation of eligibility criteria (e.g. exclusion of patients with severe pulmonary hypertension) and modification of transplant regimens (e.g. lung shielding with TBI), complications from HSCT can usually be managed in experienced hands, and TRM has dropped as a consequence. It was less than 1% for non-TBI nonmyeloablative, less than 2% for low-intensity myeloablative, and 13% for high-intensity myeloablative regimens (51). Compared to TRM, efficacy seems less influenced by intensity and type of conditioning although this may be confounded by the severity of the underlying disease.

Indications for autologous HSCT in ADs

Immunoablative therapy followed by HSCT has evolved from an experimental treatment to a salvage therapy for patients with severe ADs not responding to proven conventional therapy and/or biologicals.

Autologous HSCT has been evaluated as a treatment for severe forms of immune-mediated disorders including multiple sclerosis (MS), systemic lupus erythematosus (SLE), systemic sclerosis (SSc), rheumatoid arthritis (RA), or juvenile idiopathic arthritis (JIA). The goal of this therapy is to induce medication-free remission of disease activity by correcting the immune aberrations that promote the attack against self-tissue (“immune repair”), (see Table 1).

Results of HSCT in ADs

The success of HSCT has been measured in many ways. Clinical endpoints include the evaluation of not only the efficacy but also the safety of the procedure. Disease-free survival, sustained clinical remission, progression-free survival (PFS), overall survival, and TRM are the most common examples of clinical endpoints. Better percentages of response to HSCT have been achieved over time. Treatment-related morbidity and mortality have improved due to better patient selection and modifications of transplant regimens. However, disease specific measurements of activity or quality of life should be clearly defined for each AD.

Multiple sclerosis (MS)

The objective of AHSCT for MS is to reduce inflammation and progression of the disease for a prolonged period of time (52). Multiple sclerosis is the main indication of HSCT in ADs. There are reported benefits from HSCT in clinical disease activity and magnetic resonance imaging-detectable inflammation (53), stabilization of disease, and immunological response to therapy. Safety profiles of HSCT in MS are improving since myeloablative regimens have been changed to less intense immunoablative regimens (54).

The use of intense immune suppression by a TBI-based regimen and HSCT is not effective for patients with progressive MS and high pretransplantation disability scores (55). Dissociation of inflammation parameters and functional disability findings have been demonstrated. This raises questions regarding the future use of HSCT as an optimal strategy for this disease (56). However, the rate of brain tissue loss in patients with MS declines dramatically for the first 2 years after HSCT (57). The results of HSCT in MS are summarized in Table 4 (18, 54, 58-68).

Table 4
. Summary of reports of HSCT in multiple sclerosis.

Table 4

Summary of reports of HSCT in multiple sclerosis.

Systemic sclerosis (SSc)

Systemic sclerosis has a higher mortality when vital organs are affected. No treatment has been shown to influence the outcome or significantly improve the skin score though many forms of immunosuppression have been used. The developments in HSCT have allowed the use of profound immunosuppression followed by transplants in SSc. In trials, the predicted procedure-related mortality has been less than 10% since the elimination of TBI (69). Improvement of skin sclerosis has been observed for the first 3 years in most of the recipients. Autologous HSCT using purified CD34+ cells was effective in controlling the activity in SSc. The Th1/Th2 ratio was significantly increased for at least 3 years after AHSTC (70). In another trial, the population of B and T lymphocytes remained disturbed for at least 1 year post-transplant in SSc patients. This may reflect the persistence of an underlying disease mechanism (71). The results of HSCT in SSc are summarized in Table 5 (69, 72-76).

Table 5
. Summary of reports of HSCT in systemic sclerosis.

Table 5

Summary of reports of HSCT in systemic sclerosis.

Systemic lupus erythematosus (SLE)

According to experts’ consensus, patients with severe SLE refractory to conventional immunosuppressive treatments can achieve sustained clinical remission by undergoing AHSCT. Clinical remission has ranged from 50% to 70% at 5 years accompanied with qualitative immunological changes not seen in other types of therapy. Unfortunately, an increase in short-term mortality has been described in the majority of studies (77).

Severe cases of SLE treated with AHSCT have achieved a better prognosis. TRM has been relatively low over the long-term, and prolonged clinical remissions are reachable. “Re-education” and Treg normalization has been established as immune resetting. As a result, AHSCT for refractory SLE has become a major target (78). A true immunological remission can be obtained with HSCT in human lupus by the generation of a newly differentiated population of Treg cells (42). Transplant-related mortality of 2% and an overall 5-year survival of 84% in patients with SLE treated with AHSCT have been reported. The probability of disease-free survival at 5 years following HSCT was 50%, and secondary analysis demonstrated stabilization of renal function, significant improvement in lung function, SLEDAI (Systemic Lupus Erythematosus Disease Activity Index) score, ANA (antinuclear antibodies), and anti-dsDNA levels (17).

In a single-center study of long-term immune reconstitution, clinical remission associated with the depletion of autoreactive immunologic memory was observed in 7 patients with SLE who underwent AHSCT. These data demonstrate that depletion of autoreactive immunological memory and profound resetting of the adaptive immune system are required to reestablish self-tolerance in SLE (30). The results of HSCT in SLE are summarized in Table 6 (17, 79, 80).

Table 6
. Summary of reports of HSCT in systemic lupus erythematosus.

Table 6

Summary of reports of HSCT in systemic lupus erythematosus.

Rheumatoid arthritis (RA)

Approximately a decade ago, phase I trials in RA patients treated with AHSCT showed substantial remission of the disease in the majority of patients who had failed to see improvement from all of the available therapies at the moment (81, 82). Additional studies showed that high-dose chemotherapy (HDC) plus HSCT increased the functionality and health status of patients with severe, refractory RA with a low TRM (1.3%) (83). The use of HDC followed by AHSCT is feasible and safe and results in long-term improvement of disease activity for patients unresponsive to conventional antirheumatic drugs or TNF blocking agents. The lack of response in some patients may reflect the heterogeneity of the underlying disease process (84). However, the emergence of biological DMARD therapy in refractory RA has replaced the utilization of HSCT in RA patients. Likewise, an early diagnosis and appropriate treatment have changed the prognosis of the disease, making it less likely that RA patients will be enrolled in a HSCT study.

Juvenile idiopathic arthritis (JIA)

In this severely ill patient group, AHSCT induces a very significant and drug-free remission of the disease in the majority of the patients. However, it carries a significant morbidity and mortality risk, especially associated with macrophage activation syndrome (MAS) (85, 86). After fatal complications due to MAS, the protocol has been modified to ensure less profound depletion of T cells, better control of systemic disease before transplantation, antiviral prophylaxis after transplantation, and slow tapering of corticosteroids (22). With the recent availability of anti-TNF therapy for the treatment of JIA, failure to respond to this type of therapy should be an additional inclusion criterion for future studies of AHSCT in JIA.

Type 1 diabetes mellitus (T1D)

Promising results have been demonstrated in patients with T1D. A study showed that 20 out of 23 T1D patients became insulin-free following AHSCT treatment. Of these, 12 individuals remained insulin-independent during the entire follow-up period, while 8 subjects relapsed after an average of 18 months and had to resume insulin medication at low doses. There was no mortality reported. (87, 88).

Other ADs

Autoimmune cytopenias like autoimmune hemolytic anemia (AIHA), immune thrombocytopenic purpura (ITP), autoimmune Evans syndrome, and pure red cell aplasia (89, 90) have been a common indication for AHSCT. This type of treatment has been used less in other severe and refractory ADs, where it could be a clinical option in an experimental setting, but several reports have shown clinical response in ADs such as systemic vasculitis (91, 92), polymyositis and dermatomyositis (93, 94), and antiphospholipid syndrome (APS) associated with SLE (95).

Complications of HSCT

Mortality is the major complication in patients who undergo AHSCT, but infections are the most common complications related to AHSCT (86). In a case series study, bacterial infections were reported in 3 of 14 (21%) patients with AD and AHSCT, and viral counterpart in 11 of 14 (78%) including CMV and adenovirus infection. As late infectious complications, 7 patients (50%) developed dermatomal varicella zoster virus infection. No infection-related mortality was seen in this report (28). Recently, the frequency of infections has diminished through the use of less intensive immunosuppressive regimens and better protocol designs.

A new onset of organ-specific (96), systemic (97), or multiple ADs after AHSCT has been reported (98). A multi-center retrospective EBMT study showed that 29 of 363 (8%) patients who received a transplant for an AD developed at least one new AD after HSCT with a cumulative incidence of 7.7% after 3 years and 9.8% after 5 years (99).

The engraftment syndrome has also been reported and consists of non-infectious fever, rash, and fatigue after AHSCT and has been identified in 26% of the patients (100). Currently, HVGD is a rare complication in AHSCT, but it is common in allogeneic HSCT. Finally, treatment-associated toxicity in patients with AHSCT is also described. Cardiac and renal injuries are more common in SSc patients, ATG can cause allergic reactions, and the administration of G-CSF can induce flares of the underlying AD (101).


Autologous hematopoietic stem cell transplantation is a feasible treatment option for ADs, based on the concept of ablation of a self-reactive immune system and resetting auto-tolerance by regeneration of HSCs. Growing evidence supporting its clinical usefulness is available. Safety profiles of the interventions have improved with the modifications of protocols and the use of a less intensive immunosuppression. The future research agenda should be to push for a definition for/of better inclusion criteria for AD patients and evaluate the efficacy and cost-benefit of AHSCT compared to the best current available therapy for any specific AD.


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