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Nash

Cellular Therapy and Transplantation (CTT), Vol. 2, No. 8

Please cite this article as follows: Nash RA. Hematopoietic cell transplantation for autoimmune diseases. Cell Ther Transplant. 2010;2:e.000082.01. doi:10.3205/ctt-2010-en-000082.01

© The Author. This article is provided under the following license:
Creative Commons Attribution 3.0 Unported License
Submitted: 14 June 2010, accepted: 30 June 2010, published: 8 December 2010

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Hematopoietic cell transplantation for autoimmune diseases

Richard A. Nash, MD

Fred Hutchinson Cancer Research Center and the University of Washington School of Medicine, Seattle, WA, USA

Correspondence: Fred Hutchinson Cancer Research Center, 1100 Fairview Avenue N, D1-100, PO Box 19024, Seattle, WA 98109-1024; Phone: +1(206) 667-4978, Fax: +1(206) 667-6124, E-mail: rnash@spam is badfhcrc.org

Abstract

Autoimmune diseases may or may not have defined antigenic targets and may involve single or multiple organs. Although most autoimmune diseases can be effectively managed even if not cured, some autoimmune diseases may be refractory to conventional treatments and become life-threatening or cause critical organs to fail. This then would be the candidate population for consideration of a more aggressive approach requiring autologous or allogeneic hematopoietic cell transplantation (HCT). The clinical trials of HCT for autoimmune disease were started more than a decade ago and were based on successful preclinical studies. Preclinical studies of autologous and allogeneic HCT for autoimmune diseases have been reviewed and will not be discussed further [1,2].

Keywords: autoimmune diseases, systemic sclerosis, multiple sclerosis, hematopoietic cell transplantation

High-dose immunosuppressive therapy and autologous hematopoietic cell transplantation for autoimmune diseases: clinical experience
High-dose immunosuppressive therapy regimens

Two reports were published in the mid-late 1990s on the outcomes of concomitant autoimmune diseases after high-dose cytotoxic therapy and autologous HCT for a hematological malignancy [3,4]. A majority of the patients achieved remissions of the concomitant autoimmune diseases early after treatment, but only 5 of 15 cases had sustained responses at last follow-up in one report, and all 4 patients presented relapsed in a second report. This experience indicated that there was a substantial risk of progression of the autoimmune disease after high-dose cytotoxic/immunosuppressive therapy (HDIT) designed for treatment of a hematological malignancy. Clinical trials of HDIT and autologous HCT specifically for autoimmune diseases were designed to intensify the immunosuppressive effect compared to standard cytotoxic regimens for treating hematologic malignancies. This was achieved by depleting T cells from the autologous hematopoietic cell graft or by adding other non-cytotoxic immunosuppressive agents to the HDIT regimen for in vivo T cell depletion. The HDIT regimens that have been investigated in clinical trials have had varying intensities. High-dose cyclophosphamide as a single agent has been considered a low-intensity regimen [5]. It is highly immunosuppressive but is not myeloablative. Clinical trials of high-dose cyclophosphamide have been conducted with and without the support of autologous HCT. Regimens which included TBI or high-dose busulfan were considered high-intensity and required support with autologous HCT.

Systemic depletion of autoreactive immune effector cells was the rationale for the early clinical trials of HDIT followed by HCT for severe autoimmune diseases. These clinical trials showed high initial response rates, and a significant proportion of patients achieved sustained remissions [6,7,8,9,10]. The sustained responses observed after recovery of the lymphocyte counts at 2 years may have resulted from a late immunomodulatory effect of the HDIT regimen [11,12,13]. The intensity of the HDIT regimen may be important for the disease remission to be sustained. In a report from the EBMT registry, sustained responses were observed in 78% of patients after a regimen with high-intensity conditioning compared to 68% with intermediate and 30% with low-intensity conditioning regimens (p=0.0001) [5]. The analysis of the registry data, although informative, had some limitations including variability of the diagnoses, patient selection criteria, and treatments (as well as having imbalances between diagnosis and type of HDIT regimen). The possible benefits must be weighed against the risk when selecting the level of intensity of the conditioning regimens.

High-dose single agent cyclophosphamide followed by autologous HCT for hematopoietic support was reported as one of the more frequently used HDIT regimens [5]. When the doses of cyclophosphamide (100 vs. 200 mg/kg) were compared in a small study of patients with rheumatoid arthritis (RA), remissions were longer with the higher dose of cyclophosphamide [14]. However, all patients eventually relapsed regardless of the dose. Relapse rates were also high in a systemic sclerosis (SSc) study in which patients were treated with high-dose cyclophosphamide (200 mg/kg) alone. Four of 11 patients died by 18 months after treatment (three from progression), and another four patients had progressed and required secondary treatment [15]. The addition of antithymocyte globulin (ATG) to cyclophosphamide may improve the response rate and duration. Experience has continued to accrue with high-dose cyclophosphamide in combination with ATG [8,16,17,18]. The regimen has been effective for inducing remissions and has been well tolerated; however, a longer follow-up is still required to assess the durability of responses. Since the regimen is not myeloablative, high-dose cyclophosphamide (200 mg/kg) as a single agent without autologous HCT has also been investigated [19,20]. Without the support of an autologous hematopoietic cell graft after high-dose cyclophosphamide, the median time to recover neutrophil counts was about 2–3 days longer than with HCT, but the upper limit of the range was 7 days longer [8,20]. Only 36% of the patients were reported to have durable complete remissions. In this small experience, there did not appear to be any benefit to withholding the infusion of an autologous hematopoietic cell graft.

Treatment-related mortality was 14% and 3%, respectively, in the groups reported from the EBMT registry who received the high and the low conditioning intensity regimens, but there was no significant difference in overall survival [5]. Patients with multiple sclerosis (MS) and RA had lower treatment-related mortality than patients with systemic sclerosis (SSc) and systemic lupus erythematosus (SLE) who had significant internal organ dysfunction related to their disease. Treatment with immunosuppressive agents including corticosteroids before transplant, especially in the SLE group, likely predisposed patients to the infectious complications experienced after HDIT. Better patient selection and modifications to the treatment regimen appear to have reduced the risks of treatment-related mortality in recent years [6,9,21]. In the SCOT clinical trial in which patients with SSc are randomized between two treatment arms, either HDIT followed by autologous HCT or pulse cyclophosphamide, there was only one treatment-related death as of late 2009 [22]. This improvement was attributed to modifications made to the treatment regimen and patient selection based on insights gained from the pilot study [7,22].

Specific Autoimmune Diseases and High-Dose Immunosuppressive Therapy Followed by Autologous Hematopoietic Cell Transplantation

HDIT has been performed most commonly for MS, SSc, SLE, RA and juvenile idiopathic arthritis (JIA) [5], but promising results have also been observed in other autoimmune diseases.

Multiple sclerosis MS is an inflammatory disorder of the central nervous system manifesting as acute focal demyelination and axonal loss followed by sclerotic scarring. It is postulated that myelin proteins are targeted by autoreactive immune effector cells [23]. The pathology shows a predominant T cell response both in the demyelinated lesion and in perivascular spaces. Axonal injury is evident in both the MS lesions and the normal-appearing white matter. The clinical manifestations of the disease are manifold and include loss of vision from optic neuritis, diplopia, sensory loss and paresthesias, vertigo, fecal or urinary incontinence, impotence, intellectual decline, paroxysmal pain, recurrent infections, and loss of coordination or paralysis. Most MS patients (85%) present with relapsing-remitting disease, and about 50% will evolve to the secondary progressive type of MS over 10 years. The other 15% of patients have progressive disease from onset (primary). The standard for measuring outcome in studies of MS is the Kurtzke Expanded Disability Status Scale (EDSS) and, more recently, the Multiple Sclerosis Functional Composite (MSFC). At 20 years after onset, patients with MS had 85% of the expected survival. Despite responses to immunomodulating agents, no standard therapy is curative or has been demonstrated to prevent development of a progressive clinical course. Disease-modifying therapies in relapsing-remitting MS include interferon (IFN) beta-1a, IFN beta-1b, glatiramer acetate (GA), mitoxantrone and natalizumab [24]. Treatment reduced the clinical relapse rates by 30–68%, with mitoxantrone and natalizumab being more effective than IFN or GA. These agents, however, remain inadequate in completely preventing relapses and progression. There is no effective therapy for primary or secondary progressive MS.

Results from at least 11 clinical trials of HDIT and autologous HCT for MS have been reported from transplant centers in the Americas, Europe and Asia (Table 1) [8,25,26,27,28,29,30,31,32,33,34]. Although there was variability in the design of each of the early clinical trials, they all included patients with advanced MS and the progressive type of the disease. All patients received high-dose combination chemotherapy or total body irradiation (TBI) and cyclophosphamide. In 10 of the 11 clinical trials, the hematopoietic cell grafts consisted of “mobilized” peripheral blood cells, and seven of the trials included T cell depletion with CD34-selection. In the clinical trials reported before 2008, the overall treatment-related mortality was 2.8% (4/145) and the progression-free survival or rate of neurological stability reported in the individual clinical trials ranged from 36–95% at 2–3 years after treatment (Table 1). Five patients (3.5%) died after progression of their disease and further loss of neurological function or other complications. In a report by Saccardi et al. of 19 MS patients with high levels of disease activity based on magnetic resonance imaging (MRI) of the brain and sustained clinical deterioration, there was a marked reduction of gadolinium (Gd)-enhancing lesions in the brain after the HDIT regimen, which was sustained up to 5 years after treatment (Table 1) [31]. Although HDIT followed by autologous HCT appears highly effective for suppressing MRI findings of MS disease activity, a significant loss of brain volume has been noted after HDIT, although this appears to stabilize at 2 years after HDIT [35,36]. The brains of five patients, all with a progressive type of MS who had died at a median of 2 (1–18) months after HDIT, had ongoing active demyelination and acute axonal damage in MS lesions in the absence of substantial lymphocytic infiltration [37]. A mouse model of MS has demonstrated that the neuroinflammatory process after transplantation may be sustained predominantly by endogenous microglia/macrophages and that transplant earlier in the disease course was more effective [38]. The histopathology studies of the MS brain after HDIT would be consistent with the observations in the mouse model.

Table 1. Clinical trials of HDIT and autologous HCT for multiple sclerosis
ATG=antithymocyte globulin; B=BCNU; BEAM=BCNU/Etoposide/Cytosine arabinoside/melphalan; Bu=busulfan; Cy=cyclophosphamide; PFS=progression-free survival; PP=primary progressive; PR=progressive relapsing; RR=relapse-remitting; SP=secondary progressive; TBI=total body irradiation; EDSS=Expanded Disability Status Scale
*In brief, the functional levels of the Expanded Status Scale (EDSS) are graded from 0–10 points and include changes in increments of 0.5 points. An EDSS score of 0 indicates a normal neurological examination in all functional systems (FS). An EDSS score of 10 indicates death from MS. Most of the MS patients who entered these clinical trials of HDIT and autologous HCT had an EDSS score of 5.0–8.0. In general, the function of patients at these different EDSS scores are:
5.0 Ambulant 200m without aids, difficulty to work full day, FS grades 5
6.0 Intermittent or unilateral walking aid for 100m
7.0 Wheelchair-bound (walking <5m with assistance). Able to transfer and use wheelchair alone. Sometimes severe pyramidal grade 5
8.0 Bed- and chair-bound, self-care functions retained (arm function retained), sitting out of bed most of the day.
** One patient with progression of MS was started on interferon β after a relapse, developed a factor VIII inhibitor at 14 months and died at 28 months after HDIT and autologous HCT.

Author

Patient n

MS type
(n)

Median EDSS* (range)

Mobilization

High-dose therapy

T-cell Depletion

Follow-up Median months (range)

Treatment-/ Disease-related Mortality,
n

Clinical Result

(Fassas et al, 1997 [40]; Fassas & Nash, 2004 [32])

35

SP (19)
PP (14)
RR (2)

6.0
(4.5-8.0)

G/GM-CSF + CY

BEAM + ATG

CD34 selection

35 (3–67)

1/1**

PFS 81% at 5yrs

(Openshaw et al, 2000 [26])

5

SP

6.5
(5.5-7.5)

G-CSF only

Bu/Cy

CD34 selection

22 (17–30)

2/0

PFS 40%

(Kozak et al, 2001 [34])

10

SP

6.5
(6.0-7.5)

G-CSF + Cy

G-CSF + Cy

CD34 selection + monoclonals

8 (1–18)

0/0

90% stable or improved

(Nash et al, 2003 [28])

26

SP (17)
PP (8)
RR (1)

7.0
(5.0-8.0)

G-CSF + Prednisone

TBI/Cy + ATG

CD34 selection

27 (2–47)

1/1

76% stable or improved

(Burt et al, 2003 [29])

21

SP (14)
PR (6)
RR (1)

7.0
(3.0–8.5)

G-CSF + Cy

TBI/Cy

CD34 selection

24 (12–60)

0/2

62% stable or improved

(Saiz et al, 2004 [33])

14

SP (9)
RR (5)

6.0
(4.5–6.5)

G-CSF + Cy

BCNU/Cy + ATG

CD34 selection

37 (19–55)

0/0

PFS 86%

(Saccardi et al, 2005 [31])

19

SP (15)
RR (4)

6.5
(5.0–6.5)

G-CSF+ Cy

BEAM + ATG

None

36 (12–72)

0/0

PFS 95%
(6 yrs)

(Samijn et al, 2006 [30])

14

SP

6.0
(5.0–6.5)

None (marrow)

TBI/Cy + ATG

CD34 selection

36 (7–36)

0/1

PFS 36%

(Shevchenko et al, 2008 [26])

50

SP (27)
PR (1)
RR (11)
PP (11)

5.0
(1.5–8.0)

G-CSF + Cy

BEAM + ATG

None

Min. follow-up
9 mo

1 (3 yrs)/0

PFS 72% (6 yrs)

(Fagius et al, 2009 [27])

9

RR (9)

7.0
(3.5–8.0)

G-CSF + Cy

BEAM + ATG

None

29
(23–47)

0/0

PFS 100%

(Burt et al, 2009 [18])

21

RR (21)

3.5
(2.0–5.5)

G-CSF +Cy

Cy +ATG

None

37
(24–48)

0/0

PFS 100%


In the three studies reported since 2008 with a total of 80 patients, no treatment-related mortality was observed, although one patient died from acute myelogenous leukemia at 3 years after treatment (Table 1). No indication was given in the report if there were other risk factors for AML in this patient besides the transplant, such as previous treatment with mitoxantrone. In two of the more recent clinical trials, only patients with very active relapsing-remitting MS who were earlier in their disease course were included [18,27]. Progression-free survival was observed to be 100% in both trials at a median follow-up of 2–3 years, and a marked clinical improvement was noted. Disease activity-free survival in which disease activity was defined as relapses, activity on the brain MRI, or loss of neurological function was 62% in one study [18].

Although MRI studies in the early clinical trials showed a marked and sustained reduction in Gd-enhancing brain lesions in all the groups studied compared to baseline, it was still uncertain if the continued loss of neurological function observed in some of these progressive patients was the result of a degenerative process or a failure to completely control inflammation related to the autoimmune disease. Based on the observations now in patients transplanted earlier in the course of MS and the brain histopathology studies, continued loss of neurological function is consistent with persistent microglial/macrophage activation in the MS lesions of patients with advanced disease. Future clinical trials should be done in patients with very active relapsing-remitting MS who have failed therapy while they are still early in their disease course. The NIH-sponsored HALT MS clinical trial of HDIT followed by autologous HCT for relapsing-remitting MS completed accrual in late 2009 (n=24). A 5-year follow-up is planned to assess stability of the response. Randomized clinical trials need to be completed to confirm if there is a therapeutic benefit of HDIT and autologous HCT for MS. In Europe, the Autologous Stem cell Transplantation International Multiple Sclerosis (ASTIMS) randomized clinical trial included patients with secondary progressive MS with an EDSS of 3.5–6.5. ASTIMS was closed because of poor accrual.

Systemic sclerosis

Systemic sclerosis is an uncommon disabling autoimmune disease that is characterized by two major clinical features: 1) a non-inflammatory small vessel vasculopathy and, 2) fibrosis of the skin and multiple internal organs [41]. Antinuclear antibodies occur in 95% of SSc patients and the anti-topoisomerase I antibody (Scl-70) is found in 30–40% of subjects with diffuse cutaneous SSc. Diffuse cutaneous SSc has a higher mortality than limited cutaneous SSc and is associated with substantial morbidity. Clinical manifestations include digital ischemia/skin ulcerations from the vasculopathy, both truncal and acral scleroderma, interstitial lung disease, hypertensive renal crisis, diffuse GI disease, and myocardial involvement. The modified Rodnan skin score (mRSS) and the modified Health Assessment Questionnaire Disability Index for SSc (SHAQ) are two validated tools for evaluating the degree of scleroderma and measuring the effect of disease on overall function [42].

Immunosuppressive therapies investigated for severe SSc have been inadequate or ineffective. A 12-month course of cyclophosphamide was reported to be superior to placebo in slowing the rate of progression of SSc lung disease at 12 months after start of treatment, but later follow-up showed that the overall effect was modest and not sustained at 24 months [43,44]. However, cyclophosphamide might be considered a standard of care for individuals with SSc since no other immunosuppressive treatment has been shown in a controlled setting to be of any benefit whatsoever. Important supportive care measures for SSc patients include angiotensin-converting enzyme inhibitors for management of renal crisis, and bosentan or other agents for management of pulmonary hypertension.

A still limited number of clinical trials of HDIT and autologous HCT for SSc have been conducted. Patients included in these clinical trials had a poor prognosis based on the presence of diffuse cutaneous disease and internal organ involvement. In a single center study of high-dose cyclophosphamide as a single agent (n=10) or melphalan (n=1) and autologous HCT, major or partial responses were observed in 8 of 11 patients, but at a median of 18 months, 8 patients had relapsed or not achieved a response (Table 2) [15].

Table 2. Clinical trials of HDIT and autologous HCT for systemic sclerosis
*There was one additional death at 5 years after HDIT from lung cancer.
BL=baseline; Cy=cyclophosphamide (mobilization: 2 or 4 g/m2; treatment: 120 mg/kg in combination with TBI or 200 mg/kg if single cytotoxic agent); DLCO=diffusion capacity of the lung for carbon monoxide; EFS=event-free survival; Mel=melphalan; mRSS=modified Rodnan skin score (ranges from 0–51; increasing score indicates worsening scleroderma); PFS=progression-free survival.

Author

Patient
n

BL Median DLCO% (range)

BL Median mRSS (range)

Mobilization

High-dose therapy
(n)

T-cell depletion
(n)

Follow-up Median months (range)

Treatment-related/ Disease-related Mortality,
n

Clinical results

(McSweeney et al, 2002 [45]; Nash et al, 2007 [7])

34

61
(40–83)

30
(3–48)

G-CSF

TBI / Cy + ATG

CD34 selection

48
(12–96)

8/4

PFS – 64%
Sustained response (evaluable, n=27), 63%
Improvement in skin score (P=0.001) + stable lung function overall

(Farge et al, 2002 [15])

11

67
(48–80)

29
(13–36)

G-CSF + Cy

G-CSF + Cy

CD34 selection (n=9)

18
(1–26)

1/3

3 patients alive in remission (27%)
4 patients alive with no response or progression

(Tsukamoto et al, 2006 [46])

6

47
(25–60)

26
(15–32)

G-CSF + Cy

Cy

CD34 selection

20
(13–33)

0/0

Improvement in skin score (P=0.05) and lung function

(Loh et al, 2007 [48]; Milanetti et al, 2009 [47])

37

?
(29–86)

25
(4–41)

G-CSF + Cy

Cy + ATG

None

24
(–-60)

4/2

EFS 68%
at 5 yrs

(Vonk et al, 2008) [10]

28

55
(21–100)

32
(9–51)

G-CSF + Cy

Cy

CD34 selection

63 (12–90)

2/2*

EFS (evaluable, n=26)
64% at 5 years and 57% at 7 years


Four patients (36%) had died by 18 months after HDIT. In a later study of patients who had survived at least 6 months after high-dose cyclophosphamide only and HCT (n=26), survival was 96% and event-free survival was 64% at 5 years [10]. However, about half of the patients included in this study had diffuse cutaneous disease albeit without internal organ involvement. In the North American multicenter pilot study of a more intensive HDIT regimen consisting of TBI and cyclophosphamide in patients with diffuse cutaneous disease and internal organ involvement, 17 of 27 evaluable patients (63%) who survived at least 1 year after HDIT had sustained responses (without progression or disease activation) at a median follow-up of 4 years [7]. Patients with sustained responses had required no immune-based treatment after HDIT. There was a major improvement in the degree of scleroderma as measured by mRSS and in overall function as measured by the mHAQ at final evaluation (Figure 1A and B).

Figure 1. Change in modified Rodnan skin score (mRSS), modified Health Assessment Questionnaire (mHAQ) score, and lung function after high-dose immunosuppressive therapy (HDIT) and autologous hematopoietic cell transplantation
A determination was made whether a parameter value was statistically significantly increasing or decreasing over time using a generalized estimating equation (GEE) model. The bold black solid line represents the mean value over time for the parameter of interest. The bold black dotted line represents an estimate of the modeled linear relationship between the parameter value and time and summarizes the results of the GEE models. The gray solid lines are parameter values for individual patients. The mean mRSS and mHAQ values statistically significantly decreased with time after HDIT (both P<0.0001; panels A and B, respectively). The mean values for diffusion capacity of the lung for carbon monoxide (DLCO) adjusted for hemoglobin levels did not significantly change (P=0.50, panel C), and forced vital capacity statistically significantly increased with time (P=0.01, panel D). (This figure based on a figure originally published in Blood. Nash RA, McSweeney PA, Crofford LJ, Abidi M, et al. High-dose immunosuppressive therapy and autologous hematopoietic cell transplantation for severe systemic sclerosis: long-term follow-up of the U.S. multicenter pilot study. Blood. 2007;110:1388-1396. © the American Society of Hematology.) 

Skin biopsies confirmed that the improvement in skin score was associated with a significant decrease of dermal fibrosis (Figure 2) [7,49].

Figure 2. Resolution of dermal fibrosis after HDIT and autologous HCT
Shown are full thickness skin biopsies from a patient in the North American pilot study for the SCOT clinical trial. Skin biopsies were collected at baseline (A and B) and then at 1 (C and D) and 5 years (E and F) after HDIT from the same location. Dermal fibrosis was evaluated after staining the skin with H&E and examined under low and high power magnification. At baseline, pan-dermal sclerosis from the dermal-epidermal border to the hypodermis (subcutaneous fat) was observed. 
The reticular dermis is replaced by a dense compact collagen without normal collagen bundles or dermal appendages. (Original optic 5x. B) 
As in 1A but at higher power, the straightened dermal-subcutaneous border demonstrates the abnormal, densely packed, homogenized collagen. (Original optic 20x. C) 
A low power view of the skin biopsy at 1 year after HDIT shows crowded collagen bundles with focal areas of residual sclerosis but less than at baseline. (Original optic 5x. D) 
A higher power view of the 1-year skin biopsy from C shows collagen bundles some of which are hypereosinophilic and straightened but overall there is no longer the appearance of homogenization. (Original optic 20x. E) 
The skin biopsy at 5 years shows that the thickness of the dermis has decreased from baseline. There has been resolution of the dermal fibrosis. There is now some thinning of the collagen bundles with a relative increase in the space between the collagen bands. The dermal-epidermal border remains straightened with loss of rete ridges. (Original optic 5x. F) 
A higher power view of collagen in lower reticular dermis demonstrates a change to thin wavy collagen bundles separated by increased ground substance. (Original optic 20x) 
(This figure is based upon a figure originally published in Blood. Nash RA, McSweeney PA, Crofford LJ, Abidi M, et al. High-dose immunosuppressive therapy and autologous hematopoietic cell transplantation for severe systemic sclerosis: long-term follow-up of the U.S. multicenter pilot study. Blood. 2007;110:1388-1396. © the American Society of Hematology.)

Lung, heart and kidney function, in general, remained clinically stable (Figure 1C and D). Histological studies of the microvasculature of the skin also showed improvement after HDIT [50]. There was an increased capillary count in post-transplant SSc skin and interferon alpha, vascular endothelial cadherin and RGS5 had returned to normal levels. The treatment-related mortality was 23%, and progression-free survival was 64% at 5 years. Other studies have also suggested a major clinical effect of HDIT on skin and function [46,47]. The cumulative probability of disease progression at 5 years was 48% and the cumulative probability of survival at 5 years was 72% in registry data from EBMT [21]. Two randomized clinical trials of HDIT followed by autologous HCT for SSc are currently being conducted, one in Europe (ASTIS) and the other in North America (SCOT; website: www.sclerodermatrial.org).

Systemic lupus erythematosus

Systemic lupus erythematosus (SLE) is characterized by the presence of anti-nuclear antibodies and immune complexes [51]. Disease severity may vary from mild to life threatening, and numerous organ systems may be involved. Antinuclear antibodies, anti-double stranded DNA antibodies, and anti-Smith antibodies are present in 98%, 70% and 25% of SLE patients, respectively. Overall, the 10-year survival of patients with SLE has been reported as 75–85%, with more than 90% surviving at 5 years [52]. Standard treatment options are not curative and complete sustained remissions are rare. Antimalarials such as hydroxychloroquine reduce the frequency of disease flares, and low-dose corticosteroids are used for patients in whom disease symptoms have not been controlled by more conservative measures. Agents such as cyclophosphamide, azathioprine, rituximab and mycophenolate mofetil have also been found effective in controlling disease activity [53]. The SLE Disease Activity Index (SLEDAI) is a validated tool for following disease activity [54].

Clinical trials of HDIT with and without HCT were conducted on patients with SLE who were refractory to standard therapies. In a single center study (n=50) of HDIT and HCT, patients underwent stem cell mobilization with G-CSF and cyclophosphamide, and the autologous graft was T cell-depleted by CD34-selection [8]. The HDIT regimen consisted of high-dose cyclophosphamide (200 mg/kg) and ATG. There was a significant improvement in the SLEDAI score, renal function stabilized and titers of the anti-nuclear and anti-double stranded DNA antibodies improved after HDIT. Overall and disease-free survival at 5 years was 84% and 50%, respectively. Treatment-related mortality was 4% (two patients) and both deaths occurred before HDIT. The EBMT registry reported the experience with HDIT and autologous HCT for SLE and observed significant disease responses in 31 of 50 patients, although many remained on some maintenance therapy after transplantation [55]. In comparison, a study of high-dose cyclophosphamide (200 mg/kg) without HCT (n=14) showed that only 5 patients (36%) had durable complete remissions at a median follow-up of 27 months [20]. Although this approach avoids the re-infusion of cells, the relapse rates were comparable with or without the transplant of autologous hematopoietic cells. If there is no difference in relapse rates, then transplantation of hematopoietic cells would be expected to be beneficial due to a reduction in the time to recovery of blood cell counts. Although experience is still limited, HDIT can induce a high percentage of disease responses in patients with SLE who had otherwise been refractory to standard therapy, and remissions have been durable in a significant proportion of patients.

Rheumatoid arthritis

The pathological hallmark of Rheumatoid arthritis (RA) is synovial inflammation with proliferation of macrophages and fibroblasts. If severe, the inflamed synovium develops into an invasive pannus which destroys cartilage and bone [56]. Other complications are a vasculitis, cervical spine disease, lung nodules or interstitial fibrosis, and cardiac complications including pericarditis. Risk of progression can be predicted by prognostic factors such as increased number of affected joints, a high level of C-reactive protein, presence of rheumatoid factor, and extra-articular features of the disease [56]. The risk of mortality is increased with more severe disease activity or ≥ 1 extra-articular disease manifestation [57,58,59]. There is a mortality of approximately 30% at 5 years for patients with the highest disease activity. Many anti-cytokine or immunomodulatory agents have been approved for the treatment of RA including methotrexate, hydroxychloroquine, sulfsalazine, leflunamide, infliximab, adalimumab, etanercept, abatacept, and anakinra. B-cell targeted therapy with rituximab has recently been shown to be effective as well. The goal of standard therapy is to relieve the signs and symptoms of the disease since none of these treatments are curative. The criteria for determining response to treatment have been defined by the American College of Rheumatology [60].

Four small clinical trials of high-dose cyclophosphamide with or without ATG for patients with RA who had failed standard treatment have been reported [14,61,62,63,64,65]. There were early major responses in the majority of the patients, but on long-term follow-up, all 32 patients accrued to these clinical trials relapsed and required additional treatment. Although disease activity recurred, one study showed that after HDIT, there was a decrease in progression of joint damage compared to baseline [66]. No mortality was observed in any of the clinical trials. Seventy-six patients with RA who underwent HDIT and autologous HCT were available for analysis in the EBMT registry, and the outcomes were comparable to the experience reported from the clinical trials [67]. Major responses were observed in 67% of patients, with a significant reduction in the measures of disability. Most patients had restarted immunomodulatory treatment by 6 months after HDIT for persistent or recurrent disease activity. No treatment-related mortality was observed. The apparent difference in response of RA to HDIT compared to other autoimmune diseases might be related to immune or non-immune biological factors. More durable responses might be obtained with more intense HDIT regimens, but this may increase the risk for treatment-related mortality. Another strategy to decrease relapses or progression may be the addition of immunomodulatory therapy after HDIT.

Juvenile idiopathic arthritis

Juvenile idiopathic arthritis (JIA) is a heterogeneous group of chronic inflammatory diseases involving the joints and extra-articular tissues that begins before 16 years of age [68]. Severe disease has an effect on bone and joint development resulting in overgrowth or undergrowth of juxta-articular bone resulting in limb deformities. The macrophage activation syndrome is a potentially life-threatening complication in which there is uncontrolled activation and proliferation of macrophages and T cells. This complication may occur in 5–8% of patients with systemic JIA. The mortality is <1% and occurs mostly in the systemic JIA subtype [69]. One clinical trial of HDIT and autologous HCT in patients with treatment-refractory JIA (n=22) was reported with a median follow-up of 80 months [6]. The HDIT regimen consisted of TBI (400 cGy), cyclophosphamide, and ATG. Early in the clinical trial, two patients developed macrophage activation syndrome less than 1 month after HDIT and both died. Precautionary measures added to the treatment may have reduced this risk in later patients. Two other patients died after relapsing and restarting immunosuppressive treatment more than 1 year after HDIT. Overall and disease-free survival was 82% and 36%, respectively. There were significant sustained improvements in disease activity in the group based on disability and active joint scores. In a more recent report of 7 patients, 4 patients had sustained responses, 2 patients relapsed within 1–12 months of transplant, and 1 patient died at 4 months post-transplant [70]. In a report from the EBMT registry on 34 JIA patients, 18 (53%) were in complete remission without additional therapy at 12 to 60 months after HDIT [71]. In a small subset of poor prognosis JIA patients who fail to respond to standard treatment, HDIT and autologous HCT may be of benefit, although this may be associated with a substantial risk in a disease that is not per se life threatening.

Crohn’s disease

In a clinical trial of patients with treatment-refractory Crohn’s disease, 11 of 12 patients achieved sustained remissions at a median of 18 (7–37) months after HDIT without significant treatment-related toxicity or mortality [72]. In another study, 3 of 4 patients achieved clinical and endoscopic remissions at a median of 16.5 months after HDIT [73]. Longer follow-up is required to assess the durability of response.

Diabetes mellitus

An interesting clinical trial was performed in patients with recent-onset diabetes mellitus. Fourteen of 15 patients had prolonged periods of insulin independence after high-dose cyclophosphamide and autologous HCT [16]. In a follow-up to that report and with inclusion of 8 additional patients, 20 of 23 patients became insulin-independent after HDIT and 12 patients maintained that status for a mean of 31 months; 8 patients relapsed and required insulin again [74]. C-peptide levels were significantly increased after transplant compared to baseline. About 50% of patients may achieve a prolonged insulin-free period after HDIT but longer follow-up is required.

Immune reconstitution after high-dose immunosuppressive therapy

Natural killer (NK) cell counts recovered by 1 month and B and CD8+ T-cell counts recovered by 6–12 months after HDIT. There was a slower recovery of CD4+ T cell counts, which reach low–normal levels by 2 years [12]. Immune recovery at 2 years after HDIT was associated with increasing thymic-derived naïve CD4+ T cells (Figure 3) [11].

Figure 3. Central memory CD4+ T cells decreased and naïve CD4+ T cells increased at 2 years after HDIT and autologous HCT for MS
At the 2-year follow-up, the frequency of naïve CD4+ T cells in the blood had increased 118% as compared with pretherapy (P=0.032). Correspondingly, CM CD4+ T cells had decreased 38% at 2 years after therapy (P=0.008). The frequencies of the EM CD4+ T cells did not change significantly at the 2-year follow-up compared with the baseline. These data support the concept that there is significant immunomodulation at 2 years after HDIT and autologous HCT, and this may explain the observed durable clinical remissions in a significant proportion of patients with autoimmune disease. Reproduced with permission. © Muraro et al., 2005. J. Exp. Med. doi:10.1084/jem.20041679

It was also observed that there was an increase in T cell receptor excision circles (TRECs; a marker for recent thymic emigrants) in CD4+ T cells at 1 and 2 years after HDIT and a steady decrease over time in CD4+ central memory T cells. CD4+ effector memory cells were relatively increased at 6 months after HDIT, likely from homeostatic proliferation, but had recovered to normal levels by 2 years. There were no significant changes in the CD8+ T cell subsets. Several investigators have reported an increase in regulatory CD4+ FoxP3+ and CD8+FoxP3+ T cells, and broader clonal diversity than present before [11,13,75,76,77]. In association with the increased levels of naïve CD4+ T cells, there was hypertrophy of the thymus at 1 and 2 years compared to baseline especially in the younger patients (less than 43 years of age) [12]. This evidence suggested a thymic origin for the recovery of the CD4+ T-cell repertoire after HDIT and autologous HCT. Even though B-cell counts were very low in the first 3 months after HDIT, median serum levels of immunoglobulin G specific for tetanus toxoid, Hemophilus influenzae and Streptococcus pneumoniae, were normal [12]. There was recovery of the naïve B cell compartment in SLE patients by 1 year after HDIT [76]. The clinical responses to HDIT, which have persisted for 2 or more years in several autoimmune diseases, may be a result of these late immunomodulatory effects.

Allogeneic HCT for autoimmune diseases
Outcomes in patients with autoimmune diseases transplanted for another primary disease

Our first understanding of the effect of allogeneic HCT on human autoimmune diseases came from experience in transplanting patients with hematologic disorders who also suffered from autoimmune diseases (Table 3) [78,79,80,81,82,83,84,85,86,87,88,89,90,91,92,93,94,95].

Table 3. Outcomes in patients with autoimmune diseases transplanted with an allogeneic hematopoietic cell graft for another primary disease
Abbreviations: AML=acute myeloid leukemia; ALL=acute lymphoblastic leukemia; ANA=anti-nuclear antibody; CML=chronic myelogenous leukemia; LGL=large granular lymphocytes; MM=multiple myeloma; NHL=Non-Hodgkin lymphoma; SAA=severe aplastic anemia.
*Clinical remission but ANA remained positive.
†Relapse occurred in patient with mixed chimerism.

Autoimmune Disease

Hematologic Disease

Evaluable Patients (total) n

Remission of Autoimmune Disease after HCT, n

Outcome (alive at last follow-up), n

Follow-up

Rheumatoid arthritis (Baldwin et al, 1977 [78]; Jacobs et al, 1986 [79]; McKendry et al, 1996 [80]; Lowenthal et al, 1993 [81]; Snowden et al, 1998 [82]; Lowenthal et al, 2006 [83]; Tapprich et al, 2003 [84])

SAA (n=8), 1 MM

9

7 (2 relapses +1 transient relapse)

6

2 mos–21 yrs

Systemic lupus erythematosus (Gur-Lavi, 1999 [85])

SAA

1

1* (ANA titer +)

1

15 yrs

Psoriatic arthritis (Yin & Jowitt, 1992 [86]; Slavin et al, 2000 [87]; Snowden et al, 1998 [82]; Eedy et al, 1990 [88])

AML, CML (n=3)

4

3 (1 relapse)

3

1, 3, 5, 5 yrs

Ulcerative colitis (Yin & Jowitt, 1992 [86])

AML

1

1

1

4 yrs

Crohn’s disease [Lopez-Cubero et al, 1998 [89]

CML

5

4†

5

4.5–15.3 yrs

Multiple sclerosis (Mandalfino et al, 2000 [90]; McAllister et al, 1997 [91]; La Nasa et al, 2004 [92]; Jeffery, 2007 [93])

CML (n=2), LGL Leukemia, AML

4

3

3

1, 2, 3, 4 yrs

Autoimmune hepatitis (Vento et al, 1996 [94])

ALL

1

1

1

4 yrs

Lupus anticoagulant (Olalla et al, 1999 [95])

CML

1

1

1

5 yrs


In RA patients, sustained remissions have been observed for as long as 20 years after allogeneic HCT [83]. However, relapses were observed in 3 of the 9 reported RA patients. One of the relapses was transient with a subsequent treatment-free remission of 11 years. In one of the two sustained relapses, the HLA-identical donor was serologically positive for rheumatoid factor but without clinical disease [79]. Sustained remissions and some relapses have also been observed in patients with other concomitant autoimmune diseases after allogeneic HCT (Table 3). One patient who relapsed with Crohn’s disease had mixed hematopoietic chimerism detected at 3 months after HCT. Hinterberger et al did a literature search and identified reports of patients with an autoimmune disease who were transplanted for severe aplastic anemia or a hematologic malignancy between 1977 and 2001 [96]. Attempts were then made to update these reports. Disease-free survival after allogeneic HCT of patients with aplastic anemia (n=23) was 78% at 16 years and survival in unmaintained remission of the concomitant autoimmune disease was 64% at 13 years. The results were similar for patients with autoimmune diseases who underwent allogeneic HCT for hematologic malignancies. An association was noted between the development of GVHD and the risk for relapse of the autoimmune disease. The risk for relapse of the autoimmune disease was lower after allogeneic than after autologous HCT. There were insufficient data from the case reports/series to develop an understanding of why relapses occurred after allogeneic HCT. After allogeneic HCT from an HLA-identical sibling, one possible explanation for recurrence of the autoimmune disease may be genetic factors that are shared between the donor and recipient. Another possible explanation is the persistence of host immune cells resulting in the recurrence of disease activity.

Allogeneic hematopoietic cell transplantation for autoimmune diseases as the primary indication

The primary risks of allogeneic HCT are the morbidity and mortality associated with a delayed immune reconstitution and graft-versus-host disease (GVHD). Therefore, there has been a reluctance to consider this approach except for extreme cases of refractory autoimmune diseases. Although the risk of complications and treatment-related mortality is greater than after autologous HCT, there may be a greater potential for sustained remissions of severe autoimmune diseases after allogeneic HCT and, therefore, the possibility of an improved overall outcome. Survival after allogeneic HCT for nonmalignant hematological disorders or good-risk hematological malignancies such as chronic myelogenous leukemia in chronic phase has ranged from 85–95%. The best outcomes were observed in young patients transplanted from HLA-matched donors. No clinical trials have yet been conducted of allogeneic HCT for which an autoimmune disease was the primary indication, but a small number of cases have been reported. The largest experience has been in patients with autoimmune cytopenias [97,98,99,100]. Of the seven evaluable patients reported from the EBMT registry, five were alive and in remission at a median follow-up of 41 months [97]. One patient with Evans syndrome in the report from the EBMT registry had disease progression and died. The second patient died from treatment-related complications after HCT from an HLA-haploidentical donor. Of the three case reports of Evans syndrome in the literature, one patient relapsed and died and the other two died of transplant-related complications in complete remission [98,99,100]. There are six cases reported of allogeneic HCT for connective tissue diseases like SSc, overlap syndrome, and RA [48,101,102,103,104]. Two patients with SSc had high-dose conditioning, one of whom was alive at 5 years in disease remission with resolution of the dermal fibrosis and severe scleroderma. The four other patients received reduced intensity conditioning regimens. All patients were alive at last follow-up and in remission. Three of these patients had stable mixed hematopoietic chimerism and no history of GVHD. Regulatory immune mechanisms associated with the establishment of mixed hematopoietic chimerism may be responsible for inducing remission of the autoimmune disease [105]. Daikeler et al. reported a case series of 35 patients who had allogeneic HCT between 1984 and 2007 for a primary indication of an autoimmune disease and were reported to the EBMT registry [106]. Responses occurred in 78% of patients, but in this heavily pre-treated population, the treatment-related mortality was 22%. Relapses were again observed in a small number of cases. These registry data had significant limitations since the patient population was very heterogeneous for both treatment and disease type, as well as the fact that the data were often incomplete. Conclusions regarding the therapeutic role of allogeneic HCT for severe autoimmune diseases await the results from prospective clinical trials conducted in carefully selected patients.

Conclusions

A high rate of remission in autoimmune diseases is observed after HDIT and autologous HCT, and a significant proportion are sustained after 4–5 years. The rate and durability of response may depend on the intensity of the HDIT regimen and the type of autoimmune disease being treated. Randomized clinical trials are now being conducted in specific autoimmune diseases. The experience with allogeneic HCT as a treatment for autoimmune diseases is still limited, but promises to be highly effective. Carefully selected patients with active autoimmune disease that is life-threatening or threatening critical organ function and refractory to standard treatment should be considered as candidates for clinical trials of allogeneic HCT or HDIT followed by autologous HCT.

Acknowledgements 

Grants to acknowledge are: National MS Society- RG4183

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Please cite this article as follows: Nash RA. Hematopoietic cell transplantation for autoimmune diseases.Cell Ther Transplant.  2010;2:e.000082.01. doi:10.3205/ctt-2010-en-000082.01

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