High dose immunosuppressive therapy and stem cell transplantation in autoimmune and inflammatory diseases

International Immunopharmacology 2 (2002) 399 – 414 www.elsevier.com/locate/intimp

Review

High dose immunosuppressive therapy and stem cell transplantation in autoimmune and inf lammatory diseases Sarah J. Bingham*, John Snowden, Gareth Morgan, Paul Emery Rheumatology and Rehabilitation Research Unit, University of Leeds, 36 Clarendon Road, Leeds LS2 9NZ, UK Received 31 May 2001; accepted 14 November 2001

Keywords: Autoimmune disease; Stem cell transplantation

1. Introduction In recent years, haemopoietic stem cell transplantation (SCT) has been proposed as an experimental treatment for a wide range of autoimmune diseases including rheumatic diseases, multiple sclerosis, haematological disease and inflammatory bowel disease [1– 7]. The concept is not new. Almost three decades of animal studies in which various types of bone marrow transplantation have been shown to cure, prevent or otherwise modify the natural history of animal model of autoimmune disease have formed the basis for clinical studies. Additional support has been provided by anecdotal reports of ‘coincidental’ remission of autoimmune disease in patients undergoing bone marrow transplantation for malignancy or aplastic anaemia (Table 1), and finally, improvements in mortality and morbidity associated with SCT, namely, the use of cytokine peripheral blood stem cells in autologous SCT and more recently the use of low intensity regimens for allogeneic transplantation [30, 31].

In September 1996, the First International Meeting in Haemopoietic Stem Cell Therapy in Autoimmune Disease brought together rheumatologists, haematologists, immunologists and neurologists. Consensus guidelines subsequently formed the basis for sporadic phase I/II studies aimed at the feasibility of this approach [32]. The International Autoimmune Disease Stem Cell Project Database was set up under the auspices of the European Group for Blood and Marrow Transplantation (EBMT) and the European League against Rheumatism (EULAR). By May 2001, the registry had collected over 350 patients from 78 centers in 22 countries who had undergone SCT (almost entirely autologous), specifically for severe autoimmune disease [33]. This article aims to review the current clinical data and to discuss future directions in the new millennium. A glossary of terms used in SCT is provided (Fig. 1). As autologous SCT is strictly speaking not a form of ‘transplantation,’ many workers are starting to use the term high dose immunosuppressive therapy (HDIT) for such procedures.

2. Current experience *

Corresponding author. Tel.: +44-113-233-4940; fax: +44-113244-6066. E-mail address: [email protected] (S.J. Bingham).

Details of individual cases and small series of patients (Table 2) are increasingly featured in the

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Table 1 SCT in patients with coincidental autoimmune disease Coincidental autoimmune disease

Indication for transplant

Number Transplant type

Rheumatoid arthritis

SAA

4

Allogeneic

SAA

3

Allogeneic

Cy 200 mg/kg

CyA

SAA NHL

1 1

Allogeneic Autologous

MTX, Pr Nil

NHL

1

Autologous

NHL

1

Autologous

Cy 200 mg/kg, TBI, Pr BCNU 300 mg/m2, Et 400 mg/m2 Ara-C 800 mg/m2, Me 140 mg/m2 Bu 1.1 g, Et 2 g, Cy 120 mg/kg BEAM

Red cell aplasia NHL

1

Allogeneic

Cy 200 mg/kg, ATG

1

Autologous

NHL

1

Autologous

Cy 1.8 g/m2, BCNU 300 mg/m2, Et 400 mg/m2 BEAM

CyA, MTX, Pr, IVIg Nil

CML

1

Autologous

NHL

1

Autologous

NHL Lung malt lymphoma

1 1

Autologous Allogeneic

CML

1

Allogeneic

CML

2

(1) Allogeneic (1) Cy 120 mg/kg, TBI (2) Allogeneic (2) CyA, TBI, ATG

Myasthenia gravis

NHL Ovarian cancer

1 1

Autologous Autologous

Hepatitis

ALL

1

Allogeneic

Crohns

Leukaemia

6

Allogeneic

Ankylosing spondylitis Systemic lupus erythematosus

Sjogren’s syndrome

Multiple sclerosis

Conditioning

BCNU 800 mg/m2, Ara-C 900 mg/m2 m-AMSA 450 mg/m2, Et 0.6 g/m2 BCNU 300 mg/m2, Et 800 mg/m2, Cyt 1600 mg/m2, me 140 mg/m2

Post-transplant therapy

Ref.

Three died, one remission (4 years) One remission (11 years), one remission (13 years), one relapse at 2 years Relapse at 2 years Remission (20 months)

[8]

[9]

[10] [11]

Nil

No response

[12]

Nil

Remission for > 20 months Remission (20 months) Remission 3 years

[13]

Nil

[14] [15]

Relapse (12 months) Remission ( > 30 months)

[12]

Steroids

Relapse at 2 months, died at 20 months

[17]

Nil

Remission No response

[18] [19]

ARA-C 200 mg  2/day  4, Et 200 mg  2/day  4, Cy 1500 mg/day  4, BCNU 200 mg

TBI, Cy 120 mg/kg Et 39 mg/kg, ifo 399 mg/kg, ci 7.8 mg/g TBI, Cy 120 mg/kg, D 60 mg/m2

Outcome of autoimmune disease

Stabilised neurology (1) CyA, MTX (1) Progression (2) CyA, (2) Improved MTX, ATG Nil Relapse (day 250) Nil Relapse (6 months)

CyA, Pr, DLI

[16]

[20] [21]

[22] [12]

Remission (4 years) [23] One died, One relapse, four remission

[24]

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Table 1 (continued ) Coincidental autoimmune disease

Ulcerative colitis

Indication for transplant

Number Transplant type

Conditioning

Post-transplant therapy

Outcome of autoimmune disease

Ref.

NHL

1

Autologous

Nil

1

Autologous

Remission (7 years) Remission (2 years)

[25]

Breast cancer AML

1

Allogeneic

TBI, Et 60 mg/kg, Cy 100 mg/kg Cy 5.625 g/m2, Ci 165 mg/m2, BCNU 0.6 g/m2 TBI, Cy 120 mg/kg, D 60 mg/m2

Autoimmune Small cell 1 thrombocytopenia lung cancer Autoimmune CLL 1 haemolytic anaemia

[26]

Remission (4 years) [27]

Autologous

Nil

Remission of AITP

[28]

Autologous

Nil

Remission of CLL and AIHA for 23 months

[29]

SAA: severe aplastic anaemia, NHL: non-Hodgkins lymphoma, CML: chronic myelogenic leukaemia, ALL: acute lymphoblastic leukaemia, AML: acute myeloblastic leukaemia, CLL: chronic lymphocytic anaemia, Cy: cyclophosphamide, TBI: total body irradiation, Pr: prednisolone, BCNU: carbamustine, Et: etoposide, ARA-C: arabinoside-C, Me: melphalan, Bu: busulfan, BEAM: carmustine (2  3.4 mg/kg), etoposide (8  3.4 mg/kg), cytarabine (8  4.8 mg/kg), melphalan (8  3.3 mg/kg), ATG: anti-thymocyte globulin, Cyt: cytarabine, Ci: cisplatin, ifo: ifosamide, CyA: cyclosporin A, MTX: methotrexate, DLI: donor leucocyte infusion.

published literature along with several studies of stem cell mobilization.

3. Mobilization Phase I studies of stem cell mobilization were necessary as animal and anecdotal clinical data suggested that colony stimulating factors could flare autoimmune disease. In addition, there was the possibility that the underlying diseases and their treatments might prevent effective stem cell mobilization [34]. Most studies have focused on RA and have shown effective mobilization. Some studies have shown flare of RA [35,36], but this has not been a feature of others, possibly because of the co-administration of steroids or cyclophosphamide [37]. Caution has been advised with the use of G-CSF in MS after observing clinically significant neurological events in 4 out of 10 patients who were primarily receiving G-CSF for stem cell mobilization (one died due to respiratory failure) [38]. Three patients responded to high dose methylprednisolone and its routine use to cover mobilization was recommended. One further group also reported flare in MS and suboptimal stem cell mobilization in patients with active lupus on high dose steroids [39].

4. Rheumatoid arthritis The first published report of HDIT in RA was from Perth, Australia [36]. The patient had erosive, seropositive and polyarticular rheumatoid that was unresponsive to multiple second line therapies. In the year prior to the transplant, he had spent less than 30 days outside the hospital and had become dependent on an electric wheelchair. After the treatment with cyclophosphamide (200 mg/kg) and unmanipulated HDIT, he had marked reduction in inflammatory markers and the number of swollen joints. He was able to walk 2 km easily. In Sydney, Australia, eight patients received high dose cyclophosphamide and unmanipulated HDIT for RA in a dose escalation study [40]. The first cohort received 100 mg/kg and second received 200 mg/kg of cyclophosphamide. The procedure was well tolerated by all patients. Only transient improvement was seen in the first cohort, but the patients in the second cohort had improvements lasting beyond 17– 19 months of follow-up. In the latter group, disease activity was not completely abolished but there was a suggestion that the disease was more controllable with anti-rheumatic agents. An Australian multi-center trial in which patients receive cyclophosphamide (200 mg/kg) and then randomized to either unse-

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Fig. 1. Terms used in stem cell transplantation (SCT).

lected or selected grafts has now enrolled over 30 patients. Early analysis shows no treatment-related deaths and only one patient has failed to respond with all other patients attaining ACR 50– 100% responses although the follow-up is short (personal communication). Burt et al. [41] published four patients with resistant RA who received 200 mg/kg of cyclophosphamide, 90 mg/kg of ATG, and for one patient, 400 Gy total body irradiation. Haemopoietic rescue was with autologous CD34+-selected grafts. There was a sustained response in two patients at 9 and 20 months. In Omaha, two patients with RA received ASCT. The transplant was well tolerated and both patients achieved 80% ACR response at 1 month. They both relapsed at 6 months but responded well to salvage therapy, and at 12 months, ACR responses were 80% and 60%. One patient flared again at 18 months but improved after treatment of hypothyroidism, while the other relapsed further and had progressive disease at 15 months [42].

In Belgium, Durez et al. [43] used an intensive myeloablative regimen consisting of busulphan (16 mg/kg) and cyclophosphamide (120 mg/kg) followed by a highly purified graft to treat two cases of RA. The first was free of arthritis at 21 months posttransplantation although recovery was complicated by pneumocystis pneumonitis. A second patient made a good response but died of bronchial carcinoma at 5 months, probably unrelated to the transplant [44]. In Leeds, six patients with RA completely nonresponsive to therapy have received cyclophosphamide (200 mg/kg) with selected autografts (three male, three female, 50% rheumatoid factor-positive, age range: 24– 55 years, disease duration 3 –17 years, failed four to eight DMARDs) [45]. The procedure was tolerated well. Three patients had mild neutropenic sepsis, one had a minor Hickman line insertion site infection and one had pyrexia of unknown origin which resolved after 3 weeks. One patient had no complications. Follow-up is from 15 to 33 months. All six patients responded immediately post-transplant

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Table 2 Autologous stem cell transplantation for autoimmune disease Autoimmune disease Rheumatoid arthritis

Number Conditioning

Ref.

Decreased inflammatory markers, increased mobility ( > 6 months) 2 – 3 months of response Two response ( > 1 year), one remission Significant benefit for two patients (9 and 20 months), no response in two patients ACR 80 and 60 at 1 year, one significant response (long-term) (1) Remission at 21 months (2) Died, MRSA, Ca lung 3  ACR 20, 2  ACR 50, 1  ACR 70; five relapsed at 1 – 9 months and commenced on CYA Marked improvement in eight patients Remission ( > 24 months)

[36]

Cy 200 mg/kg

Nil

4 4 4

Nil Nil CD34-positive

2

Cy 100 mg/kg Cy 200 mg/kg Cy 200 mg/kg, ATG 90 mg/kg Cy 200 mg/kg, equine ATG 60 mg  2 Bu 16 mg, Cy 120 mg

6

Cy 200 mg/kg

12 1

Cy 200 mg/kg Cy 200 mg/kg, ATG 90 mg/kg (syngeneic) Cy 200 mg/kg, CAMPATH

CD34-positive Nil

5 1 2 8

Cy 200 mg/kg Cy 150 mg/kg Cy 200 mg/kg Cy 120 mg/kg, TBI 8 Gy, ATG 90 mg/kg

CD34-positive Nil CD34+, CAMPATH CD34-positive

3 1

Cy 200 mg/kg Fludarabine 150 mg/m2, thiotepa 10 mg/kg Cy 200 mg/kg

CD34-positive CD34-positive

One patient improved at 2 years, one patient stabilised, one patient did not respond 45% improvement up to 16 months Relapse at 2 months Stabilization At 1 year, significant reduction in mean skin score and mHAQ; lung function stabilised, two patients died at days 58 and 79 from interstitial pneumonitis Stable, improved quality of life Stable, improved quality of life

CD34-positive, T and B depletion Nil CD34-positive

Peri-transplant complications, moderate response Stabilization Improved during the 1st year

CD34-positive

CD34-positive

Two did not improve, one died Subjective and objective improvement ( > 7 months) Clinical and serological remission

[63]

CD34-positive

Clinical and serological remission

[59]

CD34-positive, T and B depletion

All neurological deficits improved promptly during 15-month follow-up 2 years remission

[64]

3

1 1 1

3 Systemic lupus erythematosus

Outcome

1

2

Systemic sclerosis

Graft manipulation

1 5 3 1

1

Cy 3 g/m2 TBI 800 cGy  4, Cy 120 mg/kg  2, ATG 15 mg/kg  6 Cy 200 mg/kg and ATG (90 mg/kg) Thiopeta 15 mg/kg, Cy 100 mg/kg Cy 200 mg/kg, ATG 90 mg/kg Cy 200 mg/kg, ATG 90 mg/kg Cy 2470 g/m2 and TBI (2.5 Gy) Thiotepa 15 mg/kg, Cy 100 mg/kg

Nil CD34-positive, CD4/8-negative CD34-positive, CD4/8-negative

Nil

T-cell depletion

T-cell depletion

[40] [40] [41] [42] [43,44] [45]

[46] [47]

[50,51]

[52] [12] [53] [54]

[55] [55] [56] [57] [58]

[59] [62]

[65] (continued on next page)

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Table 2 (continued ) Autoimmune disease

Number Conditioning 1 1 1 1 2

Cy 100 mg/kg, ATG 30 mg/kg, MP 3 g BEAM

Graft manipulation

Outcome

Ref.

T-cell depletion

>8 months of response

[66]

CD34-positive, CD2-negative CD34-positive CD34-positive

Clinical and serological remission at 9 months Transient response Death at day 62 due to engraftment failure Complete remission at 9 and 12 months without treatment Three deaths, six complete remission, three partial remission, one mild relapse

[67]

ATG 60 mg/kg, BEAM Cy, ATG, methylprednisolone Cy 200 mg/kg, CD34-positive ATG 20 mg/kg, TBI 4 Gy

1

8: T-cell depletion 12: Cy 200 mg/kg, ATG 20 mg/kg, TBI 4Gy using anti-CD2 and 1: Cy 200 mg/kg, anti-CD3 antibodies ATG 20 mg/kg 5: CD34-positive selection Cy 200 mg/kg, CD34-positive, ATG 4  2.5 mg/kg T-cell depletion Cy 200 mg/kg, CD34-positive ALG (45 mg/kg) Busulphan (16 mg/kg), CD34-positive, Cy 120 mg/kg, T-cell depletion ATG (90 mg/kg) Cy 200 mg/kg Nil

1

Cy 200 mg/kg

Polychondritis

1

Wegner’s granulomatosis PAN

1

Cy 200 mg/kg, ATG 90 mg/kg Cy 200 mg/kg

Bechets syndrome

2

Still’s disease Multiple sclerosis

1 24

JIA

13

2 1 Polymyositis

1

1

9 10

5

5

[68] [69] [70]

[71,72]

One died at day 6, one remission at 7 months Remission at 1 year

[44] [73]

Improved, stopped steroids

[74]

Stabilization of progressive disease Two harvests: Relapse at 1 year to CD34-positive selection pre-ASCT activity on one, the other not manipulated T-cell depletion Remission at 9 months

[75]

[59]

CD34-positive

Remission for 6 months

[76]

[76]

CAMPATH-1, fludarabine, Cy Melphalan 200 mg/m2

CD34-positive

Response for 18 months

[78]

CD34-positive

[77]

Cy, ATG BEAM, ATG

CD34-positive 15 — no manipulation

One complete remission at 14 months, one partial remission at 6 months Improved for 15 months 76% progression-free survival for over 3 years

Cy 120 mg/kg, TBI, MP 4 g BEAM

BCNU 300 mg/ m2, Cy 150 mg/kg, ATG 60 mg/kg Busulfan 16 mg/kg, Cy 120 mg/kg, ATG 30 mg/kg

9 — CD34+-positive CD34-positive Nil

CD34-positive

CD34-positive

Subjective and objective improvement at 5 – 17 months Improved slightly or remained stable; deceased lesions on Gd-enhanced MRI Four of five improved; reduced MRI lesions One death at 22 days, no further MRI lesions in other four patients

[79] [80]

[81] [82]

[83]

[84]

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405

Table 2 (continued ) Autoimmune disease

Number Conditioning 2

8

Immune thrombocytopenic pupura

Pemphigus vulgaris

BCNU (300 mg/m2, Cy 150 mg/kg, ATG 60 mg/kg BEAM

Graft manipulation

Outcome

Ref.

T-cell depletion

Follow-up required

[85]

In vitro or in vivo T-cell depletion

One improved significantly, two improved slightly, four stabilised, one worse 5/6 radiological improvement, 4/6 clinical improvement (1) Remission ( > 11 months) (2) Remission ( > 7 months) No response

[86]

[91]

No response

[92]

Cutaneous lesions resolved, titres deceased to zero

[94]

6

BEAM, ATG 5 mg/kg  2, CYA

Nil

2

Cy 200 mg/kg

Nil

1

CD340-positive

1

Thiopeta 10 mg/kg, Cy 150 mg/kg Cy 200 mg/kg

1

Cy 200 mg/kg

CD34-positive, T-and B-negative –

[87]

[90]

Cy: cyclophosphamide, Bu: busulfan, ATG: antithymocyte globulin, MP: methylprednisolone, TBI: total body irradiation, BEAM: carmustine (2  3.4 mg/kg), etoposide (8  3.4 mg/kg), cytarabine (8  4.8 mg/kg), melphalan (8  3.3 mg/kg), CYA: cyclosporin, BCNU: carbamustine.

3  ACR 20, 2  ACR 50, 1  ACR 70), but subsequently relapsed and cyclosporin was commenced. Following recommencing DMARDs, five patients improved (1  ACR 50, 2  ACR 70, 1  ACR remission, one improved but did not meet the ACR response criteria). In Leiden, 14 patients with progressive RA were mobilised with Cy (4 g/m2) and 12 patients proceeded to transplantation with CD34+-selected autologous grafts following 200 mg/kg of cyclophosphamide. Two patients were not transplanted; one patient’s disease improved following mobilization and the other patient developed a pulmonary embolism and was withdrawn from the study. No major unexpected toxicity was observed. Marked improvement in disease activity was seen in 8 of the 12 transplanted patients at >50% of the visits [46]. McColl et al. [47] have performed the only syngeneic SCT in autoimmune disease. A 39-year-old man with refractory seronegative RA received cyclophosphamide (200 mg/kg) and ATG (90 mg/kg) followed by PBSC from his identical twin brother. A profound remission of arthritis has been sustained beyond 24 months.

Long-term reduction in disease activity following mobilization has also been observed. A study of four patients given Cy (4 g/m2) and GCSF found that all patients improved immediately post-mobilization (1  ACR70, 2  ACR50 and 1  ACR20) [48]. Although all four patients relapsed at 4 –6 months, the disease activity in three patients remained at lower than pre-treatment levels for up to 2 years. Another analysis of the effect of a mobilising dose of Cy on a wide variety of autoimmune diseases found that of 21 patients with RA mobilised with Cy (2 or 4 g/m2) and GCSF, disease activity improved in 12 patients postmobilization [49]. Analysis of the EULAR/EBMT database also found that some patients improved following the mobilising dose of Cy alone (4 g/m2) and did not proceed to transplant [33]. If mobilization alone can induce long-term responses, this would prevent the need for full transplantation and the inherent toxicity involved. The EULAR/EBMT RA working group is currently setting up a randomised study of mobilization alone versus full ASCT. Recently, a new generation of disease-modifying agents has become available in the form of tumour necrosis factor alpha (TNFa)-blockade (Remicade

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(Centocor/Schering-Plough) and Enbrel (Wyeth)). Although these agents are highly effective in reducing disease activity in most patients, a significant number of patients do not respond and persist with active disease without conventional therapeutic options. ASCT is therefore a viable option for such patients. Indeed, further studies of ASCT in RA are likely to only recruit patients who have failed to respond to TNFa-blockade.

5. Systemic sclerosis Arguably, the most life-threatening and untreatable of connective tissue diseases, scleroderma was a natural choice for intensive therapy with SCT. However, it was predictable that in a disease with a major component of fibrosis and with significant vital organ damage, the efficacy and toxicity have been variable. The most impressive response has been in an 11year-old child with a 7-year history of systemic sclerosis who underwent treatment with high dose cyclophosphamide, CAMPATH 1-H and unmanipulated rescue. At 2 years of follow-up, there has been a substantial improvement in skin score, disability score, growth rate and general well being, with no progression of pulmonary fibrosis on high resolution CT scan [50,51]. Two further children have been transplanted at same center; pulmonary disease was stabilised in one, but progressed in the other [51]. Impressive responses have also been reported by a Dutch group, with no mortality in five patients, and on the average, 45% improvement in skin scores [52]. In contrast, Euler et al. [12] reported a 41-year-old patient with CREST syndrome who had an unmanipulated autologous SCT followed by transient improvement lasting only for 2 months. In addition, 20 further cases of patients with systemic sclerosis undergoing HDIT have been published [53 –59]. Postmortem examination of one of these patients who died 2 days following ASCT revealed extensive cardiac fibrosis as the precipitating factor rather than cardiotoxic effects of cyclophosphamide [60]. The authors suggested a cardiac biopsy pre-transplant in order to assess the risk of transplant-related toxicity. Binks et al. [61] analysed all cases of ASCT for systemic sclerosis on the European register. Forty-one patients with systemic sclerosis (37 diffuse, 4 limited)

and skin scores greater than 50% maximum score in 61% have undergone ASCT. Lung disease was present in 76%, seven patients had pulmonary hypertension and five patients had renal disease. Patients were mobilised with cyclophosphamide +/ GCSF. Thirty-eight patients had ex-vivo CD34+ stem cell selection, with additional T cell depletion in seven. Seven conditioning regimes were used, but six of these used immunoablative doses of cyclophosphamide +/ anti-thymocyte globulin +/ total body irradiation. The median duration of follow-up was 12 months (range: 3 –55 months). Following ASCT, skin scores improved by >25% in 69% of evaluable patients and deteriorated in 7%. There was no significant change in pulmonary function, but pulmonary hypertension did not deteriorate. There were no new occurrences of renal disease post-ASCT. Disease progressed in 19%. Eleven patients (27%) died of which seven (17%) were transplant-related (direct organ toxicity in four, haemorrhage in two and infection/ neutropenic fever in one). Four patients died before ASCT was carried out. Overall, the probability of survival at 1 year was 73%. The authors concluded that despite the high mortality rate, the dramatic effects on skin disease and disease-related death warranted further investigation with randomised controlled trials. A European randomised trial comparing ASCT with pulsed cyclophosphamide is now recruiting patients.

6. Systemic lupus erythematosus Although conventional treatments have improved the long-term survival rates in SLE to over 90%, dose intensification of cyclophosphamide, the principal component of conventional approaches, seems logical in the treatment of refractory cases. The first case reported is that of a 46-year-old woman with an 18year history of SLE treated with thiotepa and cyclophosphamide followed by a T cell-depleted graft. At 2 years, the patient is in good clinical remission, with a borderline antinuclear antibody positivity and has reduced the daily maintenance corticosteroid requirement from 40 to 5 –10 mg [62]. Traynor et al. [63] describe five patients with lupus who have had disease remission following ATG, Cy and CD34+ enriched grafts and three further patients with refrac-

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tory SLE received ATG, Cy and enriched grafts all entered complete remission [59]. ASCT has been used successfully to treat a case of severe cerebral lupus (bilateral optic neuritis and transverse myelitis) that was progressing despite heavy immunosuppression [64]. Four further cases with SLE have responded to HDIT for 4 months to 2 years [65 –68]. In San Antonio, USA, a patient died 62 days following ASCT due to engraftment failure [69]. After apparent primary engraftment, she became neutropenic on day 19 and received an unmanipulated back-up graft. However, this had no effect and she went on to receive unmanipulated peripheral stem cells from an HLAidentical sibling. She remained pancytopenic and died from disseminated fungal infection. Subsequent analysis of stored serum and stem cells suggested a substance in her serum that mediated graft failure and prevented engraftment after additional stem cell infusions. Two children with SLE who received autologous SCT are in remission without treatment at 9 and 12 months [70].

7. Juvenile chronic arthritis (JCA) In JCA, results were initially promising [71,72] but toxicity has been significant. Thirteen patients with progressive JCA resistant to methotrexate, cyclosporin A and corticosteroids have been transplanted in Utrecht, Leiden and Paris. Six are in a drug-free remission, three are in partial remission on medication and one has had a mild relapse treated with prednisolone. Unexpectedly, there have been three deaths due to a macrophage-activating syndrome (haemophagocytic syndrome). A further death from sepsis was reported in Belgium [44]. More promising results from Japan have recently been published [73].

8. Other rheumatological conditions A patient with severe progressive Jo-1 antibodyassociated polymyositis responded to selected ASCT following intensive conditioning with busulphan, Cy and ATG [74]. Her muscle strength and dyspnoea improved 15 months following transplant despite discontinuing all therapies including steroids. A less dramatic response was seen following ASCT in

407

another patient with severe progressive polymyositis that was not responding to high dose standard therapy including intravenous steroid [75]. She received treatment with cyclophosphamide (200 mg/kg) and an unmanipulated autograft. Relapse occurred initially, but 18 months later, she is stable on immunosuppressive medication. Another case with mixed connective tissue disease and polymyositis has received SCT [76] and responded initially with the normalization of serum muscle enzymes but relapsed at 1 year. A patient with polychondritis is in remission at 9 months post-HDIT [59]. In Heidelburg [77], two patients with Behcet’s syndrome underwent high dose chemotherapy with melphalan followed by autologous haematopoietic stem cell transplantation. One patient is in complete remission at 14 months and the other in partial remission at 6 months. Two patients with vasculitis have also undergone ASCT; one with Wegner’s granulomatosis entered complete remission for 6 months and a patient with juvenile onset polyarteritis nodosa improved following transplant but developed new autoimmune phenomena (vasculitic rash and autoimmune thyroid disease) [76,78]. A 38-year-old patient with refractory adult onset Still’s disease achieved a prolonged remission after CD34-selected ASCT [79].

9. Multiple sclerosis There have been several published cases of patients with multiple sclerosis who have undergone HDIT. The Thessaloniki group has published a median 3year follow-up in 24 patients with multiple sclerosis [80]. Fifteen received unmanipulated grafts and nine received CD34+-selected grafts. This is the first study to support a disease-modifying effect of HDIT in MS. The procedure did not abolish disease activity but there was an apparent reduction in the progression of disability. Although numbers were small, patients with secondary progressive MS had a progressionfree survival (PFS) of 76% over 3 years. This compares favourably with the data on interferon beta with a PFS of 45% over 3 years. Burt et al. [81] have treated nine patients with progressive MS with lymphocyte depleted autologous HDIT using cyclophosphamide (120 mg/kg), TBI

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(1200 Gy) and methylprednisolone (4 g). With 2 – 36 months of follow-up, no patient had progressed despite stopping all immunosuppressive medication. Three patients have improved although one patient has developed a new non-enhancing lesion on MRI at 1 year [39]. In Italy, 10 patients with rapidly evolving secondary progressive MS were transplanted [82]. Tripledose gadolinium (Gd)-enhanced scans were performed monthly, a pre-treatment period of 3 months and repeated monthly for 6 months and then 3 monthly following ASCT. The number of enhancing lesions decreased following mobilization (with Cy) and dropped to zero after conditioning (BEAM). Clinically, patients improved slightly or remained stable. The incidence of MRI abnormalities also decreased in five patients transplanted in Spain [83]. Four patients remained stable or improved (EDSS) after a median follow-up of 18 months. The number of MRI lesions decreased by a median of 11.8. Five patients with MS have been transplanted in California [84]. MRI Gd-enhancing lesions were present in three of the five patients pre-treatment and none of the four patients assessed post-therapy. Post-transplantation infections occurred in three patients and one died at day 22 from influenza A pneumonia, and one patient, who was neurologically stable, died at 19 months from S. pneumoniae sepsis. Kozak et al. [86] in the Czech Republic mobilised stem cells in 11 patients and 8 or these went on to full transplantation. One patient improved following mobilization, but stem cell mobilization failed in two patients. Three patients improved and four stabilised following transplantation. EBMT and the European Charcot Foundation (BMT-MS Study group) have published guidelines for ASCT in MS [88].

10. Haematological autoimmune diseases Marmont [89] has reviewed the published data on SCT for immune thrombocytopenia (ITP) and Evans’ syndrome (combined ITP and autoimmune haemolytic anaemia). Four cases receiving high dose therapy and autografts have shown treatment failure although in the first two patients, steroid-free remissions were achieved for over 1 year [90 – 92]. A

more impressive response was observed in a 5-yearold child receiving an HLA identical allogeneic cord blood transplant from a sibling for refractory Evans syndrome in Salt Lake City, with normalization of platelet counts and loss of transfusion requirement. Unfortunately, the patient died at 9 months from hepatitis [93].

11. Other conditions A patient with refractory pemphigus vulgaris involving oral and skin lesions received immunoablative therapy with Cy (200 mg/kg) [94]. The procedure was tolerated well and complications such as thrombocytopenia and Pseudomonas septicaemia were quickly treated. Four months later, his oral and skin lesions completely healed, and his pemphigus titres had deceased to zero despite of stopping prednisolone.

12. High dose therapy without PBSC rescue Case reports of eight patients with severe autoimmune diseases treated with high dose cyclophosphamide without haemopoietic rescue have been published [95,96]: two with RA, two with SLE, one with autoimmune haemolytic anaemia, one with ITP, one with Evans’ syndrome and one with chronic inflammatory demyelinating polyneuropathy. Patients were given cyclophosphamide (50 mg/kg/day) for 4 days. Granulocyte colony-stimulating factor (5 mg/kg/ day) was started 6 days after the last dose of cyclophosphamide and was continued until the neutrophil count was above 1  109 cells/l. This regime was well tolerated in all eight patients. The patients with autoimmune haemolytic anaemia and ITP died due to complications of their autoimmune disease. The patients with RA, Evans’ syndrome, chronic demyelinating neuropathy and one of the patients with SLE are in complete remission at 3 –21 months post-treatment. The final patient with SLE is in partial remission at 13 months. More recently, the same group published results of a cohort of 11 patients with SLE who received HDIC without stem cell rescue [97]. Over the 3 –24month follow-up, four patients achieved complete remission, two responded partially and six did not respond.

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A group in Australia has used a similar protocol for three patients with RA and one with JIA [98]. The neutrophil count recovered quickly (day 17), but all patients required antibiotics for neutropenic fever for between 2 and 8 days. There was a marked reduction in ESR (two of three patients), disability (all patients) and visual analogue scores for pain and quality of life (all patients) at 6 and 12 months post-therapy. This approach appears to have an encouraging efficacy and removes the possibility of reinfusion autoreactive cells in the autologous graft. However, patients have a longer cytopenic phase, which might translate into an increased rate of complications from infection and bleeding. In addition, there is probably limited scope for intensifying the conditioning regimen further without the use of haemopoietic rescue.

13. Mechanism of action At the EBMT meeting in 1998, Marmont outlined his ‘hopes’ for autologous SCT in autoimmune diseases. The ‘low grade hope’ was that high dose therapy achieves clinical improvement merely through the effect of the high dose cytotoxic agent on the inflammatory tissue (e.g. synovitis) followed by a protracted period of non-specific immune suppression and gradual immune reconstitution. The ‘high grade hope,’ which is supported by some animal data [99,100], was that of a re-educated immune system, where tolerance was achieved by a loss of autoreactive cells with reconstitution of the immune repertoire. This ‘high grade hope’ is also supported by allogeneic BMT in humans where the donor graft becomes tolerant to the host in the most long-term survivors, allowing discontinuation of cyclosporin A and other immunosuppressants [101]. Alternatively, if inflammatory disease is caused by immune and cytokine dysregulation secondary to an environmental trigger [102,103], ablation of the aberrant immune system, including memory lymphocytes, with regeneration de novo from haemopoietic stem cells might ‘‘reset’’ or ‘‘restore’’ the immune system to its premorbid state. The outcome may therefore depend on re-exposure to the putative environmental triggers. Most data suggest the mechanism for autologous SCT to be predominantly, if not entirely, related to

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intense immune suppression, hence justifying the term HDIT. This is based on the fact that disease activity persists, albeit at a lower level, in most cases and, in addition, the duration of immune reconstitution following autologous HSCT is similar to the duration of response in many cases [104]. In an analogy to oncology, HDIT may represent a ‘debulking’ procedure, reducing disease activity to a sub-clinical or a level where control is again possible with conventional agents. Autologous SCT/HDIT would be more attractive if a re-educated or tolerated as opposed to a non-specifically immunosuppressed immune system could be demonstrated. Animal studies supporting toleration have used more intensive cytotoxic regimens, and to date, most patients have received regimens which are not myelo- or immunoablative (such as cyclophosphamide (200 mg/kg) or BEAM). In addition, immune effectors may have been re-infused posttreatment when the autologous graft has not undergone a high degree of CD34+ cell purification. Studies looking to demonstrate a re-educated immune system in humans will require preparative regimens of sufficient intensity to prevent immune reconstitution from residual immune effectors followed by highly purified CD34+ cells. Sensitive assays to characterise immune reconstitution post-SCT, such as T cell receptor spectratyping and excision circle analysis, analysis of T helper cell subset function and even gene marking of lymphocytes, may answer questions regarding thymic processing and re-education, as well as the origin of relapse or persistent disease. Ablating and then rebuilding the human immune system may not only be of therapeutic benefit but also provide important insights into the pathophysiology of autoimmune diseases. However, such clinical studies should proceed with caution, as clearly there is the potential for delayed immune reconstitution [105 – 107].

14. Conclusions and future directions SCT has been increasingly used as a treatment for severe resistant autoimmune disease. Reports have been almost entirely of autologous SCT which have shown the procedure to be feasible in a number of diseases and although disease activity is not completely abolished, there is frequently a significant

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clinical benefit in patients for whom currently there is no alternative therapy. Analysis of registry data has shown the treatment-related mortality (TRM) at 9% to be similar to autologous procedures in lymphoma. Perhaps expectedly, more treatment-related deaths were reported in multi-organ diseases such as scleroderma and less in diseases such as RA which underpins the importance of careful patient selection in terms of general fitness for the procedure. The next stage of the evolution of HDIT will involve multicenter randomised trials to establish the place for HDIT in the treatment of severe autoimmune disorders. Further refinement could focus on optimising the patient selection, conditioning regimen, graft manipulation and exploring maintenance or salvage therapy for treatment and prevention or treatment of residual disease activity. The significant TRM clearly means that all other treatment options with lesser toxicity should be exhausted before exposing patients to the risks of HDIT. Investigation of the immunological mechanisms of response and relapse following ASCT will provide important insights into the pathogenesis of the autoimmune disease itself. Analysis of the events occurring at relapse could be used as a model of early disease. In addition, the long-term reduction in disease activity seen in some cases following ASCT may be due to alterations in immunoregulation and the reinduction of tolerance. Exploration of these immunological mechanisms may provide important information that could be used to improve the technique of ASCT and/or develop new effective therapies in the future. The curative potential of allogeneic SCT has been supported by animal studies and anecdotal reports, with evidence for a graft-versus-autoimmune effect, but the attendant risks have meant that its use has been very limited to date. Recent years have seen the development of low intensity or miniallografting techniques, where a relatively low dose immunosuppressive regimen is used to permit tolerant mixed donor –host chimaerism, which subsequently can be used as a ‘platform for immunotherapy’ with donor lymphocyte infusions [108]. Although still complicated by graft-versus-host disease and delayed immune reconstitution, early data suggest reduced mortality and morbidity in both malignant and nonmalignant conditions, and the question of their use in patients with severe autoimmune diseases has arisen.

At present, the EBMT/EULAR working party is waiting for the analysis of the safety and efficacy of this approach in greater numbers of patients for ‘conventional’ indications before specific guidelines or recommendations can be made for autoimmune diseases. In the first instance at least, procedures are likely to be limited to the minority of younger patients with HLA-matched siblings, possibly in diseases or patients that have responded poorly to HDIT. Acknowledgements This research has been funded by the Arthritis Research Campaign, UK. References [1] Marmont A. Immune ablation followed by allogenic of autologous bone marrow transplantation: a new treatment for severe autoimmune diseases? Stem Cells 1994;12:125 – 35. [2] Brooks P, Atkinson K, Hamilton J. Stem cell transplantation in autoimmune disease. J Rheumatol 1995;22:1809 – 11. [3] Burt R. BMT for severe autoimmune diseases: an idea whose time has come. Oncology 1997;11:1001 – 17. [4] Wicks I, Cooley H, Szer J. Autologous haemopoietic stem cell transplantation: a possible cure for rheumatoid arthritis? Arthritis Rheum 1997;40:1005 – 11. [5] Snowden J, Brooks P, Biggs J. Haemopoietic stem cell transplantation for autoimmune diseases. Br J Haematol 1997; 99:9 – 22. [6] Sherer Y, Shoenfeld Y. Stem cells transplantation—a cure for autoimmune diseases. Lupus 1998;7:137 – 40. [7] Marmont AM. Stem cell transplantation for severe autoimmune diseases: progress and problems. Haematologica 1998; 83:733 – 43. [8] Baldwin JL, Storb R, Thomas ED, Mannik M. Bone marrow transplantation in patients with gold-induced marrow aplasia. Arthritis Rheum 1977;20:1043 – 8. [9] Snowden J, Kearney P, Kearney A, Cooley H, Grigg A, Jacobs P, et al. Long-term outcome of autoimmune disease following allogenic bone marrow transplantation. Arthritis Rheum 1998; 41:453 – 9. [10] McKendrey R, Huebsch L, Leclair B. Progression of rheumatoid arthritis following bone marrow transplantation. Arthritis Rheum 1996;39:1246 – 53. [11] Cooley HM, Snowden JA, Grigg AP, Wicks IP. Outcome of rheumatoid arthritis and psoriasis following autologous stem cell transplantation for haematological malignancy. Arthritis Rheum 1997;40:1712 – 5. [12] Euler H, Marmont A, Bacigalupo A, Fastenrath S, Dreger P, Hoffknecht P, et al. Early recurrence or persistence of autoimmune diseases after unmanipulated autologous stem cell transplantation. Blood 1996;88:3621 – 5.

S.J. Bingham et al. / International Immunopharmacology 2 (2002) 399–414 [13] Jantuen E, Myllykangas-Luosujarvi R, Kaipiainen-Seppanen T, Nousiainen T. Autologous stem cell transplantation in a lymphoma patient with a long history of ankylosing spondylitis. Rheumatology 2000;39(5):563 – 4. [14] Roychoudhury DF, Linker CA. Pure red cell aplasia complicating an ABO-compatible allogenic bone marrow transplantation, treated successfully with antithymocyte globulin. Bone Marrow Transplant 1995;16:471 – 2. [15] Snowden J, Patton WN, O’Donnell JL, Hannah EE, Hart DNJ. Prolonged remission of longstanding systemic lupus erythematosis after autologous bone marrow transplant for nonHodgkin’s lymphoma. Bone Marrow Transplant 1997;19: 1247 – 50. [16] Meloni G, Capria S, Vignetti M, Mandelli F, Moderna V. Blast crisis of chronic myelogenous leukaemia in long-lasting systemic lupus erythematosus: regression of both diseases after autologous bone marrow transplantation. Blood 1997;89:4659. [17] Rosler W, Manger B, Repp R, Kalden JR, Gramatzki M. Autologous PBSCT in a patient with lymphoma and Sjogren’s syndrome: complete remission without control of the autoimmune disease. Bone Marrow Transplant 1998;22(2): 211 – 3. [18] Jondeau K, Job-Deslandre C, Bouscary D, Khanlou N, Menkes CJ, Dreyfus F. Remission of nonerosive polyarthritis associated with Sjogren’s syndrome after autologous hemopoietic stem cell transplantation for lymphoma. J Rheumatol 1997;24(12):2466 – 8. [19] Ferraccioli G, Damato R, De Vita S, Fanin R, Damiani D, Baccarani M. Haemopoietic stem cell transplantation (HSCT) in a patients with Sjogren’s syndrome and lung malt lymphoma cured lymphoma not the autoimmune disease. Ann Rheum Dis 2001;60(2):174 – 6. [20] McAlister LD, Beatty PG, Rose J. Allogenic bone marrow transplantation for chronic myelogenous leukaemia in a patient with multiple sclerosis. Bone Marrow Transplant 1997;19(4):395 – 7. [21] Hentschke P, Fredrikson S, Lo¨nnqvist B, Aschan J, Ringden O, Ljungman P. Allogenic stem cell transplantation for chronic myelogenous leukaemia in two patients with multiple sclerosis. Bone Marrow Transplant 1998;60:S33. [22] Salzeman D, et al. Clinical remission of myasthenia gravis (MG) in a patient (PT) after high-dose therapy and autologous transplantation with CD34+ stem cells (SC). (abstract) Blood 1994;84(suppl. 1):206a. [23] Vento S, Cainelli F, Renzini C, Ghironzi G, Concia E. Resolution of autoimmune hepatitis after bone marrow transplantation. Lancet 1996;348:544 – 5. [24] Lopez-Cubero SO, Sullivan KM, McDonald GB. Course of Crohn’s disease after allogeneic marrow transplantation. Gastroenterology 1998;114:596 – 8. [25] Kashyap A, Forman S. Autologous bone marrow transplantation for non-Hodgkin’s lymphoma resulting in long-term remission of coincidental Crohn’s disease. Br J Haematol 1998;103:651 – 2. [26] Castro J, Bentch HL, Smith L, Kalter S, Bachier C, Meneghetti C, et al. Prolonged clinical remission in patients (pts)

[27]

[28]

[29]

[30]

[31]

[32]

[33]

[34]

[35]

[36] [37]

[38]

[39]

411

with inflammatory bowel disease (IBD) after high dose chemotherapy (HDC) and autologous blood stem cell transplantation (ABSCT). (Abstract) Blood 1996;88:133a. Lui-Yin JA, Jowit SN. Resolution of immune mediated diseases following allogenic bone marrow transplantation for leukaemia. Bone Marrow Transplant 1992;9:31 – 3. Demirer T, Celebi H, Arat M, Ustun C, Demirer S, Dilek I, et al. Autoimmune thrombocytopenia in a patient with small cell lung cancer developing after chemotherapy and resolving following autologous peripheral blood stem cell transplantation. Bone Marrow Transplant 1999;24(3):335 – 7. Jindra P, Koza V, Fiser J, Vozobulova V, Svojgrova M. Autologous CD34+ cells transplantation after FAMP treatment in a patient with CLL and persisting AIHA: complete remission of lymphoma with control of autoimmune complications. Bone Marrow Transplant 1999;24(2):215 – 7. Slavin S. Immunoregulation rather than immunosuppression for prevention and treatment of autoimmune disorders. Transplant Proc 1996;28:3021 – 2. Giralt S, Estey E, Albitar M, van Biesen K, Rondon G, Anderlini P, et al. Engraftment of allogeneic hematopoietic progenitor cells with purine analog-containing chemotherapy: harnessing graft-versus-leukemia without myeloablative therapy. Blood 1997;89:4531 – 6. Tyndal A, Gratwohl A. Blood and marrow stem cell transplants in autoimmune disease: a consensus report written on behalf of the European League Against Rheumatism (EULAR) and the European Group for Blood and Bone Marrow Transplantation (EBMT). Br J Rheumatol 1997;36:390 – 2. Tyndall A. Autologous haemopoietic stem cell transplantation for severe autoimmune disease with special reference to rheumatoid arthritis. J Rheumatol 2001;28(suppl. 64):5 – 7. Snowden JA, Nink V, Cooley M, Zaunders J, Keir M, Wright L, et al. Composition and function of peripheral blood stem and progenitor cell harvested from patient with severe active rheumatoid arthritis. Br J Haematol 1998;103(3):601 – 9. Snowden JA, Biggs JC, Milliken ST, Fuller A, Staniforth D, Passuello F, et al. A randomised, blinded, placebo-controlled, dose escalation study of the tolerability and efficacy of filgrastim for haemopoietic stem cell mobilization in patients with severe active rheumatoid arthritis. Bone Marrow Transplant 1998;22(11):1035 – 41. Joske DJL. Autologous bone-marrow transplantation for rheumatoid arthritis. Lancet 1997;350:337 – 8. McGonagle D, Rawstron A, Richards S, Isaacs J, Bird H, Jack A, et al. A phase I study to address the safety and efficacy of granulocyte colony-stimulating factor for the mobilization of haemopoietic progenitor cells in active rheumatoid arthritis. Arthritis Rheum 1997;40:1838 – 42. Openshaw H, Stuve O, Antel JP, Nash R, Lund BT, Weiner LP, et al. Multiple sclerosis flares associated with recombinant granulocyte colony-stimulating factor. Neurology 2000;54 (11):2147 – 50. Burt RK, Burns W, Scheuning F, Schroeder J, Pope R, Cohen B, et al. Mobilization of peripheral blood stem cells in patients with autoimmune disease. Blood 1999;94(suppl. 1): 330a.

412

S.J. Bingham et al. / International Immunopharmacology 2 (2002) 399–414

[40] Snowden JA, Biggs JC, Milliken ST, Fuller A, Brookes PM. A phase I/II dose escalation study of intensified cyclophosphamide and autologous blood stem cell rescue in severe active rheumatoid arthritis. Arthritis Rheum 1999;42(11): 2286 – 92. [41] Burt R, Georganas C, Shroeder J, Traynor A, Stefka J, Schuening F, et al. Autologous hemopoietic stem cell transplantation in refractory rheumatoid arthritis: sustained response in two of four patients. Arthritis Rheum 1999;42(11):2281 – 5. [42] Pavletic ZS, O’Dell JR, Pirruccello SJ, Ursick MM, Haire G, Sharp G, et al. Intensive immunoablation and autologous blood stem cell transplantation in patients with refractory rheumatoid arthritis: the University of Nebraska experience. J Rheumatol 2001;28(suppl. 64):13 – 20. [43] Durez P, Toungouz M, Schandene L, Lambermont M, Goldman M. Remission and immune reconstitution after T-celldepleted stem cell transplantation for rheumatoid arthritis. Lancet 1998;352:881. [44] Durez P, Ferster A, Poungouz M, Schandene L, Kentos A, Lambermont M, et al. Autologous T cell-depleted CD34+ peripheral blood stem cell transplantation in four patients with refractory rheumatoid arthritis and juvenile chronic arthritis. Arthritis Rheum 1999;42(suppl. 9):S77. [45] Bingham S, Morgan G, McGonagle D, Isaacs J, Snowden J, Emery P. Autologous stem cell transplantation for rheumatoid arthritis—interim report of six patients. J Rheumatol 2001;28(suppl. 64):13 – 20. [46] Verburg RJ, Kruize AA, van den Hoogen FHJ, Fibbe WE, Petersen EJ, Prejijers F, et al. High-dose chemotherapy and autologous stem cell transplantation in patients with rheumatoid arthritis: results of an open study to assess feasibility, safety and efficacy. Arthritis Rheum 2001;44(4):754 – 60. [47] McColl G, Kohsaka H, Wicks I. High-dose chemotherapy and syngeneic hemopoietic stem-cell transplantation for severe, seronegative rheumatoid arthritis. Ann Intern Med 1999;131(7):507 – 9. [48] Breban M, Dougados M, Picard F, Zompi S, Marolleau J, Bocaccio C, et al. Intensified-dose (4 g/m2) cyclophosphamide and granulocyte colony-stimulating factor administration for haemopoietic stem cell mobilization in refractory rheumatoid arthritis. Arthritis Rheum 1999;42(11):2275 – 80. [49] Burt R, Fassas A, Snowden J, van Laar J, Kozak T, Wulffraat N, et al. Collection of hemopoietic stem cells from patients with autoimmune diseases. BMT 2001;28:1 – 12. [50] Martini A, Maccario R, Ravelli A, Montagna D, Benedetti F, Bonetti F, et al. Marked and sustained improvement two years after autologous stem cell transplantation in a girl with systemic sclerosis. Arthritis Rheum 1999;42(4): 807 – 11. [51] Martini A, Maccario R, Ravelli A, Montagna D, De Benedetti F, Bonetti F, et al. Efficacy and safety of autologous peripheral blood stem cell transplantation in three children with systemic sclerosis and progressive pulmonary involvement. Arthritis Rheum 2000;43(suppl. 9):S323. [52] Van den Hoogen F, van Laar J, Schattenburg A, Fibbe F, Preijers F, Breedveld F, et al. High dose cyclophosphamide followed by autologous peripheral blood stem cell transplan-

[53]

[54]

[55]

[56]

[57]

[58]

[59]

[60]

[61]

[62]

[63]

[64]

[65]

[66]

tation for the treatment of systemic sclerosis. Arthritis Rheum 1999;42(suppl. 9):S169. Prentice HG, Lowdell MW, Macdonald I, Herbert L, Wilson H, Black C. High-dose chemotherapy plus T cell-depleted autologous stem cell transplantation for the treatment of systemic sclerosis. Br J Haematol 1997;(Suppl. 1):39. Furst DE, McSweeney P, Nash R, Holmberg L, Viganego F, Nelson L, et al. High-dose immunosuppressive therapy (HDIT) with autologous stem cell transplantation (SCT) for systemic sclerosis (SSc): results in the first 8 patients. Arthritis Rheum 2000;43(suppl. 9):S392. Bertz H, Peter HH, Tyndall A, Mertelsmann R, Finke J. Longterm follow-up after high dose cyclophosphamide and CD43+ selected aPBSCT for progressive systemic sclerosis (PSS). BMT 1999;43:S33 (Suppl.). Tamm M, Gratwohl A, Tichelli A, Perruchould A, Tyndall A. Autologous haemopoietic stem cell transplantation in a patient with severe pulmonary hypertension complicating connective tissue disease. Ann Rheum Dis 1996;55:779. Bingham S, Emery P, McGonagle D, Isaacs J, Griffiths B, Morgan G, et al. Leeds experience of stem cell transplantation for autoimmune disease. Ann Rheum Dis 1999;55:779. Arrieta H, Hernandez-Maraver M, Canales R, Merino A, Martinez J, Sevilla F, et al. Autologous CD34-selected peripheral blood stem cell transplantation in a young patient with severe systemic sclerosis. Bone Marrow Transplant 2000;25:S113, (Suppl.). Rosen O, Thiel A, Massenkeil G, Hiepe F, Haupl T, Radtke H, et al. Autologous stem cell transplantation in refractory autoimmune diseases after in vivo immunoablation and ex vivo depletion of mononuclear cells. Arthritis Res 2000;2: 327 – 36. Rosen O, Massenkeil G, Hiepe F, Pest S, Hauptmann S, Radtke H, et al. Cardiac death after autologous stem cell transplantation (ASCT) for treatment of systemic sclerosis (SSc): no evidence for cyclophosphamide-induced cadiomyopathy. Bone Marrow Transplant 2001;27(6):657 – 8. Binks M, Passweg J, Furst D, McSweeney PA, Sullivan K, Besenthal C, et al. Phase I/II trail of autologous stem cell transplantation in systemic sclerosis: procedure-related mortality and impact on skin disease. Ann Rheum Dis 2001;60: 577 – 84. Marmont AM, van Lint MT, Gualandi F, Bacigalupo A. Autologous marrow stem cell transplantation for severe systemic lupus erythematosus of long duration. Lupus 1997;6: 545 – 8. Traynor A, Schroeder J, Rosa M, Mujais S, Rosen S, Bowyer S, et al. Stem cell transplantation for resistant lupus. Arthritis Rheum 1999;42(9):S170. Trysberg E, Lindgren I, Tarkowski A. Autologous stem cell transplantation in a case of treatment-resistant central nervous system lupus. Ann Rheum Dis 2000;59(3):236 – 8. Andolina M, Rabusin M, Maximova N, Parco S, Lepore L, Candusso M, et al. Autologous blood and marrow cells transplantation in chronic GVHD and in autoimmune diseases. Bone Marrow Transplant 1998;21(Suppl. 1):51. Musso M, Porretto F, Crescimanno A, Bondi F, Polizzi V,

S.J. Bingham et al. / International Immunopharmacology 2 (2002) 399–414

[67]

[68]

[69]

[70]

[71]

[72]

[73]

[74]

[75]

[76]

[77]

[78]

Scalone R, et al. Autologous peripheral blood stem and progenitor (CD34+) cell transplantation for systemic lupus erythematosus complicated by Evans syndrome. Lupus 1998;7: 492 – 4. Fouillard L, Gorin NC, Laporte JPh, Leon A, Brantus JF, Miossec P. Control of severe systemic lupus erythematosus after high dose immunosuppressive therapy and transplantation of CD34+-purified autologous stem cells from peripheral blood. Lupus 1999;8:320 – 3. Fassas A, Anagnostopoulos A, Giannaki C, Vadikolia C, Zambouli D, Papaioannou G. Autologous blood stem cell therapy for autoimmune pancytopenia due to systemic lupus erythematosus. Bone Marrow Transplant 1998;21(Suppl. 1):53. Shaughnessy PJ, Ririe DW, Ornstein DL, Kissack B, Bickford DJ, Molina R, et al. Graft-failure in a patient with systemic lupus erythematosus (SLE) treated with high dose immunosuppression and autologous stem cell rescue. Bone Marrow Transplant 2001;27(2):221 – 4. Wulffraat N, Sanders EAM, Kamphuis SM, Rijkers GT, Kuis W, Lilien M, et al. Prolonged remission without treatment after autologous stem cell transplantation for refractory childhood systemic lupus erythematosus. Arthritis Rheum 2001;44(3):728 – 34. Wulffraat N, van Royen A, Biering M, Vossen J, Kuis W. Autologous haemopoietic stem cell transplantation in four patients with refractory juvenile chronic arthritis. Lancet 1999; 353:550 – 3. Vleiger AM, Brinkman D, Quartier P, Prieur A, van Cate R, Bierings M, et al. Infection-associated MAS in 3 patients receiving ASCT for refractory juvenile chronic arthritis. Bone Marrow Transplant 2000;25:S81 (Suppl.). Nakagawa R, Kawano Y, Yoshimura E, Suzuya H, Watanabe T, Kanamaru S, et al. Intense immunosuppression followed by purified blood CD34+ cell autografting in a patient with refractory juvenile rheumatoid arthritis. Bone Marrow Transplant 2001;27(3):333 – 6. Baron F, Ribbens C, Kaye O, Fillet G, Malaise M, Beguin Y. Effective treatment of Jo-1-associated polymyositis with Tcell-depleted autologous peripheral blood stem cell transplantation. Br J Haematol 2000;110:339 – 42. Bingham S, Griffiths B, McGonagle D, Snowden JA, Morgan G, Emery P. Autologous stem cell transplantation for rapidly progressive Jo-1-positive polymyositis with longterm follow-up. Br J Haematol 2001;113:840 – 1. Myllykangas-Luosujarvi R, Jantunen E, Kaipiainen-Seppanen O, Mahlamaki E, Nousiainen T. Autologous stem cell transplantation in patients with severe rheumatic diseases: a pilot study. Blood 1999:S35 (Suppl.). Hensel M, Schlenk A, Fiehn C, Breitbart AD, Ho AD. First experience with a new protocol for haematopoietic stem cell mobilization (MOB) and transplantation in patients (pts) with autoimmune diseases (AD). Arthritis Rheum 2000;43(9): S123. Jeffrey R, Murray K, Patel A, Varsani H, Linch D, Woo P, et al. Immune reconstitution post autologous stem cell transplantation (ASCT) for paediatric vasculitis and resulting

[79]

[80]

[81]

[82]

[83]

[84]

[85]

[86]

[87]

[88]

[89]

[90]

[91]

413

changes in autoimmune disease profile. Arthritis Rheum 2000;43(9):S381. Lanza F, Dominici M, Govoni M, Moretti S, Campioni D, Corte RL, et al. Prolonged remission of refractory adult-onset Still’s disease following CD34-selected autologous peripheral blood stem cell transplantation. Bone Marrow Transplant 2000;25(12):1307 – 10. Fassas A, Anagnostopoulos A, Kazis A, Kapinas K, Sakellari I, Kimiskidis V, et al. Autologous stem cell transplantation in progressive multiple sclerosis—an interim analysis on efficacy. J Clin Immunol 2000;20(1):24 – 30. Burt R, Burns WH, Cohen B, Kalin KH, Lobeck L, Schroeder J, et al. T cell-depleted autologous hematopoietic stem cell transplantation in patients with severe autoimmune diseases. Blood 1998;20:324a (Suppl.). Mancardi G, Saccardi R, Filippi M, Gualandi F, Murialdo A, Inglese M, et al. Autologous hematopoietic stem cell transplantation suppresses Gd-enhanced MRI activity in MS. Neurology 2001 July 10;57(1):62 – 8. Saiz A, Carreras E, Berenguer J, Yague J, Martinez C, Marin P, et al. MRI and CSF oligoclonal bands after autologous hematopoietic stem cell transplantation in MS. Neurology 2001;56(8):1084 – 9. Openshaw H, Lund BT, Kashap A, Atkinson R, Sniecinski I, Weiner LP, et al. Peripheral blood stem cell transplantation in multiple sclerosis with busulfan and cyclophosphamide conditioning: report of toxicity and immunological monitoring. Biol Blood Marrow Transplant 2000;6:563 – 75. Carreras E, Saiz A, Graus F, Marin P, Urbano-Ispizusa A, Mercader JM, et al. Autologous CD34+-selected peripheral stem cell transplantation (ASCT/CD34+) for multiple sclerosis (MS). Bone Marrow Transplant 1999;6:S33 (Suppl.). Kozak T, Havrdova E, Pit’ha E, Gregora E, Pytlik R, Maaloufova P, et al. High dose immunosuppressive therapy with PBSC support in the treatment of poor risk multiple sclerosis. Bone Marrow Transplant 2000;25(5):525 – 31. Saccardi R, Mancardi G, Bacigalupo F, Gualandi A, Murialdo L, Lombardini F, et al. Autologous peripheral blood progenitor cell transplantation in multiple sclerosis: a phase I/II clinical trial. Bone Marrow Transplant 2000;25:S113 (Suppl.). Comi G, Kappos L, Clanet M, Ebers G, Fassas A, Fazekas F, et al. Guidelines for autologous blood and marrow stem cell transplantation in multiple sclerosis: a consensus report written on behalf of the European Group for Blood and Marrow Transplantation and the European Charcot Foundation: BMTMS study group. J Neurol 2000;247(5):376 – 82. Marmont AM. Immune ablation and stem cell transplantation for severe Evans syndrome and refractory thrombocytopenic pupura. Bone Marrow Transplant 1999;23(12):1215 – 6. Lim S, Kell J, Al-Sabah A, Bashi W, Bailey-Wood R. Peripheral blood stem cell transplantation for refractory autoimmune thrombocytopenic purpura. Lancet 1997;349:475. Marmont AM, van Lint MT, Occhini D, Lamparelli T, Bacigalupo A. Failure of autologous stem cell transplantation in refractory thrombocytopenic purpura. Bone Marrow Transplant 1998;22:827 – 8.

414

S.J. Bingham et al. / International Immunopharmacology 2 (2002) 399–414

[92] Skoda R, Tichelli A, Tyndall A, Hoffmann T, Gillessen S, Gratwohl A. Autologous peripheral bool stem cell transplantation in a patient with chronic autoimmune thrombocytopenia. Br J Haematol 1997;99:56 – 7. [93] Raetz E, Beatty PG, Adams RH. Treatment of severe Evans syndrome with an allogeneic cord blood transplant. Bone Marrow Transplant 1997;20(5):427 – 9. [94] Hayag MV, Cohen JA, Kerdel FA. Immunoablative high-dose cyclophosphamide without stem cell rescue in a patient with pemphigus vulgaris. J Am Acad Dermatol 2000;43(6): 1065 – 9. [95] Brodskey RA, Sensenbrenner LL, Jones RJ. Complete remission in severe aplastic anaemia after high dose cyclophosphamide without bone marrow transplantation. Blood 1996;87:491 – 4. [96] Brodskey RA, Petri M, Smith BD, Seifter EJ, Spivak JL, Styler M, et al. Immunoablative high dose cyclophosphamide without stem cell rescue for refractory, severe autoimmune disease. Ann Intern Med 1998;129:1031 – 5. [97] Petri M, Jones A, Brodskey RA. High-dose immunoablative cyclophosphamide in SLE. Arthritis Rheum 1999;42:S170 (Suppl.). [98] Pile K, Rischueller M, Jaksic W, Champion G, McNeil J, Wickham N. High dose chemotherapy without autologous stem cell reinfusion in the treatment of RA. Arthritis Rheum 2000;43(9):S291. [99] Karussis DM, Slavin S, Ben-Nun A, Ovadia H, VourkaKarussis U, Lehmann D, et al. Chronic-relapsing experimental autoimmune encephalomyelitis (CR-EAE): treatment and induction of tolerance, with high dose cyclophosphamide followed by syngeneic bone marrow transplantation. J Neuroimmunol 1992;39:201 – 10.

[100] Burt RK, Burns W, Ruvolo P, Fischer A, Shiao C, Guimaraes A, et al. Syngeneic bone marrow transplantation eliminates V beta 8.2 T lymphocytes from the spinal cord of Lewis rats with experimental allergic encephalomyelitis. J Neurosci Res 1995;41:526 – 31. [101] Sykes M, Lee LA, Sachs DH. Xenograft tolerance. Immunol Rev 1994;141:245 – 76. [102] Oldstone MBA. Molecular mimicry and autoimmune diseases. Cell 1987;50:819 – 20. [103] Shoenfeld Y. Common infections, idiotypic dysregulation, autoantibody spread and induction of autoimmune diseases. J Autoimmun 1996;9:235 – 9. [104] Mills KC, Gross TG, Varney ML, Heimann DG, Reed EC, Kessinger A, et al. Immunologic phenotype and function in bone marrow, blood stem cells and umbilical cord blood. Bone Marrow Transplant 1996;18:53 – 61. [105] Atkinson K. Reconstitution of the haemopoietic and immune system after marrow transplantation. Bone Marrow Transplant 1990;5:209 – 26. [106] Olivieri A, Brunori M, Offidani M, et al. A detailed study on immune recovery in 50 patients autotransplanted with blood progenitor cells. (abstract) Exp Hematol 1996;24:1088. [107] Hakim FT, Cepada R, Kaimei S, et al. Constraints on CD4+ recovery postchemotherapy in adults: thymic insufficiency and apoptotic decline of expanded peripheral CD4 cells. Blood 1997;90:3789 – 98. [108] Slavin S, Nagler A, Naparstek E, Kapelushnik Y, Aker M, Cividalli G, et al. Non-myeloablative stem cell transplantation and cell therapy as an alternative to conventional bone marrow transplantation with lethal cytoreduction for the treatment of malignant and non-malignant haematological diseases. Blood 1998;91:756 – 63.