|
|||||||||
|
|
|
|
|
|
|
|
|
|
|
Blood, Vol. 92 No. 10 (November 15), 1998:
pp. 3505-3514
RAPID COMMUNICATION
By
From the Departments of Medicine, Neurology, Nephrology, and
Rheumatology, Division of Hematology/Oncology & Lurie Comprehensive
Cancer Center, Northwestern University Medical School and Robert H. Lurie Cancer Center, Chicago, IL; Rush Presbyterian St Luke's Medical
Center, Multiple Sclerosis Center and Department of Neurology, Chicago,
IL; and the Departments of Neurology and Medicine, Division of
Hematology/Oncology, Medical College of Wisconsin, Milwaukee,
WI.
Multiple sclerosis, systemic lupus erythematosus, and rheumatoid
arthritis are immune-mediated diseases that are responsive to
suppression or modulation of the immune system. For patients with
severe disease, immunosuppression may be intensified to the point of
myelosuppression or hematopoietic ablation. Hematopoiesis and immunity
may then be rapidly reconstituted by reinfusion of CD34+
progenitor cells. In 10 patients with these autoimmune diseases, autologous hematopoietic stem cells were collected from bone marrow or
mobilized from peripheral blood with either granulocyte
colony-stimulating factor (G-CSF) or cyclophosphamide and G-CSF. Stem
cells were enriched ex vivo using CD34+ selection and
reinfused after either myelosuppressive conditioning with
cyclophosphamide (200 mg/kg), methylprednisolone (4 g) and antithymocyte globulin (ATG; 90 mg/kg) or myeloablative conditioning with total body irradiation (1,200 cGy), methylprednisolone (4 g), and
cyclophosphamide (120 mg/kg). Six patients with multiple sclerosis, 2 with systemic lupus erythematosus, and 2 with rheumatoid arthritis have
undergone hematopoietic stem cell transplantation. Mean time to
engraftment of an absolute neutrophil count greater than 500/µL (0.5 × 109/L) and a nontransfused platelet count greater than
20,000/µL (20 × 109/L) occurred on day 10 and 14, respectively. Regimen-related nonhematopoietic toxicity was minimal.
All patients improved and/or had stabilization of disease with
a follow-up of 5 to 17 months (median, 11 months). We conclude that
intense immunosuppressive conditioning and autologous T-cell-depleted
hematopoietic transplantation was safely used to treat these 10 patients with severe autoimmune disease. Although durability of
response is as yet unknown, all patients have demonstrated stabilization or improvement.
INTENSIVE immunosuppression and
hematopoietic stem cell transplantation has been proposed or initiated
as a therapy for patients with severe autoimmune diseases (SADS) who
have poor prognostic features.1-11 The rationale is to
maximally suppress or ablate the immune system and then rescue the
patient from prolonged cytopenias or hematopoietic failure by infusing
either autologous or allogeneic hematopoietic progenitor cells
(CD34+ cells). This approach is supported by hematopoietic
stem cell transplantation in animal autoimmune disorders and in
patients undergoing transplantation for a hematologic disease who also had a coincidental autoimmune disease. Animal autoimmune diseases may
occur spontaneously or be induced either by immunization with self-peptides or adoptive transfer of disease-initiating lymphocytes. A
spontaneous onset lupus-like illness occurs in Murthy Roth Lab lymphoproliferative (MRL/lpr) mice and New Zealand Black/New Zealand White (B/W) mice.12,13 In MRL/lpr and B/W mice, an
allogeneic transplant from a nonsusceptible strain is required to cure
disease.12,13 Alternatively, disease can be transferred
from susceptible to nonsusceptible mice after bone marrow
transplantation. In MRL/lpr mice, a single gene defect in Fas
expression, a protein that signals for apoptosis, results in a
lymphoproliferative response with lupus-like features.14,15
Therefore, it appears in these animal models that spontaneous-onset
autoimmune disease may arise from a hematopoietic stem cell defect
predisposing to immune dysregulation.
Induced autoimmune diseases require manipulation of a normal immune
system (ie, immunization) to break self-tolerance. Why a potentially
self-reactive repertoire exists is unknown, but environmental
influences are necessary to break tolerance. Experimental autoimmune
encephalomyelitis (EAE) is an induced animal autoimmune disease that
mimics multiple sclerosis (MS). EAE may be cured by allogeneic,
syngeneic, or autologous bone marrow transplantation,16-20 although the relapse rate is higher after an autologous or syngeneic transplant. In animal autoimmune disorders, genetically preordained diseases require an allogeneic transplant from a nonsusceptible strain
for cure, whereas environmentally induced disease may be cured with
either allogeneic or autologous transplantation.
Patients with aplastic anemia, leukemia, or lymphoma and a coincidental
autoimmune disease such as rheumatoid arthritis (RA), scleroderma,
Crohn's disease, or MS have been treated by hematopoietic stem cell
transplantation for their hematologic disorder.21-29 In
most reported cases this has also resulted in subsequent remission of
their autoimmune disease. Although the number of anecdotal case reports
is small, duration of remission appears better with an allogeneic graft
compared with an unmanipulated autologous graft. Virtually no
information is available on lymphocyte-depleted autologous
transplantation in patients with autoimmune diseases. Because of the
higher expected morbidity of allogeneic transplantation, consensus
conferences have recommended initiating this approach with autologous
stem cells.3
Patient Selection
MS.
Patients must have clinically definite MS using Poser criteria
supported by characteristic magnetic resonance imaging
(MRI) changes and absence of serologic or clinical signs
of other autoimmune diseases.30 In addition, the patients
must fulfill both of the following criteria: (1) failure to stabilize
active clinical progression with intravenous methylprednisolone
administered for a minimum of 3 days at 1 g per day; and (2) a Kurtzke
extended disability status scale (EDSS)31 of 5.0 to 8.0, with an increase in the EDSS by 1.5 points within the preceding 12 months in patients with an EDSS of 5.5 or less at the start of the
evaluation period or an increase of 1 point in patients with an EDSS of
6 or greater at the start of the evaluation period. The increased EDSS
must be sustained for at least 3 months before enrollment. Final
eligibility is determined by a selection and safety monitoring
committee consisting of Drs Jerry Wolinsky (University of Texas,
Houston, TX) and Henry McFarland (National Institutes of Health,
Bethesda, MD).
SLE.
Patients may be enrolled if they fulfill any one of the following
criteria: (1) biopsy-proven World Health Organization (WHO) class III
or IV glomerulonephritis that has failed to respond to NIH short course
cyclophosphamide therapy32 (500 to 1,000 mg/m2
monthly for at least 6 months), with treatment failure defined as a
failure of serum creatinine to return to normal or pre-exacerbation level; (2) vasculitis and/or immune complex deposition causing end organ signs or symptoms, eg, cerebritis, transverse myelitis, pulmonary hemorrhage, or cardiac failure, not controlled with corticosteroids and cyclophosphamide; (3) transfusion-dependent cytopenias that are immune-mediated and not controlled with danazol, prednisone, and an alkylating agent (cyclophosphamide or vincristine); or (4) catastrophic antiphospholipid syndrome, which is defined as an
antiphospholipid titer greater than 5 standard deviations above the
mean and two or more antiphospholipid related manifestations, including
either cytopenias or vascular thrombosis that failed to respond to
anticoagulant therapy.
RA.
Patients must fulfill all of the following criteria: (1) an established
clinical diagnosis of RA by the American College of Rheumatology
criteria33; (2) a positive rheumatoid factor; and (3)
failure of at least two disease-modifying agents (methotrexate, gold,
penicillamine, and hydroxychloroquine), where failure is defined as at
least six swollen joints and either 30 or more involved (swelling,
tenderness, deformity, pain on motion, and decreased motion) joints or
answering less than 75% of the Activities of Daily Living (ADL) Health
Assessments Questionnaire "without any difficulty."34
Hematopoietic Stem Cell (HSC) Procurement
Conditioning Regimen For MS, cyclophosphamide (120 mg/kg) in divided doses of 60 mg/kg/d was administered intravenously over 2 hours on days 6 and 5
and total body irradiation (TBI) was administered as 1,200 cGy divided
150 cGy twice a day on days 4, 3, 2,
and 1 in the AP/PA position with 50% lung and 30% kidney and
right lobe of the liver transmission blocks. One gram of
methylprednisolone was administered intravenously on days 4,
3, 2, and 1.
Definition of Disease Status Outcome was based on assessments before transplant and at 1, 2, 3, and 6 months and yearly after transplantation.MS. Improvement was defined as a decrease in the Kurtzke EDSS31 by at least 1 point or increase in the Scripps NRS35 by at least 10 points. Deterioration was defined as an increase in the Kurtzke EDSS by at least 1 point or decrease in the Scripps NRS by at least 10 points. Stabilization of active disease was defined as absence of any new or progressive neurologic deficits and no significant change in the EDSS or NRS scores. MRI was performed at approximately the same intervals to monitor occurrence of new lesions and activity of lesions as determined by gadolinium enhancement. SLE. Outcome was based on serology (C3, C4, anti-Ds-DNA, ANA, Sm, anti-SSA, anti-SS-B, and lupus anticoagulant), lupus disease activity index (SLEDAI),36 and response of pretransplant abnormalities in involved organ systems (eg, serum creatinine; 24-hour urine protein and creatinine clearance in nephritis; left ventricular ejection fraction in myocarditis; and chest radiograph and pulmonary function tests in pneumonitis). Improvement was defined as a 50% improvement in any baseline parameter with no deterioration in any objective parameter. RA. Assessment parameters were tender joint count, swollen joint count, patient's assessment of pain, patient's global assessment of disease, physician's global assessment, Health Assessment Questionnaire Activities of Daily Living (ADL), and acute-phase reactant value. Definition of improvement was greater than 20% improvement in both tender and swollen joint count and 20% improvement in at least three of the other five assessment parameters.37 Criteria for complete remission requires that five or more of the following be fulfilled for at least 2 consecutive months: (1) duration of morning stiffness not exceeding 15 minutes, (2) no fatigue, (3) no joint pain (by history), (4) no joint tenderness or pain on motion, (5) no soft tissue swelling in joints or tendon sheaths, and (6) erthyrocyte sedimentation rate less than 30 mm/h for a female or 20 mm/h for a male.38 Immunologic Assays Pretransplant and posttransplant, two- and three-color immunophenotyping was performed on EDTA anticoagulated whole blood. The infused stem cell products were assessed by three-color immunophenotyping. The panel of fluorescein isothiocyanate (FITC), phycoerythrin (PE), PE-cyanin 5 (PE-Cy5), or PerCp fluorochromes included antibodies to CD45 and CD34 (Becton Dickinson, Mountain View, CA), and CD3, CD4, CD8, CD29, CD45RA, CD19, CD16, and CD56 (Coulter Cytometry; Coulter, Hialeah, FL).Supportive Care Patients were treated on a hepa-filtered hematology/oncology floor. A low microbial diet, fluconazole (400 mg/d oral or intravenous), and valacyclovir (500 mg TID oral or intravenous) were started upon admission and discontinued when the absolute neutrophil count (ANC) rebounded to 500/µL. Oral ciprofloxacin (750 mg orally BID) was started upon admission and switched to intravenous piperacillin/tazobactam or cefipime when the ANC fell below 500/µL. Subcutaneous G-CSF (5 µg/kg) was started the day of hematopoietic stem cell infusion and continued until the ANC was greater than 1,000/µL for 3 consecutive days. For the first 6 months after transplantation, patients were treated with either daily oral fluconazole or itraconazole and either Bactrim DS once orally three times a week or, for patients with lupus, aerosolized pentamidine (300 mg) monthly.
Hematopoietic Stem Cell Collection In general, one to five daily 10 to 20 L apheresis were required to obtain greater than 2.0 × 106 CD34+ cells/kg after lymphocyte depletion. In 3 patients with MS, apheresis was used to supplement the bone marrow harvests (Table 1). Positive selection for CD34+ stem cells resulted in a median 2.3 log depletion of T (CD3+) and B (CD19+) cells.
Toxicity Nonhematologic toxicity was limited to grade 0-1 for the gastrointestinal system (nausea, vomiting, and diarrhea) according to NCI common toxicity criteria (Table 2). Median time to an absolute neutrophil count greater than 500/µL (0.5 × 109/L) and platelet count greater than 20,000/µL (20 × 109/L) occurred on day 10 and 14, respectively. The median time to hospital discharge was day 14 after transplant. Five patients had positive cultures from either stool (candida and clostridium), blood (staphylococcus), or percutaneous intravenous central catheter (streptococcus) during the period of neutropenia. After engraftment, no posttransplant opportunistic infections have occurred, with the exception of a single case of dermatomal varicella zoster occurring 6 months after transplantation.
MS. Pretransplant G-CSF was well tolerated without exacerbation of neurologic symptoms. Transient elevation of hepatic transaminases (5× normal) occurred in 2 patients while receiving G-CSF for stem cell mobilization. These values normalized within 7 days without intervention. Patients with MS tolerated chemotherapy, TBI, and G-CSF without neurologic deterioration or exacerbation. SLE. The first patient with lupus started transplantation while in acute renal failure with a creatinine level of 5.0 mg/dL. In this patient, dialysis was initiated before starting the conditioning regimen. High-dose chemotherapy was associated with a cell-lysis effect, acid base and electrolyte disorders, and volume disturbances. The second patient underwent transplant for recurrent alveolar hemorrhage refractory to corticosteroids and cyclophosphamide. Before starting transplantation, she required supplemental face mask oxygen. With the exception of volume and electrolyte disturbances, organ function generally stabilized or began to improve during conditioning or shortly after onset of neutropenia. RA. In both patients, conditioning was well tolerated without any pulmonary, renal, cardiac, or hepatic dysfunction. However, 1 patient had an immediate wheel and flare response to the subcutaneous test dose of ATG. After desensitization, full-dose ATG was administered by continuous intravenous infusion for 24 hours and then discontinued without administration over the last 48 hours due to urticaria. Clinical Outcome MS. All 6 patients had rapidly progressive disease despite maximal immunosuppressive therapy during the year before transplant. Since transplantation, disease has not progressed despite stopping all immunosuppressive and immune modulating medications. Posttransplant follow-up ranges from 5 to 17 months, with a median of 11 months, and 3 patients are greater than 1 year from transplant. All patients have experienced subjective and objective neurologic improvements (Table 3), but the Kurtzke EDSS remains unchanged due to its dependence in the upper range on lower extremity motor function for scoring. In contrast, the Scripps NRS, which includes more emphasis on upper extremity function, incontinence, and cognitive ability, has demonstrated a greater than 10 point improvement in 3 patients. Improvement in the NRS did not begin until several months after transplantation. The 3 patients whose NRS improved by more than 10 points had gadolinium enhancement on their pretransplant MRI and had lower EDSS scores (6.0 to 7.5). In contrast, 2 of the 3 patients who had stabilization of disease but no significant improvement did not have pretransplant gadolinium enhancement and higher pretransplant EDSS scores (8.0 to 8.5). In all 6 patients, MRI showed no new or enhancing lesions after transplantation.
SLE. Both patients have had no evidence of active disease since transplantation (Table 4). The first patient, a 24-year-old white woman, was diagnosed with SLE at 11 years of age. Her C3, C4, ANA, and anti-ds DNA have never been normal, even during clinical remissions. She was treated at various times with plasmapheresis, corticosteroids, pulse cyclophosphamide, hydroxychloroquine, methotrexate, and azathioprine, none of which allowed steroid tapering to less than 20 mg/d. At transplantation, she exhibited active lupus manifested by a malar rash, arthralgias, hematuria, diffuse abdominal pain, ascites, and a large pericardial effusion. Renal function was rapidly decreasing, with a serum creatinine level of 5.0 mg/dL (398 µmol/L), red blood cell (RBC) casts in the urine, a 24-hour urine protein level of 3.8 g, and biopsy-proven WHO class IV glomerulonephritis. Pancytopenia was present and serology and complement were abnormal (Table 4). Over the 12 months since transplant, the malar rash, arthralgias, pleural and pericardial effusions, and cytopenias have resolved. Renal function has stabilized at a creatinine level of 1.9 mg/dL and 24-hour urine protein level of 0.2 g. For the first time since disease onset 13 years ago, complement components (C3, C4) and antinuclear antibodies are normal with the patient off all immunosuppressive medications, including corticosteroids.
RA. The first patient has met the 50% response criteria for improvement (Table 5). She was a 46-year-old woman diagnosed with RA 7 years before transplantatiion. She was treated with nonsteroidal anti-inflammatory drugs, hydroxychloroquine, cyclosporine, gold, methotrexate, dapsone, sulfasalazine, minocycline, intra-articular corticosteroids, and oral prednisone at 10 to 15 mg/d for 5 years. At the time of transplantation, she had 41 tender joints and 27 swollen joints and was unable to answer any of 20 health assessment questionnaire parameters "without any difficulty." Since transplantation, the swollen and tender joint counts have been, respectively, 0 and 3 at 1 month, 4 and 7 at 3 months, 3 and 3 at 6 months, and 2 and 4 at 12 months. By 6 months, the patient's medications have been decreased to 3 mg/d of prednisone and 200 mg of hydroxychloroquine twice a day. By 8 months, corticosteroids were discontinued. Health assessment questionnaire parameters have improved with the patient answering "without any difficulty" to 14 of 20 questions at 1 month, 16 of 20 at 3 months, 17 of 20 at 6 months, and 16 of 20 at 12 months. Patient and physician assessment of disease has improved 70% and 40%, respectively. Rheumatoid factor became negative at 1 month but returned to low level positive at 3 months. Sedimentation rate, which was elevated before transplant, has remained normal for the 12 months since transplantation.
Immune Reconstitution Patients had markedly reduced numbers of CD4+ cells during the first 12 months posttransplantation and all had inverted CD4/CD8 ratios (Fig 1). CD4+ cells were almost exclusively CD45RA early posttransplantation. The number of
CD45RA+ (naive) T cells gradually increased after 6 months.
Early posttransplantation, CD4+ T cells persistently
coexpressed CD29, a marker for the helper-inducer subset. The
percentage of cells that are CD56+ (NK) increased for the
first 6 posttransplant months, returning thereafter to normal.
CD19+ (B) cells reached the normal range by 6 months.
These data indicate the safety and short-term benefit of hematopoietic stem cell transplantation for patients with severe manifestations of autoimmune disease. Although these results suggest a benefit from intense immunosuppressive therapy, it is unclear if a transplant or intense but nonablative immunosuppressive regimen is sufficient. Nevertheless, all patients responded to treatment with either stabilization of disease or improvement. The 6 patients with MS have remained off immunosuppressive medications since transplantation. Because the Kurtzke EDSS is heavily weighted by ambulation, some improvement may not be reflected in the score. Subtle improvements have occurred in most patients, including improved cognition, decreased incontinence, improved speech, correction of deviated eye gaze, less fatigue, and in 1 patient the newly reacquired ability to swim. MRIs also demonstrated absence of disease progression with no new lesions posttransplantation. Therefore, despite a rapid progression of neurologic impairment in the year preceding transplant and despite discontinuation of immunosuppression after transplantation, disease has improved or stabilized without new symptoms, signs, or MRI findings. In a report by Fassas et al,5 the Kurtzke EDSS improved after autologous hematopoietic stem cell transplantation using a non-radiation-containing chemotherapy regimen. Ex vivo lymphocyte purging was not performed, but ATG was administered in an attempt to obtain postinfusion in vivo purging. They also transplanted patients with less severe disease and a lower median EDSS. The pathophysiology of progressive MS is probably a spectrum with both active inflammatory and chronic degenerative components. Aiming for transplant during active disease as evidenced by gadolinium enhancement on MRI may result in greater functional improvement. Four patients had small volume gadolinium enhancement on pretransplant MRI. Three of these patients improved with more than a 10-point NRS increase. The 2 patients without pretransplant MRI enhancement had stabilization of disease for more than 1 year but no significant improvement in the NRS or EDSS.
The authors acknowledge the nursing staff and support from Northwestern Memorial Hospital and the Froedtert Memorial Lutheran Hospital.
Submitted May 11, 1998;
accepted August 12, 1998.
Address reprint requests to Richard K. Burt, MD, Northwestern Memorial Hospital, Wesley Pavilion, Room 1456, 250 E Superior, Chicago, IL 60611.
1. Marmont AM, van Bekkum DW: Stem cell transplantation for severe autoimmune diseases: New proposals but still unanswered questions. Bone Marrow Transplant 16:497, 1995[Medline] [Order article via Infotrieve] 2. Burt RK, Burns W, Hess A: Bone marrow transplantation for multiple sclerosis. Bone Marrow Transplant 16:1, 1995[Medline] [Order article via Infotrieve] 3. Marmont AM, Tyndall A, Gratwohl A, Vischer T: Hematopoietic precursor stem cell transplantation for autoimmune diseases. Lancet 345:978, 1995[Medline] [Order article via Infotrieve] 4. Burt RK: Bone marrow transplantation for severe autoimmune diseases (SADS): An idea whose time has come. Oncology 11:1001, 1997[Medline] [Order article via Infotrieve] 5. Fassas A, Annagnostopoulos, Kazis A, Kapinas K, Sakellari I, Kimiskidis V, Tsompanakou A: Peripheral blood stem cell transplantation in the treatment of progressive multiple sclerosis: First results of a pilot study. Bone Marrow Transplant 20:631, 1997[Medline] [Order article via Infotrieve] 6. Burt RK, Traynor AE, Cohen B, Karlin KH, Davis FA, Stefoski D, Terry C, Lobeck L, Russell EJ, Goolsby C, Rosen S, Gordon LI, Keever-Taylor C, Burns WH: T cell depleted autologous hematopoietic stem cell transplantation for multiple sclerosis: Report on the first three patients. Bone Marrow Transplant 21:537, 1998[Medline] [Order article via Infotrieve] 7. Joske DJL: Autologous bone-marrow transplantation for rheumatoid arthritis (letter). Lancet 350:337, 1997[Medline] [Order article via Infotrieve]
8.
Burt RK, Traynor AE, Ramsey-Goldman R:
Hematopoietic stem-cell transplantation for systemic lupus erythematosus (letter).
N Engl J Med
337:1777, 1997 9. Burt RK, Bums WH, Miller SD: Bone marrow transplantation for multiple sclerosis: Returning to Pandora's box. Immunol Today 18:559, 1997[Medline] [Order article via Infotrieve] 10. Tyndall A, Black C, Finke J, Winkler J, Mertlesmann R, Peter HH, Gratwohl A: Treatment of systemic sclerosis with autologous hematopoietic stem cell transplantation (letter). Lancet 349:254, 1997[Medline] [Order article via Infotrieve] 11. Krance R, Brenner M: BMT beats autoimmune disease. Nat Med 4:153, 1998[Medline] [Order article via Infotrieve]
12.
Ikehara S, Good RA, Nakamura T, Sekita K, Inoue S, Do MM, Muso E, Ogawa K, Hamashima Y:
Rationale for bone marrow transplantation in the treatment of autoimmune diseases.
Proc Natl Acad Sci USA
82:2483, 1985
13.
Ikehara S, Yasumizu R, Inaba M, Izui S, Hayakawa K, Sekita K, Toji J, Sugiura K, Iwai H, Nakamura T:
Long-term observations of autoimmune-prone mice treated for autoimmune disease by allogeneic bone marrow transplantation.
Proc Natl Acad Sci USA
86:3306, 1989 14. Cohen PL, Eisenberg RA: The lpr and gld genes in systemic autoimmunity: Life and death in the Fas lane. Immunol Today 13:427, 1992[Medline] [Order article via Infotrieve]
15.
Drappa J, Brot N, Elkon KB:
The Fas protein is expressed at high levels on double positive thymocytes and activated mature T cells in normal but not MRL/lpr mice.
Proc Natl Acad Sci USA
90:10340, 1993 16. Karussis DM, Vaurka-Karussis U, Lehmann D, Oradia H, Mizrachi-Koll R, Ben-Nun A, Abramsky O, Slavin S: Prevention and reversal of adoptively transferred, chronic relapsing experimental autoimmune encephalomyelitis with a single high dose cytoreductive treatment followed by syngeneic bone marrow transplantation. J Clin Invest 765, 1993 17. van Gelder M, Kinwel-Bohre EPM, van Bekkum DW: Treatment of experimental allergic encephalomyelitis in rats with total body irradiation and syngeneic BMT. Bone Marrow Transplant 11:233, 1993[Medline] [Order article via Infotrieve] 18. van Gelder M, van Bekkum DW: Treatment of relapsing experimental autoimmune encephalomyelitis in rats with allogeneic bone marrow transplantation from a resistant strain. Bone Marrow Transplant 16:343, 1995[Medline] [Order article via Infotrieve]
19.
Burt RK, Burns W, Rurulu P, Fischer A, Shiuo C, Guimaraes A, Barrett J, Hess A:
Syngeneic bone marrow transplantation-eliminates v
20.
Burt RK, Padilla J, Begolka WS, Dal Conto C, Miller SD:
Effect of disease stage on clinical outcome after syngeneic bone marrow transplantation for relapsing experimental autoimmune encephalomyelitis.
Blood
91:2609, 1998
21.
Meloni G, Capria SD, Vignetti M, Mandelli F:
Blast crisis of chronic myelogenous leukemia in long-lasting systemic lupus erythematosus: regression of both diseases after autologous bone marrow transplantation (letter).
Blood
89:4659, 1997 22. Lowenthal RM, Cohen ML, Atkinson K, Biggs JC: Apparent cure of rheumatoid arthritis by bone marrow transplantation. J Rheumatol 20:137, 1993[Medline] [Order article via Infotrieve] 23. McKendry RJR, Huebsch L, Leclair B: Progression of rheumatoid arthritis following bone marrow transplantation. A case report with 13 year follow-up. Arthritis Rheum 39:1246, 1996[Medline] [Order article via Infotrieve] 24. Liu Yin JA, Jowitt SN: Resolution of immune-mediated diseases following allogeneic bone marrow transplantation for leukemia. Bone Marrow Transplant 9:31, 1992[Medline] [Order article via Infotrieve] 25. McAllister LD, Beatty PG, Rose J: Allogeneic bone marrow transplantation for chronic myelogenous leukemia in a patient with multiple sclerosis: Case study. Bone Marrow Transplant 19:395, 1997[Medline] [Order article via Infotrieve] 26. Salzman P, Tami J, Jackson C, Castro J, Boldt D, Freytes C, Berenson R, LeMaistre CF: Clinical remission of myasthenia gravis after high dose chemotherapy and autologous transplantation with CD34+ stem cells. Blood 84:206a, 1994 (abstr, suppl 1) 27. Fastenrath S, Dreger P, Schmitz N: Autologous unpurged bone marrow transplantati6n in a patient with lymphoma and SLE: Short term recurrence of antinuclear antibodies. Arthritis Rheum 38:53Q-3, 1995
28.
Euler HH, Marmont AM, Bacigalupo A, Fastenrath S, Dreger P, Hoffknecht M, Zander AR, Schalke B, Hahn U, Haas R, Schmitz N:
Early recurrence or persistence of autoimmune diseases after unmanipulated autologous stem cell transplantation.
Blood
88:3621, 1996 29. Lopez-Cubero S, Sullivan K, McDonald GB: Course of Crohn's disease after allogeneic marrow transplantation. Gastroenterology 114:433, 1998[Medline] [Order article via Infotrieve] 30. Poser CM, Paty DW, Scheinberg L, McDonald I, Davis FA, Ebers GC, Johnson KP, Sibley WA, Silberg DH, Tourtellotte WW: New diagnostic criteria for multiple sclerosis: Guidelines for research protocols. Ann Neur 13:227, 1983[Medline] [Order article via Infotrieve]
31.
Kurtzke JF:
Rating neurologic impairment in multiple sclerosis: An expanded disability status scale (EDSS).
Neurology
33:1444, 1983 32. Boumpas DT, Austin HA, Vaughn EM, Klippel JH, Steinberg AD, Yarboro CH, Balow JE: Controlled trial of pulse methylprednisolone versus two regimens of pulse cyclophosphamide in severe lupus nephritis. Lancet 340:741, 1992[Medline] [Order article via Infotrieve] 33. Jacobsson LT, Knowler WC, Pillemer S, Hanson RL, Pettit DJ, McLance DR, Bennett PH: A cross-sectional and longitudinal comparison of the Rome criteria for active rheumatoid arthritis (equivalent to the American College of Rheumatology 1958 criteria) and the American College of Rheumatology 1987 criteria for rheumatoid arthritis. Arthritis Rheum 37:1479, 1994[Medline] [Order article via Infotrieve] 34. Pincus T, Summey JA, Soraci SA Jr, Wallston KA, Hummon N: Assessment of patient satisfaction in activities of daily living using a modified Stanford Health Assessment Questionnaire. Arthritis Rheum 26:1346, 1983[Medline] [Order article via Infotrieve]
35.
Sipe JC, Knobler RL, Braheny SL, Rice GP, Panitch HS, Oldstone MB:
A neurologic rating scale (NRS) for use in multiple sclerosis.
Neurology
34:1368, 1984 36. Bombardier C, Gladman DD, Urowitz MB, Carun D, Chang CH: Derivation of the SLEDAI: A disease activity index for lupus patients. Arthritis Rheum 35:630, 1992[Medline] [Order article via Infotrieve] 37. Felson DT, Anderson JJ, Boers M, Bombardier C, Furst D, Goldsmith C, Katz LM, Lightfoot R Jr, Paulus H, Strand V, Tugwell P, Weinblatt M, Williams HJ, Wolfe F, Kieszak S: American College of Rheumatology preliminary definition of improvement in rheumatoid arthritis. Arthritis Rheum 38:727, 1995[Medline] [Order article via Infotrieve] 38. Pinals RS, Masi AT, Larsen RA: Preliminary criteria for clinical remission in rheumatoid arthritis. Arthritis Rheum 24:1308, 1981[Medline] [Order article via Infotrieve] 39. Cook SD, Devereux C, Trioano R, Hofstein MP, Zito G, Hernandez E, Lavenhar M, Vidauer R, Dowling PC: Effect of total lymphoid irradiation in chronic multiple sclerosis. Lancet 1:1405, 1986[Medline] [Order article via Infotrieve] 40. Hauser SL, Dawson DM, Lehrich JR, Beal MF, Kery SU, Propper RD, Mills JA, Weiner HL: Intense immunosuppression in multiple sclerosis: A randomized three arm study of high dose intravenous cyclophosphamide, plasma exchange and ACTH. N Engl J Med 308:173, 1983[Abstract] 41. Forman SJ, Nocker P, Gallagher M: Pattern of T cell reconstitution following allogeneic bone marrow transplantation for acute hematologic malignancy. Transplantation 34:96, 1982[Medline] [Order article via Infotrieve] 42. Olsen GA, Gockerman JP, Bast RC, Borowitz M, Peters WP: Altered immunologic reconstitution after standard dose chemotherapy or high dose chemotherapy with autologous bone marrow support. Transplantation 46:57, 1988[Medline] [Order article via Infotrieve]
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
 |
|
 |
|
  K. Maeda, A. Malykhin, B. N. Teague-Weber, X.-H. Sun, A. D. Farris, and K. M. Coggeshall Interleukin-6 aborts lymphopoiesis and elevates production of myeloid cells in systemic lupus erythematosus-prone B6.Sle1.Yaa animals Blood, May 7, 2009; 113(19): 4534 - 4540. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J C Henes, F Heinzelmann, A Wacker, H P Seelig, R Klein, A Bornemann, C Faul, L Kanz, and I Koetter Antisignal recognition particle-positive polymyositis successfully treated with myeloablative autologous stem cell transplantation Ann Rheum Dis, March 1, 2009; 68(3): 447 - 448. [Full Text] [PDF]
|
|
|
|
 |
|
 C. Krishnan, A. I. Kaplin, R. A. Brodsky, D. B. Drachman, R. J. Jones, D. L. Pham, N. D. Richert, C. A. Pardo, D. M. Yousem, E. Hammond, et al. Reduction of Disease Activity and Disability With High-Dose Cyclophosphamide in Patients With Aggressive Multiple Sclerosis Arch Neurol, August 1, 2008; 65(8): 1044 - 1051. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C V Tehlirian, L K Hummers, B White, R A Brodsky, and F M Wigley High-dose cyclophosphamide without stem cell rescue in scleroderma Ann Rheum Dis, June 1, 2008; 67(6): 775 - 781. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D.R. Jeffery Failure of allogeneic bone marrow transplantation to arrest disease activity in multiple sclerosis Multiple Sclerosis, September 1, 2007; 13(8): 1071 - 1075. [Abstract] [PDF]
|
|
|
|
|
|
S. Smith-Berdan, D. Gille, I. L. Weissman, and J. L. Christensen Reversal of autoimmune disease in lupus-prone New Zealand black/New Zealand white mice by nonmyeloablative transplantation of purified allogeneic hematopoietic stem cells Blood, August 15, 2007; 110(4): 1370 - 1378. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S Wohrer, M Troch, J Zwerina, G Schett, C Skrabs, A Gaiger, U Jaeger, C. Zielinski, and M Raderer Influence of rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone on serologic parameters and clinical course in lymphoma patients with autoimmune diseases Ann. Onc., April 1, 2007; 18(4): 647 - 651. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H Tsukamoto, K Nagafuji, T Horiuchi, T Miyamoto, K Aoki, K Takase, H Henzan, D Himeji, T Koyama, K Miyake, et al. A phase I-II trial of autologous peripheral blood stem cell transplantation in the treatment of refractory autoimmune disease Ann Rheum Dis, April 1, 2006; 65(4): 508 - 514. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. W. Moss Should Patients Undergoing Chemotherapy and Radiotherapy Be Prescribed Antioxidants? Integr Cancer Ther, March 1, 2006; 5(1): 63 - 82. [Abstract] [PDF]
|
|
|
|
|
|
I. de Kleer, B. Vastert, M. Klein, G. Teklenburg, G. Arkesteijn, G. P. Yung, S. Albani, W. Kuis, N. Wulffraat, and B. Prakken Autologous stem cell transplantation for autoimmunity induces immunologic self-tolerance by reprogramming autoreactive T cells and restoring the CD4+CD25+ immune regulatory network Blood, February 15, 2006; 107(4): 1696 - 1702. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. K. Burt, A. Traynor, L. Statkute, W. G. Barr, R. Rosa, J. Schroeder, L. Verda, N. Krosnjar, K. Quigley, K. Yaung, et al. Nonmyeloablative Hematopoietic Stem Cell Transplantation for Systemic Lupus Erythematosus JAMA, February 1, 2006; 295(5): 527 - 535. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. Saccardi, G. L. Mancardi, A. Solari, A. Bosi, P. Bruzzi, P. Di Bartolomeo, A. Donelli, M. Filippi, A. Guerrasio, F. Gualandi, et al. Autologous HSCT for severe progressive multiple sclerosis in a multicenter trial: impact on disease activity and quality of life Blood, March 15, 2005; 105(6): 2601 - 2607. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D Talaulikar, K E Tymms, I Prosser, and R Smith Autologous peripheral blood stem cell transplantation with in vivo T-cell depletion for life threatening refractory systemic lupus erythematosus Lupus, February 1, 2005; 14(2): 159 - 163. [Abstract] [PDF]
|
|
|
|
|
|
A Radbruch and A Thiel Cell therapy for autoimmune diseases: does it have a future? Ann Rheum Dis, November 1, 2004; 63(suppl_2): ii96 - ii101. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
I M de Kleer, D M C Brinkman, A Ferster, M Abinun, P Quartier, J van der Net, R ten Cate, L R Wedderburn, G Horneff, J Oppermann, et al. Autologous stem cell transplantation for refractory juvenile idiopathic arthritis: analysis of clinical effects, mortality, and transplant related morbidity Ann Rheum Dis, October 1, 2004; 63(10): 1318 - 1326. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D Farge, J Passweg, J M van Laar, Z Marjanovic, C Besenthal, J Finke, H H Peter, F C Breedveld, W E Fibbe, C Black, et al. Autologous stem cell transplantation in the treatment of systemic sclerosis: report from the EBMT/EULAR Registry Ann Rheum Dis, August 1, 2004; 63(8): 974 - 981. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
I A Lisukov, S A Sizikova, A D Kulagin, I V Kruchkova, A V Gilevich, L P Konenkova, E V Zonova, E R Chernykh, O Y Leplina, T N Sentyakova, et al. High-dose immunosuppression with autologous stem cell transplantation in severe refractory systemic lupus erythematosus Lupus, February 1, 2004; 13(2): 89 - 94. [Abstract] [PDF]
|
|
|
|
 |
|
 A. Saiz, Y. Blanco, E. Carreras, J. Berenguer, M. Rovira, T. Pujol, P. Marin, T. Arbizu, and F. Graus Clinical and MRI outcome after autologous hematopoietic stem cell transplantation in MS Neurology, January 27, 2004; 62(2): 282 - 284. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. K. Burt, B. A. Cohen, E. Russell, K. Spero, A. Joshi, Y. Oyama, W. J. Karpus, K. Luo, B. Jovanovic, A. Traynor, et al. Hematopoietic stem cell transplantation for progressive multiple sclerosis: failure of a total body irradiation-based conditioning regimen to prevent disease progression in patients with high disability scores Blood, October 1, 2003; 102(7): 2373 - 2378. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Shams'ili, J. Grefkens, B. de Leeuw, M. van den Bent, H. Hooijkaas, B. van der Holt, C. Vecht, and P. Sillevis Smitt Paraneoplastic cerebellar degeneration associated with antineuronal antibodies: analysis of 50 patients Brain, June 1, 2003; 126(6): 1409 - 1418. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. S. Burks, B. G. Arnason, P. K. Coyle, C. C. Ford, A. Noronha, and K. W. Rammohan Issues and Practices in Multiple Sclerosis Neurorehabil Neural Repair, December 1, 2002; 16(4): 307 - 320. [Abstract] [PDF]
|
|
|
|
 |
|
 D. W. van Bekkum Experimental basis of hematopoietic stem cell transplantation for treatment of autoimmune diseases J. Leukoc. Biol., October 1, 2002; 72(4): 609 - 620. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. C. Marty, F. Alliot, J. Rutin, R. Fritz, D. Trisler, and B. Pessac The myelin basic protein gene is expressed in differentiated blood cell lineages and in hemopoietic progenitors PNAS, June 25, 2002; 99(13): 8856 - 8861. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. K. Burt, S. Slavin, W. H. Burns, and A. M. Marmont Induction of tolerance in autoimmune diseases by hematopoietic stem cell transplantation: getting closer to a cure? Blood, February 1, 2002; 99(3): 768 - 784. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 L. R. Wedderburn, R. Jeffery, H. White, A. Patel, H. Varsani, D. Linch, K. Murray, and P. Woo Autologous stem cell transplantation for paediatric-onset polyarteritis nodosa: changes in autoimmune phenotype in the context of reduced diversity of the T- and B-cell repertoires, and evidence for reversion from the CD45RO+ to RA+ phenotype Rheumatology, November 1, 2001; 40(11): 1299 - 1307. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G. L. Mancardi, R. Saccardi, M. Filippi, F. Gualandi, A. Murialdo, M. Inglese, M. G. Marrosu, G. Meucci, L. Massacesi, A. Lugaresi, et al. Autologous hematopoietic stem cell transplantation suppresses Gd-enhanced MRI activity in MS Neurology, July 10, 2001; 57(1): 62 - 68. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Saiz, E. Carreras, J. Berenguer, J. Yague, C. Martinez, P. Marin, M. Rovira, T. Pujol, T. Arbizu, and F. Graus MRI and CSF oligoclonal bands after autologous hematopoietic stem cell transplantation in MS Neurology, April 24, 2001; 56(8): 1084 - 1089. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. R. Zink, M. L. Vance, and T. Vance Stem Cell Transplants for Multiple Sclerosis Provide New Options for Patients and New Challenges for Home Care Home Health Care Management Practice, April 1, 2001; 13(3): 184 - 196. [Abstract] [PDF]
|
|
|
|
|
|
R. K Burt Hematopoietic Stem Cell Therapy for Multiple Sclerosis Multiple Sclerosis, December 1, 2000; 6(6): 415 - 418. [PDF]
|
|
|
|
|
|
A. Fassas High-Dose, Myeloimmunoablative Chemotherapy Followed by Autologous Stem Cell Transplantation in the Treatment of MS Multiple Sclerosis, December 1, 2000; 6(6): 421 - 422. [PDF]
|
|
|
|
|
|
H. Openshaw, O. Stuve, J. P. Antel, R. Nash, B. T. Lund, L. P. Weiner, A. Kashyap, P. McSweeney, and S. Forman Multiple sclerosis flares associated with recombinant granulocyte colony-stimulating factor Neurology, June 13, 2000; 54(11): 2147 - 2150. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. M. van Laar, R. J. Verburg, and J. K. Sont Risk taking in patients with rheumatoid arthritis: are the risks of haemopoietic stem cell transplantation acceptable? Rheumatology, June 1, 2000; 39(6): 680A - 681A. [Full Text] [PDF]
|
|
|
|
|
|
E Trysberg, I Lindgren, and A Tarkowski Autologous stem cell transplantation in a case of treatment resistant central nervous system lupus Ann Rheum Dis, March 1, 2000; 59(3): 236 - 238. [Abstract] [Full Text]
|
|
|
|
 |
|
 K. M. Sullivan, R. Parkman, and M. C. Walters Bone Marrow Transplantation for Non-Malignant Disease Hematology, January 1, 2000; 2000(1): 319 - 338. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 F. Zavala, A. Masson, K. Hadaya, S. Ezine, E. Schneider, O. Babin, and J.-F. Bach Granulocyte-Colony Stimulating Factor Treatment of Lupus Autoimmune Disease in MRL-lpr/lpr Mice J. Immunol., November 1, 1999; 163(9): 5125 - 5132. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 G. McColl, H. Kohsaka, J. Szer, and I. Wicks High-Dose Chemotherapy and Syngeneic Hemopoietic Stem-Cell Transplantation for Severe, Seronegative Rheumatoid Arthritis Ann Intern Med, October 5, 1999; 131(7): 507 - 509. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. Aristei and A. Tabilio Total-Body Irradiation in the Conditioning Regimens for Autologous Stem Cell Transplantation in Lymphoproliferative Diseases Oncologist, October 1, 1999; 4(5): 386 - 397. [Abstract] [Full Text]
|
|
|
|
|
|
L Fouillard, N C Gorin, J P. Laporte, A Leon, J F Brantus, and P Miossec Control of severe systemic lupus erythematosus after high-dose immunusuppressive therapy and transplantation of CD34+ purified autologous stem cells from peripheral blood Lupus, May 1, 1999; 8(4): 320 - 323. [Abstract] [PDF]
|
|
|
|
|
|
R. K. Burt and A. E. Traynor Hematopoietic Stem Cell Transplantation: A New Therapy for Autoimmune Disease Oncologist, February 1, 1999; 4(1): 77 - 83. [Full Text]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
 |
 |
 |
|||||||
 |
 |
 |
 |
 |
 |
 |
 |
||
| Copyright © 1998 by American Society of Hematology Online ISSN: 1528-0020 | |||||||||
Top
Abstract
Introduction
8.2 T lymphocytes from the spinal cord of Lewis rats with experimental allergic encephalomyelitis.
J Neurosci Res
41:526, 1995