RAPID COMMUNICATION
`Treatment of Autoimmune Disease by Intense Immunosuppressive Conditioning
`and Autologous Hematopoietic Stem Cell Transplantation
`
`By Richard K. Burt, Ann E. Traynor, Richard Pope, James Schroeder, Bruce Cohen, Karyn H. Karlin, Lorri Lobeck,
`Charles Goolsby, Philip Rowlings, Floyd A. Davis, Dusan Stefoski, Cass Terry, Carolyn Keever-Taylor,
`Steve Rosen, David Vesole, Maryanne Fishman, Mary Brush, Salim Mujias, Marcelo Villa, and William H. Burns
`
`Multiple sclerosis, systemic lupus erythematosus, and rheu-
`matoid arthritis are immune-mediated diseases that are
`responsive to suppression or modulation of the immune
`system. For patients with severe disease, immunosuppres-
`sion may be intensified to the point of myelosuppression or
`hematopoietic ablation. Hematopoiesis and immunity may
`then be rapidly reconstituted by reinfusion of CD34ⴙ progeni-
`tor 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 cyclophos-
`phamide and G-CSF. Stem cells were enriched ex vivo using
`CD34ⴙ selection and reinfused after either myelosuppressive
`conditioning with cyclophosphamide (200 mg/kg), methyl-
`prednisolone (4 g) and antithymocyte globulin (ATG; 90
`mg/kg) or myeloablative conditioning with total body irradia-
`tion (1,200 cGy), methylprednisolone (4 g), and cyclophospha-
`
`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 hematopoi-
`etic progenitor cells (CD34⫹ cells). This approach is supported
`by hematopoietic stem cell transplantation in animal autoim-
`mune 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 spontane-
`ous onset lupus-like illness occurs in Murthy Roth Lab lympho-
`proliferative (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 transplan-
`tation. In MRL/lpr mice, a single gene defect in Fas expression,
`a protein that signals for apoptosis, results in a lymphoprolifera-
`tive 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 re-
`lapse rate is higher after an autologous or syngeneic transplant.
`
`mide (120 mg/kg). Six patients with multiple sclerosis, 2
`with systemic lupus erythematosus, and 2 with rheumatoid
`arthritis have undergone hematopoietic stem cell transplan-
`tation. Mean time to engraftment of an absolute neutrophil
`count greater than 500/␮L (0.5 ⴛ 109/L) and a nontransfused
`platelet count greater than 20,000/␮L (20 ⴛ 109/L) occurred
`on day 10 and 14, respectively. Regimen-related nonhemato-
`poietic 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.
`r 1998byTheAmericanSocietyofHematology.
`
`In animal autoimmune disorders, genetically preordained dis-
`eases 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
`
`From the Departments of Medicine, Neurology, Nephrology, and
`Rheumatology, Division of Hematology/Oncology & Lurie Comprehen-
`sive 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.
`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.
`The publication costs of this article were defrayed in part by page
`charge payment. This article must therefore be hereby marked ‘‘adver-
`tisement’’ in accordance with 18 U.S.C. section 1734 solely to indicate
`this fact.
`r 1998 by The American Society of Hematology.
`0006-4971/98/9210-0053$3.00/0
`
`Blood,Vol 92, No 10 (November 15), 1998: pp 3505-3514
`
`3505
`
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`

`3506
`
`BURT ET AL
`
`conferences have recommended initiating this approach with
`autologous stem cells.3
`
`MATERIALS AND METHODS
`
`Patient Selection
`
`All three protocols (MS, systemic lupus erythematosus [SLE], and
`RA) are approved by the US FDA under IDE numbers BB-IDE 6440,
`BB-IDE 6559, and BB-IDE 6778, respectively. For all protocols,
`patients must be less than 60 years of age at the time of pretransplant
`evaluation and must meet the following criteria.
`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 intrave-
`nous 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 symp-
`toms, eg, cerebritis, transverse myelitis, pulmonary hemorrhage, or
`cardiac failure, not controlled with corticosteroids and cyclophospha-
`mide; (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 thrombo-
`sis 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
`
`Hematopoietic stem cells were collected from bone marrow in the
`first 3 patients, but due to low CD34⫹ cell yield,
`the graft was
`supplemented with peripheral blood stem cells (PBSCs). All subsequent
`hematopoietic stem cells were collected using only peripheral blood.
`PBSCs were mobilized with either granulocyte colony-stimulating
`factor (G-CSF; Amgen, Thousand Oaks, CA) at 10 µg/kg subcutaneous
`daily with leukapheresis beginning on day 5 or cyclophosphamide (2.0
`g/m2) and G-CSF (10 µg/kg/d) with leukapheresis initiated when the
`white blood cell count reached 1,000/µL (1.0 ⫻ 109/L). Apheresis was
`continued daily until the number of harvested progenitor cells reached a
`
`minimum of 2.0 ⫻ 106 CD34⫹ cells/kg body weight after CD34
`enrichment. The mobilized peripheral blood stem cells were lymphocyte-
`depleted via positive selection for CD34⫹ cells using the CEPRATE SC
`Stem Cell Concentrator (CellPro, Bothell, WA).
`
`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 adminis-
`tered intravenously on days ⫺4, ⫺3, ⫺2, and ⫺1.
`For lupus and RA, cyclophosphamide (200 mg/kg) was administered
`in divided doses of 50 mg/kg/d intravenously over 1 to 2 hours on days
`⫺7, ⫺6, ⫺5, and ⫺4. Antithymocyte globulin (ATG; 90 mg/kg) was
`administered in doses of 30 mg/kg/d on days ⫺6, ⫺5, and ⫺4 and
`infused over 10 to 12 hours beginning 8 to 10 hours after the infusion of
`cyclophosphamide. Methylprednisolone (1 g) was administered intrave-
`nously 30 minutes before each dose of ATG.
`
`Definition of Disease Status
`
`Outcome was based on assessments before transplant and at 1, 2, 3,
`and 6 months and yearly after transplantation.
`Improvement was defined as a decrease in the Kurtzke EDSS31
`MS.
`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 Question-
`naire 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 immunopheno-
`typing was performed on EDTA anticoagulated whole blood. The
`infused stem cell products were assessed by three-color immunopheno-
`typing. The panel of fluorescein isothiocyanate (FITC), phycoerythrin
`(PE), PE-cyanin 5 (PE-Cy5), or PerCp fluorochromes included antibod-
`ies to CD45 and CD34 (Becton Dickinson, Mountain View, CA), and
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`HEMATOPOIETIC TRANSPLANTATION OF AUTOIMMUNE DISEASE
`
`3507
`
`Table 1. Hematopoietic Stem Cell Collection in Patients With Autoimmune Diseases
`
`Patient
`
`MS #1
`MS #2
`MS #3
`MS #4
`MS #5
`MS #6
`SLE #1
`SLE #2
`RA #1
`RA #2
`
`Method of PBSC
`Collection
`
`G-CSF
`G-CSF
`G-CSF
`G-CSF
`G-CSF
`G-CSF
`Cy ⫹ G-CSF
`Cy ⫹ G-CSF
`Cy ⫹ G-CSF
`Cy ⫹ G-CSF
`
`No. of Apheresis
`
`2 plus 1 bone marrow harvest
`2 plus 1 bone marrow harvest
`2 plus 1 bone marrow harvest
`1
`1
`1
`3
`5
`2
`1
`
`CD34⫹ Cells/kg
`Infused ⫻106
`
`2.12
`3.91
`2.42
`2.57
`2.02
`2.76
`2.46
`2.0
`2.16
`6.32
`
`CD3⫹ Cells/kg
`Infused ⫻106
`(log depletion)
`
`0.50 (2.5)
`1.4 (1.93)
`1.06 (2.2)
`0.23 (2.6)
`1.04 (2.5)
`0.26 (2.86)
`1.5 (1.4)
`1.0 (2.0)
`0.86 (2.7)
`0.60 (2.5)
`
`CD19⫹ Cells/kg
`Infused ⫻106
`(log depletion)
`
`0.12 (2.51)
`1.0 (1.9)
`0.5 (1.9)
`1.28 (1.6)
`0.23 (2.3)
`0.72 (1.92)
`0.0004 (3.74)
`0.06 (2.51)
`0.12 (2.18)
`0.10 (2.43)
`
`Abbreviation: Cy, cyclophosphamide (2.0 g/m2).
`
`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. Subcutane-
`ous 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
`
`RESULTS
`
`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) accord-
`ing 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 engraft-
`ment, 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 exac-
`erbation of neurologic symptoms. Transient elevation of hepatic
`transaminases (5⫻ normal) occurred in 2 patients while receiv-
`ing 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 deteriora-
`tion 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 condi-
`
`ANC
`⬎500/µL
`(day)
`
`Platelet
`⬎20,000/µL
`
`No. of
`Days With
`Fever
`(⬎100.5)
`
`11
`11
`12
`11
`11
`10
`10
`
`8
`8
`9
`
`14
`14
`14
`12
`13
`12
`14
`
`14
`12
`12
`
`3
`9
`0
`0
`0
`0
`2
`
`2
`1
`3
`
`Patient
`
`MS #1
`MS #2
`MS #3
`MS #4
`MS #5
`MS #6
`SLE #1
`
`SLE #2
`RA #1
`RA #2
`
`Table 2. Toxicity
`
`Positive Cultures
`
`Stool-candida
`Blood-staphylococcus
`0
`0
`0
`Stool-clostridium difficile
`Blood-staphylococcus
`epidermidis
`
`0
`0
`PICC line streptococcus
`sangoisi
`
`Maximum NCI
`Toxicity, Renal
`
`1-trace hematuria
`1-trace hematuria
`0
`0
`0
`0
`3-creatinine 6.8 mg/dL
`
`2
`1-trace hematuria
`1-trace hematuria
`
`Abbreviation: PICC, percutaneous intravenous central catheter.
`
`Maximum
`NCI
`Toxicity,
`Pulmonary
`
`0
`0
`0
`0
`0
`0
`0
`
`4
`0
`0
`
`Maximum NCI
`Toxicity, Hepatic
`
`1 elevated transaminase
`3 elevated transaminase
`0
`0
`0
`1 elevated transaminase
`2 elevated transaminase
`
`3 elevated transaminase
`1 elevated transaminase
`2 elevated transaminase
`
`Maximum
`NCI
`Toxicity,
`CNS
`
`0
`0
`0
`0
`0
`0
`0
`
`0
`0
`0
`
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`3508
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`BURT ET AL
`
`tioning 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.
`In both patients, conditioning was well tolerated with-
`RA.
`out 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 administra-
`tion 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 modulat-
`ing 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 depen-
`dence 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 cogni-
`tive ability, has demonstrated a greater than 10 point improve-
`ment 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 pretrans-
`plant 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, hy-
`droxychloroquine, 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 immunosuppres-
`sive medications, including corticosteroids.
`The second patient presented at 15 years of age with flu-like
`symptoms followed by respiratory arrest. She was transferred to
`a tertiary care facility in which pulmonary biopsy showed
`
`Table 3. Clinical Outcome After Hematopoietic Stem Cell Transplantation for MS
`
`Time Since
`Transplant
`(mo)
`
`Stable or
`Improved
`Disease
`(mo)
`
`No. of
`Relapses
`
`EDSS
`Pretransplant
`and Most Recent
`Posttransplant
`
`NRS
`Pretransplant
`and Most Recent
`Posttransplant
`
`MRI
`
`Neurological Changes
`
`17
`
`16
`
`15
`
`6
`
`5
`
`5
`
`17
`
`16
`
`15
`
`6
`
`5
`
`5
`
`0
`
`0
`
`0
`
`0
`
`0
`
`0
`
`8.5/8.5
`
`15/19
`
`No new lesions
`
`8.0/8.0
`
`30/29
`
`No new lesions
`
`8.0/8.0
`
`34/37
`
`No new lesions
`
`6.5/6.0
`
`49/63
`
`No new lesions
`
`7.0/6.5
`
`6.0/6.0
`
`29/58
`
`51/61
`
`No new lesions
`
`No new lesions
`
`Improved cognition,
`decreased inconti-
`nence
`Decreased inconti-
`nence, decreased
`tremor
`Improved stamina
`and strength, now
`able to swim
`Less dysarthria, cor-
`rection of gaze
`deviation
`Improved strength
`
`Improved strength
`and cerebellar
`function
`
`Patient
`
`MS #1 secondary
`progressive
`
`MS #2 secondary
`progressive
`
`MS #3 primary pro-
`gressive
`
`MS #4 secondary
`progressive
`
`MS #5 primary pro-
`gressive
`MS #6 secondary
`progressive
`
`The EDSS is divided into 20 half points from 0 (normal) to 10 (death). Increasing points indicate worse neurologic deficits. In the higher range
`(5.0 to 8.0), the EDSS is weighted by ambulation. For example, ambulation less than 200 meters without assist is 5.0; wheelchair bound is 8.0. In
`the NRS, normal neurologic function is 100 points, whereas lower numbers indicate progressive neurologic disability.
`Abbreviations: EDSS, Kurtzke extended status disability scale21; MRI, magnetic resonance spectroscopy; NRS, Scripps Neurologic Rating
`Scale.25
`
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`

`HEMATOPOIETIC TRANSPLANTATION OF AUTOIMMUNE DISEASE
`
`3509
`
`Table 4. Clinical Outcome After Hematopoietic Stem Cell Transplantation for SLE
`
`Patient SLE #1
`
`SLEDAI score
`Hemoglobin (mg/dL)
`White blood cells/µL
`Platelets (no./µL)
`24-hour urine protien (g)
`Serum creatinine (mg/dL)
`C3 (68-164 mg/dL)
`C4 (7-47 mg/dL)
`ANA
`Anti–double-stranded DNA
`
`SLEDAI score
`Hemoglobin (mg/dL)
`Platelets (no./µL)
`Chest roentograph
`
`Pulmonary function test, DLCO
`Serum creatinine (mg/dL)
`C3
`C4
`ANA
`Anti–double-stranded DNA
`
`Pretransplant
`
`37
`6.5
`2,000
`100,000
`3.6
`5.0
`52 low
`6 low
`1:320 high
`1:160 high
`
`2 mo
`Posttransplant
`
`0
`10.0
`6,000
`240,000
`0.6
`2.6
`100 normal
`40 normal
`1:40 normal
`1:60 borderline
`
`6 mo
`Posttransplant
`
`0
`12.3
`6,100
`215,000
`0.87
`2.7
`114 normal
`35 normal
`1:40 normal
`1:60 borderline
`
`Pretransplant
`
`32
`8.0
`135,000
`Bilateral
`Infiltrates
`Alveolar
`Hemorrhage
`Vasculitis
`50% predicted
`1.3
`62 low
`10 normal
`1:1280 high
`1:320 high
`
`Patient SLE #2*
`
`2 mo
`Posttransplant
`
`0
`10.1
`236,000
`Normal
`
`50% predicted
`1.1
`190 high
`45 normal
`1:40 normal
`Negative
`
`12 mo
`Posttransplant
`
`0
`12.4
`6,100
`235,000
`0.2
`1.9
`113 normal
`35 normal
`1:80 increased
`1:60 borderline
`
`6 mo
`Posttransplant
`
`0
`11.8
`242,000
`Normal
`
`50% predicted
`1.1
`167 normal
`29 normal
`1:160 increased
`Negative
`
`The SLEDAI is a measure of activity or inflammation in nine organ systems. It has a theoretical maximum of 105 points. A normal person has a
`SLEDAI of zero.
`Abbreviation: SLEDAI, SLE disease activity index.26
`*White blood cell count and 24-hour urine protein on SLE patient no. 2 was always normal and is not included in the table.
`
`alveolar hemorrhage and vasculitis and renal biopsy showed
`WHO class IV glomerulonephritis. The ANA was 1:1,280.
`Subsequently, her disease manifested predominately as alveolar
`hemorrhage requiring intubation on a second occasion despite
`high-dose corticosteroids, plasmapheresis, and pulse cyclophos-
`phamide. Within 3 months of disease onset she was referred for
`transplantation. At the time of transplant, the patient had active
`pneumonitis manifested as hemoptysis, pulmonary infiltrates,
`and hypoxia. Since transplantation, hemoptysis and pulmonary
`
`infiltrates have resolved. Pulmonary diffusion capacity has
`remained unchanged at 50% of normal. Corticosteroids are
`being gradually tapered and have been decreased from 80 to 25
`mg/d.
`RA. The first patient has met the 50% response criteria for
`improvement (Table 5). She was a 46-year-old woman diag-
`nosed with RA 7 years before transplantatiion. She was treated
`with nonsteroidal anti-inflammatory drugs, hydroxychloro-
`quine, cyclosporine, gold, methotrexate, dapsone, sulfasalazine,
`
`Table 5. Clinical Outcome After Hematopoietic Stem Cell Transplantation for RA
`
`Pretransplant
`
`1 mo After
`Transplant
`
`27
`41
`
`0
`3
`
`Patient No. 1
`
`3 mo After
`Transplant
`
`4
`7
`
`3
`3
`
`6 mo After
`Transplant
`
`12 mo After
`Transplant
`
`Pretransplant
`
`3 mo After
`Transplant
`
`Patient No. 2
`
`2
`4
`
`18
`21
`
`4
`22
`
`65% poor
`
`35% fair-well
`
`25% well
`
`15% very well
`
`10% very well
`
`75 poor
`
`50 poor
`
`75% poor
`0%
`48 high
`
`5% very well
`60%
`
`—
`
`5% very well
`80%
`15 normal
`
`10% very well
`85%
`
`—
`
`10% very well
`80%
`15 normal
`
`67 fair
`0%
`75 high
`
`35 fair
`25%
`65 high
`
`Swollen joint count
`Tender joint count
`Patient’s global assess-
`ment of disease
`Physician global assess-
`ment of disease
`ADL % without problems
`Sed rate
`
`The ADL address ability to perform activities of daily living in eight categories: dressing and grooming, arising, eating, walking, hygiene, reach,
`grip, and other. A normal person’s ADL is 100%.
`Abbreviations: ADL, activities of daily living questionnaire24; sed rate, sedimentation rate.
`
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`

`

`3510
`
`BURT ET AL
`
`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 hydroxychlo-
`roquine twice a day. By 8 months, corticosteroids were discon-
`tinued. Health assessment questionnaire parameters have im-
`proved 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.
`The second patient was a 42-year-old woman diagnosed 7
`years before transplantation. She was treated with nonsteroidal
`anti-inflammatory drugs, hydroxychloroquine, cyclosporin, gold,
`methotrexate, sulfasalazine, intra-articular corticosteroids, and
`oral prednisone at 10 mg/d for 5 years. At
`the time of
`transplantation, she had 21 tender joints and 18 swollen joints
`and was unable to perform any of 20 health assessment
`questionnaire parameters ‘‘without any difficulty.’’ Although
`she experienced greater than a 50% reduction in swollen joints
`after transplantation, her tender joint count did not improve. At
`3 months after transplantation, she has 22 tender and 5 swollen
`joints and answers 6 health assessment questionnaire param-
`eters ‘‘without any difficulty.’’ She is currently off corticoste-
`roids but remains on 20 mg per week of methotrexate. Patient
`and physician assessment of disease has improved 25% and
`32%, respectively. Her rheumatoid factor and sedimentation
`rate remain elevated.
`
`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 posttrans-
`plant months, returning thereafter to normal. CD19⫹ (B) cells
`reached the normal range by 6 months.
`
`DISCUSSION
`
`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 immunosuppres-
`sive 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 inconti-
`nence, 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 compo-
`nents. Aiming for transplant during active disease as evidenced
`by gadolinium enhancement on MRI may result in greater
`functional improvement. Four patients had small volume gado-
`linium enhancement on pretransplant MRI. Three of these
`patients improved with more than a 10-point NRS increase. The
`2 patients without pretransp