Report on the National Institutes of Health
Workshop on Autologous Stem Cell Transplantation for Pediatric Rheumatic
Diseases
Karyl S. Barron and Carol Wallace, Co-Editors
Ann Woolfrey, Ronald M. Laxer, Raphael Hirsch, Mitchell
Horwitz, Jeffrey Siegel, Lisa Filipovich, Nico Wulffraat, Murray Passo
and Lisa G. Rider
Abstract: The National Institute of Allergy
and Infectious Disease, National Institutes of Health convened a workshop
titled The Next Step: Protocol Development for Autologous Stem Cell Transplantation
for Pediatric Rheumatic Disease, June 2000, co-chaired by Drs. Karyl Barron
and Carol Wallace. The goal of the workshop was to focus on the scientific
rationale for stem cell transplantation therapy in the Pediatric Diseases,
unique aspects of this therapy in the Pediatric Rheumatic Diseases, transplantation
issues and options, regulatory issues, and development of a DNA repository
for these diseases.
Key Indexing Terms: Stem Cell Transplantation,
Juvenile Rheumatoid Arthritis, Juvenile Idiopathic Arthritis, Dermatomyositis,
Systemic Sclerosis, Systemic Lupus Erythematosus
Source of Support: This workshop was supported
by funds from the Division of Intramural Research, National Institute of
Allergy and Infectious Diseases and the Office of Rare Diseases, National
Institutes of Health.
Author information:
Karyl S. Barron MD, Deputy Director, Division
of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes
of Health, Bethesda, Maryland
Carol Wallace MD, Associate Professor, Pediatrics,
Division of Immunology and Rheumatology, Children's Hospital and Medical
Center, Seattle, Washington
Faculty:
Ann Woolfrey MD, Assistant Member, Fred Hutchinson
Cancer Research Center, Seattle, Washington
Ronald M. Laxer MD, FRCPC, Professor, Departments
of Pediatrics and Medicine, University of Toronto, Associate Pediatrician-in-Chief and Division
of Rheumatology, The Hospital for Sick Children, Toronto, Canada
Raphael Hirsch MD, Professor of Pediatric
Rheumatology, Division of Rheumatology, Children's Hospital Medical Center, Cincinnati, Ohio
Jeffrey Siegel MD, Medical Officer, Division
of Clinical Trial Design and Analysis, Center for Biologics Evaluation and Research, Food and Drug
Administration, Rockville Maryland
Lisa Filipovich MD, Professor of Pediatrics,
Director, Immunodeficiency Program, Children's Hospital Medical Center, Cincinnati, Ohio
Nico Wulffratt MD, Department of Pediatric
Immunology, Wilhelmina Children’s Hospital, University Medical Centre Utrecht, Utrecht, The Netherlands
Mitchell Horwitz MD, Staff Clinician, Laboratory
of Host Defenses, National Institute of Allergy and Infectious Diseases, National Institutes of Health,
Bethesda, Maryland
Murray Passo MD, Clinical Director, Division
of Pediatric Rheumatology, Children's Hospital Medical Center, Cincinnati, Ohio
Lisa G. Rider MD, Staff Scientist and Medical
Officer, Division of Monoclonal Antibodies, Center for Biologics Evaluation and Research, Bethesda,
Maryland
Address correspondence and reprint requests to:
Dr. K.S. Barron
Division of Intramural Research
National Institute of Allergy and Infectious Diseases
National Institutes of Health
Building 10, Room 4A-30
Bethesda, MD 20892-1356
Email: Kbarron@nih.gov
Disclaimer: The content of the workshop moderated by
Dr. Rider does not necessarily represent the opinions of the U.S. Food
and Drug Administration.
The National Institute of Allergy and Infectious
Disease, National Institutes of Health convened a workshop entitled The
Next Step: Protocol Development for Autologous Stem Cell Transplantation
for Pediatric Rheumatic Disease, June 2000, co-chaired by Drs. Karyl Barron
and Carol Wallace. The goal of the workshop
was to focus on the immunology and science of Pediatric Rheumatic Disease
and Stem Cell Transplantation therapy, unique problems of the Pediatric
Rheumatic Diseases, transplantation issues and options, regulatory aspects,
and development of a DNA repository for these diseases. The participants
were also divided into workgroups to discuss: development of specific protocols,
disease specific inclusion criteria and optimal standard therapy as comparator
arms for future randomized trials. The following are summaries of the reports.
Pediatric Autoimmune Diseases: Why New Treatments
Are Needed
Ronald M. Laxer, MDCM, FRCPC
We have entered a new era in the treatment of the
rheumatic diseases. Would the proverbial "man on the moon", in looking
at this new era, say that with respect to current treatments, the glass
looks half-empty or half-full? Despite significant advances in the management
of patients with rheumatic diseases over the last decade, current treatments
remain inadequate for a large number of children, either because of poor
disease control, excessive toxicity of the treatment, or a combination
of the two. This review will focus on current evidence suggesting that
treatment for children with juvenile idiopathic arthritis (previously called
juvenile rheumatoid arthritis or JRA), systemic lupus erythematosus, and
juvenile dermatomyositis, remains inadequate.
Juvenile Idiopathic Arthritis (JIA)
Long-term observational studies have documented that
active disease persists in a significant percentage of patients with JIA,
and that functional class also deteriorates with time (1). More recently,
Zak and Pedersen (2) have shown that
disease activity persists in 37% of patients with JIA followed for 26 years,
and that the Steinbrocker functional class deteriorates with time, correlating
with disease duration, erosive disease at 10 year follow-up, JIA subtype,
systemic steroid treatment, and Steinbrocker functional class at 10 year
follow-up. These data were generated from patients who were evaluated and
managed in the pre-methotrexate and biologic era, and it is hoped (and
presumed) that the long-term outcomes over the next decade will show better
results.
Children with systemic onset JIA (sJIA) can have
significant ongoing morbidity, in part due to their systemic disease, arthritis,
potential medication toxicity, and possibility of developing macrophage
activation syndrome (MAS). Most of the mortality associated with JIA occurs
in this subset of patients (3). A number of studies have looked specifically
at the role of methotrexate in sJIA. Halle and Prieur reported that in
a series of 10 patients with sJIA, methotrexate did not result in a significant
reduction of fever, number of active joints, early morning stiffness, or
ability to taper prednisone (4). Similarly, Speckmaier et al., showed an
improvement in only 4 of 12 patients with sJIA who were treated with methotrexate
(5). Ravelli et al. reported that in a series of 19 children with sJIA,
12 were responders (6). Compared to the non-responders, these patients
had milder disease; it is unclear whether the methotrexate had an effect,
or what they observed was merely the natural course of patients with milder
disease. One criticism from these studies is that the doses of methotrexate
used were lower than those currently used. Two studies looked at increasing
doses of methotrexate in children with JIA (7,8). Wallace et al. treated
5 children with sJIA who had failed to respond to a standard dose of methotrexate
with doses ranging from 0.86-1.1 mg/kg/wk (7). Only one patient entered
remission. Reiff et al. used doses of methotrexate ranging from 0.46-1.2
mg/kg/wk with a mean follow up of 15 months (8). Only 5 of 13 patients
were considered responders. Radiologic progression occurred even in patients
who were responders. In another study, of 25 patients with sJIA treated
with 0.3-0.9 mg/kg/wk of methotrexate, only 10 had what the authors defined
as a complete response (9). After stopping the drug in 4 patients, 2 quickly
relapsed. Similarly, 10 of 16 patients with sJIA went into remission on
7.1-10.7 mg/m2/wk of methotrexate; 4 of those 10 quickly relapsed when
the methotrexate was stopped (10). These patients may have been those of
the early responder group described by Ravelli et al. (6). Early institution
of methotrexate in children with sJIA and prognostic indicators of poor
functional outcome did not alter the course (11). These data suggest that
methotrexate, the agent with the best proven track record for the treatment
of children with JIA, is inadequate treatment for a significant number
of children with JIA.
In a recent randomized trial, etanercept (a potent
biologic agent requiring twice weekly subcutaneous injections) resulted
in improvement in a significant number of children with polyarticular course
JIA who had failed or been intolerant of methotrexate (12). The percentage
of patients overall demonstrating core set improvement (13) of 30%, 50%
and 70% were 74%, 64% and 36% respectively. Alternatively, one could say
that despite treatment with etanercept, 36% of patients improved by less
than 50%, and 64% of patients improved by less than 70%. While fewer patients
with sJIA in this trial flared on etanercept than patients on placebo,
44% (4/9) of patients flared. Fifty percent of patients who required steroids
prior to starting etanercept flared while receiving this agent. These data
suggest that patients with more severe disease have a greater tendency
to flare. While etanercept clearly has an important role to play in the
management of children with JIA, there remain a large percentage of children
who require additional treatment. Additionally, the next few years will
likely reveal toxicity with this agent (as well as other biologics) as
we begin to see results of post-marketing surveillance studies.
Systemic Lupus Erythematosus (SLE)
The incidence of SLE in the pediatric population
is approximately 10-20 new cases per 100,000 per year. Over the last three
decades, there has been a significant improvement in the mortality rate,
largely due to earlier recognition and better supportive management. However,
ongoing, as well as long-term morbidity, remain significant clinical issues.
Morbidity from SLE must be considered in terms of a) the disease, b) the
treatment, and c) a combination of the two.
The major cause of disease-related morbidity and
mortality is related to renal disease. Three large series of children with
lupus nephritis all suggest that diffuse proliferative glomerulonephritis
(WHO Class IV) is a significant predictive factor for end-stage renal disease
and death (14-16). Clinical factors predictive of progression to end-stage
renal disease include the presence of hypertension, elevated serum creatinine,
and increasing levels of proteinuria at the time of diagnosis. Over the
last 15 years, the use of cyclophosphamide has been proposed to result
in better outcomes (17). A recent series of 16 pediatric patients treated
with the NIH protocol of intravenous cyclophosphamide monthly for 6 months,
and then every 3 months for a total of 3 years, resulted in significant
improvement in the histology, ability to reduce prednisone and normalize
serology, and normalize serology and SLEDAI scores (18). Complications
of intravenous cyclophosphamide were minimal. However, another series of
patients examined retrospectively received treatment with only high-dose
steroids prior to 1985, and high-dose steroids plus intravenous cyclophosphamide
according to a protocol similar to the NIH protocol subsequent to 1985(16).
The administration of intravenous cyclophosphamide did not appear to have
an impact on the progression to end-stage renal disease. While the complications
in studies to date have been minimal, there are no long-term outcome data
in pediatric lupus patients who have been treated with cyclophosphamide.
Concerns remain regarding bladder toxicity, alopecia and risk of infection.
Long term, the risks of malignancy and infertility are potentially significant
and likely related to the overall dose of cyclophosphamide given. Mok et
al. (19) have shown that older age
at treatment and total dose predispose to ovarian failure. However, 2 of
10 patients less than 30 years old who had received between 10 to 20 grams
of cyclophosphamide had ovarian failure.
Ionnadis et al. have recently examined risk of relapse
in patients with lupus nephritis treated with IV cyclophosphamide and noted
that, of 85 patients (33 Class III, 52 Class IV) treated with intravenous
cyclophosphamide, only 63 went into remission (20). Twenty-one of the 63
relapsed with median time to relapse of 79 months. Predictors of early
relapse were co-existent central nervous disease and the time taken to
reach the first remission. Chronic renal damage on initial biopsy and time
taken to reach first remission both predicted time taken to reach a second
remission. The authors conclude that patients with adverse prognostic factors
for a second remission should be considered for alternative therapies.
Therefore, while intravenous cyclophosphamide may offer the best current
hope for prevention of end-stage renal disease in children with Class IV
lupus nephritis, there is clearly a need for improved therapies both in
terms of efficacy and potential toxicity.
In addition to short- and medium-term morbidity,
long-term morbidity remains a significant concern for patients with lupus.
Adult studies have shown that approximately 40% of female lupus patients
have subclinical atherosclerotic disease (21). We have demonstrated a significant
incidence of coronary artery disease in a small cohort of patients (22).
This is likely due to a combination of coronary artery vasculitis, renal
disease with hypertension and effect of corticosteroids. Better immunosuppressive
therapies are required to prevent this. Other steroid-induced morbidity
includes skin disease (striae), bone disease (avascular necrosis and osteoporosis),
eye disease (cataracts and glaucoma), risk of infection, GI disease (gastritis,
pancreatitis), hypertension and concern of cerebral dysfunction. A combination
of disease and drug-induced morbidities affect the vast majority of children
and adolescents with SLE (23).
To date, there is no clearly effective therapy for
manifestations of the antiphospholipid antibody syndrome. Current recommendations
from adult studies include life-long anticoagulation at levels that are
potentially dangerous for growing active children who are frequently exposed
to minor trauma and risk of bleeding (24).
Juvenile Dermatomyositis (JDM)
The mortality of JDM has been reduced significantly
over the last several decades to less than 5 to 10 percent. However, the
quality of life in patients with JDM is significantly affected by the disease
and its treatment. Patients at most risk for poor outcomes include those
with dysphagia and ulcerative skin disease at onset, severe vasculopathy
on initial muscle biopsy and relative "undertreatment" with high-dose corticosteroids
(25-27). As with SLE, there is concern with the ongoing morbidity both
from the disease and from corticosteroids. Corticosteroid-related morbidity
is similar to that associated with SLE. Disease-related morbidity includes
manifestations of severe skin disease, including poikiloderma and chronic
skin infection. Recently, the syndrome of lipoatrophy (insulin-resistant
diabetes, hyperlipidemia, acanthosis nigricans and amenorrhea) has been
reported in approximately 10% of patients with JDM. Cutaneous calcinosis
has been reported to occur in 20 - 60% of different series of patients
with JDM. Early treatment with high doses of corticosteroids seems to reduce,
but not prevent, this complication (27). One of the most important side
effects of corticosteroid treatment is growth delay, and in a series of
patients recently reported, 14 of 33 patients with a continuous form of
JDM were noted to be at least 1 standard deviation shorter than the mean
mid-parental high at a mean of 7.7 years of follow up (28). In this series,
a full 2/3 of patients were moderately or not at all satisfied with the
long-term outcome. Forty percent of patients still had rash, 27% of patients
were still weak and 39% of patients remained on medications. Again, this
indicates that current treatments do not result in cure, patients require
ongoing treatment to control disease activity, and significant morbidity
continues both from the disease manifestations and the treatment of the
disease.
Summary
While current treatments for the major connective
diseases of childhood have had a significant impact on mortality and on
morbidity as well, a significant number of patients remain with uncontrolled
disease activity and poor outcomes. Additionally, both disease and drug-related
morbidity remain major problems. New treatments are needed to reduce both
disease-related morbidity and drug-related toxicity.
Does Autologous Stem Cell Transplantation Make
Sense for Pediatric Rheumatic Diseases?
Raphael Hirsch MD
The concept of autologous stem cell transplantation
(ASCT) was initially developed as an aggressive treatment for malignancy.
The use of this technique for the treatment of rheumatic diseases is similar.
Aggressive therapy (radiation and/or high dose chemotherapy) is given with
the intent to destroy the cells that are responsible for the inflammatory
disease. In the process, hematologic stem cells are destroyed, and rescue
is accomplished by using the patient's own stem cells which were harvested
before treatment. For the treatment of cancer, the target cell is known.
It is the tumor cell. However, the target cell or cells for each of the
rheumatologic diseases is not known.
Figure 1
is a simplified cartoon of the immune process in juvenile idiopathic
arthritis synovium. The cells shown here in the rheumatoid synovium (in
addition to other cells not depicted such as dendritic cells and NK cells),
interact with each other. Exactly what each of these cells is doing and
which one of these cells should be the target of treatment is not known.
The current, most popular hypothesis is that an autoantigen is presented
by an antigen-presenting cell to a T cell. The T cell then becomes activated
and secretes potent inflammatory mediators. These inflammatory mediators
induce adhesion molecules, angiogenesis, activate fibroblasts and inflammatory
cells, such as macrophages, into the joint. The inflammatory mediators
begin degradation of cartilage. This hypothesis has been the focus of research
for the last twenty years, but this is problematic, as there is little
data to support it. Despite intensive efforts, an autoantigen that causes
arthritis has not been identified. An additional problem is that depletion
of T cells, which supposedly are the cells mediating this cascade of events,
does not result in ablation of arthritis (as demonstrated by the disappointing
results of anti-CD4 trials). Data from collagen-induced arthritis in animals
reveal that although the initiation of the arthritis appears to be T cell
dependent, once it is established, complete depletion of T cells (as well
as the B cells) has no effect on the course of the arthritis. Thus, the
hypothesis that most investigators have been working with may not be true.
There is new data in human beings that supports a
new hypothesis, and shifts focus of key affector cells to the fibroblast
(29,30). When fibroblasts from normal synovium are placed on cartilage,
they are quiescent and non-reactive. On the other hand, if rheumatoid fibroblasts
are placed on cartilage, even isolated from other cells as well as isolated
from inflammatory mediators, they erode the cartilage aggressively. The
fibroblasts no longer behave in a normal fashion even when removed from
the inflammatory milieu of the rheumatoid synovium. The rheumatoid fibroblasts
appear to have mutated and have become aggressive in their behavior. A
possible mechanism for this change in behavior is mutation in the site
called oncogene P53 (29,30).
Incorporating this information results in a new hypothesis
of rheumatoid arthritis in which there is still an initiating antigen,
possibly bacterial, that induces a T cell autoreactive (or crossreactive)
response. This initiates inflammation in the synovium. Once inflammation
has begun, the fibroblasts mutate and become aggressive in nature. This
process allows inflammation to persist in the absence of further T cell-mediation
and results in cytokines destructive to cartilage. If this hypothesis is
true, then what is the cell that needs to be targeted in arthritis, the
T cell or the fibroblast?
In addition to challenging our basic ideas of important
affector cells in arthritis, new information challenges current concepts
of the role of synovial inflammation in cartilage destruction. The inflammatory
process has recently been demonstrated to be separate from the process
of cartilage destruction. An illustration of this concept is current data
on interleukin-1 receptor antagonist (IL1-RA) (31). IL1-RA did not perform
as a powerful anti-inflammatory agent (in terms of reduction of joint swelling),
but had significant chondroprotective effects (31-33). Rheumatoid synovium
was wrapped around cartilage and implanted into a SCID mouse. The synovium
is not rejected and becomes a model where the synovium can thrive in an
in-vivo system for a couple of months, retaining its inflammatory phenotype.
The fibroblast of the synovium will invade the cartilage that is enclosed
within the synovium. If the synovium is treated with IL-10, the inflammation
in the synovium will be dramatically inhibited, but erosion of cartilage
will continue unabated. Conversely, if the same synovium is treated with
IL-4, inflammation is not changed, but erosion is inhibited. This suggests
that the fibroblasts can be inhibited with out affecting the inflammatory
process and vice versa.
When therapy as aggressive as stem cell transplantation
is contemplated, serious consideration needs to be given to the definition
of efficacy for this treatment. Is it enough to demonstrate eradication
of inflammation, or should there also be demonstrable cartilage protection?
Back to the initial question: which cell should be targeted in new aggressive
treatments? This becomes a critical issue if one agrees with the standard
hypothesis that the T cell is the target, as most preparative regimens
for stem cell therapy, such as radiation and chemotherapy tend to spare
memory T cells. Early data emerging from stem cell therapy in adult autoimmune
disease indicate that the preparative regimen significantly halts inflammation
(as macrophages and neutrophils are destroyed). If the memory T cell is
not completely destroyed, and if this is the cell that needs to be eliminated,
then these cells will recover and disease will recur. If the fibroblast
is the cell that should be destroyed, this is problematic, because fibroblasts
tend to be resistant to the preparative regimens commonly used. An initial
anti-inflammatory response, due to the depletion of macrophages and neutrophils
would most likely occur. The patient might be initially free of disease;
however erosion could continue and disease could recur if the fibroblasts
are not destroyed by the preparative regimen.
For SLE, JDM and systemic sclerosis (SSc) the same
questions regarding the appropriateness of autologous stem cell transplantation
persist: what is the target cell that needs to be destroyed and will the
preparative regimen destroy the target cell.
Technical Considerations in Autologous Stem Cell
Transplantation
Ann Woolfrey MD
Rationale for Stem Cell Transplants in Autoimmune Diseases.
Autologous stem cell transplants offer potential to improve treatment
of refractory autoimmune diseases in three respects. First, transplants
of autologous hematopoietic stem cells (HSC) could optimize delivery of
high-dose immunosuppression by rescuing the patient from myeloablative
side effects. In this respect, ASCT can be viewed as supportive therapy
for induction of long-lasting disease remission, but not necessarily curative
therapy. Second, highly intensive immunosuppression followed by autologous
ASCT could be curative. In this respect, immune ablation followed by reconstitution
of autologous hematopoiesis might allow "resetting" of the immune system,
through induction of peripheral tolerance. Finally, complete replacement
of the defective immune system after transplantation of allogeneic HSC
from a healthy donor could ameliorate the disease.
Autologous and allogeneic SCT have been tested in
preclinical animal models. Animals with genetic susceptibility to autoimmune
states have been cured by transplantation of genetically resistant HSC.
Animal models of induced autoimmune diseases have responded to both autologous
and allogeneic SCT. Initial human experience was derived from anecdotal
observations of disease remittance following allogeneic SCT for hematologic
disorders. Over the past several years, important pilot trials have demonstrated
efficacy of autologous as well as allogeneic SCT for inducing disease remission
in patients with refractory autoimmune disorders.
The designs of cooperative trials to treat refractory
autoimmune diseases in children depend upon an understanding of important
elements involved in SCT. These include knowledge of the various types
of HSC product used for transplantation and the fundamentals of high-intensity
therapies.
Source of Hematopoietic Stem Cells
Theoretically replacement of the autoreactive immune
system would best be accomplished by transplantation of allogeneic HSC.
Nonetheless, most initial trials in humans have studied the safety and
efficacy of autologous SCT. One practical reason is that most patients
lack an HLA-identical family member donor. A second reason is that autologous
SCT has been associated with less morbidity compared to allogeneic SCT.
Comparative data derives mainly from studies of patients with solid tumors,
where outcome is affected by relapse and non-relapse causes. Most comparative
studies find survival advantage for autologous recipients, despite the
risk for reinfusion of tumor cells (34-36). The
main additional risk from allogeneic HSC is development of graft-versus-host
disease (GVHD). About 20-30% of children who receive marrow from HLA identical
siblings will develop acute GVHD (grades II-IV), 15-25 % will develop clinical
extensive chronic GVHD, and mortality from GVHD occurs in 10-20% (37).
While initial trials have studied autologous SCT primarily for reasons
of practicality and safety, current results support the efficacy of this
approach in patients with JIA, SLE, and SSc.
Hematopoietic Stem Cell Products
HSC may be obtained by collection of bone marrow
or by mobilization and collection of peripheral blood stem cells (PBSC).
Collection of each product entails different technical limitations, particularly
important for pediatric donors. Marrow donors must undergo general anesthesia
and 75% of pediatric donors will require homologous blood transfusion or
pre-operative erythropoietin injections (P.Hoffmeister, et al, submitted
for publication). PBSC donors undergo a period of mobilization followed
by 1-4 days of apheresis. Smaller donors may require insertion of central
venous catheter and may receive homologous blood for priming the apheresis
machine. While there is no difference in the number or severity of adverse
events experienced by marrow and PBSC donors, there are qualitative differences
in types of events and pace of recovery (S. Rowley, et al, submitted for
publication). PBSC may be mobilized by chemotherapy such as cyclophosphamide
followed by cytokines such as G-CSF, or cytokines alone. Both methods have
been used successfully in patients with autoimmune diseases, although there
have been reported disease flares associated with G-CSF alone.
The main advantage of PBSC is the large increase
in number of HSC that can be obtained (38). The
benefits of high HSC dose have been shown in a number of studies, and include
reduction in transplant-related mortality, shorter time to recovery of
peripheral granulocyte and platelet counts, reduction of platelet and red
cell transfusions, as well as number of days in hospital (reviewed in reference
39). Marrow and PBSC differ quantitatively
and qualitatively in the number of CD34+ cells as well as other cell subsets,
including a 10-fold increase in number of CD3 cells in PBSC. CD34+ and
CD3 cells obtained by G-CSF mobilization may be functionally different,
and together with differences in types of accessory cells, the two products
may not be equivalent in types of immune cells reinfused or the kinetics
of immune reconstitution (S. Heimfeld, unpublished).
Over the past decade PBSC has replaced marrow as
the preferred product for reconstitution of autologous hematopoiesis, primarily
due to more rapid recovery of peripheral blood counts. The only major randomized
study comparing autologous marrow to PBSC found significant differences
in time to recovery of neutrophils and platelets, number of platelet and
red blood cell transfusions, and number of hospital days ( Table 1) (40).These
differences were similar to findings in other studies including pediatric
patients receiving autologous PBSC or marrow grafts (39,41,42).Improvement
in recovery of peripheral blood counts has been associated with fewer days
of antibiotics and blood component, fewer infections, and earlier hospital
discharge. The advantage of PBSC recently was made evident in a randomized
study of HLA identical related SCT, wherein a 1.9–fold (p= 0.02 ) reduction
in mortality was seen for PBSC recipients (43).
T Cell Depletion
Both marrow and PBSC contain T lymphocytes with the
potential to reintroduce the autoreactive state. Direct depletion of T
cells from the HSC product, or negative selection, involves immunologic
or physical methods that target T cells for removal ( Table 2) (reviewed
in reference 44). Used separately or in combination,
these methods result in 2 log10 to 3 log10 depletion
of T cells. Negative selection methods are more difficult to perform technically
in PBSC products than marrow due to the greater numbers of cells, particularly
T cells, generated by the mobilization procedure. Positive selection
of the relatively small numbers of hematopoietic progenitor cells is more
feasible, and results in a highly purified product that is depleted significantly
of contaminating T cells (45,46). Alternatively,
T cell depleting agents, such as anti-thymocyte globulin (ATG), can be
given to the patient after reinfusion of HSC as a means to prevent reconstitution
of autoreactive T cells. While it is difficult to measure the degree of
T cell depletion after ATG, it produces profound reduction in circulating
T lymphocytes.
Methods to deplete T cells from the reinfused stem
cell product may reduce the chances of reintroducing autoreactive T cells,
but also are associated with increased risks for opportunistic infections
after transplant. Although uncommon after autologous SCT, reactivation
of CMV and EBV have been reported more frequently after transplants of
T cell depleted HSC (47,48). An increase in opportunistic infections following
T cell depleted ASCT may be explained by delayed immune reconstitution.
Limited data from autologous CD34+ selected SCT in adult patients with
autoimmune disease suggests prolonged delay in reconstitution of T cells,
particularly naive CD4 cells (J. Storek, unpublished).
Conditioning Regimens
Conditioning regimens for autologous transplants
are designed to eliminate the underlying disease. Because marrow function
is rescued by transplantation of HSC, maximum intensity of the regimen
is dictated by dose-limiting toxicity of nonhematopoietic organs. Delivery
of intensive immune suppression has been the basis behind conditioning
regimens for autoimmune disorders. Potent immunosuppressive agents commonly
used in ASCT regimens include ATG, alkylating agents such as cyclophosphamide
or fludarabine, and total body irradiation (TBI) or total lymphoid irradiation
(TLI).
For a given agent, the intensity of an immunosuppressive
agent must be balanced against its short and long term toxicities. Because
lymphocytes are highly sensitive to irradiation, higher levels of immune
suppression can be achieved with TBI compared to an equivalently toxic
dose of another agent (49,50). This is best
exemplified in allogeneic ASCT wherein addition of TBI to the regimen abrogates
the high rates of graft rejection found in recipients of HLA mismatched
allogeneic grafts or in presensitized aplastic patients.
The main disadvantage of TBI is the increased incidence
of long-term complications including development of cataracts, sterility,
hormonal deficiencies, and secondary malignancies. The degrees to which
these sequelae occur depend on the dose of TBI. Most data regarding risks
of TBI are derived from patients who received ³
12.0 Gy and there is comparatively little data among patients who received
lower doses (4.0-8.0 Gy which are the doses being used in protocols of
ASCT for autoimmune diseases). Risk for secondary malignancy is significantly
higher among patients treated ³
12 Gy fractionated or ³
10 Gy single dose TBI (1.8-4.4 relative risk), but not in those who received
less (1.2 relative risk) (51). Likewise, 77%
of children undergo normal pubertal development after TBI doses of ³
12.0 Gy, compared to 94% among those given less (52).
Implications for Trial Design
The endpoints of safety and efficacy must be considered
when designing a trial of ASCT, regardless of the target disease. Patients
with refractory autoimmune disorders and their rheumatologists are best
suited to decide what degree of risk is acceptable when undergoing these
experimental procedures. The most effective procedures will undoubtedly
entail the most risk. The role of pilot studies is to establish the safety
for a given ASCT procedure. To answer questions regarding the effectiveness
of each element, for example whether TBI or T cell depletion are required
for successful autologous SCT, there will need to be cooperative group
studies that address each question in a meaningful way.
Minimum Center Requirements for Autologous Stem
Cell Transplantation Protocols:
Mitchell Horwitz MD
I will discuss the four primary components of autologous
stem cell transplantation; stem cell collection, cell processing and storage,
the conditioning regimen, and supportive care.
Stem cell collection
Historically, stem cells used for autologous stem
cell transplantation were collected directly from the bone marrow. A minor
operative procedure was required to collect the graft. Patients received
general anesthesia and multiple aspirations from the posterior superior
iliac crest were performed until 10-20ml/kg of marrow was collected. The
overall complication rate for this procedure was low. When complications
arose, they were usually a consequence of general anesthesia. Excessive
bleeding or pain at the aspiration site have also been described.
During the 1990’s, peripheral blood replaced bone
marrow as the favored source for stem cells. Since few stem cells are present
in the circulation at steady state, hematopoietic growth factors such as
granulocyte-colony stimulating factor are administered to "mobilize" stem
cell. Following a 5-6 day course of cytokine therapy, large numbers of
peripheral blood stem cells can be collected from peripheral circulation
by apheresis. Many large academic medical centers have an apheresis unit
that can be adapted for peripheral blood stem cell collection. If not,
regional blood centers may be able to provide this service. The advantage
of peripheral blood stem cell collection is that the patient need not receive
general anesthesia thereby reducing the risk. Furthermore, a larger stem
cell collection is usually feasible from mobilized peripheral blood as
compared to the bone marrow.
Cell Processing
Depending on protocol design, processing of the autograft
ranges from simple cryopreservation to complex engineering such as CD34
selection and T-cell depletion. Since we are considering autologous stem
cell transplantation for autoimmune diseases, some form of T-cell depletion
may hold some appeal. Non-antibody based methods of T-cell depletion include
E-rosetting, soybean lectin agglutination and centrifugal elutriation.
Each of these methods has been adapted for clinical use. Positive selection
for hematopoietic stem cells may be accomplished by using anti-CD34 antibodies
and immunomagnetic beads. (Further discussion of this topic is found in
the section by Drs. Siegel and Rider)
Conditioning Regimens
Whether one is treating a malignancy or an autoimmune
disorder, the conditioning regimen will determine disease response. The
conditioning regimen may consist of chemotherapeutic agents, radiation
therapy or new generation biologic agents such as monoclonal antibodies.
Most pediatric oncology wards are capable of providing the equipment and
the expertise required for safe administration of these agents.
Supportive Care
Most experts would agree that given the brief period
of neutropenia observed when peripheral blood stem cells are used for transplantation,
patient rooms with laminar air flow or high efficiency particular air (HEPA)
filtration is unnecessary. The medical care team must be well versed in
management of neutropenic patients. This includes rigorous work-up of patients
who develop fever and administration of empiric broad-spectrum antibiotics
while the work-up is underway. Appropriate prophylaxis against pneumocystis
pneumonia and herpes zoster or herpes simplex infections is recommended,
especially when potent immunosuppressive conditioning regimens are combined
with T-cell depleted autografts.
The extent of blood product support is dependent
on the myelosuppressive activity of the conditioning regimen. Blood and
platelet support for 7-14 days may be necessary following some high dose
conditioning regimens, particularly for patients who have been heavily
pre-treated with alkylating agents prior to the transplant. All blood products
should be leukocyte depleted to prevent transfusion-associated graft versus
host disease. Adequate leukodepletion of all blood products should also
serve to prevent patients who are seronegative for cytomegalovirus from
primary exposure to this virus from the transfusion.
In summary, minimum center requirements for protocols
involving autologous stem cell transplantation require expertise in peripheral
blood stem cell collection, cell processing and storage, administration
of chemotherapeutic conditioning regimens and supportive care of immunocompromised
patients. With the exception of expertise and equipment necessary for complex
manipulation of the autograft such as CD34 selection, most large academic
centers have the capability of supporting such an endeavor.
Issues in Drug Development of Stem Cell Selection
Devices in Autologous Stem Cell Transplantation for Pediatric Autoimmune
Diseases
Jeffrey N. Siegel MD and Lisa G. Rider MD
The Food Drug and Cosmetic Act grants the Food and
Drug Administration (FDA) the authority to regulate unapproved devices
including CD34+ stem cell selection devices used in SCT. FDA reviews clinical
trials involving the use of unapproved devices under applications called
Investigational Device Exemptions (IDE). Devices approved for a specific
indication that are being studied for indications that are not approved,
particularly where the use involves significant risk, are also regulated
by the FDA (21CFR 812.2). New cell selection devices become marketed or
new indications become approved for already marketed cell selection devices
through the pre-market approval (PMA) process. The device manufacturer
submits a PMA application to the agency, which contains the results of
clinical trials designed to show the device is safe and effective for its
intended use.
Two CD34+ stem cell selection devices, the Nexell
Isolex 300i and the AmCell CliniMACS, have been used in SCT studies to
deplete autologous sources of stem cells of contaminating T cells in patients
with autoimmune disease. The Isolex device is approved in the U.S. "for
hematopoietic reconstitution after myeloablative therapy in patients with
CD34-negative tumors," but not for the treatment of autoimmune disease.
The AmCell device has not been approved for use in the United States. Thus,
clinical studies of SCT for autoimmune diseases that utilize either of
these devices require an IDE from the FDA.
Generally, clinical development proceeds according
to progressive phases; initially small studies are the first or early human
exposure to a product, followed by larger multi-center trials designed
to establish safety and efficacy. Early in development, when the device
is being used along with a new conditioning regimen or where there is a
novel safety issue, a small study to gain some preliminary safety experience
before exposing a larger number of patients is appropriate.
Currently, there are a number of active IDEs for
autoimmune disease indications using stem cell selection devices. Most
studies using these devises are single arm, single center studies of adult
patients. The most common indications under study are SLE, RA, SSc and
multiple sclerosis (MS). One pediatric protocol includes patients with
JIA and other autoimmune diseases.
To date, outcomes from these early studies of ASCT,
although mixed, suggest some potential for benefit (53). In studies of
ASCT in RA, SLE and SSc, some patients appear to have a marked reduction
in disease activity in the absence of concomitant disease-modifying therapies
or induction of remission for up to 3 years following transplantation.
However, late relapses, including increases in autoantibody titers without
clinical relapse, have also been observed 6 months to 2 years after the
procedure (53-57). Transplant-related mortality has been reported to be
approximately 9% overall in autoimmune diseases (57). In some studies of
SSc, however, mortality has been estimated to be as high as 25%, perhaps
partly attributable to the selection of the most seriously ill patients
with more long-standing disease. Fatal pulmonary toxicity has been reported
in SSc patients who received total body irradiation without lung shielding,
and preliminary data suggest that pulmonary toxicity may be diminished
when lung shielding is used during radiation (57).
FDA may disapprove a clinical trial of a new device
if "there is reason to believe that the risks to the subjects are not outweighed
by the anticipated benefits to the subjects and the importance of the knowledge
to be gained…" (21 CFR 812.30(b)(4)). Once the pilot studies are
performed, the limited information that can be obtained from additional
single arm, uncontrolled studies may not justify the substantial risks
of ASCT for autoimmune diseases.
Randomized controlled clinical trials, adequately
powered to establish effectiveness, are needed to determine whether ASCT
provides clinical benefit for the treatment of autoimmune diseases. However,
prior to conducting a definitive, large multi-center, randomized controlled
efficacy trial, a moderately-sized randomized controlled trial of ASCT
in autoimmune disease could be carried out, in which patients who meet
the eligibility criteria described above are randomized to either ASCT
or optimal medical management. Such trials would have the distinct advantage
over non-concurrently controlled studies in that the safety profile and
potential benefits in patients who received an ASCT procedure can be directly
compared to outcomes in patients who do not receive a transplant. A moderately
sized, randomized, controlled phase 2 trial could help in providing estimates
of the effect size in order to determine the appropriate sample size of
a subsequent pivotal trial. However, it is important to be aware that such
phase 2 studies cannot ultimately substitute for an adequately powered
phase 3 trial.
Pediatric patients represent a special situation.
When the course of the disease and the effects of the therapy are thought
to be similar in adults and children, such as might be the case with SSc
or SLE, and effectiveness is demonstrated through adequate and well-controlled
trials in adults, it may be appropriate to extrapolate efficacy results
from adult studies to children, as may be done for labeling of certain
drugs and biologics for pediatric use (21 CFR 201.57 (f) (9) (iv)). In
these cases, even if separate efficacy trials are not necessary in order
for the device to be labeled for use in pediatric patients, it would still
be important to obtain some safety experience with the device in children
and to assess response rates. This could be accomplished in open label
studies. In contrast, for indications where the pediatric disease is not
comparable to an adult condition, (e.g. systemic JIA) determination of
effectiveness may ultimately require a separate efficacy trial.
Design Issues of Particular Relevance to ASCT
Informed consent documents for patients entering
ASCT protocols should include an adequate description of the risks, including
the potential transplant-related mortality and failure to engraft, as well
as a frank discussion of the risks of secondary malignancy, sterility,
growth retardation, and secondary infections, either from the procedure
or from adjunctive agents used in the conditioning regimens (58). In patients
with MS, flares in disease activity have been associated with use of G-CSF
in the mobilization regimen (59). Of note, cases of Epstein Barr virus-associated
lymphoproliferative disease, some fatal, have been observed in patients
who received rabbit anti-thymocyte globulin (ATG) instead of the more commonly
used horse ATG.
A number of factors need to be considered when defining
inclusion criteria for ASCT protocols in pediatric autoimmune disease.
Due to the current risks associated with ASCT, patients selected for enrollment
should be at high risk of death or severe disability from the underlying
disease. Commonly used criteria include a high degree of active disease
despite treatment with all currently available therapy and the presence
of poor prognostic factors that justify the risks of this therapy.
Patients should be excluded from enrollment in ASCT
protocols if they have features placing them at unacceptable risk from
the transplant itself. Patients with ongoing infections should be excluded.
Patients unable to withstand the rigors of a transplant procedure due to
a poor functional status or organ system compromise, such as irreversible
or end-stage disease defined by significant impairment in left ventricular
ejection fraction, DLCO or creatinine clearance, and patients who have
received prior total lymphoid irradiation should be excluded from these
trials.
Patients with autoimmune disease enrolled in trials
should be closely monitored for short- and long-term toxicity. There should
be vigilant baseline screening and monitoring for occult infections, particularly
in those patients who have already received immunosuppressive therapies.
It is important to use a standardized toxicity assessment scale, such as
the National Cancer Institute’s Common Toxicity Criteria or the OMERACT
toxicity criteria, in order to systematically assess the frequency and
severity of adverse events. The protocol should specify a threshold for
the number, types and severity of adverse events that would lead to discontinuation
of enrollment. These might include unexpectedly high rates of engraftment
failure or mortality, a pre-specified number of grade 3 or 4 non-hematologic
toxicities, or transplant-related mortality exceeding a specified rate.
Adequate mobilization of autologous stem cells should be a prerequisite
to the initiation of the conditioning regimen.
For patients with systemic JIA who receive ASCT,
European experience suggests there may be an increased risk of MAS and
associated mortality in patients with active systemic disease at baseline
(60). These data suggest that JIA patients with ongoing fever or evidence
of MAS at baseline should be excluded from ASCT protocols. Patients should
be closely monitored for the development of MAS during and after ASCT through
such laboratory tests as fibrinogen, D-dimer, transaminases, and complete
blood count. Corticosteroid therapy should be tapered slowly, and when
infectious etiologies are excluded, additional steroids may need to be
given following the transplant procedure if MAS develops.
Public confidence in experimental trials depends
on complete and accurate reporting of adverse events. Investigators are
required to report unanticipated adverse device effects (ADEs 21 CFR
812.3 (s)), to their institutional review board (IRB) and to the sponsor
of the IDE within 10 working days (21 CFR 812.150(a)(1)). The sponsor
of an IDE is required to immediately conduct an evaluation of any unanticipated
ADE (21CFR 812.46) and report results to the FDA, to the IRBs of
all participating sites, and to participating investigators within 10 working
days after the sponsor of the IDE received notice of the adverse event
(21CFR 812.150(b)(1)).
Sponsors should be aware of other FDA requirements,
including the necessity of submitting all protocol changes to the Agency
prior to or, in some cases within 5 days of implementation (21CFR
812.35 (1)(3)(ii and iv). Progress reports for IDE submissions should be
filed with the Agency at least annually and should generally include the
current status of the trial, all adverse events observed to date, and any
changes in the protocol.
In conclusion, uncontrolled pilot studies of ASCT
suggest a potential for this treatment modality to be effective treatment
for patients with severe autoimmune disease, but these potential benefits
must be confirmed and weighed against significant morbidity and mortality
associated with the procedure. In designing clinical trials of ASCT in
children with autoimmune disease, every effort should be made so that patients
are not subjected to unreasonable risk. There are special safety considerations
in ASCT protocols for autoimmune diseases, particularly for pediatric patients
with systemic JIA. Finally, there is a critical need for well-designed,
randomized controlled trials of stem cell therapy of autoimmune diseases
for advancement to occur in the overall assessment of the efficacy and
safety of ASCT for these conditions.
Making A Case for A Multi-institutional Repository
of Biologic Materials for the Study of Pediatric Rheumatic Diseases Treated
with Autologous Stem Cell Transplantation
Lisa Filipovich MD
The establishment of a repository of biologic materials
from children with severe autoimmune disorders would provide a unique and
highly valuable resource for the future discovery of genes etiologic to
pediatric rheumatoid disorders, as well as a clearer understanding of which
genes are specifically engaged and upregulated as the symptomatic consequence
of the underlying genetic program. Materials to be collected would include
DNA, RNA, viably cryopreserved T cells (both resting and activated), and,
most importantly, EBV-transformed B cell lines.
With the advent of major clinical interventions,
such as autologous hematopoietic stem cell transplantation, that are currently
being applied to severe cases of rheumatoid diseases, an unprecedented
opportunity exists to elucidate pathogenic mechanisms responsible for clinical
disease, by studying gene expression during active disease (e.g. pretransplant)
and remission of disease (e.g. after transplant) in the same patient. Comparison
of gene expression between patient groups with different disease phenotypes,
by microarray techniques, could reveal common or divergent pathologic pathways
amenable to new targeted therapies.
Animal models of autoimmune disorders have taught
us that the etiology is often polygenic, and that a null mutation in a
gene seemingly critical on a given genetic background, may not prove as
pathogenic in another murine strain. Furthermore, genetic skewing of type
2 versus type 1 cytokine balance, and gender (differences in the sex hormone
milieu) predispose to symptomatic autoimmunity in murine models.
I hypothesize that children who develop severe, systemic
or multiple autoimmune complications are more likely to carry a stronger
genetic predisposition for these problems than patients who develop autoimmune
disorders as adults, where environmental exposure is required, as well
as hereditary predisposition, to express the "acquired" disease.
Severe and multiple autoimmune complications are
well-recognized complications in a number of genetically determined immunodeficiencies
with symptomatic onset in childhood. Indeed, as better antibiotics have
been developed to prevent and treat opportunistic infections and children
with certain immunodeficiencies are surviving longer, more autoimmune complications
are being observed. Autoimmune complications are seen in human disorders
where the T cell repertoire is limited and/or skewed, and when defects
in the normal balance of lymphoid proliferation vs. apoptosis occur. A
partial list of primary immunodeficiencies associated with autoimmune complications,
and arthritis in particular, are shown in Table 3. For some of these immunodeficiency
and immunoregulatory disorders the underlying gene defects are known –
such as mutations resulting in abnormal expression of MHC genes, CD40 ligand
and FAS, defects in RAG genes responsible for rearrangement of immunoglobulin
and T cell receptor genes, and microdeletions on chromosome 22 seen in
the DiGeorge Anomalad. Other immunodeficiencies, such as Common Variable
Immunodeficiency may be polygenic in etiology. For still others, the gene
responsible remains elusive.
It is also possible, indeed probable that mutations
leading to partial expression of genes responsible for severe immune/inflammatory
disorders, or a carrier state could predispose to autoimmune complications
in humans. A provocative example is provided by our recent study of perforin
gene expression in a patient with JIA who developed life-threatening macrophage
activation syndrome (MAS) – a complication symptomatically reminiscent
of the autosomal recessive genetic disorder HLH, Hemophagocytic Lymphohistiocytosis.
Recently, mutations in the perforin gene have been reported to be linked
with the development of HLH in a subset of children with that diagnosis.
FACS analysis of cytotoxic cells in carrier parents of the perforin mutation
causing HLH reveal decreased protein expression in these cell types when
compared with normal adult controls. A very similar abnormal (decreased)
pattern of perforin expression was detected in the JIA patient with MAS.
In light of the considerations described above one
can propose a battery of immune studies that could be performed as part
of the "pretransplant" gene finding protocol for children with severe autoimmune
disease who are potential candidates for autologous or allogeneic transplantation.
These are listed in Table 4.
Biologic samples to be collected both pretransplant,
and at intervals afterwards include EBV-transformed B cell lines, cryopreserved
DNA (PBMC), viably cryopreserved PBMC, cryopreserved mRNA (resting PBMC),
and cryopreserved mRNA (activated PBMC).
Finally, most proposed protocols for autologous transplantation
in autoimmune disease that have been piloted in the adult setting as "resetting
the immunoregulatory clock" involve extensive in vivo and in vitro immune
depletion aimed at ablating acquired autoimmune clones. Such immunoablation,
however, is broadly immunosuppressive and has resulted in an unacceptably
high risk of opportunistic viral infections with some protocols. For this
reason, monitoring immunoreconstitution across protocols and patient groups
could prove instructive both for purposes of monitoring posttransplant
recovery of desirable immune responses, as well as maintenance of remission
of clinical autoimmunity. Suggested studies for tracking immunoreconstitution
are listed in Table 5.
Autologous Stem Cell Transplantation for Refractory
Juvenile Idiopathic Arthritis: Current Results and Perspectives
Nico
M Wulffraat MD
A small proportion of children with systemic or polyarticular juvenile
idiopathic arthritis are refractory to combinations of nonsteroidal anti-inflammatory
drugs (NSAIDS) and immunosuppressive drugs such as methotrexate (MTX),
Cyclosporine (CsA), prednisone and anti-TNF treatment (6, 61-63). These
children challenge the pediatric rheumatologist to look for new possible
treatments. In the evaluation of such new treatments one needs to balance
a possible significant improvement of the quality of life with risk of
severe side effects. The first children with severe JIA treated with ASCT
were published earlier (64,65). We here report an extension of this study
in the Netherlands, which at present includes 14 children with JIA, with
a follow up of 3 to 40 months.
Patients
In the Dutch study, started in 1997, we included
14 patients with a follow-up of 3 to 40 months (median 20 months). The
clinical characteristics are given in Table 6. The inclusion criteria for
this trial were failure to respond to high dose MTX intramuscularly (1mg/kg/wk),
failure to respond to at least 2 DMARD’s, anti-TNF treatment (for patients
enrolled after October 1999), steroid dependency (>0.3mg/kg/day needed
to control symptoms), unacceptable toxicity to DMARD’s or steroids. Exclusion
criteria were cardio-respiratory insufficiency, chronic active infection
such as EBV, CMV, toxoplasmosis, spiking fever despite steroids, end stage
disease (Steinbrocker IV) or poor compliance.
We studied 10 children with systemic JIA and 4 with
poly articular JIA, all with progressive disease activity for more than
5 years despite the use of NSAIDS, prednisone (both maintenance dose and
pulses), cyclophosphamide pulses (750mg/m 2), MTX up to 1mg/kg/wk
IM. and CsA (2.5mg/kg/day). The clinical characteristics in all children
were a polyarticular course with erosions, osteoporosis, and stunted growth;
and in those with systemic onset disease, periods of spiking fever and
exanthema. Most of them suffered from steroid related side effects. The
mean time interval between diagnosis and transplant was 6 years (range
13 – 137 months).
Outcome measures
We used the core set of outcome variables for clinical
trials in childhood arthritis as proposed by Giannini and the Pediatric
Rheumatology International Trials Organisation group (PRINTO) (13, 66-69),
which consists of physician’s and parent/patient global assessment of disease
activity, functional ability as measured by the Childhood Health Assessment
Questionnaire (CHAQ), the number of joints with active arthritis (Fuchs
Swelling Index, FSI), the number of joints with limited range of motion
(EPM-ROM) and the erythrocyte sedimentation rate (ESR) (66-68). The evolution
of the disease in our patients was followed at a 3 months interval.
Bone Marrow harvest and T cell depletion
Unprimed bone marrow was harvested under general
anesthesia at least 1 month prior to ASCT. In patients 1 to 7 and patients
12 to 14, the graft was purged by 2 cycles of T cell depletion with CD2
and CD3 antibodies yielding a final suspension with a CD34 positive stem
cell count of 0.5 to 6.5 x 106/ Kg and less than 5 x 105 CD3
cells/Kg, and was stored in liquid nitrogen (70). In patients 8, 9, 10
and 11 the graft was purged by positive selection of CD34 positive stem
cells using the Clinimacs device. Thus a suspension was obtained containing
0.5 to 4 x 106 CD34 cells/Kg and less than 0.3 x 105
CD3 cells/Kg and was stored in liquid nitrogen.
Conditioning for ASCT
The conditioning regimen included 4 days of Anti-Thymocyte
Globulin (ATG, IMTIX, Pasteur-Merieux, France) in a dosage of 5 mg/Kg daily
from day -9 to -6, Cyclophosphamide in a dose of 50 mg/kg daily from day
-5 to -2; and low dose TBI (4 gray, single fraction) on day -1. At day
0 the frozen stem cell suspension was thawed and infused. MTX and CsA were
stopped before ASCT and prednisone was tapered after 2-6 months.
Hematological reconstitution
Neutrophil recovery (> 0.5x109/l) occurred
at day +20 to +30 and the platelet count reached 20x109/l after
16 to 35 days post ASCT. Five to 9 months after ASCT the numbers of circulating
T cells were normal (>1000/?L) with normal in vitro mitogenic responses
at 3 to 8 months after ASCT. CD4 lymphopenia (<500/?L) lasted 6 to 9
months, while the CD8 T cells returned to normal values after 3 to 4 months.
Interestingly in both CD4 and CD8 subsets, the first cells to return after
ASCT were CD45RO (memory) T cells. Nine months after ASCT the majority
of T cells were of the CD45RA (naive) phenotype.
Rheumatological Follow-up
Seven patients showed a drug free follow-up of 4
to 36 months with a more than 50% decrease in the scores of the CHAQ, the
physician’s global assessment and joint swelling (Figure 2, Figure
3 and Figure 4).
Two patients with a follow up of 3 and 4 months are clinically
in remission while the steroids have been gradually tapered.
ESR and CRP returned to near normal values within
6 weeks but were often increased during infections. In 2 patients the ESR
increased again after 3 months, with mild and transient synovitis of the
hip and knee, following VZV and tonsillitis. This relapse was very mild
with oligoarthritis and sporadic fever, and controlled easily with a 3-month
course of low dose prednisone and NSAID.
With regard to improvement as determined by the core
set criteria, 2 children showed only a partial response with a 30% improvement
of their disease. One child did not show any response and in 2 the follow
up is only 3 to 4 months. The remaining 7 all showed a more than 50% improvement.
Two patients died of a Macrophage Activation Syndrome (see below).
Growth after Auto-SCT
For each age, a mean length and standard deviations
have been described. A given length can thus be expressed as a Standard
Deviation Score (SDS) of Height for Age (71). Prior to the onset of their
disease, the children in this study had length between –0.2 and +2 SD of
the mean length for their age. During the course of their disease these
children lost 3 – 5 SDS (Figure 5).
After ASCT some of the younger children (such as patient 1 and 2 in Figure 5) show a catch up growth of 1-2 SDS, but the oldest children, with
the longest disease duration did not show catch up growth (patient 3 and
4 in Figure 5),
but their SDS did not decrease any further.
Complications
All children developed chills, fever and malaise
during infusion of ATG. During the aplastic period, blood cultures were
positive for S. epidermidis in 2 children. They responded favourable
to intravenous antibiotics. Seven patients developed a limited Varicella
Zoster virus (VZV) eruption, 3 to 18 months after ASCT, which was treated
by Acyclovir. One developed a localised atypical Mycobacterial infection.
Two patients died of a Macrophage Activation Syndrome (also known as infection-associated
hemophagocytic syndrome). The first case (patient 9) was induced by an
Epstein Barr Virus (EBV) 4 months after ASCT. At the time of the EBV infection,
her JIA was in remission. The other fatal MAS case (patient 11) occurred
18 days post transplant, while he was still in complete aplasia. The occurrence
of MAS in sJIA after ASCT may be caused by the T-cell depletion resulting
in inadequate control of macrophage activation. However there was no difference
in the number of re-infused T cells after CD 34 selection when compared
to children that did not develop MAS.
At a pediatric session of the EULAR conference held
in June 1999 in Glasgow these cases were discussed in detail. It was agreed
that the graft must contain not less than 1-5 x 105 T-cells/kg.
Furthermore, it was suggested that patients with active disease (fever),
not controlled by steroids, also be excluded from the study and that immune
suppression after autologous SCT should be tapered more slowly. In case
of unexplained fever >39°C for 48 hours, MAS must be considered and
treatment with methylprednisolone 20 mg/kg/day (in 4 divided dosages) and
Cyclosporine 2 mg/kg/day should be started immediately. If no effect is
seen within 48 hours, reinfusion of stored autologous T cells should be
considered.
Other EBMT/ABMT centers
Including our 14 patients with JIA, at present 29
patients with childhood onset JIA have been transplanted and registered
in the database of the Working Party for Autoimmune diseases of the European
Blood and Marrow Transplantation group (EBMT) from 12 centers in 10 countries
Table 7 (72). Clearly these children represent the most severe and drug
resistant forms of JIA. Of the reported 29 children, following transplantation,
16 were reported as in "drug free remission", 8 in partial remission or
relapse for which NSAIDs or low dose steroids were prescribed, and 1 as
a non-responder. The available data pertaining to the follow-up
after ASCT in these 29 children are limited and do not permit a detailed
analysis of the changes of the core set criteria. Regarding safety outcomes,
four patients have died. The cause of death was primarily infection
associated with aplasia. In 3 of these, hemophagocytosis, a well-known
complication of systemic JIA, was also present. This was preceded
by infections such as Epstein Barr Virus reactivation and disseminated
Toxoplasmosis, which may also induce hemophagocytosis.
Conclusion
In our study, ASCT induced a substantial clinical
benefit in all children with severe and drug resistant Juvenile Idiopathic
Arthritis. Prolonged prednisone free growth catch up and general well being
is a major therapeutic gain in such children. Since this approach was introduced
only 4 years ago, the current experience includes only case reports of
selected patients and a single open-label study. The results of this limited
number of patients treated with ASCT does not permit firm conclusions about
the optimal conditioning regimen, including the necessity of low dose TBI,
or the effect of T cell depletion of the graft. We chose a combination
of Cyclophosphamide and low dose TBI since this was most effective in an
animal model for arthritis (49).
It is to be noted, however, that this therapy in
patients with sJIA carries a significant risk of developing fatal MAS.
Factors that may predispose an individual to MAS, such as viral infections
must be identified and less profound T-cell depletion, control of systemic
disease prior to transplant and a slow tapering of steroids after ASCT
are advised. One of the most difficult aspects is to carefully weigh the
risks of the prolonged immunosuppression of "conventional" treatment against
those of the short but intense immunosuppression of ASCT. Furthermore this
new approach must be confirmed by randomised controlled studies in multicenter
trials. For this purpose we propose a randomised trial with 3 arms, including
a control arm with continuation of conventional therapy, ASCT with a T
cell depleted graft and ASCT with a full (non depleted) graft. With a predicted
response rate of 70% in the ASCT arms and 35% in the control arm, a total
of 36 patients must be included in each arm. Given the rarity of such treatment-resistant
disease, such a trial should be multicenter with 10 to 15 participating
centers. For such a trial, registry forms have been developed by joint
effort of ABMT and EBMT.
DAY 2 - WORKSHOPS
Below are reports from individual working groups that the participants
were divided among. The pediatric transplantation participants were asked
to discuss protocol development for studies beyond pilot investigations.
Simultaneously, participating pediatric rheumatologists were divided into
small work groups with instructions to develop entry and exclusion criteria
for autologous SCT for studies beyond pilot investigations and to determine
the optimal standard therapy for comparison in future randomized, controlled
studies.
Protocol Development: Consensus Meeting
Murray Passo MD., moderator
Four pediatric rheumatologists met with the transplanter participants
to develop protocol (or protocols) for stem cell transplantation for pediatric
autoimmune disease that would be used in the next phase of investigations
in randomized controlled trials. An interactive, collaborative process
known as Nominal Group Technique (NGT) was employed to generate a list
of specific components of the stem cell transplantation process in order
to establish consensus on a defined national protocol. In total, there
were 21 participants suggesting questions and ideas that were discussed
in detail.
Multiple protocols were discussed during the first day of this workshop.
These protocols were based on individual transplanter beliefs and experiences,
resources, prior protocol development, and institutional factors. Several
assumptions were made prior to consensus development:
1. There exists a paucity of children with autoimmune
disease who will require stem cell transplantation for refractory disease
management.
2. Given #1, there needs to be a consensus on the
design of the protocol for stem cell transplantation to conduct a meaningful
study for safety and efficacy.
There were several procedural aspects that emerged during
presentations the first day. Questions derived from those procedures set
the format for discussion prior to generating a consensus. These questions
included the following:
1. Graft source: peripheral blood stem cells versus
bone marrow stem cells.
2. Mobilization of the stem cells with G-CSF with
or without cyclophosphamide.
3. T-cell depletion/CD34 selection, specific methodology.
4. Conditioning/preparative phase, including aspects
such as total body irradiation, Fludarabine, BuCy, and cyclophosphamide
dosage (120-200 mg/kg).
5. Other transplant issues, such as supportive care
issues, data collection, case report forms, etc., were presented as potential
issues for discussion.
The format above was presented to spawn the consensus
meeting, whereupon participants quickly decided that we were not ready
to embark on protocol development. Numerous questions needed to be discussed
before the group could invest in discussion of a specific nationwide protocol.
Utilizing the Nominal Group Technique, we elicited
ideas, generating discussion of these for clarification and evaluation.
Each participant ranked these ideas anonymously, thus generating five top-ranking
questions to be answered before we could embark on a protocol:
1. The leading question was definition of achievement
of disease remission, including duration and event-free survival. This
was emphasized in regard to autologous stem cell transplantation.
2. Establish the safety, both morbidity and mortality,
of stem cell transplantation.
3. Uniform agreement on two specific features,
(a) reporting using the same forms, and (b) tracking eligible patients
(with or without transplantation). This was particularly notable since
we do not have a control group built into the current protocols, which
was mandated as essential by the Federal Drug Administration participants.
A control group would be patients who either did not receive transplantation
or received a different treatment.
4. Biologic questions, including the basic pathophysiology
of the autoimmune diseases and the impacts of stem cell transplantation.
A subcategory of this question included development of a data and tissue
repository.
5. Autologous bone marrow transplantation versus
allogeneic--which is more efficacious? Can the morbidity/mortality of allogeneic
transplant be reduced to an "acceptable" level (especially as viewed by
the pediatric rheumatologists)?
In summary, ideas were generated which required more
time to discuss before a specific protocol (or protocols) could be developed
and accepted nationwide. Due to time limitation it was suggested that a
Delphi Technique be employed to seek consensus. This technique is a similar
consensus technique done by serial questionnaires through the mail and
would be conducted within the next several months. This process is being
developed currently and will be reported on separately.
Workgroup: JIA Criteria for Study Comparing ASCT
and Best Standard Therapy
Carol Wallace MD, moderator
This workshop used the nominal group technique for
discussion and development of appropriate inclusion and exclusion criteria
for JIA for use in potential future randomized controlled trials of autologous
stem cell transplantation. In addition, a definition of "best standard
therapy" was discussed and developed, with the intent that it would serve
as the control arm in future studies. As regards inclusion and exclusion
criteria, there was considerable discussion as to WHEN would be the ideal
time for ASCT? How many agents needed to be tried, keeping in mind the
concerns of progressive joint destruction as well as possible cumulative
toxicities from therapy? If mortality from ASCT could become < 3%, patients
could potentially receive ASCT earlier in their course. Given the intensity
of the conditioning regimens, and the agents usually involved, there was
consensus that in future studies, ASCT could be an alternative to cyclophosphamide
therapy. From this discussion, the "best standard therapy" for JIA to compare
to ASCT then evolved to include cyclophosphamide. Below are the conclusions
of this workshop.
Inclusion Criteria
1. The diagnosis of systemic onset or polyarticular
course disease must be certain according to ACR criteria.
2. Duration of disease at least one year.
3. There must be evidence of active inflammatory
disease during at least the last 6 months
despite aggressive treatment. Evidence of
active inflammatory disease is defined by either a or b:
a. Evidence of active inflammatory disease in at
least 5 joints, including 2 critical joints. Critical joints are defined
as neck, shoulders, elbows, wrists, hips, knees, and ankles. Active inflammatory
disease is defined as joint swelling or effusion OR limitation of range.
b. Evidence of inflammatory disease in at least 4
joints including 2 critical joints AND 2 of the following:
-
6 months of active systemic features requiring corticosteroid
therapy of ³
0.25 mg/kg/d - defined by of at least 2 of the following: fever, growth
failure, serositis, pericarditis/myocarditis, lymphadenopathy, hepatosplenomegaly,
or interstitial pneumonitis.
-
Elevated erythrocyte sedimentation rate ³
1.5 times upper limit of normal.
-
Presence of erosive disease assessed by radiologic imaging
study
-
Rheumatoid factor positive disease.
-
Previous episode of severe MAS requiring hospitalization.
4. There must be evidence of unresponsiveness
to or unacceptable toxicity (defined below)
from aggressive therapy. Evidence for unresponsiveness
includes continued disease activity despite ALL of the following:
a. Inability to taper below £
0.25 mg/kg/d of prednisone or unacceptable toxicity.
b. Methotrexate (1.0 mg/kg/week SC or IM, up to
40 mg/week) for at least 3 months or until unacceptable toxicity.
c. Combination therapy consisting of: steroid pulse 30
mg/kg/week (1 gm max) or daily oral prednisone ³
0.25 mg/kg/d, and TNF antagonist, and either MTX and CSA or MTX and FK506
Evidence for unacceptable toxicity includes
at least two of the criteria defined below.
1. Failure to grow (dropping 2 SD or <3% for height)
related to corticosteroid use.
2. Severe osteoporosis (e.g.: vertebral or pathologic
fractures) related to corticosteroid use.
3. Avascular necrosis.
4. Severe, corticosteroid-induced, psychiatric disease.
5. Increase in serum creatinine >30% over baseline
on at least 2 separate occasions related to CSA use.
6. Hypertension requiring treatment related to medication
use. Diastolic or systolic pressure persistently higher than the acceptable
range for a given age.
7. Elevation of liver enzymes > 5 times the upper
limit of normal on at least 2 separate occasions related to MTX use.
8. Intractable gastrointestinal toxicity, from DMARDs
or MTX unresponsive to anti-emetics.
9. Recurrent serious infections due to treatment.
10. Steroid induced diabetes or pancreatitis.
Exclusion Criteria
1. Patients with fever >39o C.
2. Cytopenia- Absolute neutrophil count <1000
or platelet count <100,000 AND bone marrow aspirate or biopsy consistent with production
defect (depletion of neutrophil precursors or megakaryocytes) OR myelodysplasia.
3. Serious CNS damage precluding significant functional
recovery.
4. End-stage glomerulonephritis or renal disease.
Creatinine clearance <40 ml/minute/1.73m2.
5. Patients with DLCO <70% who have pulmonary
disease caused by processes other than the primary autoimmune disorder,
as documented by CXR or chest CT, including infectious pneumonia or aspiration
pneumonia.
6. End-stage cardio-pulmonary disease (including any
of the following):
a. DLCO <45%
b. Severe pulmonary hypertension (PAP >50) without
potential for significant improvement.
c. Uncontrolled malignant arrhythmia.
d. Clinical evidence of congestive heart failure
(New York Class III-IV) or ejection fraction <50%.
7. Severe liver dysfunction within one month prior to
transplantation. Bilirubin > 2.5 mg/dL or AST >300 U/L on 2 sequential
tests. Patients with myositis and AST >300 U/L are not excluded if it can
be demonstrated that elevated AST is not due to intrinsic liver dysfunction
(enzyme profile, hepatic ultrasound, or liver biopsy not compatible with
hepatitis or liver dysfunction).
8. Active viral hepatitis, including hepatitis A, hepatitis
B, and hepatitis C.
9. Patients with positive serology for toxoplasmosis.
10. HIV positive patients are excluded due to high
risk for acceleration or reactivation of viral replication.
11. Active life-threatening infections not responsive
to therapy.
12. Other disease or organ dysfunction that would
limit survival to less than 30 days.
13. No potential for improvement in function of affected
organ systems.
14. Known hypersensitivity to murine or equine proteins
or > to E. > > coli-derived products.
15. Known primary immunodeficiency disease.
Best Standard Therapy:
1. Solumedrol 30 mg/kg/week (1qm max)
2. Daily steroid ³ 0.25 mg/kg/day prednisone
3. MTX 1 mg/kg SC (or IM or IV) weekly (40 mg/kg/week max)
4. Cyclophosphamide 500-1,000 mg/m2 IV monthly
Workgroup: Systemic Sclerosis and Juvenile Dermatomyositis/Polymyositis
Lisa G. Rider MD, moderator
This workgroup was devoted to developing appropriate inclusion criteria
for a potential future randomized control trial of autologous stem cell
transplantation in pediatric patients with systemic sclerosis (SSc) and
juvenile dermatomyositis (JDM)/polymyositis (JPM). In addition the group
discussed a potential design for a randomized trial and appropriate outcome
criteria for such patients. Using nominal group technique to derive consensus,
the participants first agreed that SSc patients with interstitial lung
disease (ILD), pulmonary hypertension, or active, progressive cutaneous
disease would be potentially appropriate subgroups to include in trials
of SCT, due to their established poor prognoses and the current absence
of fully efficacious therapies for these complications (73-75). As has
been previously adapted by adult ASCT protocols, the participants agreed
to maintain general inclusion criteria for SSc patients as those with disease
duration of < 3 years from the first non-Raynaud’s symptom (73).
In addition, the group agreed to include patients with one of three possible
organ-specific criteria:
1. ILD with a DL-CO < 70% predicted with a decline in
DL-CO of > 10%, despite receiving > 3 months of optimal cyclophosphamide
therapy (73). Optimal cyclophosphamide therapy was considered to be 500
– 1000 mg/m2 monthly administered intravenously or 2 mg/kg/day
orally (76,77).
2. Pulmonary hypertension. Preliminary criteria were agreed to be
a pulmonary artery pressure > 10% of the upper limit of normal for age,
but further refinement is needed in this criterion pending input from pediatric
cardiologists.
3. Active, progressive cutaneous disease, with a Rodnan skin score
> 16 and/or > 10% progression in skin scores over a 3 month interval and
concomitant evidence of internal organ involvement (73), despite treatment
with at least methotrexate in a dose of 1 mg/kg/week parenterally and prednisone
1 mg/kg/day.
One potential design of a randomized controlled trial in scleroderma
was discussed: to randomize patients to receive an ASCT or to continue
best standard therapy. The participants felt that patients randomized to
best standard therapy should potentially continue to receive this for >
3 additional months, and if they then met the above-stated inclusion criteria
at that time, they would be declared a treatment failure and offered open
label ASC. For patients with ILD related to SSc, patients could be randomized
to ASCT or to continue receiving cyclophosphamide therapy. If the DL-CO
worsens to < 50% predicted, the participants felt that such patients
could be a candidate for early escape from best standard therapy, and then
offered ASCT. For pulmonary hypertension, appropriate best standard therapy
was agreed to be vasodilator therapy, including Epoprostenol (Flolan),which
has recently been approved for the treatment of pulmonary hypertension
associated with scleroderma (78). However, the group felt it would be appropriate
to terminate patients from best standard therapy (the placebo arm) if left
ventricular ejection fraction declined below a certain level (not determined
at this meeting), but remained > 50%, which would be an absolute exclusion
criteria (73). For patients with cutaneous disease, best standard therapy
was agreed by the participants to be methotrexate and prednisone. Early
escape from this therapy was not considered appropriate for skin disease.
The group agreed with the current exclusion criteria
for subjects with scleroderma for autologous SCT. These included signs
of end stage disease, including a DL-CO < 45% predicted or a left ventricular
ejection fraction < 50% (73).
Assessment of outcome measures for a trial of pediatric
SSc patients was also addressed. Discussion was limited by the fact that
fully validated measures do not currently exist for scleroderma. The participants
felt appropriate outcome measures may include pulmonary function testing
(FVC, DL-CO) and high resolution CT scan, with a quantitative scoring system
for patients with ILD. For patients with pulmonary hypertension, pulmonary
artery pressures would be an appropriate primary outcome in a trial. In
patients with skin disease, Rodnan skin scores were considered a validated
primary outcome measure (79). Similar to current protocols for ASCT in
adult SSc, the group adopted secondary outcome assessments for all scleroderma
patients as physician and parent/patient global assessments of disease
activity, as well as a validated measure of physical function, such as
the Childhood Health Assessment Questionnaire (80).
The group more briefly considered appropriate inclusion
criteria for a randomized controlled trial of ASCT in pediatric patients
with JDM or JPM. Consensus was reached that such patients would be appropriate
candidates for a randomized trial if they have evidence of one of the following
complications indicative of a poor prognosis or severe, recalcitrant disease
activity (81):
1. ILD with a DL-CO < 70% predicted with
a decline in DL-CO of > 10% over a 3 month period. Failure to respond,
or to have developed serious or unacceptable toxicity to optimal doses
of prednisone, methotrexate, as well as cyclophosphamide or cyclosporine,
prior to entering a randomized ASCT protocol (82).
2. Severe gastrointestinal or cutaneous ulcerations.
Failure to respond, or to have developed serious or unacceptable toxicity
to optimal doses of prednisone, methotrexate, and cyclophosphamide, administered
for > 3 months each, prior to entering a randomized ASCT protocol
(81).
3. Severe myositis resulting in Steinbrocker functional
class 3 or 4, with a disease duration > 6 months and persistent
active disease based upon evidence from serum muscle enzymes, magnetic
resonance imaging, electromyography or muscle biopsy. Patients with severe
myositis should have received several agents for 4 months duration for
each agent, or to have experienced serious or unacceptable toxicity to
these agents, prior to entering a ASCT protocol. This included prior receipt
of optimal prednisone therapy in combination with at least 2 of the following:
methotrexate, intravenous gammaglobulin, cyclosporine, cyclophosphamide
and tacrolimus (81).
For pediatric patients with JDM or JPM, a similar potential
design for a randomized controlled trial of ASCT was discussed: to randomize
patients to receive ASCT or to receive best standard therapy. The participants
felt it was appropriate for those randomized to best standard therapy to
continue this for > 3 additional months and then if patients met
the above stated inclusion criteria, to declare them a non-responder and
offer open label ASCT. For patients with severe myositis, randomization
could be to a different immunomodulatory agent, rather then continuing
the same agent for 3 additional months, and an appropriate duration was
felt to be 4 months prior to declaring the patient a treatment failure.
For JDM/JPM patients with ILD, criteria for early escape from best standard
therapy were agreed to be similar to SSc.
In summary, randomized controlled trials of ASCT
in pediatric patients with SSc or JDM/JPM were thought to be optimally
performed in patients with poor prognostic factors who also demonstrate
recalcitrant disease activity despite adequate courses of standard of care
therapy currently available for such complications. A potential trial design
for such patients is to randomize patients to receive ASCT vs. continue
background therapy at a time point 3 - 4 months after currently available
optimal therapy has been initiated. For patients who continued on background
therapy and continued to deteriorate at a time 3 – 4 months after randomization,
patients could be declared non-responders and then offered open label ASCT.
Patients receiving background therapy could also have the possibility of
early escape sooner if disease activity progressed while remaining on background
therapy.
Workgroup: Systemic lupus erythematosus.
Ronald
M. Laxer MD, moderator
The workgroup developed draft consensus guidelines regarding appropriate
inclusion criteria for patients with systemic lupus erythematosus (SLE)
undergoing autologous stem cell transplantation and discussed "best treatment"
to use as a control arm. We felt strongly that to really assess the impact
of such treatment, long-term studies will need to be done. It will be critical
to ensure that patients have reversible disease before undergoing ASCT.
Inclusion Criteria
1. Patients must fulfill at least 4/11 ACR Classification Criteria
for the diagnosis of SLE.
2. Disease for at least 6 months duration.
3. There must be evidence of unresponsiveness to or unacceptable toxicity from "standard aggressive" therapy (see below). There must be
evidence of active disease (versus progressive chronic change) for at least the last 6 months despite standard aggressive treatment. Evidence of active
disease can include at least one of the following:
a. Active glomerulonephritis, Class IV, biopsy proven (we did not
agree as to what time frame the biopsy needed to be done to define active/irreversibility);
b. Active CNS SLE (cerebritis, seizures, organic brain syndrome, psychosis not related to prednisone);
c. Active hematologic cytopenia, i.e. thrombocytopenia, or hemolytic anemia not supportable by transfusion therapy and failing intravenous immune
globulin, anti-D, danazol;
d. Thrombotic thrombocytopenic purpura that is plasmapheresis dependent;
e. Active pulmonary disease, defined by high resolution CT scanning,
BAL or pulmonary function testing, including pulmonary hemorrhage, pulmonary
hypertension, interstitial lung disease;
f. Transverse myelitis.
g. Anti-phospholipid antibody syndrome with organ infarction
While standard aggressive therapy is debatable for many of the clinical scenarios, we reached consensus that high dose
daily corticosteroids (2 mg/kg/day in 3 divided doses for 6-8 weeks followed by consolidation and a slow taper) with 6 months of IV monthly cyclophosphamide
(500-1000 mg/m2) would need to be failed to enter patients into
ASCT protocols. The debates about "standard aggressive therapy" centered upon the role of azathioprine, mycophenolate mofetil (MMF), cyclosporine
and additional cyclophosphamide. The recent data on MMF suggest that it may be effective for lupus nephritis (83), but its place in the treatment
of SLE is not yet defined. Some members felt that a failure of cyclophosphamide might suggest changing to MMF; others felt that MMF should be used before
cyclophosphamide and that failing cyclophosphamide, whenever it was used, was enough to define a "treatment failure". This is an evolving field and
the criteria will change as we learn more about MMF and other new treatments for SLE. We did not feel that plasmapheresis had to be attempted.
Evidence for unacceptable toxicity includes:
1. Steroid induced diabetes or pancreatitis
2. Severe osteoporosis related to corticosteroid use
3. Avascular necrosis
4. Treatment-related leukopenia and/or thrombocytopenia
5. Hemorrhagic cystitis
6. Recurrent serious infections due to treatment
One potential design of a randomized controlled trial in SLE would be to randomize patients to either ASCT or to continue best
standard therapy. The participants felt that patients randomized to best standard therapy should potentially continue to receive this for up to
6 months, and then if they met the above agreed to indications, they would be declared a treatment failure and be eligible for open-label ASCT. For
patients who are not randomized to the ASCT group but continue to deteriorate over the 6 months, they could be declared non-responders and then offered
open-label ASCT. Patients randomized to best standard therapy could also have the possibility of early escape sooner if disease activity progressed
while remaining on this therapy.
Although the randomization arm for treatment failure
was not agreed upon, the following options were discussed:
1. Continuing 6 months of IV cyclophosphamide;
2. Changing to oral cyclophosphamide 1.5-2.5 mg/kg/day;
3. MMF
4. Increasing prednisone, assuming that the reason to change therapy was NOT steroid toxicity.
While treatment outcomes were not discussed, they should include:
1. Organ-specific outcomes (e.g. improvement in renal function, improvement in mental status, improvement in hemoglobin and platelet
count)
2. Disease-activity measures (e.g., SLEDAI, SLAM, BILAG, all of which may be used in SLE in children and adolescents)
3. Disease-damage measures
4. Quality of life and health related quality of life measures.
Acknowledgements
The authors wish to thank the Office of Rare Diseases, National
Institutes of Health and the Division of Intramural Research, National
Institute of Allergy and Infectious Diseases, National Institutes of Health
for supporting this workshop. In addition, Drs. Siegel and Rider thank
Ms. Bette Goldman and Drs. William Schwieterman, Kathryn Stein, Karen Weiss,
and Jay Siegel for critical reading of the manuscript.
References
1. Wallace CA, Levinson JE. Juvenile rheumatoid arthritis: outcome
and treatment for the 1990s. Rheum Dis Clin North Am 1991;17(4):891-905.
2. Zak M, Pedersen
FK. Juvenile chronic arthritis into adulthood: a long-term follow-up study.
Rheumatology (Oxford) 2000; 39: 198-204.
3. Baum
J, Gutowska G. Death in juvenile rheumatoid arthritis. Arthritis Rheum
1977; 20S: 253-255
4. Halle F, Prieur
AM. Evaluation of methotrexate in the treatment of juvenile chronic arthritis
according to the subtype. Clin Exp Rheumatol 1991; 9: 297-302.
5. Speckmaier
M, Findeisen J, Woo P, Hall A, Sills JA, Price T, et al. Low-dose methotrexate
in systemic onset juvenile chronic arthritis. Clin Exp Rheumatol 1989;7:647-50.
6. Ravelli
A, Ramenghi B, Di Fuccia G, Ruperto N, Zonta L, Martini A. Factors associated
with response to methotrexate in systemic-onset juvenile chronic arthritis.
Acta Paediatr 1994;83:428-32.
7. Wallace
CA, Sherry DD. Preliminary report of higher dose methotrexate treatment
in juvenile rheumatoid arthritis. J Rheumatol 1992;19:1604-7.
8. Reiff A, Shaham B, Wood BP, Bernstein BH, Stanley
P, Szer IS. High dose methotrexate in the treatment of refractory juvenile
rheumatoid arthritis. Clin Exp Rheumatol 1995;13:113-8.
9. Gottlieb
BS, Keenan GF, Lu T, Ilowite NT. Discontinuation of methotrexate treatment
in juvenile rheumatoid arthritis. Pediatrics 1997;100:994-7.
10. Ravelli
A, Viola S, Ramenghi B, Beluffi G, Zonta LA, Martini A. Radiologic progression
in patients with juvenile chronic arthritis treated with methotrexate.
J Pediatr 1998;133:262-5.
11. Speigel
LR, Schneider R, Lang BA, Birdi N, Silverman ED, Laxer RM, et al. Early
predictors of poor functional outcome in systemic-onset juvenile rheumatoid
arthritis-a multicenter cohort study. Arthritis Rheum 2000; 43:2402-9.
12. Lovell DJ, Giannini EH, Reiff A, Cawkwell GD,
Silverman ED, Nocton JJ, et al. Etanercept in children with polyarticular
juvenile rheumatoid arthritis. N Engl J Med 2000;342:763-9.
13. Giannini
EH, Ruperto N, Ravelli A, Lovell DJ, Felson DT, Martini A. Preliminary
definition of improvement in juvenile arthritis. Arthritis Rheum 1997;40(7):1202-9.
14. McCurdy
DK, Lehman TJ, Bernstein B, Hanson V, King KK, Nadorra R, et al. Lupus
nephritis: prognostic factors in children. Pediatrics 1992; 89:240-6.
15. Yang
LY, Chen WP, Lin CY. Lupus nephritis in children-a review of 167 patients.
Pediatrics 1994; 94:335-40.
16. Baqi
N, Moazami S, Singh A, Ahmad H, Balachandra S, Tejani A. Lupus nephritis
in children: a longitudinal study of prognostic factors and therapy. J
Am Soc Nephrol 1996; 7:924-9.
17. Steinberg
AD, Steinberg SC. Long-term preservation of renal function in patients
with lupus nephritis receiving treatment that includes cyclophosphamide
versus those treated with prednisone only. Arthritis Rheum 1991;34: 945-50.
18. Lehman
TJ, Onel K. Intermittent intravenous cyclophosphamide arrests progression
of the renal chronicity index in childhood systemic lupus erythematosus.
J Pediatr 2000; 136:243-7.
19. Mok
CC, Lau CS, Wong RW. Risk factors for ovarian failure in patients with
systemic lupus erythematosus receiving cyclophosphamide therapy. Arthritis
Rheum 1998;41: 831-7.
20. Ioannidis
JP, Boki KA, Katsorida ME, Drosos AA, Skopouli FN, Boletis JN, et al. Remission,
relapse, and re-remission of proliferative lupus nephritis treated with
cyclophosphamide. Kidney Int 2000; 57:258-64.
21. Urowitz
MB, Gladman DD. Evolving spectrum of mortality and morbidity in SLE. Lupus
1998; 8:253-5.
22. Gazarian
M, Feldman BM, Benson LN, Gilday DL, Laxer RM, Silverman ED. Assessment
of myocardial perfusion and function in childhood systemic lupus erythematosus.
J Pediatrics 1998; 132:109-16.
23. Lacks S, White P.
Morbidity associated with childhood systemic lupus erythematosus. J Rheumatol
1990; 17:941-5.
24. Khamashta
MA, Cuadrado MJ, Mujic F, Taub NA, Hunt BJ, Hughes GR. The management of
thrombosis in the antiphospholipid-antibody syndrome. N Engl J Med 1995;
332:993-7.
25. Taieb A, Guichard
C, Salamon R, Maleville J. Prognosis in juvenile dermatopolymyositis: a
cooperative retrospective study of 70 cases. Pediatr Dermatol 1985; 2:275-81.
26. Crowe
WE, Bove KE, Levinson JE, Hilton PK. Clinical and pathogenetic implications
of histopathology in childhood polydermatomyositis. Arthritis Rheum 1982;
25:126-39.
27. Bowyer SL, Blane CE, Sullivan DB, Cassidy JT.
Childhood dermatomyositis: factors predicting functional outcome and development
of dystrophic calcification. J Pediatr 1983; 103: 882-8.
28. Huber
AM, Lang B, LeBlanc CM, Birdi N, Bolaria RK, Malleson P, et al. Medium-
and long-term functional outcomes in a multicenter cohort of children with
juvenile dermatomyositis. Arthritis Rheum 2000; 43:541-9.
29. Aupperle
KR, Boyle DL, Hendrix M, Seftor EA, Zvaifler NJ, Barbosa M, Firestein GS. Regulation of synoviocyte
proliferation, apoptosis, and invasion by the p53 tumor suppressor gene.
Am J Pathol 1998; 152:1091-98.
30. Tak,
PP, Zvaifler NJ, Green DR, Firestein GS. Rheumatoid arthritis and p53: how oxidative stress
might alter the course of inflammatory diseases. Immunol Today 2000; 21:78-82.
31. Jiang,
YH, Genant K, Watt I, Cobby M, Bresnihan B, Aitchison R, McCabe D. A multicenter, double-blind,
dose-ranging, randomized, placebo-controlled study of recombinant human interleukin-1 receptor
antagonist in patients with rheumatoid arthritis: radiologic progression and correlation of Genant
and Larsen scores. Arthritis Rheum 2000; 43:1001-9.
32. Muller-Ladner
UC, Evans H, Franklin BN, Roberts CR, Gay RE, Robbins PD, Gay S. Gene transfer of cytokine inhibitors
into human synovial fibroblasts in the SCID mouse model. Arthritis Rheum 1999; 42:490-7.
33. Jorgensen
C, Apparailly F, Canovas F, Verwaerde C, Auriault C, Jacquet C, Sany J. Systemic viral
interleukin-10 gene delivery prevents cartilage invasion by human rheumatoid synovial
tissue engrafted in SCID mice. Arthritis Rheum 1999; 42:678-85.
34. Stein
RS, Greer JP, Goodman S, Kallianpur A, Ahmed MS, Wolff SN. High-dose therapy
with autologous or allogeneic transplantation as salvage therapy for small
cleaved cell lymphoma of follicular center cell origin. Bone Marrow Transp 1999;
23:227-33.
35. Matthay KK, Seeger RC, Reynolds CP, Stram DO,
O'Leary MC, Harris RE, et al. Allogeneic versus autologous purged bone
marrow transplantation for neuroblastoma: a report from the Childrens Cancer
Group. J Clin Onc 1994; 12:2382-9.
36. Ladenstein R, Lasset C, Hartmann O, Klingebiel
T, Bouffet E, Gadner H, et al. Comparison of auto versus allografting as
consolidation of primary treatments in advanced neuroblastoma over one
year of age at diagnosis: report from the European Group for Bone Marrow
Transplantation. Bone Marrow Transp 1994; 14:37-46.
37. Sullivan
KM. Graft-versus-host disease. In: Thomas ED, Blume KG, Forman SJ,
editors. Hematopoietic Cell Transplantation. Malden, MA: Blackwell Science,
Inc.:1999: 515-36.
38. Theilgaard-Monch K, Raaschou-Jensen K, Andersen
H, Russell CA, Vindelov L, Jacobsen N, et al. Single leukapheresis products
collected from healthy donors after the administration of granulocyte colony-stimulating
factor contain ten-fold higher numbers of long-term reconstituting hematopoietic
progenitor cells than conventional bone marrow allografts. Bone Marrow
Transpt 1999; 23: 243-9.
39. Demirer T, Bensinger WI, Buckner CD. Peripheral
blood stem cell mobilization for high-dose chemotherapy. J Hematother 1999;
8:103-13.
40. Schmitz N, Linch DC, Dreger P, Goldstone AH,
Boogaerts MA, Ferrant A, et al. Randomized trial of filgrastim-mobilized
peripheral blood progenitor cell transplantation versus autologous bone
marrow transplantation in lymphoma patients. Lancet 1996; 347:353-7.
41. Figuerres E, Haut PJ, Olzewski M, Kletzel M.
Analysis of parameters affecting engraftment in children undergoing autologous
peripheral blood stem cell transplants. Bone Marrow Transpt 2000;
25: 583-8.
42. Perentesis JP, Katansis
E, DeFor TE, Neglia J, Ramsay N. Autologous stem cell transplantation for
high-risk pediatric solid tumors. Bone Marrow Transpt 1999; 24:
609-15.
43. Bensinger W, Martin P, Clift R, et al. A prospective
randomized trial of peripheral blood stem cells (PBSC) or marrow (BM) for
patients undergoing allogeneic transplantation for hematologic malignancies.
Blood 1999; 94:368a.
44. Kernan NA. T-cell depletion for the prevention
of graft-versus-host disease. In: Thomas ED, Blume KG, Forman SJ,
editors. Hematopoietic Cell Transplantation. Malden, MA: Blackwell Science,
Inc.,1999: 186-96.
45. Rowley SD, Loken M, Radich J, Kunkle LA, Mills
BJ, Gooley T, et al. Isolation of CD34+ cells from blood stem cell components
using the Baxter Isolex system. Bone Marrow Transpt 1999; 21: 1253-62.
46. Handgretinger R, Lang P, Schumm M, Taylor G,
Neu S, Koscielnak E, et al. Isolation and transplantation of autologous
peripheral CD34+ progenitor cells highly purified by magnetic-activated
cell sorting. Bone Marrow Transpt 1998; 21: 987-93.
47. Holmberg LA, Boeckh M, Hooper H, Leisenring W,
Rowley S, Heimfed S, et al. Increased incidence of cytomegalovirus disease
after autologous CD34-selected peripheral blood stem cell transplantation.
Blood 1999; 94: 4029-35.
48. Chao NJ, Berry GJ, Advani R, Horning SJ, Weiss
LM, Blume KG. Epstein-Barr virus-associated lymphoproliferative disorder
following autologous bone marrow transplantation for non-Hodgkin’s lymphoma.
Transplantation 1993; 55:1425-8.
49. Van Bekkum DW. Conditioning regimens for the
treatment of experimental arthritis with autologous bone marrow transplantation.
Bone Marrow Transpt, 2000; 25:357-64.
50. Dutreix J, Girinski T, Cosset JM, Bernard A,
Pico J, Baume D, et al. Blood cell kinetics and total body irradiation.
Radiother Oncol 1987; 9:119-29.
51. Curtis RE, Rowlings PA, Deeg HJ, Shriner DA,
Socie G, Travis LB, et al. Solid cancers after bone marrow transplantation.
N Engl J Med 1997; 336:897-904.
52. Sanders JE. Growth and development after hematopoietic
cell transplantation. In: Thomas ED, Blume KG, Forman SJ, editors.
Hematopoietic Cell Transplantation. Malden, MA: Blackwell Science, Inc.,
1999:764- 5.
53. Marmont AM. New horizons in the treatment of
autoimmune diseases: Immunoablation and stem cell transplantation. Annu.
Rev Med. 2000; 51:115-34.
54. Burt RK, Georganas C, Schroeder J, Traynor A,
Stefka J, Schuening F, et al. Autologous hematopoietic stem cell transplantation
in refractory rheumatoid arthritis: sustained response in two of four patients.
Arthritis Rheum. 1999; 42:2281-5.
55. Traynor AE, Schroeder J, Rosa RM, Cheng D, Stefka
J, Mujais S, et al. Treatment of severe systemic lupus erythematosus with
high-dose chemotherapy and haemopoietic stem-cell transplantation: a phase
I study. Lancet 2000; 26:701-7.
56. Martini A, Maccario R, Ravelli A, Montagna D,
De 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; 42:807-11.
57. Tyndall A, Fassas A, Passweg J, Ruiz de Elvira
C, Attal M, Brooks P, et al. Autologous haematopoietic stem cell transplants
for autoimmune disease: feasibility and transplant related mortality. Autoimmune
Disease and Lymphoma Working Parties of the European Group for Blood and
Marrow Transplantation, the European League Against Rheumatism and the
International Stem Cell Project for Autoimmune Disease. Bone Marrow Transplant
1999; 24:729-34.
58. van Bekkum DW. Effectiveness and risks of total
body irradiation for conditioning in the treatment of autoimmune disease
with autologous bone marrow transplantation. Rheumatology [Oxford] 1999;
38:757-61.
59. 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; 54:2147-50.
60. Quartier P, Prieur AM, Fischer A. Haemopoietic
stem-cell transplantation for juvenile chronic arthritis. Lancet 1999;
353:1885-6.
61. Cassidy JE, Petty RE. Juvenile Rheumatoid Arthritis.
In: Cassidy JE and Petty RE, editors. Textbook of Pediatric Rheumatology,
3rd edn. Philadelphia: W B Saunders; 1995:133-223.
62. Gäre BA, Fasth A. The natural history of
juvenile chronic arthritis: A population based cohort study. I. Onset and
disease process. J Rheumatol 1995, 22: 295-307.
63. Gäre BA, Fasth A. The natural history of
juvenile chronic arthritis: A population based cohort study. II. Outcome.
J Rheumatol 1995, 22:308-19
64. Wulffraat NM, van Royen A, Bierings M, Vossen
JM, Kuis W. Autologous haematopoietic stem cell transplantation in four
patients with refractory juvenile chronic arthritis. Lancet 1999;
353: 550-3
65. Wulffraat NM, Sanders LA and Kuis W. Autologous
hemopoietic stem cell transplantation for children with refractory autoimmune
disease. Curr Rheumatol Rep 2000, 2:316-23.
66. Ruperto N, Ravelli A, Falcini F, Lepore L, De
Sanctis R, Zulian F, et al. Performance of the preliminary definition
of improvement in juvenile chronic arthritis patients treated with methotrexate.
Ann Rheum Dis 1998, 57:38-41.
67. Singh G, Athreya BH, Fries JF, Goldsmith DP.
Measurement of health status in children with juvenile rheumatoid arthritis.
Arthritis Rheum 1994, 37:1761-9.
68. Fuchs HA and Pincus T. Reduced joint counts
in controlled clinical trials in rheumatoid arthritis. Arthritis Rheum
1994, 37:470-5
69. Len C, Ferraz MB, Goldenberg J, Oliveira LM, Araujo
PP, Quaresma MR, et al. Paediatric Escola Paulista de Medicina Range of
Motion Scale: A reduced joint count scale for general use in juvenile rheumatoid
arthritis. J Rheumatol 1999, 26:909-13.
70. Slaper-Cortenbach IC, Wijngaarden-duBois MJ,
de Vries-van Rossen A, Borst HP, van der Lelie HG, Verdonck LF, et al.
The depletion of T cells from haematopoietic stem cell transplants. Rheumatology
1999, 38: 751-4.
71. Gerver WJM and Bruin de R. Paediatric morphometrics,
a reference manual. Scientific publisher Bunge, Utrecht, the Netherlands,
1996.
72. Vlieger AM, Brinkman D, Quartier P, Prieur AM,
ten Cate R, Bierings M, et al. Infection Associated Macrophage
Activating Syndrome in 3 Patients Receiving Autologous Stem Cell Transplantation
(AUTO-SCT) for Refractory JCA. Bone Marrow Transplant 2000, 25 (suppl
1, S81).
73. Clements PJ, Furst DE. Choosing appropriate patients
with systemic sclerosis for treatment by autologous stem cell transplantation.
J Rheumatol 1997; (suppl 48) 24: 85-8.
74. Bryan C, Knight
C, Black CM, Silman AJ. Prediction of five-year survival following presentation
with scleroderma: Development of a simple model using three disease factors
at first visit. Arthritis Rheum 1999; 42:2660-5.
75. Nagy Z, Czirjak L. Predictors of survival in 171
patients with systemic sclerosis (scleroderma). Clin Rheumatol 1997; 16: 454-60.
76. White B, Moore WC, Wigley FM, Qing Xiao H,
Wise RA. Cyclophosphamide is associated with pulmonary function and survival
benefit in patients with scleroderma and alveolitis. Ann Intern Med 2000;
132: 947-54.
77. Davas EM, Peppas C, Maragou M, Alvanou E, Hondros
D, Dantis PC. Intravenous cyclophosphamide pulse therapy for the treatment
of lung disease associated with scleroderma. Clin Rheumatol 1999; 18: 455-61.
78. Badesch DB, Tapson
VF, McGoon MD, Brundage BH, Rubin LJ, Wigley FM, et al. Continuous intravenous
Epoprostenol for pulmonary hypertension due to the scleroderma spectrum
of disease: A randomized controlled trial. Ann Intern Med 2000; 132: 425-34.
79. Clements
PJ, Lachenbruch PA, Ng SC, Simmons M, Sterz M, Furst DE. Skin score. A
semiquantitative measure of cutaneous involvement that improves prediction
of prognosis in systemic sclerosis. Arthritis Rheum 1990; 33:1256-63.
80. Clements PJ, Wong
WK, Hurwitz EL, Furst DE, Mayes M, White B, et al. Correlates of the disability
index of the health assessment questionnaire: a measure of functional impairment
in systemic sclerosis. Arthritis Rheum 1999; 42:2372-80.
81. Rider
LG, Miller FW. Classification and treatment of the juvenile idiopathic
inflammatory myopathies. Rheum Dis Clin North Am 1997; 23: 619-55.
82. Adams EM, Plotz PH. The treatment of myositis.
How to approach resistant disease. Rheum Dis Clin North Am 1995; 21:179-202.
83. Chan TM, Li FK, Tang CS, Wong RW, Fang GX, Ji
YL, et al. Efficacy of mycophenolate mofetil in patients with diffuse proliferative
lupus nephritis. Hong Kong-Guangzhou Nephrology Study Group. N Engl J Med
2000; 343:1156-62.
Back to the Top of this Page
|
