close

Вход

Забыли?

вход по аккаунту

?

High-dose cyclophosphamide with stem cell rescue for severe rheumatoid arthritisShort-term efficacy correlates with reduction of macroscopic and histologic synovitis.

код для вставкиСкачать
ARTHRITIS & RHEUMATISM
Vol. 46, No. 3, March 2002, pp 837–839
© 2002, American College of Rheumatology
CONCISE COMMUNICATION
Table 1. Arthroscopic findings at baseline and following autologous
stem cell transplantation
DOI 10.1002/art.10093
High-dose cyclophosphamide with stem cell rescue for
severe rheumatoid arthritis: short-term efficacy
correlates with reduction of macroscopic and
histologic synovitis
Month
Macroscopic synovitis VAS score*
Microscopic findings†
CD3
CD45RO
CD4
CD8
Stroma
Lining layer
CD34
Number
Intensity
CD20
Vascularity
Autologous stem cell transplantation (SCT) has been
proposed as therapy for severe autoimmune diseases (1), and
a small number of patients with rheumatoid arthritis (RA)
have received such transplants (2). The European League
Against Rheumatism and the European Bone Marrow Transplant Group have issued treatment guidelines (3) and established a registry of patients undergoing autologous SCT (4).
The principle mechanism of action of autologous SCT is
unclear, and there is no published information about its effects
in the synovium, the principal target organ in RA.
We now report the case of a patient who was diagnosed
with seronegative RA in 1996 at age 21 years. Between 1996
and 1998, she was treated unsuccessfully with sulfasalazine, 1
gm twice daily (neutropenia), intramuscular gold, 50 mg/week
(no response), oral and subcutaneous methotrexate, 20 mg/
week (no response), and cyclosporine, 350 mg/day (no response). In July 1998, she was referred to the General Infirmary at Leeds for evaluation for autologous SCT. Baseline
assessment revealed very active disease, with impaired functional ability and quality of life. Following counseling regarding the risks and possible outcomes, consent was obtained for
autologous SCT with arthroscopy at baseline, 3 months, and at
relapse (for research purposes).
Baseline arthroscopy revealed marked synovitis with
villous formation and increased vascularity. Histologic examination showed infiltration with inflammatory cells (Tables 1
and 2 and Figure 1). Disease-modifying antirheumatic drugs
(DMARDs) (except prednisolone, 10 mg) were stopped prior
to mobilization. Stem cells were mobilized with cyclophosphamide (2 gm/m2) and granulocyte colony-stimulating
factor (lenograstim, 263 ␮g/day). The patient became neutro-
0
3
9
64
20
82
1
2
3
1
3
3
0
0
0
0
1
1
2
3–4
2
1
1
1
3
2
1
1
2
2
0
2
1
1
1
1
* VAS ⫽ visual analog scale; score 0–100 mm.
† Graded as 0, no stained cells in sample; 1, ⬍25% cells stained; 2,
25–50% cells stained; 3, 50–75% cells stained; or 4, ⬎75% cells
stained.
penic during the mobilization phase (nadir 0.6 ⫻ 109
neutrophils/liter), and intravenous antibiotic therapy (gentamicin and piperacillin/tazobactam) was started following an episode of pyrexia. The graft contained 4.05 ⫻ 106 CD34⫹
cells/kg, resulting in a purified product containing 1.6 ⫻ 106
CD34⫹ cells/kg (95.3% pure CD34) following positive CD34⫹
and negative CD4/8 selection using the Isolex 300i cell selection system (Baxter, Norfolk, UK).
Six weeks later, she was readmitted for conditioning
with cyclophosphamide, 50 mg/kg, which was given on days 5,
4, 3, and 2 prior to stem cell reinfusion (total 200 mg/kg). Stem
cells were reinfused on day 0, and reconstitution occurred
rapidly (neutrophil count ⬎1.0 ⫻ 109 cells/liter, platelet count
⬎50 ⫻ 109 cells/liter by day 14). During this period, she had an
Table 2. Laboratory and clinical findings at baseline and following autologous stem cell transplantation
Month
Laboratory
C-reactive protein, mg/liter (normal ⬍10)
Peripheral blood, cells ⫻ 109/liter
CD3 (normal 0.77–2.68)
CD4 (normal 0.53–1.76)
CD8 (normal 0.30–1.03)
B cell (normal 0.06–0.66)
Clinical*
Swollen joint count
Tender joint count
ACR response, %
0
1
3
6
9
12
15
18
105
15
13
15
114
303
249
94
0.8
0.56
0.23
0.12
0.34
0.11
0.31
0.18
0.42
0.15
0.22
0.15
0.37
0.12
0.22
0.01
0.66
0.3
0.34
0.43
0.74
0.43
0.28
0.46
0.85
0.51
0.31
0.43
0.57
0.31
0.24
0.15
16
21
–
9
7
20
6
14
20
7
10
50
3
10
0
14
11
0
37
32
0
12
18
0
* Swollen joint count based on 56 joints; tender joint count based on 58 joints; ACR response ⫽ response according to the American College of
Rheumatology preliminary definition of rheumatoid arthritis improvement (5).
837
838
CONCISE COMMUNICATION
Figure 1. Arthroscopic findings before and after autologous stem cell transplantation in a patient with
seronegative rheumatoid arthritis. Left panels, Macroscopic appearance of synovium. a, Before therapy, the
synovium is hyperemic, and marked villous formation is apparent. b, At 3 months, when patient showed a
dramatic clinical response, most villi are avascular and white (arrowheads), although 1 villus remains vascularized
and swollen (arrow). c, At 9 months, the synovial villous vascularity has become confluent again. Right panels,
Microscopic appearance of synovium stained immunohistochemically with a monoclonal antibody to CD3,
showing d, synovial tissue with abundant CD3⫹ T cells, e, synovial tissue devoid of CD3⫹ cells, and f,
reappearance of a dense CD3⫹ T cell infiltrate.
episode of neutropenic sepsis related to the Hickman line
insertion site and was treated with intravenous vancomycin and
aztreonam. She had no other complications, apart from mild
mucositis, and was discharged on day 24.
Immediately following SCT, a dramatic reduction in
disease activity occurred, and the patient was able to discontinue all DMARDs. Three months after SCT, planned arthroscopy of her left knee revealed very little inflammation and
reduced vascularity compared with baseline (Tables 1 and 2
and Figure 1). However, a single villus remained inflamed and
vascular. Immunohistochemical staining revealed a marked
reduction in all T cell subsets (CD3, CD4, CD8, CD45RO), B
cells (CD20), and macrophages (CD68), and a reduction in
CD34 staining predominantly related to endothelial cell expression in the synovium (Table 1 and Figure 1). At the
6-month review, the dramatic reduction in disease activity was
maintained, and the patient reached 50% response according
to American College of Rheumatology criteria (5).
CONCISE COMMUNICATION
Nine months after SCT, the patient experienced widespread relapse of disease. Arthroscopy of her left knee revealed increased synovitis and early invasive pannus (Figure 1).
Immunohistochemistry studies revealed increased infiltration
of CD3⫹, CD4⫹, CD45RO⫹, and, to a lesser extent, CD8⫹
cells (Tables 1 and 2 and Figure 1). Treatment with oral
cyclosporine (350 mg/day) was started, followed by oral methotrexate (20 mg/week) because of continued disease activity.
At the 15-month assessment, the level of disease activity was
still unacceptable, and anti–tumor necrosis factor therapy was
started. However, this treatment was accompanied by an
exacerbation of arthritis and was discontinued after 2 infusions. The patient is currently receiving leflunomide, 20 mg/
day.
This patient received a manipulated graft that had
undergone positive CD34 and negative T cell selection. It is
possible that purification of the graft may reduce the rate of
relapse, but some clinicians fear that this may be at the expense
of poor reconstitution and increase the risk of subsequent
infection. Although peripheral blood CD3, CD4, and CD8
levels did not return to the normal range until 15 months after
autologous SCT, the patient had no infectious complications
following discharge. High-dose chemotherapy and highly selected autologous SCT with double selection did induce a
dramatic reduction in disease activity, both clinically and on
macroscopic and histologic evaluation of the synovium. When
relapse occurred at 9 months, arthroscopy revealed florid
synovitis consistent with clinical disease, and histologic evaluation of synovium showed increased numbers of CD3 and CD4
cells despite flow cytometry of peripheral blood lymphocytes
showing prolonged cell depletion. A correlation between synovial lymphocyte infiltration and clinical disease, along with
disparity between circulating and synovitic lymphocyte repopulation suggests either synovitic T cell proliferation or ongoing
recruitment from significantly depleted peripheral blood. In
our patient, increased numbers of CD45RO⫹ cells indicated
the presence of memory or primed rather than naive T cells.
These results suggest a pathogenic role for T cells, even in
established RA.
839
Sarah Bingham, MA, MRCP
Douglas Veale, MD, FRCP, FRCPI
Ursula Fearon, PhD
John D. Isaacs, PhD, FRCP
Gareth Morgan, MB BS, PhD, MRCP, MRCPath
Paul Emery, MA, MD, FRCP
University of Leeds
Leeds, UK
Dennis McGonagle, MRCPI
Halifax General Hospital and
University of Leeds
Leeds, UK
Richard Reece, MB BCh, MRCP
Huddersfield Royal Infirmary
University of Leeds
Leeds, UK
Roy Clague, MD, FRCP
Nobles Hospital
Isle of Man, UK
John A. Snowden, BSc (Hons), MD, MRCP, MRCPath
Leicester Royal Infirmary
Leicester, UK
1. Snowden J, Brooks P, Biggs J. Haemopoietic stem cell transplantation for autoimmune diseases. Br J Haematol 1997;99:9–22.
2. Bingham SJ, Snowden JA, Emery P. Autologous blood stem cell
transplantation as therapy for autoimmune diseases. Ann Med
2000;32:615–21.
3. Tyndall A, Gratwohl A. Blood and marrow stem cell transplants in
autoimmune disease: a consensus report written on behalf of the
European League Against Rheumatism (EULAR) and the European Group for Blood and Bone Marrow Transplantation (EBMT).
Br J Rheumatol 1997;36:390–2.
4. Tyndall A, Fassas A, Passweg J, Ruiz de Elvira C, Attal M, Brooks P,
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, et al. Autologous haemopoietic stem cell
transplants for autoimmune disease–feasibility and transplant-related
mortality. Bone Marrow Transplant 1999;24:729–34.
5. Felson DT, Anderson JJ, Boers M, Bombardier C, Furst D, Goldsmith
C, et al. American College of Rheumatology preliminary definition of
improvement in rheumatoid arthritis. Arthritis Rheum 1995;38:
727–35.
Документ
Категория
Без категории
Просмотров
0
Размер файла
1 309 Кб
Теги
stem, efficacy, dose, reduction, high, arthritisshort, cyclophosphamide, cells, severa, macroscopic, synovitis, terms, correlates, rescue, rheumatoid, histological
1/--страниц
Пожаловаться на содержимое документа