ARTHRITIS & RHEUMATISM
Vol. 52, No. 8, August 2005, pp 2272–2276
© 2005, American College of Rheumatology
Long-Term Followup of Health Status in Patients With
Severe Rheumatoid Arthritis After High-Dose Chemotherapy
Followed by Autologous Hematopoietic Stem Cell Transplantation
Y. K. O. Teng, R. J. Verburg, J. K. Sont, W. B. van den Hout,
F. C. Breedveld, and J. M. van Laar
Objective. High-dose chemotherapy (HDC) fol-
lowed by autologous hematopoietic stem cell transplan-
tation (HSCT) is a new treatment for patients with
severe, refractory rheumatoid arthritis (RA). The
present study was undertaken to assess the health
status of patients with severe RA over a long-term
followup period after treatment with HDC ? HSCT.
Methods. Health status and utility scores were
assessed in 8 patients before and after treatment with
HDC ? HSCT. Patients were followed up for 5 years
posttransplantation. Health status was assessed by the
Health Assessment Questionnaire (HAQ), the RAND-36
version of the Short Form 36 (SF-36) health survey, and
the Arthritis Impact Measurement Scales (AIMS). Util-
ity scores were calculated using the EuroQol (EQ-5D)
questionnaire and the SF-36–derived utility index
(called the SF-6D), from which quality-adjusted life
years (QALYs) were derived.
Results. Most measures of health status improved
compared with baseline in the first 2 years posttrans-
plantation, notably HAQ and AIMS scores and scores
on the functional status, general health, and health
change summary scales of the RAND-36 version of the
SF-36. Utility scores derived from the EQ-5D question-
naire and the SF-6D also increased significantly after
transplantation. This was reflected in the 0.28 QALYs
gained compared with baseline. For a putative 50-year-
old RA patient with a life expectancy of 20 years, a
threshold analysis revealed that HDC ? HSCT yielded
more QALYs than conventional therapy when
treatment-related mortality (TRM) was <2.8%.
Conclusion. HDC ? HSCT temporarily increased
the functionality and health status of patients with
severe, refractory RA. With a reported TRM of 1.3%,
HDC ? HSCT can be considered a realistic treatment
option for patients with severe RA.
Rheumatoid arthritis (RA) is a chronic disease
that results in significant morbidity, impaired quality of
life, and a reduced life expectancy (1,2). High-dose
chemotherapy (HDC) followed by autologous hemato-
poietic stem cell transplantation (HSCT) is a new treat-
ment strategy for patients with severe RA (3,4). Several
pilot studies have shown remarkable clinical improve-
ment for up to 2 years in patients with previously
refractory RA, as measured by Disease Activity Scores
with physical examination of all 44 joints (DAS44) (5)
and C-reactive protein levels (4,6). Although no cure
was observed, sensitivity to disease-modifying antirheu-
matic drug (DMARD) therapy was restored after trans-
We previously reported a clinical decision analy-
sis using Markov modeling to estimate quality-adjusted
life years (QALYs) resulting from HDC ? HSCT versus
conventional therapy. The model predicted that HDC ?
HSCT could be superior if treatment-related mortality
(TRM) remained low (7). However, so far, it remains
unclear whether long-term health status in patients with
severe RA is actually enhanced by a treatment involving
Supported by the Dutch Arthritis Association (grant NR
Y. K. O. Teng, MD, R. J. Verburg, MD, J. K. Sont, PhD,
W. B. van den Hout, PhD, F. C. Breedveld, MD, J. M. van Laar, MD:
Leiden University Medical Center, Leiden, The Netherlands.
Drs. Teng and Verburg contributed equally to this work.
Address correspondence and reprint requests to J. M. van
Laar, MD, Department of Rheumatology, C4-R, Leiden University
Medical Center, PO Box 9600, 2300 RC Leiden, The Netherlands.
Submitted for publication February 3, 2005; accepted in
revised form May 9, 2005.
HDC ? HSCT, which is important in clinical decision-
making regarding the treatment of these patients.
The purpose of this study was to assess the health
status of patients with severe RA over a long-term
followup period after treatment with HDC ? HSCT. In
addition, we calculated the valuation of the patients’
health expressed in utilities in order to establish whether
HDC ? HSCT results in a gain in QALYs.
PATIENTS AND METHODS
Patient selection. Seven women and 1 man (mean age
43 years [range 35–51 years], mean disease duration 13 years
[range 7–20 years]) were treated at Leiden University Medical
Center (LUMC) with HDC ? HSCT as part of a multicenter
phase I/II trial (6). Patients had an established diagnosis of
RA according to the 1987 revised criteria of the American
College of Rheumatology (formerly, the American Rheuma-
tism Association) (8), had progressively erosive disease with
large joint involvement, and had disease that was refractory to
DMARDs, including the maximal tolerable dose of methotrex-
ate (MTX) and combination therapy. In addition, 4 patients
had disease that did not respond to tumor necrosis factor
(TNF) blockade. All patients were rheumatoid factor positive
and had high DAS44 scores at baseline (mean 5.4 [range
3.82–7.24]) as defined by the criteria of the European League
Against Rheumatism (EULAR) (9). The protocol was ap-
proved by the Ethics Committee of LUMC, and all patients
provided written informed consent.
Study design. Patients were followed up at 3-month
intervals for the first year posttransplantation, 6-month inter-
vals in the second year posttransplantation, and once more at
5 years posttransplantation. Clinical outcome, health status,
and utility were assessed at all time points, except for the
clinical outcome at 5 years.
Clinical outcome. Clinical responses were categorized
according to the EULAR response criteria (9). Functionality
was measured using the standard disability index of the Health
Assessment Questionnaire (HAQ) (10).
Health status assessments. Health status was mea-
sured using the Arthritis Impact Measurement Scales (AIMS)
and the Short Form 36 (SF-36) health survey. The AIMS is
a reliable instrument, validated for use in The Netherlands
as the Dutch AIMS, which measures health status in a multi-
dimensional manner using specific scales, summary com-
ponents, and overall impact measures (11). In the present
study, the Arthritis Impact visual analog scale (VAS) was
used because it is a good indicator of the impact of RA on
patients’ general health (12). The RAND-36 version of the
SF-36 assesses patients’ health status across 9 dimensions,
from which the following 4 summary scales are constructed:
1) functional status, the summary scale of physical func-
tioning, social functioning, physical role limitations, and emo-
tional role limitations; 2) well-being, the summary scale of
mental health, vitality, and pain; 3) general health; and 4)
health change (13).
Utility and QALYs. Utility is the valuation of a pa-
tient’s health on a scale from 0 (death) to 1 (optimal health).
Utilities were measured using the EuroQol (EQ-5D) question-
naire (14) and the SF-36–derived utility index, called the
SF-6D (13). In both instruments, patients describe their health
status using a classification system. Utilities for these descrip-
tions are obtained from large representative study populations
in the UK, based on a time trade-off procedure for the EQ-5D
questionnaire and on a standard gamble procedure for the
SF-6D (15). Because sustained improvement of utility (and not
the individual measurements) is important for patients,
QALYs were calculated as the area under the curve (AUC)
from the SF-6D utility scores of the patients who underwent
HDC ? HSCT.
Lifetime QALY model for comparing treatments.
The observed QALYs were used in a decision model to assess
the preferred therapy in a putative 50-year-old RA patient
with a life expectancy of 20 years. In this model, conventional
treatment was compared with HDC ? HSCT by applying a
range of hypothetical values of TRM for HDC ? HSCT.
For conventional therapy, it was assumed that utility re-
mained stable at baseline values. For patients who under-
went HDC ? HSCT, utility was assumed to follow the
observed 5-year utility curve and to remain equal to baseline
values for the following 15 years. In accordance with economic
evaluations, utilities of future years were discounted at 3%,
thus reducing the importance of later years. Using a thresh-
old analysis, we determined the TRM below which HDC ?
HSCT rendered more QALYs compared with conventional
Statistical analysis. Statistical analysis was performed
using the Statistical Package for Social Sciences (SPSS for
Windows 11.0; SPSS, Chicago, IL). P values less than or equal
to 0.05 were considered significant. To assess whether there
was a significant difference in health status scores up to 9
months after transplantation compared with baseline, one-way
analyses of variance (ANOVAs) were performed. Student’s
t-tests were used to explore at which time points after treat-
ment the changes in health status scores from baseline were
Clinical results. Eight patients with severe, re-
fractory RA were treated with HDC ? HSCT. Six
months after transplantation, 4 patients showed good
improvement, 2 showed moderate improvement, and 2
showed no improvement according to the EULAR
response criteria. Two patients fulfilled the criteria of
good improvement both 1 year and 2 years after trans-
plantation, while 5 patients and 4 patients, respectively,
showed moderate improvement, and 1 patient and 2
patients, respectively, showed no improvement. All pa-
tients had a relapse of disease activity leading to rein-
stitution of MTX. After 2 years posttransplantation,
dosages of MTX ranged from 5 mg/week to 17.5 mg/
week in 7 patients, and 1 patient received leflunomide
TREATMENT OF SEVERE RA WITH HDC ? HSCT2273
after MTX treatment failed. Three patients also took
prednisone at dosages of 7.5–10 mg/day (16). Of note, all
patients showed renewed sensitivity to these DMARDs.
Health status maximally improved within 9 months after
transplantation, with 4 patients (50%) taking MTX.
Nausea, vomiting, and alopecia were observed in all
patients, as reported earlier (6). Grade 3 toxicity (ac-
cording to the criteria of the World Health Organization
) was observed in 1 patient, who had elevated levels
of bilirubin, aspartate aminotransferase, and alanine
aminotransferase, as well as intolerable diarrhea requir-
ing antibiotic therapy.
Functionality, as measured by the HAQ, showed
significant improvements within the first 9 months, with
a maximal decrease of mean ? SD HAQ scores from
1.59 ? 0.27 before transplantation to 0.97 ? 0.18 at 3
months (P ? 0.02) (Figure 1a). ANOVAs also showed a
significant decrease in the HAQ scores (P ? 0.048).
Although mean ? SD HAQ scores steadily increased up
to 1.25 ? 0.18 at 5 years, they did not reach pretreatment
values. Even though these values did not differ signifi-
cantly from those at baseline, the observed changes of
?0.22 units are considered clinically significant (18).
Improvements in health status. ANOVAs per-
formed for the Arthritis Impact VAS of the AIMS
showed a significant decrease over the 9-month period
posttransplantation (P ? 0.015), with a maximal de-
crease in the mean ? SD Arthritis Impact scores from
5.14 ? 0.81 to 2.09 ? 0.88 at 3 months (P ? 0.02)
Three of the 4 summary scales of the generic
measure RAND-36 showed significant improvements in
mean ? SD health status scores compared with baseline
during the first 9 months after transplantation. Patients’
reported scores on functional status increased sig-
nificantly from 44.6 ? 9.73 to 65.5 ? 7.03 (P ? 0.04).
These scores on functional status gradually decreased
during followup, but they remained above pretreatment
values throughout the 5 years of followup (Figure 1c).
Scores on well-being also improved from 55.6 ? 5.19 to
70.9 ? 5.81 (P ? 0.09) (Figure 1d). General health
scores improved from 50.6 ? 4.17 to 63.1 ? 5.90 at 6
months (P ? 0.05) (Figure 1e). Health change scores
improved significantly from 37.5 ? 11.6 to 81.3 ? 10.3 at
6 months (P ? 0.01) (Figure 1f). ANOVAs showed
significant improvement on the summary scale of health
change (P ? 0.015).
Increased utility scores and QALYs. Mean ? SD
utility scores measured by the EQ-5D questionnaire
increased significantly from 0.59 ? 0.02 before trans-
plantation to 0.67 ? 0.04 within 9 months (P ? 0.03)
(Figure 2a). During the same period, SF-6D utility
scores also increased significantly from 0.59 ? 0.11 to
0.72 ? 0.12 (P ? 0.04) (Figure 2b).
The total QALYs, calculated as the AUC from
the SF-6D utility scores, were 1.4 in the first 2 years
posttransplantation and 3.3 after 5 years. Compared
with baseline utilities, this increase equals an improve-
ment of 0.28 QALYs.
Figure 1. Health status of 8 patients with severe, refractory rheuma-
toid arthritis who underwent high-dose chemotherapy followed by
autologous hematopoietic stem cell transplantation. a, Scores on the
Health Assessment Questionnaire (HAQ). Lower scores indicate
better health. b, Scores on the Arthritis Impact visual analog scale of
the Arthritis Impact Measurement Scales. Lower scores indicate better
health. c–f, Scores on the 4 summary scales of the RAND-36 version of
the Short Form 36 health survey. Higher scores indicate better health.
Values are the mean ? SD. ? ? P ? 0.05 versus baseline.
2274TENG ET AL
Lifetime QALY model. Using a threshold analy-
sis, we calculated whether the gained QALYs, as com-
pared with the baseline utilities, could compensate for
the TRM of HDC ? HSCT. Assuming a life expectancy
of 20 years for a 50-year-old patient with severe RA, we
found that HDC ? HSCT equals conventional therapy
in terms of QALYs when the TRM is 2.8% (Figure 3).
For a younger patient with a life expectancy of 30 years,
the threshold of TRM would decrease to 2.2%.
The aim of this study was to analyze the health
status of patients with previously refractory RA during 5
years following HDC ? HSCT. Our study demonstrates
significant improvement in health status, notably in the
first 9 months posttransplantation. We also showed that
utility scores improved for patients who underwent
HDC ? HSCT, and that the QALYs gained for RA
patients treated with HDC ? HSCT outweighed those
for RA patients treated with conventional therapy when
TRM was ?2.8%.
The European Group for Blood and Marrow
Transplantation reported that TRM after HDC ?
HSCT occurred in 1 of 76 RA patients (1.3%) (4).
Therefore, our study indicates that in a hypothetical
50-year-old RA patient with a life expectancy of 20
years, HDC ? HSCT results in superior health status
compared with conventional therapy. Of note, it should
be taken into account that the threshold for TRM is
higher in older patients with shorter life expectancy
because TRM leads to a smaller QALY loss.
To our knowledge, this is the first comprehensive
study on the long-term followup of the health status of
patients with severe, refractory RA. The health status of
these patients improved after HDC ? HSCT mainly in
the first 9 months posttransplantation and lasted for as
long as 2 years. HAQ scores improved by ?0.22 units,
considered clinically significant, during the complete
followup period. Furthermore, utilities increased as
measured by 2 different generic measures, the SF-6D
and the EQ-5D questionnaire. Despite conceptual dif-
ferences, both utility measures yielded very similar
results. In addition, using the AIMS, we found signifi-
cant improvement in the impact of arthritis on the health
status of patients who underwent HDC ? HSCT. Inter-
estingly, there were 2 nonresponders within this group of
patients. HDC ? HSCT had more pronounced effects
on health status and utility scores in the group of 6
responders (data not shown).
The remarkable improvement in health status
after HDC ? HSCT was mainly achieved during the first
9 months posttransplantation. Because conventional
DMARD therapy was reinstituted in 50% of the patients
at 9 months, it can be assumed that the improved health
status of RA patients is related directly to HDC ?
HSCT. Indirectly, HDC ? HSCT caused renewed sen-
sitivity to DMARD therapy in all patients, which ac-
counted for the prolongation of health status improve-
ment up to 2 years or even up to 5 years.
A limitation of our study is that we could not
Figure 2. a, Utility scores as measured by the EuroQol (EQ-5D)
questionnaire (n ? 8 patients). b, Utility scores as measured by the
Short Form 36 health survey–derived utility index (SF-6D) (n ? 8
patients). Values are the mean ? SD. ? ? P ? 0.05 versus baseline.
Figure 3. Threshold analysis for treatment-related mortality (TRM)
of high-dose chemotherapy (HDC) followed by autologous hemato-
poietic stem cell transplantation (HSCT) in a putative 50-year-old
rheumatoid arthritis patient with a 20-year life expectancy. The
analysis determines the threshold TRM above which HDC ? HSCT
results in superior quality-adjusted life years (QALYs) compared with
continued conventional therapy, based on the assumption that conven-
tional therapy results in stable QALYs over the 20-year period. A
TRM ?2.8% favors HDC ? HSCT as the preferred treatment
compared with continued conventional therapy.
TREATMENT OF SEVERE RA WITH HDC ? HSCT 2275
correct for a placebo effect, since HDC ? HSCT was Download full-text
tested as an investigational treatment in a nonrandom-
ized pilot study. Other limitations were the small num-
ber of patients enrolled in this study and the lack of
adequate data on health status in a control group of
patients with severe RA. We postulated that health
status and utility scores were, at best, stable at baseline
values for patients with severe RA treated with conven-
tional therapy (19).
We estimated an improvement of 0.28 QALYs
for patients with severe RA treated with HDC ? HSCT.
Wong et al (2) showed a comparable improvement of
0.33 QALYs over a 1-year period in RA patients treated
with a TNF-blocking agent combined with MTX com-
pared with MTX alone, based on data from the Anti–
Tumor Necrosis Factor Trial in Rheumatoid Arthritis
with Concomitant Therapy and from the Arthritis,
Rheumatism, and Aging Medical Information System
(1). However, those patients had less severe disease
activity than our patients who underwent HDC ?
HSCT, and the safety and tolerability of continued
TNF-blocking therapy still have to be confirmed (2).
From our data, it can be concluded that HDC ?
HSCT improves the health status of patients with severe
RA. Nevertheless, the treatment is not curative, as
reflected in the return of health status to near-baseline
levels after 2–5 years posttransplantation. Therefore,
new experimental therapies should aim at prolonging
the initial benefit of high-dose immunosuppression with-
out significantly increasing TRM.
1. Wong JB, Ramey DR, Singh G. Long-term morbidity, mortality,
and economics of rheumatoid arthritis. Arthritis Rheum 2001;44:
2. Wong JB, Singh G, Kavanaugh A. Estimating the cost-effective-
ness of 54 weeks of infliximab for rheumatoid arthritis. Am J Med
3. Verburg RJ, Toes RE, Fibbe WE, Breedveld FC, van Laar JM.
High dose chemotherapy and autologous hematopoietic stem cell
transplantation for rheumatoid arthritis: a review. Hum Immunol
4. Snowden JA, Passweg J, Moore JJ, Milliken S, Cannell P, van Laar
J, et al. Autologous hemopoietic stem cell transplantation in
severe rheumatoid arthritis: a report from the EBMT and
ABMTR. J Rheumatol 2004;31:482–8.
5. Van der Heijde DM, van ’t Hof MA, van Riel PL, van de Putte LB.
Development of a disease activity score based on judgment in
clinical practice by rheumatologists. J Rheumatol 1993;20:538–41.
6. Verburg RJ, Kruize AA, van den Hoogen FH, Fibbe WE, Petersen
EJ, Preijers F, et al. High-dose chemotherapy and autologous
hematopoietic stem cell transplantation in patients with rheuma-
toid arthritis: results of an open study to assess feasibility, safety,
and efficacy. Arthritis Rheum 2001;44:754–60.
7. Verburg RJ, Sont JK, Vliet Vlieland TP, Landewe RB, Boers M,
Kievit J, et al. High dose chemotherapy followed by autologous
peripheral blood stem cell transplantation or conventional phar-
macological treatment for refractory rheumatoid arthritis? A
Markov decision analysis. J Rheumatol 2001;28:719–27.
8. Arnett FC, Edworthy SM, Bloch DA, McShane DJ, Fries JF,
Cooper NS, et al. The American Rheumatism Association 1987
revised criteria for the classification of rheumatoid arthritis.
Arthritis Rheum 1988;31:315–24.
9. Van Gestel AM, Prevoo ML, van ’t Hof MA, van Rijswijk MH, van
de Putte LB, van Riel PL. Development and validation of the
European League Against Rheumatism response criteria for rheu-
matoid arthritis: comparison with the preliminary American Col-
lege of Rheumatology and the World Health Organization/Inter-
national League Against Rheumatism criteria. Arthritis Rheum
10. Fries JF, Spitz PW, Kraines RG, Holman HR. Measurement of
patient outcome in arthritis. Arthritis Rheum 1980;23:137–45.
11. Taal E, Jacobs JW, Seydel ER, Wiegman O, Rasker JJ. Evaluation
of the Dutch Arthritis Impact Measurement Scales (DUTCH-
AIMS) in patients with rheumatoid arthritis. Br J Rheumatol
12. Taal E, Seydel ER, Jacobs JW, Wiegman O, Rasker JJ. [The
Dutch Arthritis Impact Measurement Scales (DUTCH-AIMS):
assessment of physical and psychosocial aspects of health in
rheumatoid arthritis]. Gedrag Gezondheid 1989;17:69–74. In
13. Brazier J, Roberts J, Deverill M. The estimation of a preference-
based measure of health from the SF-36. J Health Econ 2002;21:
14. Brooks R. EuroQol: the current state of play. Health Policy
15. Hurst NP, Kind P, Ruta D, Hunter M, Stubbings A. Measuring
health-related quality of life in rheumatoid arthritis: validity,
responsiveness and reliability of EuroQol (EQ-5D). Br J Rheu-
16. Verburg RJ, Sont JK, van Laar JM. Reduction of joint damage in
severe rheumatoid arthritis by high-dose chemotherapy and autol-
ogous stem cell transplantation. Arthritis Rheum 2005;52:421–4.
17. Miller AB, Hoogstraten B, Staquet M, Winkler A. Reporting
results of cancer treatment. Cancer 1981;47:207–14.
18. Wells GA, Tugwell P, Kraag GR, Baker PR, Groh J, Redelmeier
DA. Minimum important difference between patients with rheu-
matoid arthritis: the patient’s perspective. J Rheumatol 1993;20:
19. Uhlig T, Smedstad LM, Vaglum P, Moum T, Gerard N, Kvien TK.
The course of rheumatoid arthritis and predictors of psychological,
physical and radiographic outcome after 5 years of follow-up.
Rheumatology (Oxford) 2000;39:732–41.
2276TENG ET AL