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Long-term treatment with methotrexate or tumor necrosis factor ╨Ю┬▒ inhibitors does not increase epstein-barr virus load in patients with rheumatoid arthritis.

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Arthritis & Rheumatism (Arthritis Care & Research)
Vol. 57, No. 5, June 15, 2007, pp 762–767
DOI 10.1002/art.22783
© 2007, American College of Rheumatology
ORIGINAL ARTICLE
Long-Term Treatment With Methotrexate or
Tumor Necrosis Factor ␣ Inhibitors Does Not
Increase Epstein-Barr Virus Load in Patients With
Rheumatoid Arthritis
NATHALIE BALANDRAUD,1 SANDRINE GUIS,1 JEAN BAPTISTE MEYNARD,2 ISABELLE AUGER,3
JEAN ROUDIER,1 AND CHANTAL ROUDIER1
Objective. We previously demonstrated that patients with rheumatoid arthritis (RA) have a 10-fold systemic EpsteinBarr virus (EBV) overload, very similar to that observed in healthy organ transplant recipients. Our objective was to
monitor EBV load over time in patients with RA receiving methotrexate, infliximab, or etanercept to detect possible
immunosuppression-associated EBV dysregulation, as described in posttransplant lymphoproliferative disease.
Methods. The EBV load in the peripheral blood mononuclear cells (PBMCs) from 19 patients receiving methotrexate, 68
patients receiving infliximab, and 48 patients receiving etanercept was monitored for durations ranging from 6 months
to 5 years using a real-time polymerase chain reaction assay previously developed for that purpose. The effect of
treatment duration on EBV load and the link between the Disease Activity Score in 28 joints and EBV load were analyzed
by generalized estimating equations.
Results. Methotrexate tended to decrease EBV load over time, but this did not reach significance. Tumor necrosis factor
␣ (TNF␣) inhibitors did not significantly modify EBV load over time. Finally, high disease activity was significantly
associated with high EBV load.
Conclusion. Long-term usage of methotrexate or TNF␣ inhibitors in patients with RA does not significantly influence EBV
load in PBMCs.
KEY WORDS. Rheumatoid arthritis treatment; Epstein-Barr virus load; Lymphoma.
INTRODUCTION
Patients with rheumatoid arthritis (RA) have an impaired
immune response to Epstein-Barr virus (EBV). These patients have high-titer antibodies to EBV antigens (1). T
lymphocytes from their peripheral blood are less efficient
Supported by grants from INSERM, Société Française de
Rhumatologie, Association pour la Recherche sur la Polyarthrite, PHRC 2003.
1
Nathalie Balandraud, MD, PhD, Sandrine Guis, MD,
PhD, Jean Roudier, MD, PhD, Chantal Roudier, PharmD,
PhD: INSERM Unité 639, and the Hôpital La Conception,
Assistance Publique Hopitaux de Marseille, Marseille,
France; 2Jean Baptiste Meynard, MD: Institut de Médecine
Tropicale du service de Santé des armées, Marseille,
France; 3Isabelle Auger, PhD: INSERM Unité 639, Marseille,
France.
Address correspondence to Jean Roudier, MD, PhD,
INSERM UMR 639, Faculté de Médecine, 13005, Marseille,
France. E-mail: jean.roudier@medecine.univ-mrs.fr.
Submitted for publication August 4, 2006; accepted in
revised form December 8, 2006.
762
at controlling the outgrowth of EBV-infected B cells (2).
Patients with RA have more EBV-infected B cells than
normal individuals (3). Disease activity is associated with
lower T cell responses to the EBV replication protein
gp110 (4). Finally, we recently demonstrated that patients
with RA have a 10-fold systemic EBV overload, very similar to that observed in healthy organ transplant recipients
(5). Remarkably, both patients with RA and solid-organ
transplant recipients are at increased risk to develop lymphoma (6 – 8). In the absence of immunosuppressive therapy, severity of the disease and inflammation seem to
increase the risk of lymphoma in patients with RA (9).
Current treatment of RA routinely includes potentially
immunosuppressive medications such as methotrexate
and tumor necrosis factor ␣ (TNF␣) inhibitors and is suspected to increase the risk of developing lymphoma. In
solid-organ transplant recipients receiving immunosuppressants, emergence of lymphoma can be predicted by
monitoring EBV load in peripheral blood mononuclear
cells (PBMCs). EBV load ⬎1,000 copies per 500 ng of
PBMC DNA is considered a limit above which patients are
Epstein-Barr Virus Load in RA
763
Table 1. Characteristics of patients*
Characteristic
Methotrexate
(n ⴝ 19)
Infliximab
(n ⴝ 68)
Etanercept
(n ⴝ 57)
All
(n ⴝ 144)
Women, no. (%)
Age, years
Disease duration, years
SE, no. positive/no. tested (%)
15 (78.9)
55.9 ⫾ 13.5
10.4 ⫾ 7.2
13/19 (68.4)
51 (74.9)
60.0 ⫾ 12.3
14.8 ⫾ 8.8
51/68 (74.6)
47 (82.5)
58.5 ⫾ 14.3
12.3 ⫾ 11.1
52/57 (91.2)
112 (77.7)
59 ⫾ 12.8
13.2 ⫾ 9.6
116/144 (80.6)
* Values are the mean ⫾ SD unless otherwise indicated. SE ⫽ shared epitope.
at risk of developing EBV-associated posttransplant lymphoproliferative disorder, a condition characterized by
polyclonal EBV-positive B lymphocyte proliferation,
which can evolve into EBV-positive B cell lymphoma
(7,8).
We investigated whether long-term usage of methotrexate or TNF␣ inhibitors in patients with RA, whose EBV
control is already impaired, could increase EBV load and
therefore put these patients at risk of developing lymphoma, as already demonstrated in solid-organ transplant
recipients. Therefore, we monitored EBV load in the
PBMCs of 144 patients with RA receiving methotrexate or
TNF␣ inhibitors (infliximab or etanercept) for periods
ranging from 6 months to 5 years (mean followup duration
23 months for methotrexate, 28 months for infliximab, and
17 months for etanercept) using a real-time fluorescent
polymerase chain reaction (PCR) assay that we developed
previously (5).
We found that long-term treatment of patients with RA
with methotrexate tended to decrease EBV load in PBMCs,
but this did not reach significance. Similarly, long-term
treatment with infliximab or etanercept did not significantly modify EBV load in patients with RA.
PATIENTS AND METHODS
Patients and controls. A total of 144 patients with RA
(satisfying the 1987 American College of Rheumatology
[formerly the American Rheumatism Association] criteria
[10]) from the rheumatology ward at Hôpital La Conception, Marseille, France, were followed for times ranging
from 6 months to 5 years. Nineteen patients received methotrexate (7.5–12.5 mg/week); 68 patients received infliximab (3 mg/kg for 8 weeks), associated or not associated
with methotrexate; 48 patients received etanercept (25 mg
twice per week), associated or not associated with methotrexate; and 9 patients received etanercept after infliximab.
Three patients were first included in the methotrexate
group, then in the infliximab group. Four patients were
first included in the methotrexate group, then in the etanercept group. None of the patients received any prophylactic antiviral therapy. Baseline characteristics of patients
are presented in Table 1. Peripheral blood samples were
obtained every 6 months for EBV DNA assay.
DNA preparation. Human genomic DNA was isolated
from 10 ml of heparinized blood. Mononuclear cells were
isolated by isopyknic centrifugation through Ficoll-His-
topaque (Sigma, St. Louis, MO) and processed through
Qiagen Genomic-tips 100/G (Qiagen, Courtaboeuf, France)
according to the Qiagen genomic DNA handbook. DNA
was resuspended in 10 mM Tris, pH 8 and was quantified
by real-time PCR with a LightCycler (Roche, Mannheim,
Germany) as previously described (11).
Quantification of EBV copy number. Approximately
500 ng of DNA from peripheral blood lymphocytes was
used for EBV DNA assay by quantitative real-time PCR as
described previously (5). Briefly, a 214-bp segment of the
highly conserved long internal repeat region 1 of EBV was
amplified by quantitative real-time PCR using hybridization probes (Tib-Molbiol, Berlin, Germany) and a LightCycler. The Raji cell line was used as an external EBV standard. Each sample was tested in duplicate and assayed
twice. For final results, EBV copy numbers in test samples
were calculated for 500 ng of DNA.
Statistical analysis. The effect of treatment duration on
EBV load and the link between the Disease Activity Score
in 28 joints (DAS28) and EBV load were tested using
generalized estimating equations (12), taking into account
the interdependence of the observations made for the same
individual. EBV load was the dependent variable and
treatment duration or DAS28 was the independent variable.
The gamma law was used to describe the distribution of
EBV load. To check the sensitivity of estimations to this
hypothesis, results were compared with those obtained
using the normal law as the distribution law. The link
function used was the canonical link for the family
(gamma or normal).
Two different correlation structures were used: exchangeable (the correlation between observations for the
same individual at different times is constant) and independent (the correlation between observations for the
same individual at different times is independent). The
sandwich robust variance estimator was used. Analysis
was performed using Stata software, version 9 (StataCorp,
College Station, TX).
RESULTS
EBV loads are expressed in viral copy number per 500 ng
of PBMC DNA (Table 2). A total of 739 samples were
tested. For most patients the first quantification was performed after the beginning of the treatment. Results of a
0–542
0–542
(63.4)
(65.3)
2.0
2.1
13.6
16.4
22.6 ⫾ 12.6
0–542
0–82.6
(71.5)
(85.7)
0.17
1.90
40.6
12.6
16.7 ⫾ 6.3
0–66
0–246
(31)
(64.6)
0
2.1
4.7
17.7
17.1 ⫾ 9.0
0–186
0–542
(85.3)
(69.1)
4.2
2.4
12.0
16.3
28.3 ⫾ 11.9
1–80.2
0–21.3
(100)
(58)
9.6
1.2
18.1
3.9
22.9 ⫾ 13.3
0–34
(89)
0.6
1.9
NT
* EBV load range, median, and mean are expressed in viral copy number per 500 ng of DNA and are given for the first and the last quantifications of the study. Results of a previous study (5) are given
for comparison. NT ⫽ not tested.
† Methotrexate, infliximab, etanercept, and miscellaneous disease-modifying antirheumatic drugs.
Treatment
(n ⴝ 84)†
0–185
(88)
8.84
15.6
NT
EBV range
(% positive)
EBV median
EBV mean
Followup duration,
mean ⫾ SD months
First
Last
First
Last
First
Last
First
Last
First
Etanercept, after
infliximab (n ⴝ 9)
Etanercept
(n ⴝ 48)
Infliximab
(n ⴝ 68)
Methotrexate
(n ⴝ 19)
No treatment
(controls)
(n ⴝ 100)
Previous study (5)
Table 2. Epstein-Barr virus (EBV) load in patients with rheumatoid arthritis receiving different treatments*
Last
Balandraud et al
All
(n ⴝ 144)
764
previous study are also given in Table 2 for comparison
(135 samples from 84 patients with RA treated with various disease-modifying antirheumatic drugs [DMARDs],
methotrexate, infliximab, or etanercept and 100 healthy
controls were tested using the same assay as in our study,
developed for the purpose of testing EBV load [5]). All
quantifications for all patients are shown in Figure 1: loads
at first and last quantification are given, load increase is in
red, load decrease is in green, and load stability is in blue,
taking into account the former load. Time 0 is the first day
of therapy.
Methotrexate tends to decrease EBV load. Nineteen patients received methotrexate. In all of these patients, EBV
was detectable at the onset of the study. EBV loads ranged
from 1 to 80 copies per 500 ng of DNA, the mean load was
18 copies per 500 ng of DNA, and the median load was 9.6
copies per 500 ng of DNA (Table 2).
Over time, EBV load decreased in 11 patients, was
stable in 7 others, and increased slightly in 1 patient.
Indeed, Figure 1A shows mostly blue squares (load stability) and green squares (load decrease). At the end of
the study, EBV was detectable in only 53% of patients.
EBV loads ranged from 0 to 21 copies per 500 ng of DNA,
the mean load was 3.8 copies per 500 ng of DNA, and the
median load was 1.2 copies per 500 ng of DNA. These
data suggest that methotrexate decreases EBV load over
time, almost bringing it down to the levels observed in
controls (mean 1.9, median 0.6) (Table 2). Nonetheless,
this trend was not significant when the data were analyzed with generalized estimating equations: P ⫽ 0.61
under the hypothesis of normal law and exchangeable
correlation, P ⫽ 0.73 under normal law and independent
correlation, P ⫽ 0.51 under gamma law and exchangeable correlation, and P ⫽ 0.71 under gamma law and
independent correlation.
In most patients, TNF inhibitors do not influence EBV
load. Sixty-eight patients received infliximab. At the onset of the study, 85% of these patients had detectable EBV.
EBV loads ranged from 0 to 186 copies per 500 ng of DNA,
the mean load was 12 copies per 500 ng of DNA, and the
median load was 4.2 copies per 500 ng of DNA (Table 2).
EBV load was stable in 54 patients receiving treatment,
decreased in 8 patients, and increased in 6 patients. Figure
1B shows slightly more green squares (load decrease) than
red squares (load increase) in accordance with overall load
stability. At the end of the study, 63% of patients had
detectable EBV. EBV loads ranged from 0 to 542 copies per
500 ng of DNA, the mean load increased to 16 copies per
500 ng of DNA, and the median load decreased to 2.4
copies per 500 ng of DNA. In 1 patient, EBV load increased
from 7 to 542 copies per 500 ng of DNA. This patient’s
treatment was switched to etanercept and EBV load decreased sharply afterwards. Analysis of the evolution of
EBV loads over time in patients receiving infliximab, by
generalized estimating equations, did not demonstrate any
significant change: P ⫽ 0.16 under the hypothesis of normal law and exchangeable correlation, P ⫽ 0.57 under
normal law and independent correlation, P ⫽ 0.06 under
Epstein-Barr Virus Load in RA
765
Figure 1. Variation of Epstein-Barr virus load in patients with rheumatoid arthritis receiving
A, methotrexate, B, infliximab, and C, etanercept. Load is expressed in viral copy number
per 500 ng of DNA. Load at first quantification is in the white squares. Load at last
quantification is also given. Load increase is in red, load decrease is in green, and load
stability is in blue, taking into account the former load. An empty white box means that no
quantification was performed. Time 0 is the first day of therapy.
gamma law and exchangeable correlation, and P ⫽ 0.50
under gamma law and independent correlation.
Forty-eight patients received etanercept. At the onset of
the study, 31% had detectable EBV. EBV loads ranged
from 0 to 66 copies per 500 ng of DNA, the mean load was
4.7 copies per 500 ng of DNA, and the median load was 0
copies per 500 ng of DNA (Table 2). EBV load was stable in
33 patients receiving treatment, decreased in 6 patients,
and increased in 11 patients (Figure 1). Figure 1C shows
slightly more red squares (load increase) than green
squares (load decrease) in accordance with overall load
stability. At the end of the study, 64% of patients had
detectable EBV. EBV loads ranged from 0 to 246 copies per
500 ng of DNA, the mean load increased to 17.7 copies per
500 ng of DNA, and the median load increased to 2.1
copies per 500 ng of DNA. Analysis of the evolution of
EBV loads over time in patients receiving etanercept, by
generalized estimating equations, did not demonstrate any
significant change: P ⫽ 0.38 under the hypothesis of normal law and exchangeable correlation, P ⫽ 0.67 under
766
Balandraud et al
DISCUSSION
Figure 2. Epstein-Barr virus (EBV) load was assayed in 529 blood
samples from patients with rheumatoid arthritis and plotted
against the Disease Activity Score in 28 joints, showing positive
correlation between disease activity and EBV load in peripheral
blood lymphocytes.
normal law and independent correlation, P ⫽ 0.09 under
gamma law and exchangeable correlation, and P ⫽ 0.63
under gamma law and independent correlation.
Nine patients received etanercept after infliximab and
were analyzed as a separate group. In these patients, after
infliximab and before etanercept treatment, EBV loads
ranged from 0 to 542 copies per 500 ng of DNA, the mean
load was 81.2 copies per 500 ng of DNA, and the median
load was 0.17 copies per 500 ng of DNA. After etanercept
treatment, EBV loads ranged from 0 to 82 copies per 500 ng
of DNA, the mean load decreased to 12.6 copies per 500 ng
of DNA, and the median load increased to 1.9 copies per
500 ng of DNA.
Disease activity is associated with increased EBV load.
Whenever possible, disease activity was evaluated by calculating the DAS28 score (13). Both EBV load and DAS28
score were available for 529 blood samples. We tested
whether EBV loads correlated with DAS28 scores using
generalized estimating equations (12). EBV load was the
dependent variable and DAS28 activity was the independent variable. Two different correlation structures were
used: exchangeable and independent.
We found that higher DAS28 scores were associated
with higher EBV loads (Figure 2). This correlation was
significant for each hypothesis (normal law or gamma law)
made on the distribution of EBV loads in patients with RA
receiving treatment: P ⫽ 0.033 under the hypothesis of
normal law and exchangeable correlation, P ⫽ 0.0047 under normal law and independent correlation, and P ⱕ
0.0001 for gamma law and either exchangeable correlation
or independent correlation.
Other factors. Sex, age, and HLA–DR genotype were not
significantly different between the 3 groups (Table 1) and
did not influence either EBV load over time (data not
shown).
In patients with RA, impaired control of EBV infection
results in high EBV load in PBMCs (5). This increase in
EBV load (10 times that of healthy controls) is similar to
that observed in healthy transplant recipients receiving
immunosuppressants (7,8) and has also been described in
patients with systemic lupus erythematosus (14). Of interest, both transplant recipients and patients with RA develop lymphoma more often than healthy controls (6 –
8,15). In transplant recipients, lymphoma usually contain
the EBV genome and are preceded by polyclonal expansion of EBV-positive B cells. At that time, EBV load in
peripheral blood B cells progressively increases. A load of
1,000 copies of EBV per 500 ng of PBMC DNA is considered a level above which transplant recipients are at increased risk of developing lymphoma (7,8).
The EBV status of lymphoma developing in patients
with RA is still controversial. A recent study of 343 lymphoma that occurred between 1964 and 1995 in patients
with RA from Sweden, before TNF blockers were used,
demonstrated that although most lymphoma were B cell
derived, only 12% contained the EBV genome (16). This
finding is consistent with our observation that methotrexate decreases EBV load over time in patients with RA
(Figure 1 and Table 2). This number is very different from
that observed in lymphoma developing in transplant recipients, which are almost always EBV positive. However,
because TNF blockers were not used before 1995, this
study does not indicate whether lymphoma developing in
patients treated with TNF suppressors are similarly EBV
negative. Our results shed some light on this issue. Indeed,
we investigated whether long-term treatment of RA with
methotrexate, a first-line DMARD, or TNF inhibitors, a
second-line treatment, could impair EBV control and facilitate the emergence of EBV-positive B cell malignancies.
Long-term treatment of 19 patients with methotrexate
decreased EBV load to a level observed in controls. This
suggested partial EBV clearing from patients’ PBMCs.
Therefore, our data do not support the hypothesis that
methotrexate may impair the control of EBV replication
and do not explain the 4 cases of EBV-positive, immunosuppression-type lymphoma that occurred in patients
with RA receiving methotrexate and that regressed after
withdrawal of methotrexate (17).
Long-term followup of 128 patients with RA treated
with TNF inhibitors demonstrated stability of EBV load
over time in most patients. EBV load reached 542 copies
per 500 ng of DNA in only 1 patient receiving infliximab
and reached 250 copies per 500 ng of DNA in 1 patient
receiving etanercept. These increases account for higher
means in these groups. In the patient reaching 542 copies,
we found no evidence of B cell proliferative disease or
lymphoma.
Therefore, in most patients with RA, methotrexate and
TNF inhibitors do not impair control of EBV replication as
much as immunosuppressive agents in transplant recipients. However, we have to acknowledge the fact that lymphoma occurring in patients with RA treated with TNF
blockers are very uncommon. Indeed, while following
18,572 patients for 3 years, Wolfe and Michaud only ob-
Epstein-Barr Virus Load in RA
served 29 cases of lymphoma, which is roughly 1 case of
lymphoma in 640 patients, over 3 years (15). Therefore,
our study may fail to detect a very rare population of
fragile (possibly genetically) patients who are at risk of
developing lymphoma when treated with methotrexate or
TNF blockers.
Our study also highlights the correlation between disease activity (as assessed by the DAS28 index) and EBV
load. This correlation may only reflect the fact that disease
activity is associated with hyperactivation of B cells,
which in turn may facilitate the replication of EBV and
lead to high EBV loads. Alternatively, disease flares may
be associated with lowered EBV-specific immunity. This
has already been observed when studying T cell responses
to gp110, a glycoprotein of the late replicative cycle whose
recognition is critical in controlling EBV replication (4).
In short, we have monitored EBV load in the PBMCs of
144 patients with RA treated with methotrexate and/or
TNF inhibitors. EBV load was stable over the years. The
main prediction carried by this result is that lymphoma
developing in patients with RA treated with TNF inhibitors should differ from EBV-positive posttransplant lymphoma.
767
5.
6.
7.
8.
9.
10.
11.
AUTHOR CONTRIBUTIONS
Dr. J. Roudier had full access to all of the data in the study and
takes responsibility for the integrity of the data and the accuracy
of the data analysis.
Study design. Balandraud, J. Roudier, C. Roudier.
Acquisition of data. Balandraud, Guis, Auger, C. Roudier.
Analysis and interpretation of data. Balandraud, J. Roudier, C.
Roudier.
Manuscript preparation. Balandraud, J. Roudier, C. Roudier.
Statistical analysis. Meynard.
12.
13.
14.
REFERENCES
1. Alspaugh MA, Henle G, Lennette ET, Henle W. Elevated levels of antibodies to Epstein-Barr virus antigens in serum and
synovial fluids of patients with rheumatoid arthritis. J Clin
Invest 1981;67:1134 – 40.
2. Tosato G, Steinberg A, Blaese RM. Defective EBV-specific
suppressor T-cell function in rheumatoid arthritis. N Engl
J Med 1981;305:1238 – 43.
3. Tosato G, Steinberg AD, Yarchoan R, Heilman CA, Pike SE, De
Seau, et al. Abnormally elevated frequency of Epstein-Barr
virus-infected B cells in the blood of patients with rheumatoid
arthritis. J Clin Invest 1984;73:1789 –95.
4. Toussirot E, Wendling D, Tiberghien P, Luka J, Roudier J.
15.
16.
17.
Decreased T cell precursor frequencies to Epstein-Barr virus
glycoprotein Gp110 in peripheral blood correlate with disease
activity and severity in patients with rheumatoid arthritis.
Ann Rheum Dis 2000;59:533– 8.
Balandraud N, Meynard JB, Auger I, Sovran H, Mugnier B,
Reviron D, et al. Epstein-Barr virus load in the peripheral
blood of patients with rheumatoid arthritis: accurate quantification using real-time polymerase chain reaction. Arthritis
Rheum 2003;48:1223– 8.
Mellemkjaer L, Linet MS, Gridley G, Frisch M, Moller H,
Olsen JH. Rheumatoid arthritis and cancer risk. Eur J Cancer
1996;32A:1753–7.
Baldanti F, Grossi P, Furione M, Simoncini L, Sarasini A,
Comoli P, et al. High levels of Epstein-Barr virus DNA in
blood of solid-organ transplant recipients and their value in
predicting posttransplant lymphoproliferative disorders.
J Clin Microbiol 2000;38:613–9.
Kimura H, Morita M, Yabuta Y, Kuzushima K, Kato K, Kojima
S, et al. Quantitative analysis of Epstein-Barr virus load by
using a real-time PCR assay. J Clin Microbiol 1999;37:132– 6.
Baecklund E, Askling J, Rosenquist R, Ekbom A, Klareskog L.
Rheumatoid arthritis and malignant lymphomas [review].
Curr Opin Rheumatol 2004;16:254 – 61.
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.
Pieri Balandraud N, Roudier J, Roudier C. Quantification of
human genomic DNA using retinoic X receptor B gene. In:
Dietmaier W, Wittwer C, Sivasubramanian N, editors. Rapid
cycle real time PCR, methods and applications: genetics and
oncology. Heidelberg (Germany): Springer-Verlag; 2002. p.
27–33.
Zeger SL, Liang KY, Albert PS. Models for longitudinal data:
a generalized estimating equation approach [published erratum appears in Biometrics 1989;45:347]. Biometrics 1988;44:
1049 – 60.
Fransen J, van Riel PL. The Disease Activity Score and the
EULAR response criteria. Clin Exp Rheumatol 2005;23 Suppl
39:S93–9.
Kang I, Quan T, Nolasco H, Park SH, Hong MS, Crouch J, et al.
Defective control of latent Epstein-Barr virus infection in systemic lupus erythematosus. J Immunol 2004;172:1287–94.
Wolfe F, Michaud K. Lymphoma in rheumatoid arthritis:
the effect of methotrexate and anti–tumor necrosis factor
therapy in 18,572 patients. Arthritis Rheum 2004;50:1740 –
51.
Baecklund E, Iliadou A, Askling J, Ekbom A, Backlin C,
Granath F, et al. Association of chronic inflammation, not its
treatment, with increased lymphoma risk in rheumatoid arthritis. Arthritis Rheum 2006;54:692–701.
Georgescu L, Quinn GC, Schwartzman S, Paget SA. Lymphoma in patients with rheumatoid arthritis: association with
disease state or methotrexate treatment. Semin Arthritis
Rheum 1997;26:794 – 804.
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