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Tumor necrosis factor therapy and the risk of serious infection and malignancy in patients with early rheumatoid arthritisA meta-analysis of randomized controlled trials.

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ARTHRITIS & RHEUMATISM
Vol. 63, No. 6, June 2011, pp 1479–1485
DOI 10.1002/art.30310
© 2011, American College of Rheumatology
Tumor Necrosis Factor Therapy and the Risk of
Serious Infection and Malignancy in Patients With
Early Rheumatoid Arthritis
A Meta-Analysis of Randomized Controlled Trials
Andrew E. Thompson,1 Scott W. Rieder,2 and Janet E. Pope1
tions or the rate of malignancies between the anti-TNF
therapy group and the control group.
Conclusion. Whereas other meta-analyses have
shown an increased risk of serious infection and malignancy in patients receiving anti-TNF therapy, the results of the present meta-analysis show that there is not
an increased risk when the patients have early disease
and have not previously been treated with DMARDs
and/or MTX.
Objective. To conduct a meta-analysis of the rates
of serious infection and malignancy in patients with
early rheumatoid arthritis (RA) who have started anti–
tumor necrosis factor (anti-TNF) therapy and had not
received treatment with disease-modifying antirheumatic drugs (DMARDs) or methotrexate (MTX).
Methods. A systematic literature search was conducted through the summer of 2009. All studies included were randomized, double-blind, placebocontrolled trials involving patients with early RA who
were started on anti-TNF therapy without prior
DMARD/MTX use. Six trials met the inclusion criteria
for the meta-analysis, comprising a total of 2,183 patients receiving biologic therapy and 1,236 patients
receiving MTX. The data extracted were from published
trials.
Results. A pooled odds ratio (OR) (determined
using Mantel-Haenszel methods, with a continuity correction designed for sparse data) was calculated for
serious infections (requiring hospitalization) and malignancies, comparing anti-TNF therapy to MTX control. The pooled OR for serious infections was 1.28 (95%
confidence interval [95% CI] 0.82–2.00) and that for
malignancies was 1.08 (95% CI 0.50–2.32). There was no
significant difference in either the rate of serious infec-
The efficacy of tumor necrosis factor (TNF)
inhibition has been shown in numerous trials, both in
patients with early rheumatoid arthritis (RA) and in
those with established RA (1). As a result, TNF inhibition has significantly improved the signs and symptoms,
function, radiographic progression, and quality of life for
patients with RA.
The most important side effects of TNF inhibition are the risks of serious infection and the potential
for malignancy. Although product monographs include
warnings and precautions about these side effects, they
do not provide an estimate of risk. The risk of serious
infections is likely increased in the first 6–12 months of
therapy (2). A meta-analysis of randomized controlled
trials of patients starting TNF monoclonal antibody
therapy showed that these patients have an increased
risk of serious infection (3). This early increased risk of
infection was also observed in an inception cohort of RA
patients starting anti-TNF treatment, and was also confirmed in a meta-analysis of patients treated with etanercept (a TNF inhibitor) (4,5). The risk of solid and
hematopoietic malignancies with TNF inhibition is much
less clear. Meta-analyses of clinical trial data have
revealed conflicting results (3,5). An increased risk of
malignancy has not been observed in the majority of
Mr. Rieder is recipient of a summer research grant from
Roche Canada.
1
Andrew E. Thompson, MD, MHPE, FRCPC, Janet E. Pope,
MD, FRCPC: University of Western Ontario and St. Joseph’s Health
Care, London, Ontario, Canada; 2Scott W. Rieder, BSc: University of
Western Ontario, London, Ontario, Canada.
Address correspondence to Andrew E. Thompson, MD,
MHPE, FRCPC, Rheumatology Centre, St. Joseph’s Health Care, 268
Grosvenor Street, PO Box 5777, London, Ontario N6A 4V2, Canada.
E-mail: andy.thompson@sjhc.london.on.ca.
Submitted for publication May 4, 2010; accepted in revised
form February 10, 2011.
1479
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THOMPSON ET AL
Cochrane Collaboration. The present analysis was conducted
by adhering to the QUOROM statement on quality of reports
on meta-analyses of randomized controlled trials (6).
Using the NCBI database, we extracted data from the
inception of the analysis until August 2009, searching for the
terms early rheumatoid arthritis, biologics, anti-TNF therapy,
adalimumab, infliximab, etanercept, golimumab, certolizumab,
and randomized controlled trials. We also cross-referenced the
citations from all of the articles selected and from current
meta-analyses on this subject.
Study selection and outcomes. All studies were scored
by 2 independent reviewers (AET and SWR). A study was
included if it met the eligibility criteria and received a Jadad
quality score of ⱖ3 (7). The Jadad score is a procedure to
independently assess the methodologic quality of a clinical trial
and is the most widely used meta-analysis assessment tool (8).
We included randomized controlled trials that involved
treatment with any of the currently licensed anti-TNF biologic
agents (adalimumab, etanercept, golimumab, certolizumab,
and infliximab). In addition, patients with RA were required to
have a disease duration of ⬍3 years since diagnosis, and were
currently not being treated with a disease-modifying antirheumatic drug (DMARD) or biologic agent. All patients had to be
allocated to receive either a biologic monotherapy versus
placebo or biologic therapy plus DMARD therapy versus
placebo, for at least 6 months.
patients in registry databases, with the exception of a
risk of lymphoma and melanoma found in some registries (2).
The challenge with regard to current metaanalysis data and on-going registry data is that the
information has been obtained from heterogeneous
populations of patients with varying degrees of comorbidity. This heterogeneity makes it very difficult to
understand and communicate the risk in individual
patients. It is important to know whether early RA has
the same risk of serious infection or risk of malignancy
as that in older patients with longstanding RA and
multiple comorbidities.
The goal of this study was to estimate the risk of
serious infection and risk of malignancy through a
meta-analysis of randomized controlled trials of antiTNF therapy in patients with early RA.
PATIENTS AND METHODS
Information sources and search strategy. The data
from all of the selected studies were extracted and analyzed
using a predefined, peer-reviewed assessment written by the
Table 1. Characteristics of the trials of anti-TNF therapy included in the meta-analysis*
Adalimumab in
ERA
Trial sites
Trial size, no. of
patients
Treatment arm
Experimental
Control
No. of study arms
Age, mean years
Female, %
Duration of
disease, mean
months
RF positive, %
Taking steroids, %
SJC, mean
CRP, mean mg/dl
DAS, mean
HAQ score, mean
ASPIRE
COMET
ERAS
PREMIER
SWEFOT
Australia, Europe,
North America
542
North America
Australia, Europe,
North America
799
Sweden
148
Europe, North
America
1,040
ADA ⫹ MTX
Inflix. ⫹ MTX
Etan. ⫹ MTX
Etan.
Inflix. ⫹ MTX
MTX
MTX
MTX
MTX
ADA ⫹ MTX or
ADA mono
MTX
2
47
56
9
3
50
72
11
2
51
74
10
2
50
75
12
3
52
75
9
MTX ⫹ SSZ
⫹ HCQ
2
52
77
6
95
NA
10
2.9–3.8
NA
1.3
72
38
22
2.6–3.0
NA
1.5
70 (CCP)
50
17
3.6–3.7
NA
1.6
88
40
24
3.3–4.4
NA
NA
100
36
22
3.9–4.1
NA
1.5
67
7
NA
NA
4.8
1.3
United Kingdom
632
258
* Full descriptions of the anti–tumor necrosis factor (anti-TNF) trials are provided in refs. 14–19. ERA ⫽ Early Rheumatoid Arthritis; ASPIRE ⫽
Active-Controlled Study of Patients Receiving Infliximab for the Treatment of Rheumatoid Arthritis of Early Onset; COMET ⫽ Comparison of
Methotrexate Monotherapy With a Combination of Methotrexate and Etanercept in Active, Early, Moderate to Severe Rheumatoid Arthritis;
ERAS ⫽ Early Rheumatoid Arthritis Study; PREMIER ⫽ Multicenter, Randomized, Double-Blind Clinical Trial of Combination Therapy With
Adalimumab Plus Methotrexate versus Methotrexate Alone or Adalimumab Alone in Patients With Early, Aggressive Rheumatoid Arthritis who
had not had Previous Methotrexate Treatment; SWEFOT ⫽ Addition of Infliximab Compared With Addition of Sulfasalazine and Hydroxychloroquine to Methotrexate in Patients With Early Rheumatoid Arthritis; ADA ⫽ adalimumab; MTX ⫽ methotrexate; Inflix. ⫽ infliximab; Etan. ⫽
etanercept; mono ⫽ monotherapy; SSZ ⫽ sulfasalazine; HCQ ⫽ hydroxychloroquine; RF ⫽ rheumatoid factor; CCP ⫽ cyclic citrullinated peptide;
NA ⫽ not available; SJC ⫽ swollen joint count; CRP ⫽ C-reactive protein; DAS ⫽ Disease Activity Score; HAQ ⫽ Health Assessment
Questionnaire.
ANTI-TNF THERAPY AND SERIOUS INFECTION/MALIGNANCY RISK IN EARLY RA
Table 2. Summary of serious infections*
Trial, randomization
No. of patients
with serious
infections
Adalimumab in ERA
Adalimumab ⫹ MTX
MTX
ASPIRE
Infliximab ⫹ MTX
MTX
COMET
Etanercept ⫹ MTX
MTX
ERAS
Etanercept ⫹ MTX
MTX
PREMIER
Adalimumab ⫹ MTX
MTX
SWEFOT
Infliximab ⫹ MTX
MTX ⫹ sulfasalazine
⫹ plaquenil
3/75
2/73
40/749
6/291
5/274
8/268
12/415
6/217
12/542
7/257
1/128
1/130
Description of infections
No opportunistic infections
reported
Tuberculosis (n ⫽ 4) and
sepsis (n ⫽ 3) in
infliximab group
No opportunistic infections;
1 case of disseminated
herpes zoster in MTX
group
No opportunistic infections
and no deaths from
infection in either group
Pleural tuberculosis (n ⫽ 1)
in adalimumab group;
death due to infection
(n ⫽ 1) in MTX group
No opportunistic infections
or deaths reported
* See Table 1 for definitions.
The 2 primary outcomes examined were serious infection (requiring hospitalization) and malignancy. Our primary
data sources were from the published data. Serious infection
was defined according to the definition given within each trial
protocol.
Statistical analysis. We used a fixed-effects metaanalysis to assess the pooled data, because of the rareness of
outcomes in the trials. Results are expressed as the odds ratio
1481
(OR) with 95% confidence interval (95% CI). Using the ORs
from each trial, we constructed a pooled data table using
Mantel-Haenszel methods. Inconsistency across the trials was
measured by calculating the I2 statistic. All statistical tests and
creation of forest plots were carried out with Review Manager
version 5 software (9).
RESULTS
Included studies. Of the 548 published reports
retrieved on the initial search, 503 were initially excluded on the basis of the title and abstract (exclusions
for lack of control groups, no anti-TNF therapy, patients
without RA, or no randomization). Of the remaining 45
studies, 39 were not eligible because the patients with
RA had a disease duration of ⬎3 years (in trials of
golimumab, etanercept, or certolizumab therapy [10–
13]), patients had been previously treated unsuccessfully
with DMARDs, or the Jadad quality score for the study
(7) was below the cutoff level of 3. Thus, 6 trials were
considered eligible for inclusion in our meta-analysis
(14–19).
The included trials were fairly homogeneous in
terms of patient characteristics (Table 1). Among the 6
trials, the mean age ranged from 47 years to 52 years,
⬃56–77% of the patients were female, the disease
duration ranged from 6 months to 12 months, and at
least two-thirds of the patients in each trial were rheumatoid factor positive. The mean swollen joint count was
substantial in all 6 trials, ranging from 10 to 24, and the
scores for disability were high in all 6 trials, with a
Figure 1. Effect of anti–tumor necrosis factor antibody therapy (experimental group), compared with control therapy, on the occurrence of serious
infections in patients with rheumatoid arthritis. Results are shown as forest plots, with values expressed as the pooled odds ratio with 95%
confidence interval (95% CI), determined using the Mantel-Haenszel (M-H) test. ERA ⫽ Early Rheumatoid Arthritis; ASPIRE ⫽ ActiveControlled Study of Patients Receiving Infliximab for the Treatment of Rheumatoid Arthritis of Early Onset; COMET ⫽ Comparison of
Methotrexate Monotherapy With a Combination of Methotrexate and Etanercept in Active, Early, Moderate to Severe Rheumatoid Arthritis;
ERAS ⫽ Early Rheumatoid Arthritis Study; PREMIER ⫽ Multicenter, Randomized, Double-Blind Clinical Trial of Combination Therapy With
Adalimumab Plus Methotrexate versus Methotrexate Alone or Adalimumab Alone in Patients With Early, Aggressive Rheumatoid Arthritis who
had not had Previous Methotrexate Treatment; SWEFOT ⫽ Addition of Infliximab Compared With Addition of Sulfasalazine and Hydroxychloroquine to Methotrexate in Patients With Early Rheumatoid Arthritis.
1482
THOMPSON ET AL
Table 3. Summary of malignancies*
Trial, randomization
No. of patients
with
malignancies
Adalimumab in ERA
Adalimumab ⫹ MTX
MTX
ASPIRE
Infliximab ⫹ MTX
MTX
No reported malignancies
0/75
0/73
4/749
0/291
COMET
Etanercept ⫹ MTX
MTX
4/274
4/268
ERAS
Etanercept ⫹ MTX
MTX
5/415
2/217
PREMIER
Adalimumab ⫹ MTX
MTX
6/542
4/257
SWEFOT
Infliximab ⫹ MTX
MTX ⫹ sulfasalazine
⫹ plaquenil
* See Table 1 for definitions.
Description of
malignancies
0/128
0/130
Endometrial cancer,
pancreatic cancer, colon
cancer, acute myeloid
leukemia
Breast cancer (n ⫽ 3),
prostate cancer (in
etanercept group);
chronic lymphocytic
leukemia, epidermoid
cancer of the tongue,
basal cell carcinoma,
Bowen’s disease (in
MTX group)
Breast cancer, lung cancer,
carcinoid lung cancer,
Hodgkin’s lymphoma,
prostate cancer (in
etanercept group); colon
cancer, bladder cancer
(in MTX group)
Ovarian cancer, prostate
cancer, breast cancer,
multiple myeloma, colon
cancer, metastatic
cancer with unknown
primary (in adalimumab
group); lymphoma,
melanoma, prostate
cancer, breast cancer (in
MTX group)
No reported malignancies
reported mean Health Assessment Questionnaire score
ranging from 1.3 to 1.6. Overall, 3,419 patients with RA
were randomized to receive either a TNF inhibitor or
MTX treatment.
Risk of serious infection. Review of the published
data from the 6 randomized controlled trials revealed
that a serious infection occurred in 73 (3.3%) of 2,183
patients with RA who had received at least one dose of
a TNF inhibitor, compared with 30 (2.4%) of 1,236
patients in the control treatment groups (Table 2).
Statistical heterogeneity was low (I2 ⫽ 11%) and not
beyond variations that could be due to chance (P ⫽
0.27). The risk of serious infection in patients treated
with a TNF inhibitor was not statistically significantly
different than that in MTX-treated controls, and numerically was only slightly increased in the TNF inhibitor
group compared with MTX controls (OR 1.28, 95% CI
0.82–2.00) (Figure 1). For this meta-analysis of the risk
of serious infections, we calculated the power to detect
an increased risk in patients treated with a TNF inhibitor. Using a post hoc procedure, the effect size for the
estimate of risk of serious infections in the studies was
calculated to be 0.19. Given the large sample size, the
power of the meta-analysis was found to be sufficient
(99% power to detect a significant difference in the rate
of serious infections between the groups), given the
small effect size.
Risk of malignancy. Review of the published data
from the 6 randomized controlled trials revealed that
malignancies occurred in 19 (0.87%) of 2,183 patients
with RA who had received at least one dose of a TNF
inhibitor, and in 10 (0.81%) of 1,236 control patients
(Table 3). Statistical heterogeneity was low (I2 ⫽ 0%)
Figure 2. Effect of anti–tumor necrosis factor antibody therapy (experimental group), compared with control therapy, on the occurrence of
malignancy in patients with rheumatoid arthritis. Results are shown as forest plots, with values expressed as the pooled odds ratio with 95%
confidence interval, determined using the Mantel-Haenszel test. See Figure 1 for definitions.
ANTI-TNF THERAPY AND SERIOUS INFECTION/MALIGNANCY RISK IN EARLY RA
and was not beyond variations that could be due to
chance (P ⫽ 0.77). The risk of malignancy was not
increased in patients treated with a TNF inhibitor
compared with control patients treated with MTX (OR
1.08, 95% CI 0.50–2.32) (Figure 2).
For this meta-analysis of the risk of malignancy,
we calculated the power to detect an increased risk in
patients treated with a TNF inhibitor. Using a post hoc
procedure, the effect size for the estimate of risk of
malignancies in the studies was calculated to be 0.11.
Given the large sample size, the power of the metaanalysis was deemed sufficient to detect a significant
difference between groups (89%), making the possibility
of a Type II error highly unlikely.
DISCUSSION
This meta-analysis did not show any significant
differences in the risk of infection or risk of malignancy
between patients with early RA treated with anti-TNF
therapy and those treated with MTX. With regard to the
risk of malignancy, prior meta-analyses have shown
similar rates of malignancy in the anti-TNF treatment
arm of the selected studies (3,5) (Table 4). The only
meta-analysis to show a statistically significant increase
in the risk of malignancy included trials involving monoclonal antibody therapy (3). In that analysis, the rate of
malignancy in the control arm was much lower than the
rate reported in our analysis or in the meta-analysis of
trials of etanercept. This finding is not explained. The
results of the present meta-analysis provide continued
support to the existing observational data showing that a
globally increased risk of malignancy has not been found
with anti-TNF therapy (20–25).
Although these observations are reassuring, caution must be exercised when interpreting these results,
since the duration of the trials included in this metaanalysis ranged from 6 months to 12 months. No assurances regarding the long-term risk of malignancy are
provided. Moreover, it would be inappropriate to generalize the results of this meta-analysis to a pediatric
population.
With regard to the risk of serious infection, this
meta-analysis did not find an increased risk of infection
in patients with newly diagnosed RA treated with antiTNF therapy. The mean age of the patients with newly
diagnosed RA in the anti-TNF trials included in this
analysis ranged from 47 years to 52 years, as compared
to a mean age of 53–57 years in those with established
RA (26–28). This finding may be explained by the fact
that younger patients with recent-onset RA may have
fewer infectious complications, attributable to a lower
1483
Table 4. Risk of malignancy among studies from prior meta-analyses
and the ERAS trial*
Study,
year (ref.)
Bongartz et al,
2006 (3)
Bongartz et al,
2009 (5)
ERAS, 2000 (16)
Treatment arm
Anti-TNF
Control
Odds ratio (95% CI)
0.8
0.2
1.1
0.7
1.84 (0.79–4.28)
0.9
0.8
1.08 (0.50–2.32)
3.3 (1.2–9.1)
* Values for each treatment arm are the rate of malignancy, expressed
as a percentage. The odds ratio with 95% confidence interval (95% CI)
shows the likelihood of the occurrence of malignancy in anti-TNF–
treated patients compared with control patients. See Table 1 for other
definitions.
rate of associated comorbidities. A review of observational research designs has shown a higher risk of
infections in patients with RA in the first few months
following anti-TNF initiation, followed by a reduction in
risk with increasing duration of use (2). The findings in
the patients with newly diagnosed RA starting anti-TNF
therapy in our analysis are not consistent with these
observational database results. Although our findings
are promising, screening of participants prior to entry
into a randomized controlled trial would likely reduce
the risk of infection.
There are several limitations to our metaanalysis. Our search of publications on Medline and the
references of the key articles may not reveal all of the
relevant published articles. Our only source of data was
from published results of randomized controlled trials,
and access to raw data would result in a more rigorous
analysis. However, we believe that this would be unlikely
to significantly change the results.
A potential source of bias in the included trials
was the higher number of withdrawals in the control
group, due to treatment inefficacy, which hinders subsequent ascertainment of events in the control group. This
occurred in 4 of the 6 included trials. Any bias associated
with loss of safety data as a result of these withdrawals
would lead to a smaller difference in the rate of serious
adverse events between treatment and control groups.
This meta-analysis has not shown an increased
risk of malignancy or serious infections in patients with
newly diagnosed RA treated with anti-TNF therapy.
However, further review of this population of patients in
an observational inception cohort would be important to
confirm and strengthen these findings.
AUTHOR CONTRIBUTIONS
All authors were involved in drafting the article or revising it
critically for important intellectual content, and all authors approved
1484
THOMPSON ET AL
the final version to be published. Dr. Thompson 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 conception and design. Thompson, Pope.
Acquisition of data. Thompson, Rieder.
Analysis and interpretation of data. Thompson, Rieder, Pope.
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meta, patients, therapy, early, necrosis, factors, serious, controller, arthritis, malignant, randomized, analysis, trials, infectious, risk, tumors, rheumatoid
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