BRIEF OBSERVATIONAll-cause Mortality Associated withTNF-a .docx

BRIEF OBSERVATION
All-cause Mortality Associated with
TNF-a Inhibitors in Rheumatoid Arthritis:
A Meta-Analysis of Randomized Controlled Trials
Lucile Poiroux, MD, Yannick Allanore, MD, PhD, André
Kahan, MD, PhD, Jérôme Avouac, MD, PhD
Paris Descartes University, Sorbonne Paris Cité, Rheumatology
A Department, Cochin Hospital, Paris, France
Funding: This
Conflict of In
Authorship: A
conception, design
Requests for re
Université Paris D
rue du Faubourg S
E-mail address
0002-9343/$ -see
http://dx.doi.org/1
ABSTRACT
OBJECTIVE: To compare mortality data obtained from
randomized controlled trials for the 5 tumor necrosis
factor-a (TNF-a) inhibitors used in the treatment of rheumatoid
arthritis.
METHODS: A systematic review of articles published up to
November 2014 was performed using electronic

databases. We included randomized, controlled trials, with a
follow-up period of at least 24 weeks,
comparing TNF-a inhibitors to placebo or disease-modifying
antirheumatic drugs. The primary outcome
was the occurrence of all-cause mortality.
RESULTS: Twenty-three studies were selected. These articles
included 6525 patients in the anti-TNF-a
group and 3523 in the control group. The duration of patient
follow-up ranged from 24 to 104 weeks. The
risk of all-cause mortality in patients receiving TNF-a inhibitors
was not significantly different from those
receiving the comparator (odds ratio 1.32; 95% confidence
interval, 0.76-2.29). Subgroup analyses with
respect to the molecule used, the dose received, the use of TNF-
a inhibitors as monotherapy or combination
therapy, or the quality of the trial did not modify the findings.
CONCLUSION: This meta-analysis performed on a large
number of patients and including the 5 TNF-a
inhibitors currently available shows no increased risk of
medium-term all-cause mortality in patients with
rheumatoid arthritis.
� 2015 Elsevier Inc. All rights reserved. � The American
Journal of Medicine (2015) -, ---
KEYWORDS: Meta-analysis; Mortality; Rheumatoid arthritis;
TNF-a inhibitors
Tumor necrosis factor-a (TNF-a) inhibitors are the most
widely used first-line biologic therapy for the treatment of
rheumatoid arthritis. Much has been written on the concern
that TNF-a inhibitors may increase the risk of malignancy,
infections, and other serious adverse events.1,2 However,
studies of the potential risks of this drug class on the “hard
endpoint” mortality are scarce and have provided conflicting
results.3 A previous meta-analysis reported no evidence of
increased mortality associated with any TNF-a inhibitor in
rheumatoid arthritis. However, the analysis was limited to
research received no funding.

terest: None.
ll authors had access to the data and participated in the
, writing, editing, and final approval of the manuscript.
prints should be addressed to Jérôme Avouac, MD, PhD,
escartes, Service de Rhumatologie A, Hôpital Cochin, 27
aint-Jacques, Paris 75014, France.
: [email protected]
front matter � 2015 Elsevier Inc. All rights reserved.
0.1016/j.amjmed.2015.07.020
the 3 TNF-a inhibitors available at this period and mainly
included short-term safety data.4 Thus, our aim was to
assess the risk of medium-term all-cause mortality upon the
5 currently available TNF-a inhibitors in rheumatoid
arthritis through a meta-analysis of randomized controlled
trials.
METHODS
Data Sources and Literature Search
We searched randomized controlled trials using MEDLINE
via PubMed, the Cochrane databases, Embase, Google
Scholar, and manual searches of reference lists from sys-
tematic reviews and original publications. Studies published
in English were identified from January 1, 2000 to
November 1, 2014. The search terms included TNF alpha
inhibitors; adalimumab; etanercept; certolizumab pegol;
infliximab; golimumab; rheumatoid arthritis; Randomized
controlled trials, mortality; English; All adults. Our
mailto:[email protected]
http://dx.doi.org/10.1016/j.amjmed.2015.07.020
2 The American Journal of Medicine, Vol -, No -, - 2015
research was limited to English language and human clinical
trials.

Inclusion Criteria
We defined the target population as adults with rheuma-
CLINICAL SIGNIFICANCE
� Tumor necrosis factor-a inhibitors show
no increased risk of medium-term all-
cause mortality.
� The type of molecule and the dose
received do not modify this finding.
toid arthritis diagnosed according
to the 1987 American College
of Rheumatology criteria.5 In-
terventions included all 5 currently
available TNF-a inhibitors. Eligi-
ble comparators included placebo
and conventional disease-modifying
antirheumatic drugs (DMARDs).
The primary outcome of this study
was the occurrence of all-cause
mortality defined on an intention-
to-treat basis. To better reflect the drug effect on the poten-
tial risk of death, included studies have to report a minimum of
24 weeks of the study duration.
Methodological Quality
The articles that fulfilled the inclusion criteria underwent
quality appraisal by using the Jadad scale.6
Data Extraction
Two investigators (LP and JA) independently extracted
data from articles using a customized form, available
Figure 1 Flow diagram of articles evaluated for incl
from the authors. Disagreements were resolved by
consensus.
Statistical Analysis

We used the Mantel-Haenszel method for calculating the
usion and exclusion. RA ¼ r
weighted summary odds ratio un-
der the fixed-effect model. Next,
the heterogeneity was incorpo-
rated to calculate summary odds
ratios under the random-effects
model (DerSimonian and Laird).7
Statistical heterogeneity was
tested by Q-test (c2) and I2 sta-
tistic calculation.8 All statistical
tests and creation of forest plots
were conducted with MedCalc
software (v11.4.4; Ostend, Belgium). Additional subgroup
analyses were planned to check whether they would sub-
stantially change the findings.
RESULTS
Included Studies
The results of the article selection process are reported in
Figure 1. Among the 495 studies initially analyzed, 23 studies
fulfilled our inclusion criteria (Table 1).9-31 The median study
duration was 46 weeks (range: 24 to 104 weeks). This analysis
included 10,048 patients: 6525 were treated with TNF-a
heumatoid arthritis.
Table 1 Characteristics of Trials Included in the Analysis
Reference
Mean Disease
Duration (Y)
Placebo TNF-a Inhibitor

Trial Duration
(Wk) Jadad Scoren Type Type Dose n
Kremer et al, 20109 8.3 129 Methotrexate Golimumab 2-4
mg/kg/3 mo 257 48 4
Emery et al, 200910 3.4 160 Methotrexate Golimumab 50 or 100
mg/4 wk 318 24 5
Quinn et al, 200511 0.6 10 Methotrexate Infliximab 3 mg/kg 10
54 4
St. Clair et al, 200412 0.9 291 Methotrexate Infliximab 3 or 6
mg/kg 749 54 5
Keystone et al, 200413 11.0 200 Methotrexate Adalimumab 20
mg/wk or 40 mg/2 wk 419 52 3
Furst et al, 200314 10.4 318 Disease-modifying
antirheumatic drugs
Adalimumab 40 mg/2 wk 318 24 3
Smolen et al, 201315 6.8 200 Methotrexate Etanercept 25 or 50
mg/wk 404 28 5
Klareskog et al, 200416 6.8 228 Methotrexate Etanercept 25
mg/2 wk 231 52 4
Combe et al, 200617 6.2 50 Sulfasalazine Etanercept 25 mg/2
wk 101 24 3
Smolen et al, 200918 6.2 127 Methotrexate Certolizumab 200
mg or 400 mg/2 wk 492 24 3
Fleischmann et al, 200919 9.6 109 Placebo Certolizumab 400
mg/2 wk 111 24 5
Keystone et al, 200820 6.2 199 Methotrexate Certolizumab 200
or 400 mg/2 wk 783 52 4
Durez et al, 200721 0.4 14 Methotrexate Infliximab 3 mg/kg 15
46 2
Lipsky et al, 200022 10.6 88 Methotrexate Infliximab 3-10
mg/kg 340 52 3
Kavanaugh et al, 201323 0.3 517 Methotrexate Adalimumab 40
mg/2 wk 515 78 4

Van Vollenhoven et al, 201124 8.6 76 Methotrexate
Adalimumab 40 mg/2 wk 79 26 2
Choy et al, 201225 9.6 121 Methotrexate Certolizumab 400
mg/2 wk 126 24 5
Breedveld et al, 200626 0.8 257 Methotrexate Adalimumab 40
mg/2 wk 268 52 3
Miyasaka et al, 200827 9.4 87 Placebo Adalimumab 20-40 mg
or 80 mg/2 wk 265 24 3
van de Putte et al, 200428 10.9 110 Placebo Adalimumab 20-40
mg/wk or 2 wk 434 26 5
Schiff et al, 200829 7.7 110 Methotrexate Infliximab 3 mg/kg
165 24 4
Leirisalo-Repo et al, 201330 0.3 49 Disease-modifying
antirheumatic drugs
Infliximab 3 mg/kg 50 104 5
Bejarano et al, 200831 0.7 73 Methotrexate Adalimumab Not
reported 75 56 5
TNF ¼ tumor necrosis factor.
Poiroux
et
al
TN
F-a
Inhibitors
in
Rheum
atoid
A

rthritis
3
Table 2 Events Reported in Trials
Reference TNF-a Inhibitor Dose of TNF-a Inhibitor
Deaths, n Cause of Death
DosePlacebo TNF-a Inhibitor Placebo TNF-a Inhibitor
Kremer et al, 20109 Golimumab 2-4 mg/kg/3 mos 0 1 0
Myocardial infarction Normal/high
Emery et al, 200910 Golimumab 50 or 100 mg/4 wk 0 2 0
Suicide, cardiorespiratory arrest
after surgery
Normal/high
Quinn et al, 200511 Infliximab 3 mg/kg 0 0 0 0 Normal
St Clair et al, 200412 Infliximab 3 or 6 mg/kg 2 2 Respiratory
failure due
to methotrexate,
upper
gastrointestinal
bleed
Cardiac arrest, metastatic pancreatic
cancer
Normal/high

Keystone et al, 200413 Adalimumab 20 mg/wk or 40 mg/2 wk 0
3 0 Multiple fractures, urosepsis,
complications of chemotherapy
for lymphoma
Normal
Furst et al, 200314 Adalimumab 40 mg/2 wk 0 1 0 Necrotizing
fasciitis Normal
Smolen et al, 201315 Etanercept 25 or 50 mg/wk 0 2 0
Pulmonary embolism, septicemia Low/normal
Klareskog et al, 200416 Etanercept 25 mg 2/wk 1 1 Pulmonary
embolism Stroke and pneumonia Normal
Combe et al, 200617 Etanercept 25 mg 2/wk 0 0 0 0 Normal
Smolen et al, 200918 Certolizumab 200 mg or 400 mg/2 wk 0 2
0 Myocardial infarction, fracture and
shock
Low/normal
Fleischmann et al, 200919 Certolizumab 400 mg/2 wk 0 0 0 0
Normal
Keystone et al, 200820 Certolizumab 200 or 400 mg/2 wk 1 5
Myocardial infarction Hepatic neoplasm, cardiac arrest,
cerebral stroke, myocardial
necrosis, cardiac arrest
Low/normal
Durez et al, 200721 Infliximab 3 mg/kg 0 0 0 0 Normal
Lipsky et al, 200022 Infliximab 3-10 mg/kg 3 5 Not reported
Not reported Normal/high
Kavanaugh et al, 201323 Adalimumab 40 mg/2 wk 1 6 Sudden
death Septic shock, right ventricular

failure, unknown cause, acute
respiratory distress, two
interstitial lung disease
Normal
Van Vollenhoven et al, 201124 Adalimumab 40 mg/2 wk 0 0 0 0
Normal
Choy et al, 201225 Certolizumab 400 mg/2 wk 0 0 0 0 Normal
Breedveld et al, 200626 Adalimumab 40 mg/2 wk 1 1
Pneumonia Ovarian cancer Normal
Miyasaka et al, 200827 Adalimumab 20-40 mg or 80 mg/2 wk 0
2 0 Interstitial lung disease, cerebral
hemorrhage
Low/normal/high
van de Putte et al, 200428 Adalimumab 20-40 mg/wk or 2 wk 1
3 Complications of bowel
obstruction
Metastatic adenocarcinoma,
cholangiocarcinoma, myocardial
infarction
Low/normal/high
Schiff et al, 200829 Infliximab 3 mg/kg 0 1 0 Fibrosarcoma
Normal
Leirisalo-Repo et al, 201330 Infliximab 3 mg/kg 0 1 0 Not
reported Normal
Bejarano et al, 200831 Adalimumab Not reported 0 0 0 0 Not
reported
TNF ¼ tumor necrosis factor.

4
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Figure 2 Forest plot of trials comparing tumor necrosis factor-a
inhibitors to comparators for the
risk of all-cause mortality in patients with rheumatoid arthritis.
Heterogeneity: Q ¼ 7.87; df ¼ 22, P ¼
.99, I2 < 25%.
Poiroux et al TNF-a Inhibitors in Rheumatoid Arthritis 5
inhibitors and 3523 were treated with placebo or conventional
DMARDs.

Primary Outcome: Mortality of Any Cause Upon
TNF-a Inhibitors Compared with Controls
During the study duration, 34/6525 (0.52%) deaths were
observed in patients treated with TNF-a inhibitors, compared
with 10/3523 (0.28%) deaths in those treated with conven-
tional DMARDs/placebo (P ¼ .113) (Table 2).9-31 Thus, the
risk of death of any cause in patients receiving TNF-a in-
hibitors was not significantly different from those receiving
the comparator (odds ratio [OR] 1.32; 95% confidence in-
terval [CI], 0.76-2.29) (Figure 2). The results were consistent
across trials (Q ¼ 7.87, P ¼ .99, and I2 < 25%).
Subgroup analysis within the type of comparator did not
modify previously observed results. The OR of mortality of
patients receiving TNF-a inhibitors used as monotherapy vs
placebo was 1.04 (95% CI, 0.20-5.34), and the OR of
Table 3 Odds Ratio for All-cause Mortality According to the
Molecule
Total
Adalimumab
n ¼ 2373
Golimumab
n ¼ 575
Rheumatoid
arthritis
(OR, 95% CI)
1.32
95% CI, 0.76-2.29
2.17
95% CI, 0.83-5.68

2.02
95% CI, 0.23-
CI ¼ confidence interval; OR ¼ odds ratio.
mortality of patients receiving TNF-a inhibitors used in
combination therapy vs conventional DMARDs was 1.36
(95% CI, 0.76-2.43).
Secondary Analyses
Subgroup Analyses with Respect to Each Molecule.
Individually, each molecule analyzed separately did not
show an increased risk of mortality of any cause (Table 3).
Subgroup Analysis with Respect to the Dose of TNF-a
Inhibitors. To address the potential dose impact, we com-
pared the mortality event rates according to TNF-a inhibitor
dose (high dose, defined by a dose higher than usual TNF-a
inhibitor dose as per package insert, vs usual dose). High
dose of TNF-a inhibitors was not significantly associated
with a significant increase in risk of mortality (OR 0.97;
95% CI, 0.26-3.54 vs 1.43; 95% CI, 0.79-2.59 for the usual
dose).
Used
Certolizumab
n ¼ 1512
Infliximab
n ¼ 1329
Etanercept
n ¼ 736
18.19
1.19
95% CI, 0.27-5.18

0.70
95% CI, 0.27-1.81
1.28
95% CI, 0.23-7.25
6 The American Journal of Medicine, Vol -, No -, - 2015
Subgroup Analysis with Respect to the Quality of Evi-
dence. Most of our comparison analyses reached a high level
of quality of evidence, with a mean Jadad score of 3.87 � 1.01
(Table 1).9-31 We compared studies with a high quality (Jadad
score >3) to those with a lower quality (Jadad score �3). The
results did not appear to differ substantially. In high-quality
studies, the OR for mortality of any cause was 1.60 (95%
CI, 0.78-3.30), and in lower-quality studies, the OR was 0.99
(95% CI, 0.42-2.31).
To help address the potential impact of the calendar time,
we also compared mortality according to calendar year of
publication (before and after 2006). The summary ORs
for mortality were both not significant for these 2 time pe-
riods (0.80; 95% CI, 0.37-1.76 before and 2.03; 95% CI,
0.91-4.52 after 2006).
DISCUSSION
A recent meta-analysis has underlined the higher risk of
overall serious adverse events in certolizumab pegol-treated
patients and the significant increase in the risk of serious
infections in patients on adalimumab, certolizumab pegol,
and infliximab, which might suggest a potential higher risk
of mortality.1 This hypothesis has not been confirmed in our
meta-analysis, which covered the same time period and
compared the 5 currently available TNF-a inhibitors for the
risk of mortality, an undisputed hard endpoint. Indeed, the

use of TNF-a inhibitors is not associated in our study with
an increased risk of medium-term mortality.
Several registries have suggested a reduction of the risk of
mortality in patients with rheumatoid arthritis treated with
TNF-a inhibitors.32-34 Several factors may explain this
discrepancy, especially the inclusion of highly selected
patients in randomized controlled trials compared with unse-
lected patients in registries, and the longer time of drug
exposure in the latter. This may suggest that registries may be
more adequate to address the impact of TNF-a inhibitors on
overall mortality. However, our results are consistent with data
extractedfromtheBritishSocietyforRheumatologyBiologics
Registers and with the meta-analysis of Leombruno.4,35
Strengths of our meta-analysis are its large sample size, an
indirect comparison among the 5 available molecules, the
presence of a control group obtained through a process of
randomization, the quality of data extracted from a majority of
high-quality randomized controlled trials, and the absence of
heterogeneity among included trials. Limitations of our meta-
analysis included the generalization of our results and the
absence of long-term exposition on TNF-a inhibitors. Insuf-
ficient data were provided to perform a subgroup analysis
according to the duration of use of TNF-a inhibitors. More-
over, effect of TNF-a inhibitors on mortality may occur after
discontinuation of these drugs, and this aspect could not be
assessed in our meta-analysis.
In conclusion, this meta-analysis shows that treatment
with TNF-a inhibitors is not associated with a higher risk
of medium-term mortality of any cause in patients with
rheumatoid arthritis. These results are reassuring for this
duration, given that these therapies are highly effective at
controlling symptoms and reducing disability and damage.
Further studies are warranted to assess the long-term effect

of TNF-a inhibitors on mortality.
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first-line therapy for early-onset rheumatoid arthritis. Arthritis
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2009;60(8):2272-2283.

3. Quinn MA, Conaghan PG, O’Connor PJ, Karim Z, Greenstein
A,
Brown A, et al. Very early treatment with infliximab in addition
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methotrexate in early, poor-prognosis rheumatoid arthritis
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magnetic resonance imaging evidence of synovitis and damage,
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sustained benefit after infliximab withdrawal: Results from a
twelve-
month randomized, double-blind, placebo-controlled trial.
Arthritis
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4. St. Clair EW, van der Heijde DMFM, Smolen JS, Maini RN,
Bathon JM, Emery P, et al. Combination of infliximab and
metho-
trexate therapy for early rheumatoid arthritis: A randomized,
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trial. Arthritis Rheum. 2004;50(11):3432-3443.
5. Keystone EC, Kavanaugh AF, Sharp JT, Tannenbaum H, Hua
Y,
Teoh LS, et al. Radiographic, clinical, and functional outcomes
of
treatment with adalimumab (a human anti-tumor necrosis factor
monoclonal antibody) in patients with active rheumatoid
arthritis
receiving concomitant methotrexate therapy: A randomized,
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1411.
6. Furst DE, Schiff MH, Fleischmann RM, Strand V, Birbara
CA,

Compagnone D, et al. Adalimumab, a fully human anti tumor
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anti-
rheumatic therapy for the treatment of rheumatoid arthritis:
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STAR (Safety Trial of Adalimumab in Rheumatoid Arthritis).
J Rheumatol. 2003;30(12):2563-2571.
7. Smolen JS, Nash P, Durez P, Hall S, Ilivanova E, Irazoque-
Palazuelos F,
et al. Maintenance, reduction, or withdrawal of etanercept after
treatment
with etanercept and methotrexate in patients with moderate
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10. Smolen J, Landewé RB, Mease P, Brzezicki J, Mason D,
Luijtens K,
et al. Efficacy and safety of certolizumab pegol plus
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controlled trial. Ann Rheum Dis. 2009;68(6):797-804.
11. Fleischmann R, Vencovsky J, van Vollenhoven RF,
Borenstein D,
Box J, Coteur G, et al. Efficacy and safety of certolizumab
pegol
monotherapy every 4 weeks in patients with rheumatoid arthritis
failing
previous disease-modifying antirheumatic therapy: the
FAST4WARD
study. Ann Rheum Dis. 2009;68(6):805-811.
12. Keystone E, Heijde DVD, Mason D, Landewé R,
Vollenhoven RV,
Combe B, et al. Certolizumab pegol plus methotrexate is
significantly
more effective than placebo plus methotrexate in active
rheumatoid
arthritis: Findings of a fifty-two-week, phase III, multicenter,
ran-
domized, double-blind, placebo-controlled, parallel-group
study.
Arthritis Rheum. 2008;58(11):3319-3329.
13. Durez P, Malghem J, Toukap AN, Depresseux G, Lauwerys
BR,
Westhovens R, et al. Treatment of early rheumatoid arthritis: A
ran-
domized magnetic resonance imaging study comparing the
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methotrexate alone, methotrexate in combination with

infliximab, and
methotrexate in combination with intravenous pulse
methylpredniso-
lone. Arthritis Rheum. 2007;56(12):3919-3927.
14. Lipsky PE, van der Heijde DM, St. Clair EW, Furst DE,
Breedveld FC,
Kalden JR, et al. Infliximab and methotrexate in the treatment
of
rheumatoid arthritis. N Engl J Med. 2000;343(22):1594-1602.
15. Kavanaugh A, Fleischmann RM, Emery P, Kupper H,
Redden L,
Guerette B, et al. Clinical, functional and radiographic
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achieving stable low disease activity and remission with
adalimumab
plus methotrexate or methotrexate alone in early rheumatoid
arthritis:
26-week results from the randomised, controlled OPTIMA
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16. Van Vollenhoven RF, Kinnman N, Vincent E, Wax S,
Bathon J.
Atacicept in patients with rheumatoid arthritis and an
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response to methotrexate: Results of a phase II, randomized,
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17. Choy E, McKenna F, Vencovsky J, Valente R, Goel N,
VanLunen B,
et al. Certolizumab pegol plus MTX administered every 4 weeks
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effective in patients with RA who are partial responders to

MTX.
Rheumatology. 2012;51(7):1226-1234.
18. Breedveld FC, Weisman MH, Kavanaugh AF, Cohen SB,
Pavelka K,
Vollenhoven Rv, et al. The PREMIER study: A multicenter, ran-
domized, double-blind clinical trial of combination therapy with
adalimumab plus methotrexate versus methotrexate alone or
adali-
mumab alone in patients with early, aggressive rheumatoid
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who had not had previous methotrexate treatment. Arthritis
Rheum.
2006;54(1):26-37.
19. Miyasaka N. The CHANGE Study Investigators. Clinical
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in highly disease-affected rheumatoid arthritis patients in Japan
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20. Van de Putte LBA. Efficacy and safety of adalimumab as
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in patients with rheumatoid arthritis for whom previous disease
modifying antirheumatic drug treatment has failed. Ann Rheum
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2004;63(5):508-516.
21. Schiff M, Keiserman M, Codding C, Songcharoen S, Berman
A,
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double-

blind, placebo-controlled study in patients with rheumatoid
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2008;67(8):1096-1103.
22. Leirisalo-Repo M, Kautiainen H, Laasonen L, Korpela M,
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Kaipiainen-Seppänen O, et al. Infliximab for 6 months added on
combination therapy in early rheumatoid arthritis: 2- year
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857.
23. Bejarano V, Quinn M, Conaghan PG, Reece R, Keenan A-M,
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7.e1 The American Journal of Medicine, Vol -, No -, - 2015

http://refhub.elsevier.com/S0002-9343(15)00697-X/sref58All-
cause Mortality Associated with TNF-α Inhibitors in
Rheumatoid Arthritis: A Meta-Analysis of Randomized
Controlled TrialsMethodsData Sources and Literature

SearchInclusion CriteriaMethodological QualityData
ExtractionStatistical AnalysisResultsIncluded StudiesPrimary
Outcome: Mortality of Any Cause Upon TNF-α Inhibitors
Compared with ControlsSecondary AnalysesSubgroup Analyses
with Respect to Each MoleculeSubgroup Analysis with Respect
to the Dose of TNF-α InhibitorsSubgroup Analysis with Respect
to the Quality of
EvidenceDiscussionReferencesAppendixAppendix 1: References
of included studies
Neurourology and Urodynamics 24:267^272 (2005)
Acupuncture for Nocturnal Enuresis in Children:
A Systematic Review and Exploration of Rationale
Wendy F. Bower,1* M. Diao,1 J.L. Tang,2,3 and C.K. Yeung1
1Department of Surgery, Division of Paediatric Surgery and
Paediatric Urology,
The Chinese University of Hong Kong, Hong Kong
2Department of Community and Family Medicine, The Chinese
University of Hong Kong, Hong Kong
3Hong Kong Branch of the Chinese Cochrane Centre, The
Chinese University of Hong Kong, Hong Kong
Objectives: This review identi¢ed reports of acupuncture for
childhood nocturnal enuresis, with
the aim of ascertaining whether acupuncture is e⁄cacious and or
better than standard therapy for
treating enuresis. Materials and Methods: Studies of children of
either gender <18 years of age
who received acupuncture treatment for nocturnal enuresis,
were considered. The primary outcome

measure was change in the mean number of wet episodes
following treatment. Electronic searching
was supplemented by hand searching of western medicine and
traditional Chinese medicine (TCM)
journals along with English language alternative medicine
journals. Trials were assessed for quality
and sources of bias. Meta-analysis was performed and the
overall weighted odds ratio (OR) and
associated 95% con¢dence interval (CI) were computed using
the ¢xed e¡ect model; the Forest plot
was used to demonstrate results. Results: Two hundred six
abstracts were identi¢ed, of which 11
studies were eligible for data extraction. All the trials were of
low methodological quality.There was
some evidence that acupuncture is useful for nocturnal enuresis
when used in conjunction with
other treatment that may also include a di¡erent form of
acupuncture (OR 3.98, CI: 2.2^7.2). When
one form of acupuncture is compared with another there was
marked heterogeneity, implying that
some forms of acupuncture are e¡ective. Conclusion: This
review provides tentative evidence for
the e⁄cacy of acupuncture for the treatment of childhood
nocturnal enuresis. Due to the low meth-
odological quality of studies, evidence to identify, which
parameters of acupuncture work best, is
lacking. More rigorous trials are clearly warranted. Neurourol.
Urodynam. 24:267 ^272, 2005.
� 2005 Wiley-Liss, Inc.
Key words: acupuncture;Chinesemedicine;meta-
analysis;nocturnalenuresis
INTRODUCTION
Current treatment of nocturnal enuresis includes chemical

manipulation of neuromuscular structures and diuresis, and
behavioral initiatives to impact arousal and bladder storage.
Traditional Chinese medicine (TCM) claims that Chinese
acupuncture induces a decrease in the number of wet epi-
sodes (by 76% and 98% [Zhong, 1986; Tuzuner et al., 1989]),
improves bladder storage capacity, and enhances arousal
from sleep in order to void [Bjorkstrom et al., 2000; Serel
et al., 2001; Honjo et al., 2002]. A reduction in uninhibited
bladder contractions has also been reported following acu-
puncture [Minni et al., 1990; Kachan et al., 1993].
Acupuncture is believed to normalize bladder function by
invigorating the kidney, spleen and brain, calming the mind,
and adjusting Qi of the lungs, vital energy and blood. The
word itself is originally derived from Latin and refers to
‘‘piercing with a sharp instrument.’’ The practice utilizes the
concept of 12 primary meridians or energy channels along
which are distributed 360 acupuncture points. Each point is
located in an area of low electrical resistance and sites used to
treat bladder dysfunction appear to coincide with innerva-
tion by spinal sacral segments S2 through S4. Stimulation of
these acupoints by manual pressure, penetration of the skin,
heating, the application of laser, electrotherapy, or moxibus-
tion is thought to induce homeostatic changes [Berman,
2001]. Most practitioners agree that optimal results will be
obtained if a patient experiences the spread of treatment sen-
sation (including numbness, heaviness, distension, and sore-
ness) beyond the acupuncture site, a condition known as deqi
[Wu et al., 1999; Hui et al., 2000].
This review aimed to identify reports across both Asian
and English language literature relating to the use of acu-
puncture for nocturnal enuresis in children and to perform
meta-analyses.The speci¢c objectives were to ascertain if acu-
puncture is e⁄cacious and or better than standard therapy

*Correspondence to: Wendy F. Bower, Department of Surgery,
Division of
Paediatric Surgery and Paediatric Urology,The Chinese
University of Hong
Kong, Prince of Wales Hospital, Shatin, NT, Hong Kong.
E-mail: [email protected]
Received 27 July 2004; Accepted 2 December 2004
Published online 24 March 2005 inWiley InterScience
(www.interscience.wiley.com)
DOI 10.1002/nau.20108
� 2005 Wiley-Liss, Inc.
for enuresis, and also to identify and explore any sources of
heterogeneity.
MATERIALS AND METHODS
Studies of children of either gender, who were under the
age of 18 years and received acupuncture treatment for noc-
turnal enuresis, were considered. Studies were excluded if
they considered adults, neurogenic bladder dysfunction,
patients with active infection/in£ammation/implanted neu-
romodulating devices or structural/metabolic disorders ren-
dering function of the urinary tract atypical. Electrotherapy
intervention applied away from recognized bladder/spleen/
kidney acupuncture points was also an exclusion criteria.
As it is di⁄cult to include a sham or placebo group in
acupuncture studies only a small number of randomized
controlled trials were expected, and the review therefore
included non-randomized trials of acupuncture, prospective
cohorts, and alternative allocation trials.

‘‘Acupuncture’’ treatment required needles to be inserted
into acupoints; twisting, pressure application, moxibustion
(the application of heat resulting from the burning of a small
bundle of tightly bound herbs over targeted acupoints), or
additional electrical current was also accepted. The review
initially sought to di¡erentiate between techniques, combina-
tion of points used, and treatment frequency and duration.
The primary outcome measure was change in number
of wet nights per week following cessation of acupunc-
ture. Studies reported this as cure, however the de¢nition
was not uniformly stated. A secondary measure planned
was change in number of spontaneous arousals to void per
week. Adverse events were also considered.
The search covered the period 1980^2003 and considered
trials reported in any language, with a focus on studies
described in Chinese and other Asian languages. The follow-
ing data sources were searched electronically: Cochrane
Controlled Trials Register; Complimentary medicine ¢eld of
Cochrane collaboration; MEDLINE (1980^2003); EMBASE
(1980^2003); CISCOM; NCCAM; PROQUEST; DARE;
AMED; ACME; CMB: Chinese Biomedical Disk; Japanese
medical database. Hand searching was undertaken in 23 Wes-
tern Medicine Chinese Journals, 11 TCM Journals and 6
English language alternative medicine journals, and regional
and national acupuncture conference proceedings. Review
papers were scrutinized, along with reference lists from iden-
ti¢ed trials.
Keywords used in the electronic search included: acu-
puncture; complimentary medicine; alternative medicine;
fringe medicine; acupressure; acustimulation; needle acu-
puncture; needling; moxibustion; TCM; Chinese medicine;
incontinence; bladder dysfunction; voiding dysfunction;

enuresis; nocturnal enuresis; overactive bladder; detrusor
instability; urge incontinence; urge syndrome. The search
strategy speci¢ed randomized controlled trials/random allo-
cation/clinical trials/placebo or sham trials.
Two investigators scrutinized abstracts, obtained hard
copies to assess eligibility, and coded relevant trials before
data extraction. Study details were examined separately and
classi¢ed on the basis of methodology. Study eligibility de-
tails noted included: type of study, participants, intervention,
control and outcome measures. Data was extracted using a
standardized form.
Trials were scrutinized for quality aspects known to be
associated with sources of bias: allocation concealment, ran-
domization, blinding of assessors, subjects and data analysis
personnel, intention-to-treat analysis and withdrawal or loss
to follow-up. The Jadad score was used to the measure reduc-
tion of bias [Jadad et al., 1996]. Maximum possible score on
this instrument is 5 and the minimum, indicating the highest
level of bias, is zero.
Heterogeneity was explored using subgroup analysis
[DerSimonian and Laird, 1986]. The methodological quality
was identi¢ed as one of the determinants of heterogeneity
and assessed similarly. Given the large heterogeneity the
overall weighted odds ratio (OR) and the associated 95% con-
¢dence interval (CI) were computed by using the random
e¡ect model. The Forest plot was used to demonstrate the
details of the results. Statistical analysis utilized SAS.
RESULTS
Electronic searching of the Chinese databases revealed
129 potentially eligible abstracts describing the use of acu-
puncture for nocturnal enuresis. English electronic databases

revealed 50 abstracts, of which 17 were considered possible
trials and retrieved for scrutiny. After hand-searching a
further 27 potentially eligible abstracts were identi¢ed. In
total 206 abstracts were available. After rejecting papers that
did not actually consider children, did not describe results,
used concomitant co-interventions, reported only day symp-
toms, or included less than 10 subjects, 84 potentially eligible
studies remained. Of these, 75 studies originated from main-
land China, 2 from Japan and 7 from Europe.
Table I describes the characteristics of the 84 studies iden-
ti¢ed. It can be seen that only 11 studies were ultimately eli-
gible for review and analysis, whilst the rest were excluded
because of single group design, lack of relevance to nocturnal
enuresis, comparison of di¡erent forms of acupuncture, and
lack of outcome measures. Table II summarizes the key char-
acteristics of the eligible studies: type of comparison, dura-
tion of treatment, length of follow-up, and rate of cure.
None of the studies attempted to sub-classify enuresis.
No authors reported baseline or post-treatment measures
of arousal to void at night, and there was a similar lack of
reported adverse events. A secondary aim of the review was
to identify and explore sources of heterogeneity. However,
study design was uniformly poor and both description of
symptoms and mode of application of acupuncture were
inadequate, preventing further analysis.
268 Bower et al.
Table III shows the quality of each trial as scored accord-
ing to the Jadad criteria. As the maximum individual study
score is 5, it can be seen that all the trails failed to meet evi-
dence-based medicine levels of bias minimization. None of

the studies reported the use of placebo or sham acupuncture.
Whilst patients were allocated to di¡erent treatment groups,
randomization methods were not discussed by any of the
authors.
Figure 1 shows the meta-analysis forest plot for enuresis
cure in three studies (four comparisons, only one study ran-
domized) that considered acupuncture in conjunction with
another therapy when compared to the other therapy alone.
The combined results show that acupuncture can further sig-
ni¢cantly reduce the number of wet nights when used in
addition to either another form of acupuncture or Chinese
herbal medicine. The Funnel plot and symmetrical testing
showed no obvious evidence of publication bias.
The comparison of conventional acupuncture and another
acupuncture or Chinese therapy is reported in Figure 2.
Whilst there was no overall signi¢cant di¡erence, (which
is well expected given the nature of comparisons), there is
obvious heterogeneity among the studies suggesting that
some forms of acupuncture might be more e¡ective than
others. An examination of the individual studies showed:
(1) conventional acupuncture was signi¢cantly better than
both normal saline injections over acupoints (B2) and auri-
cular seed embedding (B3); neither of these two studies
being randomized. (2) Acupuncture was signi¢cantly less
e¡ective than needle embedding (B8) and vitamin injections
(B9); both of these studies being randomized. The asymme-
try test of the funnel plot did not suggest obvious publication
bias.
The ¢nal meta-analysis compared laser acupuncture with
the current gold-standard medication used in the manage-
ment of nocturnal enuresis. It can be seen from Figure 3
that the outcome favors medication but was not signi¢cantly

better than acupuncture.
TABLE I. Characteristics of Papers Considered for
Eligibility of Inclusion in Systematic Review
Study characteristics
Number
of studies
excluded
Number
of studies
included
Single group design 56
Comparison between two di¡erent forms
of acupuncture
6
Not a trial 2
Not relating to enuresis 9
Acupuncture as the control group 3
Acupuncture compared to another traditional
Chinese medicine (TCM) treatment
7
Acupuncture compared to western medication 1
Total 73 11
TABLE II. Subjects, Comparison Intervention, and Results
Reported in Trials of Acupuncture for Nocturnal Enuresis
Author(s) and year

of publication
Number
of subjects Type of comparison
Duration
of treatment
(** not stated)
Follow-up
post treatment
Cure with
acupuncture (%)
Cure with
comparative
treatment (%)
Cai [1987] 361 Acupuncture versus auricular needle
embedding (B1)
** 1 month 97/193 (50) 41/108 (38)
Acupuncture versus saline injection (B2) 97/193 (50) 14/60 (23)
Ji and Zhou [2000] 138 Acupuncture and auricular seed
embedding
versus auricular seed embedding (A1)
** 6 months 29/37 (78) 17/49 (35)
Acupuncture versus auricular seed embedding (B3) 35/52 (67)
17/49 (35)
Li and Xue [1996] 96 Acupuncture versus catgut embedding
(B4) ** 6 months 13/32 (41) 35/64 (55)
Liu and Shen [1990] 110 Acupuncture versus photomagnetic

laser (B5) 2 weeks 6 months 38/52 (73) 44/58 (76)
Lu [2000] 97
Head and body acupuncture and auricular seed
embedding versus body acupuncture and
auricular seed embedding (A2)
4 weeks 6 months 19/35 (54) 12/32 (37)
Body acupuncture and auricular seed embedding
versus auricular seed embedding (A3)
12/32 (37) 5/30 (17)
Radmayr et al. [2001] 40 Laser acupuncture versus antidiuretic
medication (C1) 1^3 months 6 months after
treatment
13/20 (65) 15/20 (75)
Ren [1987] 91 Needle acupuncture versus laser acupuncture
(B6) ** Not stated 16/38 (42) 26/53 (49)
Wang and Zhang [1999] 170 Acupuncture versus needle
embedding (B7) 9^30 days 6 months 35/50 (70) 73/80 (91)
Acupuncture versus catgut embedding (B8) 35/50 (70) 23/40
(58)
Xiao and Zhang [2001] 84 Acupuncture and herbal medicine
versus herbal
medicine (A4)
3 weeks Not stated 40/43 (93) 31/41 (76)
Xiao [1997] 42 Acupuncture versus vitamin injections over
acupuncture points (B9)

** Not stated 6/18 (33) 16/24 (66)
Xu [1997] 45 Acupuncture versus moxibustion (B10) ** 6
months 12/15 (80) 22/30 (73)
Acupuncture for Nocturnal Enuresis in Children 269
DISCUSSION
Research from as early as 1958 identi¢ed spinal and per-
ipheral nerves and their terminals dispersed within 5 mm of
known acupuncture meridians. Nerves from such acupunc-
ture points fed into the same area of the spine as certain vis-
cera that have long been linked with such points [Cai, 1992].
More recently high concentrations of neuroendocrine trans-
mitters and hormones have been identi¢ed at acupuncture
points. Furthermore, needling or mechanical stimulation at
these points induces release and spread of neurotransmitter
substances [Omura, 1989; Kashiba and Ueda, 1991]. Addition
of electrical stimulation during acupuncture induces endor-
phin release that generates a more potent e¡ect on the con-
centration of neuropeptides in the animal hippocampus and
occipital cortex than manual acupuncture [Bucinskaite et al.,
1994]. An autonomic response occurs during acupuncture, as
evidenced by signi¢cantly reduction in average heart rate
during treatment [Wu et al., 1999].
Functional magnetic imaging (fMRI) has recently been
used to investigate neurobiological mechanisms underlying
acupuncture therapy. Needling to a depth of 2 cm at ST36
(a point commonly utilized in the treatment of nocturnal
enuresis) provoked activation of the hypothalamus, limbic
system, and nucleus accumbens [Wu et al., 1999]. Both the

hypothalamus and the nucleus accumbens have descending
projections and interconnections with periaqueductal gray
matter (PAG), important in the modulation of bladder activ-
ity. Control stimulation did not produce increased activity in
the same deep structures, and needles left in situ without
manipulation did not produce any fMRI signal changes
[Wu et al., 1999; Hui et al., 2000]. Electroacupuncture con-
sistently induced greater magnitude signal increases than
manual acupuncture.
Thus, there is sound evidence to accept that peripheral-
ly applied acupuncture stimulates sensory nerves, increa-
ses the release of neurotransmitters, neuropeptides, and
hormones and increases cutaneous blood £ow and microcir-
culation [Cai, 1992]. Neural impulses to the spinal cord are
up-regulated and act on ascending pathways to the brain,
creating the potential to modulate central nervous system
functions [Shen, 2001].
Given such a theoretical framework it is encouraging that
this systematic review provides some evidence in support of
the e⁄cacy of acupuncture for nocturnal enuresis. This holds
even though the criteria for success was strict, i.e., ‘‘cure.’’
Given that TCM routinely constitutes a number of modal-
ities rather than individual techniques, ¢ndings from this
review support the practice of acupuncture within a combi-
nation therapy framework.
Interpretation of results was limited by quality aspects
of the studies. All the Chinese data comprised clinical
reports and lacked patient sub-group classi¢cation, detailed
methodology, and analysis. Post-treatment changes in blad-
TABLE III. Jadad Trial Quality Scores

Author(s) and year of publication Randomization
Double
blinding
Withdrawal or
drop-out
Total Jadad score
(possible total ¼ 3)
Ji and Zhou [2000] 0 0 0 0
Xiao and Zhang [2001] 0 0 0 0
Lu [2000] 0 0 0 0
Ren [1987] 0 0 0 0
Xiao [1997] 1 0 0 1
Li and Xue [1996] 1 0 0 1
Xu [1997] 0 0 0 0
Liu and Shen [1990] 1 0 0 1
Cai [1987] 0 0 0 0
Wang and Zhang [1999] 1 0 0 1
Radmayr et al. [2001] 1 0 0 1
Fig. 1. Comparison of acupuncture in combination with other
therapy versus other therapy alone.
270 Bower et al.
der storage, arousal, and detrusor activity were not report-
ed, making it di⁄cult to associate gains with underlying phy-
siological changes. Short post-treatment follow-up, being
6 months or less, was another limiting factor.
It proved impossible to ascertain whether acupuncture
was more e⁄cacious than standard treatment for nocturnal

enuresis since the comparative treatments were dissimilar
(Fig. 2). A smaller di¡erence in treatment outcome would
therefore be expected. In addition, some of the interventions
that are compared to acupuncture have an unknown e⁄cacy,
making it di⁄cult to interpret results. However, the results
are highly heterogeneous, some show statistically signi¢cant
results, and some of the 95% CI exclude each other. These
¢ndings do seem to give further support for an e⁄cacy of
some forms of acupuncture, if not all. If every one of the
compared acupunctures were ine¡ective, the large hetero-
geneity would not have been observed. An alternative expla-
nation could be di¡erence in the quality of the trials.
Whilst acupuncture was signi¢cantly more e¡ective than
either embedding seeds into the ear or saline injections over
acupuncture points, needle embedding and vitamin in-
jections over acupoints were signi¢cantly more useful than
acupuncture. Clearly there is inconsistency since similar
interventions produced such disparate results. Even though
an investigator bias in favor of the test intervention would
be expected when comparing novel treatments with standard
practice, this is not substantiated. The evidence thus suggests
that some forms of acupuncture are more e¡ective than other
forms of either acupuncture or novel TCM modalities. No
conclusions can be drawn as to which treatment forms are
consistently superior for children with nocturnal enuresis.
The comparison of western medicine’s current gold-
standard treatment, the antidiuretic hormone vasopressin,
with acupuncture, showed no signi¢cant di¡erence between
the two modalities. The sample size might be considered in-
adequate and the omission of sub-classi¢cation of children
and a control group, study £aws. However, the lack of
greater e⁄cacy for pharmacotherapy is a positive ¢nding for
acupuncture.

Increasing scienti¢c understanding of acupuncture-
induced physiological changes, coupled with signi¢cant posi-
tive ¢ndings from this review, supports the need for further
and rigorous high quality trials of the e⁄cacy of acupuncture
for nocturnal enuresis. E¡ect of acupuncture on the known
imbalances underlying western medicine understanding of
nocturnal enuresis (small bladder capacity, poor arousal abil-
ity, and nocturnal polyuria) would be clari¢ed with the in-
clusion of initial urodynamic investigations, standardized
Fig. 2. Comparison of conventional acupuncture and another
acupuncture therapy.
Fig. 3. Comparison of acupuncture with antidiuretic medication.
Acupuncture for Nocturnal Enuresis in Children 271
symptom scoring, and sub-group classi¢cation. It would be
helpful to stratify patients accordingly and thence compare
acupuncture (�other TCM modalities) with the enuresis
alarm and combination western medicine therapies.
CONCLUSION
This review provides tentative evidence for the e⁄cacy of
acupuncture in the treatment of childhood nocturnal enur-
esis. Due to the low methodological quality of studies, evi-
dence to identify, which parameters of acupuncture work
best, is lacking. More rigorous trials are clearly warranted.
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272 Bower et al.
Antibiotics in Acute Bronchitis: A Meta-analysis
Stephen Bent, MD, Sanjay Saint, MD, MPH, Eric Vittinghoff,
PhD, Deborah Grady, MD, MPH
PURPOSE: Most patients with acute bronchitis who seek med-
ical care are treated with antibiotics, although the effectiveness
of this intervention is uncertain. We performed a meta-analysis
of randomized, controlled trials to estimate the effectiveness of
antibiotics in the treatment of acute bronchitis.
SUBJECTS AND METHODS: English-language studies pub-
lished January 1966 to April 1998 were retrieved using
MEDLINE, bibliographies, and consultation with experts. Only
randomized trials that enrolled otherwise healthy patients with
a diagnosis of acute bronchitis, used an antibiotic in the treat-
ment group and a placebo in the control group, and provided
sufficient data to calculate an effect size were included.
RESULTS: We identified eight randomized controlled trials
that satisfied all inclusion criteria. These studies used one of
three antibiotics (erythromycin, doxycycline, trimethoprim/
sulfamethoxazole). The use of antibiotics decreased the dura-
tion of cough and sputum production by approximately one-
half day (summary effect size 0.21; 95% CI, 0.05 to 0.36). For
specific symptoms, there were nonsignificant trends favoring
the use of antibiotics: a decrease of 0.4 days of purulent sputum
(95% CI, 20.1 to 0.8), a decrease of 0.5 days of cough (95% CI,

20.1 to 1.1), and a decrease of 0.3 days lost from work (95% CI,
20.6 to 1.1).
CONCLUSION: This meta-analysis suggests a small benefit
from the use of the antibiotics erythromycin, doxycycline, or
trimethoprim/sulfamethoxazole in the treatment of acute bron-
chitis in otherwise healthy patients. As this small benefit must
be
weighed against the risk of side effects and the societal cost of
increasing antibiotic resistance, we believe that the use of anti-
biotics is not justified in these patients. Am J Med. 1999;107:
62– 67. q1999 by Excerpta Medica, Inc.
A
cute bronchitis is a common clinical disorder
characterized by the acute onset of cough and
sputum production in a patient with no history of
chronic pulmonary disease and no evidence of pneumo-
nia or sinusitis. This definition excludes patients with
acute exacerbation of underlying pulmonary disorders,
in whom a previous meta-analysis found that antibiotic
use led to a small, statistically significant benefit (1). The
effectiveness of antibiotics in patients with acute bronchi-
tis remains uncertain, although the disorder is the tenth
most common diagnosis seen by physicians in the United
States, accounting for 10 million office visits annually (2).
The etiology of acute bronchitis is unclear. Most stud-
ies have identified viruses (adenovirus, rhinovirus, coro-
navirus, influenza, parainfluenza, respiratory syncytial
virus, and coxsackievirus) as the cause in the majority of
patients (3–14). Atypical bacteria, including Mycoplasma
pneumoniae, Chlamydia pneumoniae, and Legionella spe-
cies, have been reported to cause 5% to 25% of cases of
acute bronchitis (15–17), and typical bacteria (Streptococ-
cus pneumoniae, Haemophilus influenzae, Branhamella

catarrhalis) have been recovered from the sputum in 7%
to 44% of patients (8,18,19). However, the importance of
positive bacterial cultures from sputum is not known,
because many of these pathogens are part of the oropha-
ryngeal flora (3,9,20 –22). Recent evidence suggests that
some bronchitis in adults may be caused by Bordetella
pertussis and parapertussis, which are better known for
their role in causing whooping cough in children (23).
The majority of patients diagnosed with acute bronchi-
tis in the United States are treated with antibiotics (24 –
27). In a nationwide survey of .1,500 physicians, Gonza-
les et al (25) found that two-thirds of patients without
underlying lung disease who were diagnosed with acute
bronchitis were treated with antibiotics. In another sur-
vey, 75% of children with a diagnosis of acute bronchitis
were given a prescription for antibiotics (26).
Although antibiotics are often used in the treatment of
acute bronchitis, their efficacy is uncertain. Clinical trials
examining this issue have yielded conflicting results (28 –
37), and qualitative reviews are similarly inconclusive
(7,9,17,38,39). Widespread antibiotic use carries a sub-
stantial cost, puts patients at risk for medication side ef-
fects, and promotes antibiotic resistance.
To clarify the optimal treatment of this disorder, we
performed a meta-analysis to determine whether antibi-
otics were beneficial in patients with acute bronchitis.
Using explicit inclusion and exclusion criteria and ac-
cepted quantitative methods (40 – 42), a meta-analysis
provides summary estimates of effectiveness that may
clarify the disparate results of previous trials (43).
METHODS

Literature Review
The literature review began with a computerized
MEDLINE search using the subheading “bronchitis, drug
From the Departments of Medicine (SB, SS, DG) and
Epidemiology and
Biostatistics (DG, EV), University of California, San Francisco,
School
of Medicine, San Francisco, California; Medical Service, San
Francisco
Veterans Affairs Medical Center (SB, SS, DG), San Francisco,
Califor-
nia. Dr Saint is now affiliated with the University of Michigan,
Division
of General Medicine, Department of Internal Medicine.
Requests for reprints should be addressed to Stephen Bent, MD,
Gen-
eral Internal Medicine Section, San Francisco Veterans Affairs
Medical
Center 111A1, 4150 Clement Street, San Francisco, California
94121.
Manuscript submitted August 5, 1998, and accepted in revised
form
February 24, 1999.
62 q1999 by Excerpta Medica, Inc. 0002-9343/99/$–see front
matter
All rights reserved. PII S0002-9343(99)00167-9
therapy” and the term “xs acute disease,” and included
English-language articles published between January

1966 and April 1998. The reference lists of all retrieved
articles were scanned, and experts were consulted to iden-
tify potential trials not identified in the MEDLINE search.
Inclusion criteria consisted of the following: random-
ized trials using an antibiotic in the treatment group and
a placebo in the control group; subjects with acute bron-
chitis, no history of chronic lung disease, and pneumonia
excluded by chest radiograph or clinical exam; therapy
for at least 5 days; and the presentation of sufficient data
to calculate the difference in efficacy between the treat-
ment and the placebo as a continuous variable. Studies
were excluded if they were nonexperimental in design or
if they compared one antibiotic with another without a
placebo arm.
For each study, two authors independently abstracted
the author, journal title, year of publication, sample size,
average age of subjects, antibiotic regimen used, major
outcome measure(s), and the inclusion and exclusion cri-
teria. Discrepancies in the abstracted data were resolved
by consensus.
Analysis
The eight eligible studies did not use a common outcome
measure. When several outcomes were available from
one study, we chose “days of sputum production” as the
main outcome, because this symptom is most character-
istic of the disease (4). For studies that did not include the
outcome “days of sputum production,” we chose the out-
come in the study that was the most clinically similar
(sputum production score, cough amount score). We
transformed each outcome into units of standard devia-
tion, thus giving a comparable effect size for different
outcomes. The study-specific effect size was the differ-
ence in the mean outcome for the antibiotic and placebo

groups, divided by the pooled standard deviation of the
outcome measure in that study. The summary effect size
across studies was calculated as a weighted average of the
study-specific effect sizes, with weights equal to the in-
verse of the estimated variance. The significance of the
summary effect size, standardized by its estimated vari-
ance, was assessed by comparing it with the standard nor-
mal distribution. A test for heterogeneity was calculated
by comparing the weighted average of the squared differ-
ences between summary and study-specific effect sizes
with an appropriate X2 distribution, with the same
weights being used. These calculations used standard for-
mulas (44), which assume that the outcomes are nor-
mally distributed and the sample sizes are approximately
equal in the antibiotic and placebo groups.
We also calculated summary mean differences for all
outcomes reported by four or more studies. The sum-
mary measure was the weighted average of the difference
between the antibiotic and placebo groups in the mean
outcome measure for each study. Weights were given by
the inverse of the variance of each mean difference, esti-
mated using the pooled standard deviation for each
study. Tests of the significance of the observed summary
mean differences and of heterogeneity were also per-
formed (44).
We examined the potential for publication bias using
the correlation between the number of subjects and the
effect size in each study. If small studies with negative
results were less likely to be published, then the correla-
tion between number of subjects and effect size would be
large. If there was not any publication bias, then there
should not be a significant correlation between the num-
ber of subjects and the effect size.

RESULTS
Our search identified 203 reports, including 10 random-
ized, placebo-controlled trials of antibiotics for the treat-
ment of acute bronchitis (28 –37). Two (28,31) of these
studies had to be excluded because insufficient data were
presented in the original articles, and attempts to retrieve
the necessary data from the authors were unsuccessful.
The remaining eight trials, all of which used one of three
antibiotics (erythromycin, doxycycline, trimethoprim/
sulfamethoxazole), were included in the meta-analysis.
Reasons for exclusion are listed in Table 1. The character-
istics of the 10 randomized controlled trials, including the
two that were excluded because of insufficient data, are
shown in Table 2.
The overall summary effect size was 0.21 (95% CI, 0.05
to 0.36) indicating a small (about one-fifth of a standard
deviation), statistically significant benefit from the use of
antibiotics (Figure), equivalent to approximately one half
day less of cough and sputum production.
Three outcomes were reported by at least four studies
(Table 3). Although each of these results favor antibiotics,
none was statistically significant. For days of purulent
Table 1. Reasons for Exclusion of Reports Retrieved from Lit-
erature Search
Reason for Exclusion
Number
of Reports
Not original data 74

No control group 87
Main intervention was not antibiotic therapy 16
Patients with COPD were included 11
Main intervention was prophylaxis 1
Subjects had another infectious disorder
(sinusitis, bronchiolitis)
4
Insufficient data presented 2
Total excluded 195
COPD 5 chronic obstructive pulmonary disease.
Antibiotics in Acute Bronchitis/Bent et al
July 1999 THE AMERICAN JOURNAL OF MEDICINEt
Volume 107 63
sputum, the summary mean difference was 0.4 (95% CI,
20.1 to 0.8); the mean difference was 0.5 (95% CI, 20.1
to 1.1) for days of cough and 0.3 (95% CI, 20.6 to 1.1) for
days lost from work. The effect of antibiotic treatment on
days lost from work was very small, and unlike days of
cough and sputum production, did not approach statis-
tical significance.
A test for heterogeneity was not significant for the
overall summary effect size (P 5 0.37) or for days of spu-
tum production (P 5 0.50), suggesting that these results
are homogenous and can be combined. A test for heter-
ogeneity was significant for the summary mean difference
for days lost from work (P 5 0.03) and days of cough

Table 2. Randomized Trials of Antibiotics in Acute Bronchitis
First Author, Year
(reference)
No. of
Subjects Antibiotic
Main Outcome
Measure
Study Result
(95% CI)*
Standardized Effect
Size (95% CI)†
Howie, 1970 (31) 836 Demethyl-chlortetracycline Average days
of
purulent spit
0.3‡ Not available‡
Stott, 1976 (33) 207 Doxycycline Days of yellow spit 0.6 (20.2
to 1.4) 0.20 (20.08 to 0.48)
Franks, 1984 (30) 54 Trimethoprim/sulfamethoxazole Cough
amount score 0.2 (20.2 to 0.6)§ 0.25 (20.30 to 0.79)
Williamson, 1984
(34)
69 Doxycycline Days of purulent
sputum

20.2 (21.2 to 0.8) 20.09 (20.57 to 0.38)
Brickfield, 1986
(28)
50 Erythromycin Sputum production
score
0.2‡¶ Not available‡
Dunlay, 1987 (29) 45 Erythromycin Sputum production
score on day 10
0.5 (0.1 to 0.9)# 0.80 (0.20 to 1.41)
Scherl, 1987 (32) 31 Doxycycline Days of sputum 1.9 (20.2 to
4.0) 0.64 (20.08 to 1.36)
Verheij, 1994 (35) 140 Doxycycline Days of productive
cough
0.5 (20.4 to 1.4) 0.18 (20.15 to 0.52)
Hueston, 1994
(36)
23 Erythromycin Days of productive
cough
20.4 (22.4 to 1.6) 20.21 (21.14 to 0.72)
King, 1996 (37) 91 Erythromycin Days of sputum
production
0.7 (21.3 to 2.7) 0.14 (20.27 to 0.55)

* Result is the mean in the antibiotic group minus the mean in
the placebo group for the main outcome measure. A positive
result indicates a benefit
from antibiotics. A negative result indicates a benefit from
placebo.
† Effect size is the difference between the mean outcome in the
antibiotic and placebo groups divided by the pooled standard
deviation.
‡ These studies did not provide data that allowed calculation of
a confidence interval or a continuous outcome measure, and
therefore could not be
included in the overall summary effect size.
§ Cough amount score was a patient-reported score on a severity
scale of 1 to 3.
¶ Sputum production score was a patient-reported score on a
severity scale of 1 to 4.
# Sputum production score was a patient-reported score on a
severity scale of 1 to 5.
CI 5 confidence interval.
Figure. Effect sizes and summary overall estimate. Effect size is
the difference between the mean outcome in the antibiotic and
placebo groups divided by the pooled standard deviation. Hor-
izontal lines denote 95% confidence intervals. Dots represent
point estimates.
Table 3. Summary Mean Differences between Antibiotic and
Placebo Groups
Outcome Measure
(reference)
Summary Mean
Difference (95% CI)*
Days of purulent sputum (6 trials)

(32–37)
0.4 days (20.1–0.8)
Days of cough (4 trials) (32–35) 0.5 days (20.1–1.1)†
Time off work (6 trials) (32–37) 0.3 days (20.6–1.1)†
* Summary mean difference is the weighted average of the
difference
between the antibiotic and placebo groups in the mean outcome
mea-
sure for each study.
† A test of heterogeneity was statistically significant.
CI 5 confidence interval.
64 July 1999 THE AMERICAN JOURNAL OF MEDICINEt
Volume 107
(P 5 0.05), suggesting that these outcomes may have
been derived from studies that used different methods.
There was no correlation between study size and overall
effect size (r 5 20.13, P 5 0.75).
DISCUSSION
Randomized controlled trials evaluating the efficacy of
antibiotics in acute bronchitis have had inconsistent re-
sults. Of the eight trials included in our meta-analysis,
four showed no benefit from the use of antibiotics (32–
34,36), whereas four reported a benefit (29,30,35,37).
Part of the discrepancy may be because studies used dif-

ferent outcome measures, some of which are of uncertain
clinical importance. For example, the outcome measures
in one trial that reported a statistically significant benefit
from antibiotics included a reduction in mean tempera-
ture from 37.38C to 36.98C and a reduction in the use of
antihistamines (30).
Because the published trials used several outcome
measures, we used the standardized effect size, expressed
in units of standard deviation, to quantitate the overall
effect of antibiotic therapy. We chose the outcome that is
most characteristic of acute bronchitis (days of sputum
production) in the six studies where it was available, and
we used the most similar outcome in the two other stud-
ies (cough amount score, sputum production score). We
found a small, statistically significant benefit to the use of
antibiotics in patients with acute bronchitis approxi-
mately equal to one-fifth of a standard deviation unit. To
relate the observed benefit in the summary effect size to
clinical variables, we also calculated summary mean dif-
ferences for all outcomes that were reported by at least
four trials (duration of sputum production, duration of
cough, and days lost from work), all of which showed
small, nonsignificant trends favoring the use of antibiot-
ics. Our meta-analysis suggests that patients with acute
bronchitis who are treated with antibiotics have a reduc-
tion in the duration of cough and sputum production of
approximately one half day.
Our results should be interpreted with caution. As with
all meta-analyses, we assumed that the individual trials
are sufficiently similar to provide a meaningful summary.
The studies did have several important differences. They
took place in different geographic locations, used three
different antibiotics (erythromycin, doxycycline, tri-
methoprim/sulfamethoxazole), and were conducted

during a 20-year period. However, despite these differ-
ences, statistical tests for heterogeneity did not show dif-
ferences between studies for the main outcome, or for the
outcome of sputum production. Although different anti-
biotics were used, all groups were treated for at least 5
days, and the spectrum of organisms covered by the var-
ious antibiotics was similar.
We identified 10 randomized controlled trials in our
literature review. Results from two of these trials could
not be included because insufficient data were reported
(28,31). Both of these trials showed no benefit from the
use of antibiotics. Thus, their exclusion tended to bias our
results in favor of antibiotics. In addition, the summary
effect size may have been overestimated if publication
bias made it more likely that studies showing benefit were
published, whereas those showing no benefit were not. If
there was publication bias, small studies with negative
findings should have been unlikely to be published,
whereas small studies with positive findings should have
been more likely to be published, leading to a correlation
between study size and effect size. We found no such
correlation.
We used similar methodology to an earlier meta-anal-
ysis that examined the effect of antibiotics in patients with
acute exacerbations of chronic obstructive pulmonary
disease (1). That study reported a summary effect size of
0.22 (95% CI, 0.10 to 0.34), also indicating a small, sta-
tistically significant benefit from the use of antibiotics.
Patients who were treated with antibiotics had a modest
improvement in peak expiratory flow of approximately
11 L/min compared with those treated with placebo. Al-
though the magnitude of benefit from antibiotic treat-
ment in that meta-analysis is similar to that in the current
meta-analysis, such a benefit may be more important for

a patient with underlying lung disease who has less func-
tional reserve.
The costs of widespread antibiotic use are great for
both patients and society. They include prescription
costs, medication side effects, and an increase in antibi-
otic resistance. Several studies have shown that wide-
spread antibiotic use leads to the development of resistant
organisms (45– 47). Antibiotic use for acute bronchitis
constitutes a substantial portion of all antibiotic use in the
United States, accounting for 9% of all prescriptions writ-
ten for children (26). Furthermore, side effects of antibi-
otics used for acute bronchitis are common, occurring in
10% to 36% of patients (28 –31,33,35,37). The practice of
routinely giving antibiotics for acute bronchitis encour-
ages patients to expect antibiotics for subsequent epi-
sodes (48), which adds to the cycle of medication costs,
side effects, and antibiotic resistance. We believe that
there should be a clear, substantial benefit to antibiotics
to justify these costs.
Some authors have suggested that certain subgroups of
patients with acute bronchitis may benefit from antibiot-
ics (9,35,39). In a study of 140 patients randomly assigned
to treatment with doxycycline or placebo, Verheij et al
(35) reported that doxycycline resulted in clinical benefit
among patients older than 55 years and in those who felt
ill at study entry. However, approximately 30% of the
patients in that study had abnormalities on lung auscul-
tation and therefore may have had conditions such as
July 1999 THE AMERICAN JOURNAL OF MEDICINEt
Volume 107 65

pneumonia that would show a large benefit from antibi-
otic treatment (49). Others have suggested treating pa-
tients who test positive for Mycoplasma pneumoniae or
Chlamydia pneumoniae (39), although there is no evi-
dence from randomized trials to support this practice. In
a randomized trial using erythromycin to treat acute
bronchitis, King et al (37) found no difference in out-
comes between patients who tested positive and those
who tested negative for Mycoplasma pneumoniae. More
research is needed to determine if there are subgroups of
patients who are likely to have a substantial benefit from
treatment with antibiotics.
The studies included in this meta-analysis examined
the effect of one of three different antibiotics (erythromy-
cin, doxycycline, trimethoprim/sulfamethoxazole). None
of the studies used one of the newer macrolide or floro-
quinolone antibiotics. We are not aware of any random-
ized, placebo-controlled trials of these agents in adults
with acute bronchitis. Future studies should determine
the risks and benefits associated with use of these newer
antibiotics.
In summary, we found a statistically significant benefit
from the use of antibiotics in acute bronchitis. Treatment
reduced the duration of cough and sputum production
by approximately one half day. The decision to use anti-
biotics for the treatment of adults with acute bronchitis
must be weighed against the costs associated with wide-
spread use of these agents. In healthy patients with acute
bronchitis who have no evidence of chronic pulmonary
disease, we believe that the small benefit associated with
antibiotic treatment does not outweigh the risk of side
effects and the increase in antibiotic resistance.

Note Added in Proof: After this paper was submitted, a
meta-analysis on a similar topic was published: Smucny
JJ, Becker LA, Glazier RH, McIsaac W. Are antibiotics
effective treatment for acute bronchitis? A meta-analysis.
J Fam Pract. 1998;47:453– 460.
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