Clinical Rheumatology (2018) 37:439–450

https://doi.org/10.1007/s10067-017-3966-1

ORIGINAL ARTICLE

Risk of serious infections in biological treatment of patients

with ankylosing spondylitis and non-radiographic axial
spondyloarthritis: a meta-analysis
Sen Wang 1 & Qian He 1 & Zongwen Shuai 1

Received: 5 July 2017 / Revised: 24 October 2017 / Accepted: 18 December 2017 / Published online: 30 December 2017
# International League of Associations for Rheumatology (ILAR) 2017

Abstract
The objective of the study is to quantitatively assess the risk of serious infections in patients with axial spondyloarthritis (AS) and
non-radiographic axial spondyloarthritis (nr-axSpA) treated by biologics enrolled in randomized controlled trials (RCTs). A
systematic literature searches of MEDLINE (via PubMed), EMBASE, the Cochrane Library and abstracts archives of the annual
scientific meetings of both the American College of Rheumatology (ACR) and the European League Against Rheumatism
(EULAR) was conducted through October 2015. The RCTs that compared the safety of any biologics treatment for AS or nr-
axSpA with placebo and/or non-steroidal anti-inflammatory drugs (NSAIDs) and/or conventional disease modifying antirheu-
matic drugs (DMARDs) with a minimum of 12 weeks of follow-up were selected independently by 2 reviewers. Twenty-five
RCTs with data from 2403 patients were analyzed in the analysis. Patients included active AS in 21 studies and nr-axSpA in 4
studies were treated by 5 TNF inhibitors (adalimumab, certolizumab, etanercept, golimumab and infliximab) and 3 non-TNF
inhibitors (sarilumab, tocilizumab, secukinumab). The risk of serious infections has no difference and numerically was only
slightly increased in patients with AS and nr-axSpA treated by biologics compared with controls (OR = 1.42; 95%CI 0.58–3.47).
Stratified analysis yielded the pooled risk differences (RDs) of 0.00 (95%CI, − 0.01 to 0.01), 0.01 (95%CI − 0.01 to 0.03), − 0.00
(95%CI −0.01 to 0.01), 0.00 (95%CI − 0.02 to 0.02), 0.01 (95%CI −0.01 to 0.03) and 0.01 (95%CI −0.02 to 0.04) for
adalimumab, certolizumab, etanercept, golimumab, infliximab and non-TNF inhibitors respectively. There are also no significant
effect of biologics on serious infections was observed compared with controls in patients with AS (p = 0.29) and nr-axSpA (p =
0.89). The use of biologics among patients with AS and nr-axSpA included in RCTs was not significantly associated with an
increased risk of serious infections compared with placebo or NSAIDs or DMARDs.

Keywords Axial spondyloarthritis . Biological treatment . Serious infections . TNF inhibitors

Introduction worldwide prevalence of approximately 0.5–1% of the gener-

al population, AS has a peak onset in the second and third
Axial spondyloarthritis, an group of immune-mediated arthri- decades of life and affects men about twice as frequently as
tis, could be classified into two forms according to modified women [5, 6].
New York criteria and ASAS-defined spondyloarthritis (SpA) The first-line medication recommended for AS is non-
for ankylosing spondylitis (AS) and non-radiographic axial steroidal anti-inflammatory drugs (NSAIDs), but many pa-
spondyloarthritis (nr-axSpA), respectively [1, 2]. AS is the tients have inadequate response for single NSAIDs therapy
prototypic form and a main outcome of an inter-related group [7]. Conventional disease modifying antirheumatic drugs
of conditions now named spondyloarthritides [3, 4]. With a (DMARDs), sulfasalazine and methotrexate, are of limited
use or are not effective for patients especially with axial dis-
ease [7–10].
* Zongwen Shuai Available biologics, including tumor necrosis factor (TNF)
lscszw0569@aliyun.com
inhibitors and other biological agents, are new class of
1
Department of Rheumatology and Immunology, The First Affiliated disease-modifying therapy option for rheumatoid arthritis
Hospital of Anhui Medical University, Hefei 230022, China (RA) and AS [11–20]. Biologics have been reported to show
440 Clin Rheumatol (2018) 37:439–450

large clinical improvement and radiographic deceleration axSpA; (2) compare the severe adverse events (SAEs) includ-
compared with sulfasalazine or methotrexate [9, 21–23]. ing serious infection of any of the biologics against any
However, basic science research suggests that the most impor- NSAID, DMARD and/or placebo; (3) complete at least
tant side effects of biologics are the risk of serious infections in 12 weeks of follow-up. Trials were excluded if they were
patients with RA and AS [24, 25]. The different results were open-labeled studies without a control group or had no reports
achieved from the previous meta-analyses of the risk of seri- of original publications, had no descriptions of adverse events,
ous infections in patients treated by biological drugs for RA or could not confirm whether the SAEs is infectious. The
[26–29]. The early meta-analysis including only TNF inhibi- serious infection was defined as infection that requires antimi-
tor indicated a higher absolute risk of serious infections in AS crobial therapy or hospitalization, or associated with death, or
patients treated with biologics compared with placebo, how- according to the definition given within each trial protocol
ever, without significant difference [30]. In addition, no sys- [26, 27, 29].
temic review was conducted to evaluate the risk of infections
in patients with nr-axSpA treated by biologics.
Accordingly, it has been debated about what extent therapy Statistical analysis
with biologics for axial spondyloarthritis might be associated
with an increase in serious infections. Unlike previous analy- Mantel-Haenszel method with a fixed-effects model meta-
ses, more trials including TNF and non-TNF inhibitor are now analysis of dichotomous outcomes were conducted. Data were
available for a conclusive study to address this question. We combined and expressed as odds ratios (ORs) with their asso-
aimed to compare the risk of serious infections in AS and nr- ciated 95% confidence intervals (95%CI) according to differ-
axSpA between biological treatments and non-biological ent biological agents. The absolute risk difference (RD) of
treatments through a meta-analysis of randomized controlled serious infections for each trial were also calculated. The for-
trials (RCTs). est plots present measures of inconsistency across the trials
(Cochrane Q statistic, by calculating Chi2 and the I2 statistic)
and a test for overall effect (Z). Finally, funnel plots and
Methods Egger’s regression test were produced to help detect potential
publication bias. All statistical tests and construction of forest
Data sources and search strategy plots were carried out with Review Manager (RevMan) soft-
ware (version 5.3, Copenhagen, The Nordic Cochrane Centre)
A systematic search of the literature was conducted in the and Comprehensive Meta-Analysis (CMA) software (version
databases MEDLINE (via PubMed), EMBASE and the 3.3.070, Englewood, USA).
Cochrane Library from inception to March 2017 using the
search terms: spondyloarthritis or spondyloarthritides; biolog-
ical product or biologics; randomized controlled trial;
etanercept (or (p75): Fc fusion protein), infliximab (or cA2),
adalimumab (or D2E7), certolizumab, golimumab,
secukinumab, sarilumab, and tocilizumab. Additionally, refer-
ences from relevant studies were also included into the search.
Searches were restricted to clinical trials, phase II, III or IV,
and English language. Moreover, to locate the unpublished
studies, we also retrieved electronic abstract databases of the
American College of Rheumatology (2001–2017) and the
European League Against Rheumatism from 2001 to 2017.

Data abstraction and study validity assessment

Double-blind RCTs studies were considered to be available if

any of the eight biological drugs were included and serious
infections were reported. The trials were initially screened on
the basis of their titles and/or abstracts by two reviewers (Sen
Wang and Qian He).
Fig. 1 Meta-analysis study selection. AS: ankylosing spondylitis; nr-
To be eligible for inclusion in this meta-analysis, trials had axSpA: non-radiographic axial Spondyloarthritis. a TNF inhibitors and
to receive a Jadad quality score of ≥ 3 [31] and (1): include non-TNF biologics. b Adalimumab. c Certolizumab. d Etanercept. e
only patients with axial spondyloarthritis including AS and nr- Golimumab. f Infliximab. g Non-TNF biologics
Table 1 Characteristics of the randomized controlled trials of biotherapies in AS included in these meta-analyses for serious infections

Source Disease No. of No. of No. of Active treatment Control group (no. Other medication Duration of
characteristics randomized participants participants group (no. of of participants*) during trial trial, week
participants treated completed the participants*)
follow-up

TNF inhibitors
Van et al., 2006 [38, 39] Active AS 315 NR 296 Adalimumab 40 mg Placebo (107) NSAIDs or DMARDs 24
with/without oth- every other week for or Corticosteroids
er SpA 24 weeks (208)
Clin Rheumatol (2018) 37:439–450

Haibel et al., 2008 [12] Active nr-axSpA 46 46 46 Adalimumab 40 mg Placebo (24) None 12
every other week for
12 weeks (22)
Horneff et al., 2012 [42] Juvenile onset AS 32 32 30 Adalimumab 40 mg Placebo (15) NSAIDs or 12
refractory to every other week for Corticosteroids
NSAIDs 12 weeks (17)
Sieper (A) et al., 2013 [43] Active nr-axSpA in- 192 185 179 Adalimumab 40 mg Placebo (97) NSAIDs or DMARDs 12
adequate to every other week for or Prednisone
NSAIDs 12 weeks (95)
Huang et al., 2014 [45] Active AS 344 344 337 Adalimumab 40 mg Placebo (115) NSAIDs or DMARDs 12
inadequate to every other week for or analgesics
NSAIDs 12 weeks (229)
Landewé et al., 2014 [17] Axial 325 NR 298 Certolizumab 200 mg Placebo (107) NSAIDs or DMARDs 24
spondyloarthritis every 2 weeks;
including AS; 400 mg every
inadequate to 4 weeks (218)
NSAIDs
Gorman et al., 2002 [33] Active AS despite 40 40 37 Etanercept 25 mg twice Placebo (20) NSAIDs or DMARDs 28
accepted weekly for 4 months or Corticosteroids
treatments (20)
Brandt et al., 2003 [13] Active AS 33 30 29 Etanercept 25 mg twice Placebo for 6 weeks NSAIDs 30
weekly for 12 weeks and then
(16) Etanercept 25 mg
twice weekly for
6 weeks (17)
Davis et al., 2003 [35] Active AS 277 NR 246 Etanercept 25 mg twice Placebo (139) NSAIDs or DMARDs 24
weekly for 24 weeks or Prednisone
(138)
Van der Heijde (E) et al., 2006 [38, 39] Active AS 356 356 321 Etanercept 25 mg twice Placebo (305) NSAIDs or DMARDs 12
weekly and 50 mg or Corticosteroids
weekly (51)
Braun et al., 2011 [7, 22] Active AS 566 566 521 Etanercept 50 mg once Sulfasalazine NR 16
weekly for 16 weeks 3 g/day for
(379) 16 weeks (187)
Dougados et al., 2011 [41] Severe active AS 82 NR 77 Etanercept 50 mg Placebo (43) NSAIDs or DMARDs 12
injection once or analgesics
weekly for 12 weeks
(39)
Dougados et al., 2014 [44] 225 215 206 Etanercept 50 mg Placebo (114) NSAIDs 12
weekly (111)
441
Table 1 (continued)
442

Source Disease No. of No. of No. of Active treatment Control group (no. Other medication Duration of
characteristics randomized participants participants group (no. of of participants*) during trial trial, week
participants treated completed the participants*)
follow-up

Active nr-axSpA in-

adequate to
NSAIDs
Calin et al., 2004 [36] Active AS 84 84 82 Etanercept 25 mg twice Placebo (39) DMARDs 12
weekly for 12 weeks
(45)
Inman et al., 2008 [40] Active AS 356 355 338 Golimumab 50 or Placebo (78) NSAIDs or DMARDs 24
inadequate to 100 mg every or Corticosteroids
NSAIDs or 4 weeks for
DMARDs 24 weeks (278)
Bao et al., 2014 [15] Active AS 213 213 203 Golimumab 50 mg at Placebo then escape DMARDs 24
week 0 and every to Golimumab
4 weeks (108) 50 mg every
4 weeks at week
16 or 24 (105)
Braun et al., 2002 [32] Severe active AS 70 69 66 Infliximab 5 mg/kg at Placebo (35) NSAIDs 12
weeks 0, 2, 6 (35)
Van den Bosch et al., 2002 [34] Active AS and active 19 19 19 Infliximab 5 mg/kg at Placebo (10) Not allowed DMARDs 12
AS with weeks 0, 2, and 6 (9)
peripheral arthritis
Marzo-Ortega et al., 2005 [23] Active AS 42 41 35 Infliximab 5 mg/kg at Placebo + MTX NSAIDs or 30
weeks 0,2,6,14, 7.5 mg twice a Corticosteroids
22 + MTX 7.5 mg week (14)
twice a week (28)
van der Heijde (I) et al., 2005 [37] Active AS 279 277 274 Infliximab 5 mg/kg at Placebo (78) NSAIDs, 24
weeks 0, 2, 6, 12, 18 acetaminophen or
(201) tramadol
Barkham et al., 2009 [14] Active AS 40 40 39 Infliximab 5 mg/kg at Placebo (20) NSAIDs 16
weeks 0, 2, 6, 12 (20)
Sieper (I) et al., 2014 [18, 46] Active nr-axSpA not 158 157 141 Infliximab 5 mg/kg at Placebo + Naproxen NR 28
refractory to weeks 0, 2, 6, 12, 18, 1000 mg daily
NSAIDs 24 + naproxen (52)
1000 mg daily (106)
Non-TNF biologics
Sieper (S) et al., 2014 [18, 46] Active AS 301 300 261 Sarilumab 100 mg q2w Placebo (50) NSAIDs or DMARDs 12
inadequate to (49); 150 mg q2w or Prednisone
NSAIDs (50); 100 mg qw
(52); 200 mg q2w
(50); 150 mg qw (50)
(251)
Baeten et al., 2013 [16] Active AS 30 30 18 Secukinumab 2 × 10 Placebo (6) NSAIDs or DMARDs 28
mg/kg at day 1 and or Prednisone
day 22 (24)
Sieper (T) et al., 2014 [18, 46] 102 102 99 Placebo (51) 12
Clin Rheumatol (2018) 37:439–450
Clin Rheumatol (2018) 37:439–450 443

Abbreviations: NSAIDs: non-steroidal anti-inflammatory drugs; DMARDs: disease-modifying antirheumatic drugs; MTX: methotrexate; NR: not reported in original publication; Abbreviations in
Results
Duration of
trial, week Search results and trial characteristics

The initial implementation of search strategy yielded 2403

NSAIDs or DMARDs
or Corticosteroids
potentially relevant citations and 118 duplicates were exclud-
Other medication

parentheses after study author: A: adalimumab; E: etanercept; I: infliximab; S: sarilumab; T: tocilizumab. *Numbers of participants who received at least 1 dose of the study drug
ed across databases. After review of titles and/or abstracts,
during trial

2057 citations were excluded and 228 full-text articles were

retrieved for further evaluation. After full text identification,
204 citations were excluded for the following reasons: review
articles; study design does not meet criteria; not clinical con-
Control group (no.

trolled trials; not patients with AS or nr-axSpA; long-term

of participants*)

extensions; or no reports of serious infections. Ultimately, 25

articles were retained for our analysis (Fig. 1) [12–19, 22, 23,
32–46].
All of 25 studies were randomized double-blind con-
trolled trials with a follow-up of 12–30 weeks, patients
every 4 weeks; (51)
Tocilizumab 8 mg/kg

diagnosed according to modified New York criteria and

Active treatment

ASAS-defined axial SpA for AS and nr-axSpA respec-

participants*)
group (no. of

tively [1, 2]. Patients included active AS in 20 studies,

juvenile onset AS in 1 study [42] and nr-axSpA in 4
studies [12, 43, 44, 46]. All patients have active disease
defined by a Bath Ankylosing Spondylitis Disease
Activity Index (BASDAI) score of ≥ 4 (range 0–10) in
completed the

24 trials and the patient’s/physician’s global assessment

participants

follow-up

of disease activity in one trial [33].

No. of

Intention-to-treat analysis included all randomized pa-

tients was performed in this meta-analysis, thus a total
of 4527 patients including 2699 received biologics and
participants

1828 treated by placebo or NSAIDs or DMRADs.

treated
No. of

However, only 92.73% (4198/4527) patients completed

the follow-up in trials. Patients in treatment group were
treated by 5 TNF inhibitors (adalimumab, certolizumab,
randomized
participants

etanercept, golimumab and infliximab in 5, 1, 8, 2, and

No. of

6 trials respectively) and 3 non-TNF inhibitors including

2 monoclonal anti-body against IL-6R (sarilumab, toci-
lizumab) [18, 19] and a human anti-IL-17A monoclonal
antibody (secukinumab) [16]. In 2 trials, data were com-
inadequate to
characteristics

bined for different dosages of golimumab (50 and

NSAIDs
Active AS

100 mg subcutaneously every 4 weeks) or certolizumab

Disease

(200 mg every 2 weeks and 400 mg every 4 weeks),

and the incidence of serious infections were 0/138 and
2/140 or 2/111 and 0/107 respectively [17, 40]. The
detailed characteristics of these trials are summarized
in Tables 1 and 2.

Risk of serious infection in axial spondyloarthritis

Table 1 (continued)

Of the total 4527 patients in 25 trials, serious infections were

reported in 16 patients in the treatment groups (adalimumab 2,
certolizumab 2, etanercept 2, golimumab 3, infliximab 4 and
Source

non-TNF inhibitors 3) and 6 patients in the control groups.

Using the Mantel-Haenszel method with a continuity
444 Clin Rheumatol (2018) 37:439–450

Table 2 Summary of serious

infections in the randomized Source Active No. of active treated No. of controls with ≥ 1
placebo-controlled trials included treatment patients with ≥ 1 serious serious infection/total in
in these meta-analyses infection/total in treat- controls (incidence %)
ment groups (incidence
%)

Van der Heijde (A) et al., 2006 Adalimumab 0/208 (0) 1/107 (0.93)
[38, 39]
Haibel et al., 2008 [12] 0/22 (0) 0/24 (0)
Horneff et al., 2012 [42] 1/17 (5.88) 0/15 (0)
Sieper(A) et al., 2013 [43] 0/95 (0) 0/97 (0)
Huang et al., 2014 [45] 1/229 (0.44) 0/115 (0)
Total 2/571 (0.35) 1/358 (0.28)
Landewé et al., 2014 [17] Certolizumab 2/218 (0.92) 0/107 (0)
Total 2/218 (0.92) 0/107 (0)
Gorman et al., 2002 [33] Etanercept 0/20 (0) 0/20 (0)
Brandt et al., 2003 [13] 0/16 (0) 0/17 (0)
Davis et al., 2003 [35] 2/138 (1.45) 1/139 (0.72)
Van der Heijde (E) et al., 2006 [38, 0/51 (0) 2/305 (0.66)
39]
Braun et al, 2011 [7, 22] 0/379 (0) 0/187 (0)
Dougados (SPINE) et al., 2011 0/39 (0) 0/43 (0)
[41]
Dougados et al., 2014 [44] 0/111 (0) 1/114 (0.88)
Calin et al., 2004 [36] 0/45 (0) 0/39 (0)
Total 2/799 (0.25) 4/864 (0.46)
Inman et al., 2008 [40] Golimumab 2/278 (0.72) 1/78 (1.28)
Bao et al., 2014 [15] 1/108 (0.93) 0/105 (0)
Total 3/386 (0.78) 1/183 (0.55)
Braun et al., 2002 [32] Infliximab 1/35 (2.86) 0/35 (0)
Van den Bosch et al., 2002 [34] 0/9 (0) 0/10 (0)
Marzo-Ortega et al., 2005 [23] 0/28 (0) 0/14 (0)
Van der Heijde (I) et al., 2005 [37] 2/201 (1) 0/78 (0)
Barkham et al., 2009 [14] 0/20 (0) 0/20 (0)
Sieper (I) et al, 2014 [18, 46] 1/106 (0.94) 0/52 (0)
Total 4/399 (1.00) 0/209 (0)
Baeten et al., 2013 [16] Secukinumab 1/24 (4.17) 0/6 (0)
Sieper (S) et al., 2014 [18, 46] Sarilumab 1/251 (0.4) 0/50 (0)
Sieper (T) et al., 2014 [18, 46] Tocilizumab 1/51 (1.96) 0/51 (0)
Total 3/326 (0.92) 0/107 (0)
Total of all biologics 16/2699 (0.59) 6/1828 (0.33)

Serious infection was defined as requiring antimicrobial therapy or hospitalization, or associated with death, or
according to the definition given within each trial protocol. Abbreviations in parentheses after study author: A:
adalimumab; E: etanercept; I: infliximab; S: sarilumab; T: tocilizumab

correction, the risk of serious infections has no difference and methods without corrections for 0 cell counts (Peto OR =
numerically was only slightly increased in patients with AS or 1.60; 95%CI 0.66–3.86).
nr-axSpA treated by biologics compared with controls (OR = Stratified analysis according to different biologics dose
1.42; 95%CI 0.58–3.47). Statistical heterogeneity was signif- yielded the pooled RDs of 0.00 (95%CI, − 0.01 to 0.01),
icant low (Chi2 = 2.15, I2 = 0%) and not beyond variations that 0.01 (95%CI − 0.01 to 0.03), − 0.00 (95%CI − 0.01 to 0.01),
could be due to chance (p = 0.83) (Fig. 2a). Estimates 0.00 (95%CI − 0.02 to 0.02), 0.01 (95%CI − 0.01 to 0.03) and
remained no statistically significant when applying the Peto 0.01 (95%CI − 0.02 to 0.04) for adalimumab, certolizumab,
Clin Rheumatol (2018) 37:439–450 445

A. TNF inhibitors and non-TNF biologics

B. Adalimumab

C. Certolizumab

D. Etanercept

Fig. 2 Risk of serious infections in patients with axial spondyloarthritis proportional to the marker size. Abbreviations in parentheses following
treated with biological agents versus controls. Forest plots for the meta- study author: S: sarilumab; T: tocilizumab. a Patients with AS. b Patients
analysis of risk of serious infection associated with treatment with bio- with nr-axSpA
logics in patients with AS and nr-axSpA. The weight of each study is

etanercept, golimumab, infliximab and non-TNF inhibitors Risk of serious infections in AS and nr-axSpA
respectively. Treatment of both TNF inhibitors and non-TNF
inhibitors have did not increase the risk of serious infections in Twenty-one trials including 3906 patients including 2365 pa-
patients with AS and nr-axSpA. No heterogeneity between the tients treated by biologics and 1541 treated by placebo or
RCTs for the serious infection was detected (I2 = 0%, p > 0.1) NSAIDs or DMRADs fulfilled the criteria for analysis of
(Fig. 2b–g). AS. Patients of 92.8% (3626/3906) completed the follow-up
446 Clin Rheumatol (2018) 37:439–450

E. Golimumab

F. Infliximab

G. Non-TNF biologics

Fig. 2 (continued)

in trials. Serious infections were reported in 15 patients in the heterogeneity was detected in the meta-analysis (I2 = 0%,
treatment groups and 5 patients in the control groups. p = 0.86) (Fig. 3b).
According to the Mantel-Haenszel method with fixed model,
no significant effect of biologics on serious infection was ob- Analysis of sensitivity and publication bias
served compared with controls (RD = 0.00, 95%CI -0.00-
0.01) (p = 0.29). Heterogeneity analysis for the serious infec- A sensitivity analysis was performed by the sequential omis-
tion demonstrated no inconsistency among the studies (I2 = sion of individual studies. The result revealed that the signif-
0%, p = 1.0) (Fig. 3a). icance estimate of the overall pooled RD was not influenced
Only 4 studies met the selection criteria in patients with nr- by omitting any single study. Using the continuity correction,
axSpA. And patients in treatment group received adalimumab results were similar to the Mantel-Haenszel RD. The publica-
in 2 trials, etanercept and infliximab in 1 trial respectively. tion bias was evaluated by a funnel plot, which showed no
Total 621 patients with nr-axSpA including 334 and 287 re- significant evidence of asymmetry. Additionally, there were
ceived biologics therapy and controls respectively, and 92.1% no changes in the effect sizes according to the classic fail-safe
(572/621) of all patients finished the follow-up visits. Meta- N (p = 0.35), Orwin fail-safe N (risk difference in observed
analysis using Mantel-Haenszel method with fixed model studies is 0.002), the Duval and Tweedie’s trim and fill (Q =
demonstrated that there was also no difference of the risk of 7.14) and Begg and Mazumdar rank correlation analysis with
serious infections in patients treated by biologics and controls or without Kendall’s continuity correction (p = 0.20 and p =
(RD = −0.00, 95%CI -0.02-0.01) (p = 0.89). No significant 0.21 respectively). Quantification of the publication bias was
Clin Rheumatol (2018) 37:439–450 447

Fig. 3 Risk of serious infections A. Patients with AS

in patients with AS and nr-axSpA
treated with biological agents
versus controls. Forest plots for
the meta-analysis of risk of
serious infection associated with
treatment with biologics in
patients with AS and nr-axSpA.
The weight of each study is
proportional to the marker size.
Abbreviations in parentheses
following study author: A:
adalimumab; E: etanercept; I:
infliximab; S: sarilumab; T:
tocilizumab

B. Patients with nr-axSpA

also performed by an Egger’s regression which suggested no biologics from 25 randomized trials, and this larger sample
significant bias of the analysis (p = 0.19). size can provide a more comprehensive estimate of the risk
of serious infections. This meta-analysis did not reveal a risk
difference of serious infections for patients with AS and nr-
Discussion axSpA treated by biologics compared with controls. The over-
all results were generally consistent with the risk trends report-
Serious infections are low incidence but severe and even fatal ed in the individual trials.
adverse of biologics for patients with axial spondyloarthritis. The findings have practical implications. The introduction
However, the risk of serious infections for these patients re- of biologics has been the most substantial development in the
ceiving biological treatment and the magnitude of this effect treatment of spondyloarthritides in the past few years [3, 16,
are still unclear. The previous meta-analysis suggested a 18, 19]. However, high risk of infection is one of the most
higher absolute risk of serious infections in patients with AS important contraindications for patients intended to be treated
receiving TNF inhibitors compared with placebo, however, with biologics especially TNF inhibitors [47–49]. The find-
without statistically significant difference [30]. As the ings could provide more data for patients at the time when
counting trials have being conducted, evidence can now be decisions about treatment with biological drugs are made.
drawn from data for 4527 patients with AS and nr-axSpA This meta-analysis was conducted using all available literature
treated with not only TNF inhibitors but also other non-TNF sources focused on the biologics treatment for AS and nr-
448 Clin Rheumatol (2018) 37:439–450

axSpA published till our search operations. Therefore, we 4. Brown MA, Kenna T, Wordsworth BP (2016) Genetics of ankylos-
ing spondylitis—insights into pathogenesis. Nat Rev Rheumatol
consider these results to be comprehensive and valid.
12(2):81–91. https://doi.org/10.1038/nrrheum.2015.133
However, some limitations in our analysis, as well as in the 5. Akkoc N, Khan MA (2005) Overestimation of the prevalence of
individual studies, need to be noticed when interpreting the ankylosing spondylitis in the Berlin study: comment on the article
data. The individual study indicated that high-dose by Braun et al. Arthritis Rheum 52(12):4048–4049. https://doi.org/
10.1002/art.21492
golimumab (100 mg every 4 weeks) seemed to increase the
6. Lopez-Olivo MA, Tayar JH, Martinez-Lopez JA, Pollono EN,
risk of serious infections comparing with low-dose (50 mg Cueto JP, Gonzales-Crespo MR, Fulton S, Suarez-Almazor ME
every 4 weeks) in patients with AS [40]. The latest meta- (2012) Risk of malignancies in patients with rheumatoid arthritis
analysis in rheumatoid arthritis also demonstrated that treated with biologic therapy: a meta-analysis. JAMA 308(9):898–
908. https://doi.org/10.1001/2012.jama.10857
standard- and high-dose (but not low-dose) biological drugs
7. Braun J, van den Berg R, Baraliakos X, Boehm H, Burgos-Vargas
are related to increase of serious infections compared with R, Collantes-Estevez E, Dagfinrud H, Dijkmans B, Dougados M,
traditional DMARDs [26]. However, without adequate data, Emery P, Geher P, Hammoudeh M, Inman R, Jongkees M, Khan M,
we could not conducted the systemic meta-analysis for the risk Kiltz U, Kvien T, Leirisalo-Repo M, Maksymowych W, Olivieri I,
Pavelka K, Sieper J, Stanislawska-Biernat E, Wendling D,
of serious infections in patients treated with different dose-age
Ozgocmen S, van Drogen C, van Royen B, van der Heijde D
of biologics. On the other hand, meta-analyses of rare events (2011) 2010 update of the ASAS/EULAR recommendations for
are challenging because of the inherent difficulties in the han- the management of ankylosing spondylitis. Ann Rheum Dis
dling the value of zero cells [26]. Besides, the extracted data in 70(6):896–904. https://doi.org/10.1136/ard.2011.151027
the meta-analysis, as well as in some original articles, were 8. Roychowdhury B, Bintley-Bagot S, Bulgen DY, Thompson RN,
Tunn EJ, Moots RJ (2002) Is methotrexate effective in ankylosing
presented in the form of intention to treat rather than as-treated spondylitis? Rheumatology (Oxford) 41(11):1330–1332. https://
analyses, which might underestimate the serious infection doi.org/10.1093/rheumatology/41.11.1330
risk. To address this issue, we did several analyses using dif- 9. Regel A, Sepriano A, Baraliakos X, van der Heijde D, Braun J,
ferent statistical models to produce ORs and Peto ORs, which Landewé R, van den Bosch F, Falzon L, Ramiro S (2017)
Efficacy and safety of non-pharmacological and non-biological
leads to the consistent results. pharmacological treatment: a systematic literature review informing
In conclusion, this meta-analysis has not shown a different the 2016 update of the ASAS/EULAR recommendations for the
risk of serious infections in patients with AS and nr-axSpA management of axial spondyloarthritis. RMD Open 3(1):e000397.
treated with biologics compared with controls. However, as https://doi.org/10.1136/rmdopen-2016-000397
10. Macfarlane GJ, Barnish MS, Jones EA, Kay L, Keat A, Meldrum
the exist of heterogeneity of original trials in terms of nation- KT, Pathan E, Sturrock RD, Zabke C, McNamee P, Jones GT
ality, disease duration and activity, and previous and concom- (2015) The British Society for Rheumatology Biologics Registers
itant treatment other than biologics, interpretation of our esti- in Ankylosing Spondylitis (BSRBR-AS) study: protocol for a pro-
mates of risk of serious infections should be made with spective cohort study of the long-term safety and quality of life
outcomes of biologic treatment. BMC Musculoskelet Disord
caution. 16(1):347. https://doi.org/10.1186/s12891-015-0805-x
11. Nam JL, Ramiro S, Gaujoux-Viala C, Takase K, Leon-Garcia M,
Compliance with ethical standards Emery P, Gossec L, Landewe R, Smolen JS, Buch MH (2014)
Efficacy of biological disease-modifying antirheumatic drugs: a
Disclosures None. systematic literature review informing the 2013 update of the
EULAR recommendations for the management of rheumatoid ar-
Financial support None. thritis. Ann Rheum Dis 73(3):516–528. https://doi.org/10.1136/
annrheumdis-2013-204577
12. Haibel H, Rudwaleit M, Listing J, Heldmann F, Wong RL, Kupper
H, Braun J, Sieper J (2008) Efficacy of adalimumab in the treatment
References of axial spondylarthritis without radiographically defined
sacroiliitis: results of a twelve-week randomized, double-blind,
placebo-controlled trial followed by an open-label extension up to
1. van der Linden S, Valkenburg HA, Cats A (1984) Evaluation of week fifty-two. Arthritis Rheum 58(7):1981–1991. https://doi.org/
diagnostic criteria for ankylosing spondylitis. A proposal for mod- 10.1002/art.23606
ification of the New York criteria. Arthritis Rheum 27(4):361–368. 13. Brandt J, Khariouzov A, Listing J, Haibel H, Sörensen H,
https://doi.org/10.1002/art.1780270401 Grassnickel L, Rudwaleit M, Sieper J, Braun J (2003) Six-month
2. Rudwaleit M, van der Heijde D, Landewe R, Listing J, Akkoc N, results of a double-blind, placebo-controlled trial of etanercept
Brandt J, Braun J, Chou CT, Collantes-Estevez E, Dougados M, treatment in patients with active ankylosing spondylitis. Arthritis
Huang F, Gu J, Khan MA, Kirazli Y, Maksymowych WP, Mielants Rheum 48(6):1667–1675. https://doi.org/10.1002/art.11017
H, Sorensen IJ, Ozgocmen S, Roussou E, Valle-Onate R, Weber U, 14. Barkham N, Keen HI, Coates LC, O'Connor P, Hensor E, Fraser
Wei J, Sieper J (2009) The development of assessment of AD, Cawkwell LS, Bennett A, McGonagle D, Emery P (2009)
SpondyloArthritis international society classification criteria for ax- Clinical and imaging efficacy of infliximab in HLA-B27-positive
ial spondyloarthritis (part II): validation and final selection. Ann patients with magnetic resonance imaging-determined early
Rheum Dis 68(6):777–783. https://doi.org/10.1136/ard.2009. sacroiliitis. Arthritis Rheum 60(4):946–954. https://doi.org/10.
108233 1002/art.24408
3. Braun J, Sieper J (2007) Ankylosing spondylitis. Lancet 369(9570): 15. Bao C, Huang F, Khan MA, Fei K, Wu Z, Han C, Hsia EC (2014)
1379–1390. https://doi.org/10.1016/S0140-6736(07)60635-7 Safety and efficacy of golimumab in Chinese patients with active
Clin Rheumatol (2018) 37:439–450 449

ankylosing spondylitis: 1-year results of a multicentre, randomized, review and meta-analysis of rare harmful effects in randomized
double-blind, placebo-controlled phase III trial. Rheumatology controlled trials. JAMA 295(19):2275–2285. https://doi.org/10.
(Oxford) 53(9):1654–1663. https://doi.org/10.1093/rheumatology/ 1001/jama.295.19.2275
keu132 28. Salliot C, Dougados M, Gossec L (2009) Risk of serious infections
16. Baeten D, Baraliakos X, Braun J, Sieper J, Emery P, van der Heijde during rituximab, abatacept and anakinra treatments for rheumatoid
D, McInnes I, van Laar JM, Landewé R, Wordsworth P, arthritis: meta-analyses of randomised placebo-controlled trials.
Wollenhaupt J, Kellner H, Paramarta J, Wei J, Brachat A, Bek S, Ann Rheum Dis 68(1):25–32. https://doi.org/10.1136/ard.2007.
Laurent D, Li Y, Wang YA, Bertolino AP, Gsteiger S, Wright AM, 083188
Hueber W (2013) Anti-interleukin-17A monoclonal antibody 29. Thompson AE, Rieder SW, Pope JE (2011) Tumor necrosis factor
secukinumab in treatment of ankylosing spondylitis: a randomised, therapy and the risk of serious infection and malignancy in patients
double-blind, placebo-controlled trial. Lancet 382(9906):1705– with early rheumatoid arthritis: a meta-analysis of randomized con-
1713. https://doi.org/10.1016/S0140-6736(13)61134-4 trolled trials. Arthritis Rheum 63(6):1479–1485. https://doi.org/10.
17. Landewe R, Braun J, Deodhar A et al (2014) Efficacy of 1002/art.30310
certolizumab pegol on signs and symptoms of axial 30. Fouque-Aubert A, Jette-Paulin L, Combescure C, Basch A, Tebib J,
spondyloarthritis including ankylosing spondylitis: 24-week results Gossec L (2010) Serious infections in patients with ankylosing
of a double-blind randomised placebo-controlled phase 3 study. spondylitis with and without TNF blockers: a systematic review
Ann Rheum Dis 73(1):39–47. https://doi.org/10.1136/ and meta-analysis of randomised placebo-controlled trials. Ann
annrheumdis-2013-204231 Rheum Dis 69(10):1756–1761. https://doi.org/10.1136/ard.2008.
18. Sieper J, Porter-Brown B, Thompson L, Harari O, Dougados M 098822
(2014) Assessment of short-term symptomatic efficacy of toci- 31. Jadad AR, Moore RA, Carroll D, Jenkinson C, Reynolds DJM,
lizumab in ankylosing spondylitis: results of randomised, placebo- Gavaghan DJ, McQuay HJ (1996) Assessing the quality of reports
controlled trials. Ann Rheum Dis 73(1):95–100. https://doi.org/10. of randomized clinical trials: is blinding necessary? Control Clin
1136/annrheumdis-2013-203559 Trials 17(1):1–12. https://doi.org/10.1016/0197-2456(95)00134-4
19. Sieper J, Braun J, Kay J, Badalamenti S, Radin AR, Jiao L, Fiore S, 32. Braun J, Brandt J, Listing J, Zink A, Alten R, Golder W, Gromnica-
Momtahen T, Yancopoulos GD, Stahl N, Inman RD (2015) lhle E, Kellner H, Krause A, Schneider M, Sörensen H, Zeidler H,
Sarilumab for the treatment of ankylosing spondylitis: results of a Thriene W, Sieper J (2002) Treatment of active ankylosing spondy-
phase II, randomised, double-blind, placebo-controlled study litis with infliximab: a randomised controlled multicentre trial.
(ALIGN). Ann Rheum Dis 74(6):1051–1057. https://doi.org/10. Lancet 359(9313):1187–1193. https://doi.org/10.1016/S0140-
1136/annrheumdis-2013-204963 6736(02)08215-6
20. Cludts I, Spinelli FR, Morello F, Hockley J, Valesini G, Wadhwa M 33. Gorman JD, Sack KE, Davis JC Jr (2002) Treatment of ankylosing
(2017) Anti-therapeutic antibodies and their clinical impact in pa- spondylitis by inhibition of tumor necrosis factor alpha. N Engl J
tients treated with the TNF antagonist adalimumab. Cytokine 96: Med 346(18):1349–1356. https://doi.org/10.1056/NEJMoa012664
16–23. https://doi.org/10.1016/j.cyto.2017.02.015 34. Van Den Bosch F, Kruithof E, Baeten D et al (2002) Randomized
21. Baraliakos X, Listing J, Brandt J, Haibel H, Rudwaleit M, Sieper J, double-blind comparison of chimeric monoclonal antibody to tu-
Braun J (2007) Radiographic progression in patients with ankylos- mor necrosis factor alpha (infliximab) versus placebo in active
ing spondylitis after 4 yrs of treatment with the anti-TNF-alpha spondylarthropathy. Arthritis Rheum 46(3):755–765. https://doi.
antibody infliximab. Rheumatology (Oxford) 46(9):1450–1453. org/10.1002/art.511
https://doi.org/10.1093/rheumatology/kem166 35. Davis JC Jr, Van Der Heijde D, Braun J et al (2003) Recombinant
22. Braun J, van der Horst-Bruinsma IE, Huang F, Burgos-Vargas R, human tumor necrosis factor receptor (etanercept) for treating an-
Vlahos B, Koenig AS, Freundlich B (2011) Clinical efficacy and kylosing spondylitis: a randomized, controlled trial. Arthritis
safety of etanercept versus sulfasalazine in patients with ankylosing Rheum 48:3230–3236
spondylitis: a randomized, double-blind trial. Arthritis Rheum 36. Calin A, Dijkmans BA, Emery P, Hakala M, Kalden J, Leirisalo-
63(6):1543–1551. https://doi.org/10.1002/art.30223 Repo M, Mola EM, Salvarani C, Sanmartí R, Sany J, Sibilia J,
23. Marzo-Ortega H, McGonagle D, Jarrett S, Haugeberg G, Hensor E, Sieper J, van der Linden S, Veys E, Appel AM, Fatenejad S
O'connor P, Tan AL, Conaghan PG, Greenstein A, Emery P (2005) (2004) Outcomes of a multicentre randomised clinical trial of
Infliximab in combination with methotrexate in active ankylosing etanercept to treat ankylosing spondylitis. Ann Rheum Dis
spondylitis: a clinical and imaging study. Ann Rheum Dis 64(11): 63(12):1594–1600. https://doi.org/10.1136/ard.2004.020875
1568–1575. https://doi.org/10.1136/ard.2004.022582 37. van der Heijde D, Dijkmans B, Geusens P, Sieper J, DeWoody K,
24. Sampaio-Barros PD, van der Horst-Bruinsma IE (2014) Adverse Williamson P, Braun J, Ankylosing Spondylitis Study for the
effects of TNF inhibitors in SpA: are they different from RA? Best Evaluation of Recombinant Infliximab Therapy Study Group
Pract Res Clin Rheumatol 28(5):747–763. https://doi.org/10.1016/ (2005) Efficacy and safety of infliximab in patients with ankylosing
j.berh.2014.10.001 spondylitis: results of a randomized, placebo-controlled trial
25. Ozguler Y, Hatemi G, Ugurlu S, Seyahi E, Melikoglu M, Borekci S, (ASSERT). Arthritis Rheum 52(2):582–591. https://doi.org/10.
Atahan E, Ongen G, Hamuryudan V (2016) Re-initiation of bio- 1002/art.20852
logics after the development of tuberculosis under anti-TNF thera- 38. van der Heijde D, Da Silva JC, Dougados M, Geher P, van der
py. Rheumatol Int 36(12):1719–1725. https://doi.org/10.1007/ Horst-Bruinsma I, Juanola X, Olivieri I, Raeman F, Settas L,
s00296-016-3575-3 Sieper J, Szechinski J, Walker D, Boussuge MP, Wajdula JS,
26. Singh JA, Cameron C, Noorbaloochi S, Cullis T, Tucker M, Paolozzi L, Fatenejad S, for the Etanercept Study 314
Christensen R, Ghogomu ET, Coyle D, Clifford T, Tugwell P, Investigators (2006) Etanercept 50 mg once weekly is as effective
Wells GA (2015) Risk of serious infection in biological treatment as 25 mg twice weekly in patients with ankylosing spondylitis. Ann
of patients with rheumatoid arthritis: a systematic review and meta- Rheum Dis 65(12):1572–1577. https://doi.org/10.1136/ard.2006.
analysis. Lancet 386(9990):258–265. https://doi.org/10.1016/ 056747
S0140-6736(14)61704-9 39. van der Heijde D, Kivitz A, Schiff MH, Sieper J, Dijkmans BAC,
27. Bongartz T, Sutton AJ, Sweeting MJ, Buchan I, Matteson EL, Braun J, Dougados M, Reveille JD, Wong RL, Kupper H, Davis JC,
Montori V (2006) Anti-TNF antibody therapy in rheumatoid arthri- ATLAS Study Group (2006) Efficacy and safety of adalimumab in
tis and the risk of serious infections and malignancies: systematic patients with ankylosing spondylitis: results of a multicenter,
450 Clin Rheumatol (2018) 37:439–450

randomized, double-blind, placebo-controlled trial. Arthritis placebo-controlled trial. Arthritis Rheumatol 66(8):2091–2102.
Rheum 54(7):2136–2146. https://doi.org/10.1002/art.21913 https://doi.org/10.1002/art.38721
40. Inman RD, Davis JC Jr, Heijde D et al (2008) Efficacy and safety of 45. Huang F, Gu J, Zhu P, Bao C, Xu J, Xu H, Wu H, Wang G, Shi Q,
golimumab in patients with ankylosing spondylitis: results of a Andhivarothai N, Anderson J, Pangan AL (2014) Efficacy and
randomized, double-blind, placebo-controlled, phase III trial. safety of adalimumab in Chinese adults with active ankylosing
Arthritis Rheum 58(11):3402–3412. https://doi.org/10.1002/art. spondylitis: results of a randomised, controlled trial. Ann Rheum
23969 Dis 73(3):587–594. https://doi.org/10.1136/annrheumdis-2012-
41. Dougados M, Braun J, Szanto S, Combe B, Elbaz M, Geher P, 202533
Thabut G, Leblanc V, Logeart I (2011) Efficacy of etanercept on 46. Sieper J, Lenaerts J, Wollenhaupt J, Rudwaleit M, Mazurov VI,
rheumatic signs and pulmonary function tests in advanced ankylos- Myasoutova L, Park S, Song Y, Yao R, Chitkara D, Vastesaeger
ing spondylitis: results of a randomised double-blind placebo-con- N, on Behalf of All INFAST Investigators (2014) Efficacy and
trolled study (SPINE). Ann Rheum Dis 70(5):799–804. https://doi. safety of infliximab plus naproxen versus naproxen alone in pa-
org/10.1136/ard.2010.139261 tients with early, active axial spondyloarthritis: results from the
42. Horneff G, Fitter S, Foeldvari I, Minden K, Kuemmerle-Deschner double-blind, placebo-controlled INFAST study, part 1. Ann
J, Tzaribacev N, Thon A, Borte M, Ganser G, Trauzeddel R, Rheum Dis 73(1):101–107. https://doi.org/10.1136/annrheumdis-
Huppertz HI (2012) Double-blind, placebo-controlled randomized 2012-203201
trial with adalimumab for treatment of juvenile onset ankylosing 47. Braun J, Davis J, Dougados M, Sieper J, van der Linden S, van der
spondylitis (JoAS): significant short term improvement. Arthritis Heijde D (2006) First update of the international ASAS consensus
Res Ther 14(5):R230. https://doi.org/10.1186/ar4072 statement for the use of anti-TNF agents in patients with ankylosing
43. Sieper J, van der Heijde D, Dougados M, Mease PJ, Maksymowych spondylitis. Ann Rheum Dis 65(3):316–320. https://doi.org/10.
WP, Brown MA, Arora V, Pangan AL (2013) Efficacy and safety of 1136/ard.2005.040758
adalimumab in patients with non -radio graphic axial 48. Yun H, Xie F, Delzell E, Chen L, Levitan EB, Lewis JD, Saag KG,
spondyloarthritis: results of a randomised placebo-controlled trial Beukelman T, Winthrop K, Baddley JW, Curtis JR (2015) Risk of
(ABILITY-1). Ann Rheum Dis 72(6):815–822. https://doi.org/10. hospitalised infection in rheumatoid arthritis patients receiving bio-
1136/annrheumdis-2012-201766 logics following a previous infection while on treatment with anti-
44. Dougados M, van der Heijde D, Sieper J, Braun J, Maksymowych TNF therapy. Ann Rheum Dis 74(6):1065–1071. https://doi.org/10.
WP, Citera G, Miceli-Richard C, Wei JCC, Pedersen R, Bonin R, 1136/annrheumdis-2013-204011
Rahman MU, Logeart I, Wajdula J, Koenig AS, Vlahos B, Alvarez 49. Desai RJ, Bateman BT, Huybrechts KF et al (2017) Risk of serious
D, Bukowski JF (2014) Symptomatic efficacy of etanercept and its infections associated with use of immunosuppressive agents in
effects on objective signs of inflammation in early nonradiographic pregnant women with autoimmune inflammatory conditions: co-
axial spondyloarthritis: a multicenter, randomized, double-blind, hort study. BMJ 356:j895