Rheumatology, 2024, 00, 1–9

https://doi.org/10.1093/rheumatology/keae003
Advance access publication 18 January 2024
Original Article
Rheumatology

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Clinical science
Comparative risk of incident and recurrent acute anterior
uveitis across different biological agents in patients with
ankylosing spondylitis
1,† 2,†
Oh Chan Kwon , Hye Sun Lee , Juyeon Yang2, Min-Chan Park1,*
1
Division of Rheumatology, Department of Internal Medicine, Yonsei University College of Medicine, Seoul, South Korea
2
Biostatistics Collaboration Unit, Yonsei University College of Medicine, Seoul, South Korea
*Correspondence to: Min-Chan Park, Yonsei University College of Medicine, Gangnam Severance Hospital, 211 Eonjuro, Gangnam-gu, Seoul 06273, Korea.
E-mail: mcpark@yuhs.ac
†
O.C.K. and H.S.L. contributed equally.

Abstract
Objective: To evaluate the comparative risk of incident and recurrent acute anterior uveitis (AAU) across different biological DMARDs
(bDMARDs) in patients with AS.
Methods: A retrospective nationwide cohort study was conducted on 34 621 patients with AS without a previous history of AAU using a national
claims database. Patients were followed-up from 2010 to 2021. The comparative risk of incident and recurrent AAU across different bDMARDs
was examined using multivariable time-dependent Cox models and counting process (Anderson–Gill) models, respectively.
Results: The adjusted hazard ratios (aHRs) and 95% CIs for incident AAU (bDMARDs non-exposure as reference) were: adalimumab 0.674
(0.581–0.891), etanercept 1.760 (1.540–2.012), golimumab 0.771 (0.620–0.959), infliximab 0.891 (0.741–1.071) and secukinumab 1.324 (0.794–
2.209). Compared with adalimumab exposure, etanercept [aHR 2.553 (2.114–3.083)], infliximab [aHR 1.303 (1.039–1.634)] and secukinumab
[aHR 2.173 (1.273–3.710)] exposures showed a higher risk of incident AAU. The aHRs and 95% CIs for recurrent AAU (bDMARDs non-exposure
as reference) were: adalimumab 0.798 (0.659–0.968), etanercept 1.416 (1.185–1.693), golimumab 0.874 (0.645–1.185), infliximab 0.926 (0.729–
1.177) and secukinumab 1.257 (0.670–2.359). Compared with adalimumab exposure, etanercept exposure [aHR 1.793 (1.403–2.292)] was asso-
ciated with a higher risk of recurrent AAU.
Conclusion: Our data suggest preference for bDMARDs in the following order: adalimumab/golimumab > infliximab > secukinumab > etaner-
cept (for incident AAU prevention) and adalimumab > golimumab/infliximab/secukinumab > etanercept (for recurrent AAU prevention).

Received: 18 September 2023. Accepted: 15 December 2023

C The Author(s) 2024. Published by Oxford University Press on behalf of the British Society for Rheumatology.
V
All rights reserved. For permissions, please email: journals.permissions@oup.com
2 Oh Chan Kwon et al.

Graphical abstract

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Keywords: ankylosing spondylitis, uveitis, tumour necrosis factor inhibitor, interleukin-17 inhibitor.

Rheumatology key messages

• Data on comparative risk of acute anterior uveitis (AAU) according to different biological DMARDs in AS are limited.
• For incident AAU, the risk was lower in the following order: adalimumab/golimumab > infliximab > secukinumab > etanercept.
• For recurrent AAU, the risk was lower in the following order: adalimumab > golimumab/infliximab/secukinumab > etanercept.

Introduction the risk of AAU in patients with AS have indicated a clear

Acute anterior uveitis (AAU) is the most common extra-
musculoskeletal manifestation of AS, occurring in 23–26% of
patients with AS [1, 2]. AAU characteristically tends to recur
in patients with AS [3] and is therefore an important element
to consider when selecting therapeutic options for such
patients [4, 5].
TNF inhibitors (TNFis), which are biological DMARDs
(bDMARDs) approved for AS treatment [4–6], effectively
control disease activity in AS [7]. Compared with pre-
exposure or placebo, exposure to mAb TNFis, such as adali-
mumab, certolizumab pegol, golimumab and infliximab, has
been shown to significantly lower the incidence rate of AAU
in patients with AS [8–11]. On the other hand, previous
reports on the effect of etanercept exposure on AAU in
patients with AS have shown mixed results [11–13]. Some
studies reported a lower incidence rate of AAU after etaner-
cept exposure (vs pre-exposure) [11, 12]; conversely, another
study observed a higher incidence rate of AAU after etaner-
cept exposure (vs pre-exposure) [13]. Registry data compar-
ing the effects of adalimumab, infliximab and etanercept on
advantage of adalimumab and infliximab over etanercept
[13]. Based on these data, mAb TNFis are the preferred
bDMARDs in patients with AS who have a history of recur-
rent AAU [4, 5].
However, currently it remains unclear whether a particular
TNFi exerts a more favourable effect on the incidence of AAU
in patients with AS who do not have a previous history of
AAU. Previous studies included patients with and without a
previous history of AAU and analysed the overall AAU epi-
sodes instead of examining the incident and recurrent AAU
episodes separately [8–13]. Consequently, these preclude
drawing a conclusion as to whether a particular TNFi is more
effective in preventing incident AAU in patients with AS with-
out a previous history of AAU.
IL-17 inhibitors (IL-17is) are bDMARDs with a different
mode of action from that of TNFis. While IL-17is have also
been proven to be effective in suppressing the inflammatory
burden in AS [14, 15], their effect on AAU has been less stud-
ied than that of TNFis [4]. A comparative analysis using regis-
try data revealed that secukinumab was associated with a
Biologicals and AAU risk in AS
higher risk of AAU than mAb TNFis in patients with SpA
[16]; however, this previous analysis did not compare the risk
of AAU between secukinumab exposure and bDMARD non-
exposure [16]. It is possible that secukinumab exerts a neutral
or even protective effect on AAU with a relatively smaller
magnitude than mAb TNFis, resulting in a higher risk of AAU
than with mAb TNFis [16]. A meta-analysis of randomized
controlled trials showed that the risk of AAU was not in-
creased by IL-17is exposure when compared with that with
placebo exposure; however, the median duration of placebo-
controlled period was only 16 weeks, which is relatively short
to draw a conclusion [17]. Therefore, the comparative risk of
AAU between IL-17is exposure and bDMARDs non-
exposure remains unclear. Additionally, as in previous studies
on TNFis, patients with and without a previous history of
AAU were included in studies on IL-17is [16, 17]. Thus, the
effect of IL-17is on incident AAU in patients with AS without
a previous history of AAU also remains unclear.
By using data from a national claims database, the present
study aimed (i) to investigate the comparative effect of various
bDMARDs on the prevention of incident AAU in patients
with AS without a previous history of AAU and (ii) to evalu-
ate the comparative risk of recurrent AAU across different
bDMARDs in patients with AS.
Methods
Data source and study cohort
This retrospective nationwide cohort study used data
obtained from the Health Insurance Review and Assessment
Service (HIRA) database, which is a Korean nationwide regis-
try covering 97% of South Korea’s entire population and
containing comprehensive data on demographics, disease di-
agnoses and medical treatments [18].
From the HIRA database, patients with claims data for AS be-
tween January 2009 and December 2021 were initially selected.
AS was defined as International Classification of Diseases, Tenth
Revision (ICD-10) code M45 with Rare Intractable Disease
(RID) code V140 [19]. The RID code is assigned to patients who
fulfil a uniform diagnostic criteria provided by the Korean
National Health Insurance [18]. A total of 71 001 patients with
AS were identified. Among these patients, those who (i) were di-
agnosed with AS prior to 2010 (n ¼ 25 943), (ii) were exposed
to bDMARDs prior to AS diagnosis (n ¼ 758), (iii) had a history
of AAU prior to AS diagnosis (n ¼ 9420) and (iv) developed
AAU within 3 months after being diagnosed with AS (n ¼ 259)
were subsequently excluded. Patients who developed AAU
within 3 months after AS diagnosis were excluded to avoid the
possibility of misclassifying prevalent AAU cases as incident
AAU cases. Finally, the remaining 34 621 patients composed the
study cohort (Fig. 1). These patients were followed up from the
date of AS diagnosis (referred to as the index date) until the date
of AAU occurrence, last date with claims data, or 31 December
2021, whichever came first.
Ethics approval
This study was conducted in accordance with the principles em-
bodied in the Declaration of Helsinki and was approved by the
Institutional Review Board (IRB) of the Gangnam Severance
Hospital (IRB approval no.: 3-2022-0159), which waived the
requirement for the acquisition of informed consent from
patients owing to the retrospective nature of this study.
3
Exposure
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The exposure of interest was bDMARDs, namely, adalimu-
mab, etanercept, golimumab, infliximab, ixekizumab and
secukinumab. The national reimbursement policy of South
Korea specifies that bDMARD therapy could be initiated for
a patient with an active disease despite treatment with non-
steroidal anti-inflammatory drugs (NSAIDs) with or without
conventional synthetic DMARDs for at least 3 months.
According to the national reimbursement policy, IL-17is are
approved as second- or later-line bDMARDs. For first-line
bDMARD, any TNFi (adalimumab, etanercept, golimumab
or infliximab) can be used interchangeably. Given that
bDMARD exposure changed over time, each patient contrib-
uted person-time to one or more bDMARD exposures.
Outcomes and covariates
In this study, incident and recurrent AAU (ICD-10 codes H20
and H22.1) [16] were assessed as the study outcomes.
Incident AAU was defined as the first episode of AAU, and re-
current AAU was defined as a subsequent episode occurring
at least 3 months after the first episode [20].
Presence of IBD (ICD-10 codes K50 and K51) [16] and pso-
riasis (ICD-10 code L40) [16] during follow-up was assessed
as covariates. The use of MTX, SSZ, glucocorticoids, non-
selective NSAIDs and selective cyclooxygenase-2 (COX-2)
inhibitors during follow-up was also assessed as covariates.
Statistical analyses
Patient characteristics are presented as means 6 S.D. and
numbers (%) for continuous and categorical variables, respec-
tively. The incidence rate of AAU during bDMARD non-
exposure and each bDMARD exposure was estimated. As the
exposure to bDMARDs varied over time, time-dependent
Cox regression models were used to estimate hazard ratios
(HRs) and 95% CIs for incident AAU. Each bDMARD expo-
sure was compared first with bDMARD non-exposure and
subsequently with adalimumab exposure. Univariable models
were performed, followed by multivariable models adjusted
for age, sex, presence of IBD and psoriasis, and use of MTX,
SSZ, glucocorticoids, non-selective NSAIDs and selective
COX-2 inhibitors.
Counting process (Anderson–Gill) models were used to assess
the HRs and 95% CIs for recurrent AAU. Each bDMARD ex-
posure was compared first with bDMARD non-exposure and
subsequently with adalimumab exposure. Multivariable models
were adjusted for the aforementioned covariates.
To reduce the possibility of confounding by indication, we
performed sensitivity analyses by stratifying the bDMARDs
into first-line and second-line bDMARDs. The comparative
risks of first-line and second-line bDMARDs, respectively, on
incident and recurrent AAU were assessed.
All P-values were two-sided, and statistical significance was
set at P < 0.05. Statistical analyses were performed using SAS
version 9.4 (SAS Institute, Cary, NC, USA).
Results
Patient characteristics and incidence rate of AAU
Of the total 34 621 patients (mean age: 41.2 6 17.2 years;
male sex: 70.6%) included in the study, 34 621, 4004, 2099,
2120, 1603, 325 and 23 patients contributed person-time to
4 Oh Chan Kwon et al.
bDMARD non-exposure, adalimumab exposure, etanercept
exposure, golimumab exposure, infliximab exposure, secuki-
numab exposure and ixekizumab exposure, respectively
(Fig. 1). Table 1 presents the prevalence of IBD and psoriasis,
as well as the medications used during follow-up.
The incidence rates of AAU during bDMARDs non-
exposure, adalimumab exposure, etanercept exposure, goli-
mumab exposure, infliximab exposure, secukinumab expo-
sure and ixekizumab exposure were 1.68, 1.38, 3.46, 1.39,
1.82, 2.59 and 0.00 per 100 person-years, respectively
(Table 2). Compared with bDMARDs non-exposure, the risk
difference of incident AAU for adalimumab exposure, etaner-
cept exposure, golimumab exposure, infliximab exposure and
secukinumab exposure was –0.003, 0.018, –0.003, 0.001 and
0.009, respectively. Number needed to treat/harm for each ex-
posure compared with bDMARD non-exposure is shown in
Table 2. As the observation duration of ixekizumab exposure
was too short (14.5 person-years), ixekizumab exposure was
not included in the subsequent analyses.
Risk of incident AAU across different bDMARDs
Table 3 presents the HRs for incident AAU according to
bDMARD exposure. Adalimumab exposure [adjusted HR
(aHR) 0.674, 95% CI 0.581–0.891] and golimumab expo-
sure (aHR 0.771, 95% CI 0.620–0.959) were associated with
a lower risk of incident AAU than bDMARD non-exposure.
Conversely, etanercept exposure (aHR 1.760, 95% CI 1.540–
2.012) was associated with a higher risk of incident AAU
Figure 1. Summary of the study cohort and exposures. TNFis: TNF inhibitors; IL-17is: IL-17 inhibitors
than bDMARD non-exposure. Infliximab and secukinumab
exposures showed no differences with respect to the risk of in-
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cident AAU compared with bDMARD non-exposure.
When compared with adalimumab exposure, etanercept ex-
posure (aHR 2.553, 95% CI 2.114–3.083), infliximab expo-
sure (aHR 1.303, 95% CI 1.039–1.634) and secukinumab
exposure (aHR 2.173, 95% CI 1.273–3.710) were associated
with a higher risk of incident AAU. No difference in the risk
of incident AAU was observed between golimumab and adali-
mumab exposures (Table 3).
Risk of recurrent AAU across different bDMARDs
Table 4 presents the HRs for recurrent AAU according to
bDMARD exposure. Adalimumab exposure (aHR 0.798,
95% CI 0.659–0.968) was associated with a lower risk of re-
current AAU than bDMARD non-exposure, whereas etaner-
cept exposure (aHR 1.416, 95% CI 1.185–1.693) was
associated with a higher risk of recurrent AAU. Golimumab,
infliximab and secukinumab exposures showed no significant
differences in terms of the risk of recurrent AAU compared
with bDMARD non-exposure,
When compared with adalimumab exposure, etanercept ex-
posure (aHR 1.793, 95% CI 1.430–2.292) was associated
with a higher risk of recurrent AAU. Golimumab, infliximab
and secukinumab exposures did not pose a higher or lower
risk of recurrent AAU compared with adalimumab exposure
(Table 4).
Biologicals and AAU risk in AS 5

Sensitivity analyses Discussion

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In the sensitivity analysis (Table 5), the comparative risk of The present nationwide cohort study revealed that, when
first-line bDMARDs on incident and recurrent AAU was simi- compared with bDMARD non-exposure, adalimumab expo-
lar to that observed in the main analysis. The comparative sure was associated with a lower risk of incident and recur-
risk of second-line bDMARDs also revealed similar results to rent AAU; conversely, etanercept exposure was associated
the main analysis, except that infliximab exposure (aHR with a higher risk of incident and recurrent AAU. Compared
0.275, 95% CI 0.103–0.734) was significantly associated with bDMARD non-exposure, golimumab exposure was as-
with a lower risk of incident AAU compared with bDMARD sociated with a lower risk of incident AAU but not recurrent
non-exposure, and that adalimumab exposure (aHR 0.971, AAU, whereas infliximab and secukinumab exposures
95% CI 0.766–1.230) was not significantly associated with a showed no differences with respect to the risk of incident and
lower risk of recurrent AAU compared with bDMARD non- recurrent AAU. With adalimumab exposure as a comparator,
exposure. etanercept exposure was found to be associated with a higher
risk of incident and recurrent AAU; however, the risk of inci-
dent and recurrent AAU did not differ with golimumab expo-
sure. Compared with adalimumab exposure, infliximab and
Table 1. Characteristics of the study population secukinumab exposures were associated with a higher risk of
incident AAU but not recurrent AAU. Our study results are of
N ¼ 34 621
value, as the present study provides comprehensive data on
Demographics the comparative risk of incident and recurrent AAU sepa-
Age, years, mean 6 S.D. 41.2 6 17.2 rately, across different bDMARDs.
Male, n (%) 24 452 (70.6) The absolute incidence rates of AAU during bDMARD ex-
Comorbidities, n (%) posure (adalimumab, 1.38 per 100 person-years; etanercept,
IBD 1036 (3.0)
3.46 per 100 person-years; golimumab, 1.39 per 100 person-
Psoriasis 2130 (6.2)
Medications, n (%) years; infliximab, 1.82 per 100 person-years; and secukinu-
MTX 5452 (15.8) mab, 2.59 per 100 person-years) were relatively lower than
SSZ 19 463 (56.2) those reported by a previous study (adalimumab, 4.0 per 100
Glucocorticoids 28 270 (81.7) person-years; etanercept, 7.5 per 100 person-years; golimu-
Non-selective NSAIDs 31 668 (91.5) mab, 6.8 per 100 person-years; infliximab, 2.9 per 100
Selective COX-2 inhibitors 17 870 (51.6)
person-years; and secukinumab, 6.8 per 100 person-years)
COX-2: cyclooxygenase-2. [16]. The present study exclusively included patients without

Table 2. Incidence rates of AAU

Events Person-years Incidence rate per Risk difference Number needed

100 person-years (95% CI) to treat/harm

Non-exposure 2301 137 236.3 1.68 (1.61–1.74) Ref. Ref.

Adalimumab 197 14 256.9 1.38 (1.19–1.57) –0.003 339.12a
Etanercept 245 7085.7 3.46 (3.03–3.88) 0.018 56.15b
Golimumab 85 6133.6 1.39 (1.09–1.68) –0.003 343.80a
Infliximab 122 6710.7 1.82 (1.50–2.14) 0.001 707.62b
Secukinumab 15 578.2 2.59 (1.30–3.89) 0.009 108.98b
Ixekizumab 0 14.5 0.00 (0.00–0.00)
a
Number needed to treat.
b
Number needed to harm. AAU: acute anterior uveitis.

Table 3. Risk of incident AAU according to bDMARDs exposure

Univariable model Multivariable model

Crude HR (95% CI) P Adjusted HRa (95% CI) P

bDMARDs non-exposure vs
Adalimumab 0.829 (0.716–0.958) 0.011 0.674 (0.581–0.891) <0.001
Etanercept 2.064 (1.809–2.354) <0.001 1.76 (1.54–2.012) <0.001
Golimumab 0.86 (0.692–1.068) 0.173 0.771 (0.62–0.959) 0.019
Infliximab 1.081 (0.901–1.297) 0.400 0.891 (0.741–1.071) 0.218
Secukinumab 1.657 (0.995–2.757) 0.052 1.324 (0.794–2.209) 0.282
Adalimumab vs
Etanercept 2.5 (2.072–3.016) <0.0001 2.553 (2.114–3.083) <0.001
Golimumab 1.022 (0.791–1.321) 0.8682 1.084 (0.837–1.404) 0.541
Infliximab 1.301 (1.038–1.631) 0.0225 1.303 (1.039–1.634) 0.022
Secukinumab 2.077 (1.221–3.534) 0.007 2.173 (1.273–3.71) 0.005
a
Adjusted for age, sex, IBD, psoriasis, MTX, SSZ, glucocorticoids, non-selective NSAIDs and selective cyclooxygenase-2 inhibitors. AAU: acute anterior
uveitis; bDMARDs: biological DMARDs; HR: hazard ratio.
6 Oh Chan Kwon et al.
Table 4. Risk of recurrent AAU according to bDMARDs exposure
Univariable model
Crude HR (95% CI)
bDMARDs non-exposure vs
Adalimumab 0.815 (0.674–0.986)
Etanercept 1.429 (1.198–1.705)
Golimumab 0.879 (0.649–1.191)
Infliximab 0.945 (0.745–1.200)
Secukinumab 1.276 (0.682–2.386)
Adalimumab vs
Etanercept 1.730 (1.356–2.209)
Golimumab 1.078 (0.761–1.527)
Infliximab 1.141 (0.852–1.527)
Secukinumab 1.625 (0.845–3.125)
a
Adjusted for age, sex, IBD, psoriasis, MTX, SSZ, glucocorticoids, non-selective NSAIDs and selective cyclooxygenase-2 inhibitors. AAU: acute anterior
uveitis; bDMARDs: biological DMARDs; HR: hazard ratio.
a previous history of AAU, whereas the previous study in-
cluded patients irrespective of a previous history of AAU [16].
A previous history of AAU is associated with a higher risk of
AAU occurrence [21]. As all patients included in our study
were AAU-naı̈ve, this might have contributed to the relatively
lower incidence rate of AAU in our study. This difference
highlights the importance of analysing incident and recurrent
AAU separately instead of assessing both together as overall
AAU. Our study has strength in that we separately analysed
incident and recurrent AAU. In addition, we exclusively in-
cluded patients with AS. The prevalence of AAU differs
among different subtypes of SpA [2, 22, 23]; hence, the homo-
geneous population could also be another strength of our
study.
Similar to studies on the overall incidence of AAU [8, 10,
13], we found that adalimumab and golimumab exposures
were associated with a lower risk of incident AAU, whereas
etanercept exposure was associated with a higher risk of inci-
dent AAU. On the other hand, we observed different results
with respect to the effect of infliximab on incident AAU com-
pared with those of previous studies on the overall incidence
of AAU [11]. In our study, although infliximab exposure
showed a trend towards a lower risk of incident AAU (aHR
0.891, 95% CI 0.741–1.071) compared with bDMARD non-
exposure, statistical significance was not achieved. Moreover,
when compared with adalimumab exposure, infliximab expo-
sure was associated with a 30% higher risk of incident AAU
(aHR 1.303, 95% CI 1.039–1.634). There is some evidence in-
dicating that adalimumab is more effective than infliximab in
improving non-infectious uveitis [24, 25], which supports our
finding. A multicentre study comparing the efficacy of adali-
mumab and infliximab for uveitis in patients with Behçet’s dis-
ease showed that adalimumab was more efficacious in
improving vitritis and best-corrected visual acuity than inflixi-
mab [24]. Moreover, a meta-analysis comparing the efficacy
of adalimumab and infliximab for non-infectious uveitis
revealed that adalimumab was more efficacious than inflixi-
mab in improving central macular thickness and best-
corrected visual acuity [25]. Although the underlying mecha-
nism for the more favourable effect of adalimumab than inflix-
imab on non-infectious uveitis is currently unclear, our finding
adds to the previous evidence that adalimumab is more effec-
tive than infliximab in lowering the risk of incident AAU in
patients with AS without a previous history of AAU as well.
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Multivariable model
P Adjusted HRa (95% CI) P
0.036 0.798 (0.659–0.968) 0.022
<0.001 1.416 (1.185–1.693) <0.001
0.406 0.874 (0.645–1.185) 0.385
0.644 0.926 (0.729–1.177) 0.531
0.445 1.257 (0.670–2.359) 0.476
<0.0001 1.793 (1.403–2.292) <0.001
0.6739 1.081 (0.762–1.533) 0.663
0.3774 1.169 (0.871–1.570) 0.297
0.146 1.659 (0.857–3.214) 0.133
A comparative analysis using Swedish registry data
reported an 2-fold higher risk of AAU with secukinumab
than with adalimumab (aHR 2.32, 95% CI 1.16–4.63) [16].
We also found that secukinumab exposure was associated
with an 2-fold higher risk of incident AAU than adalimu-
mab exposure (aHR 2.173, 95% CI 1.273–3.710). In addi-
tion, we compared secukinumab exposure vs bDMARD non-
exposure, which was not assessed in the previous study [16],
and found that secukinumab exposure was not associated
with a higher risk of incident AAU than bDMARD non-
exposure (aHR 1.324, 95% CI 0.794–2.209). This indicates
that although secukinumab is disadvantageous compared
with adalimumab with regard to the prevention of incident
AAU, secukinumab itself does not increase the risk of incident
AAU and has a neutral effect on incident AAU. This is in con-
trast to etanercept, which was associated with a higher risk of
incident AAU when compared not only with adalimumab ex-
posure (aHR 2.553, 95% CI 2.114–3.083) but also with
bDMARD non-exposure (aHR 1.760, 95% CI 1.540–2.012).
This suggests that etanercept itself can increase the risk of in-
cident AAU. Although the exact biologic explanation for this
observation is unclear, possible paradoxical induction of
AAU by etanercept has been suggested previously [26]. Taken
together, from the perspective of preventing incident AAU in
patients with AS without a previous history of AAU, our
results suggest preference for bDMARDs in the following or-
der: (i) adalimumab or golimumab, (ii) infliximab, (iii) secuki-
numab and (iv) etanercept.
The effect of each bDMARD exposure compared with
bDMARD non-exposure was attenuated in the analysis
assessing the comparative risk of recurrent AAU across differ-
ent bDMARDs from in the analysis assessing the comparative
risk of incident AAU. Previous history of AAU is strongly as-
sociated with higher risk of AAU onward [21], which could
be a possible explanation for the attenuated effect of each
bDMARD on risk of recurrent AAU than on risk of incident
AAU. That is, in the setting of recurrent AAU, the medications
may have less impact because the risk of AAU is inherently
high. Nonetheless, the favourable effect of adalimumab expo-
sure (aHR 0.674, 95% CI 0.581–0.891 for incident AAU;
and aHR 0.798, 95% CI 0.659–0.968 for recurrent AAU)
and unfavourable effect of etanercept exposure (aHR 1.760,
95% CI 1.540–2.012 for incident AAU; and aHR 1.416,
95% CI 1.185–1.693 for recurrent AAU) compared with
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Biologicals and AAU risk in AS
Table 5. Sensitivity analysis: comparative risk of first-line and second-line bDMARDs exposure on incident and recurrent AAU

Risk of incident AAU Risk of recurrent AAU

Univariable model Multivariable model Univariable model Multivariable model

a
Crude HR (95% CI) P Adjusted HR (95% CI) P Crude HR (95% CI) P Adjusted HRa (95% CI) P

First-line therapy
bDMARDs non-exposure vs
Adalimumab 0.760 (0.650–0.889) <0.001 0.565 (0.482–0.663) <0.001 0.825 (0.675–1.009) 0.061 0.796 (0.650–0.976) 0.028
Etanercept 1.831 (1.584–2.116) <0.001 1.423 (1.228–1.650) <0.001 1.495 (1.250–1.787) <0.001 1.463 (1.221–1.753) <0.001
Golimumab 0.731 (0.580–0.921) 0.008 0.622 (0.493–0.784) <0.001 0.790 (0.580–1.077) 0.136 0.778 (0.571–1.062) 0.114
Infliximab 1.048 (0.870–1.263) 0.618 0.787 (0.651–0.950) 0.013 1.031 (0.806–1.319) 0.805 0.994 (0.776–1.274) 0.963
Adalimumab vs
Etanercept 2.419 (1.972–2.968) <0.001 2.444 (1.990–3.001) <0.001 1.805 (1.401–2.325) <0.001 1.823 (1.413–2.351) <0.001
Golimumab 0.966 (0.736–1.269) 0.806 1.010 (0.767–1.330) 0.944 0.955 (0.668–1.366) 0.801 0.953 (0.666–1.366) 0.795
Infliximab 1.361 (1.075–1.723) 0.011 1.350 (1.066–1.710) 0.013 1.261 (0.930–1.710) 0.135 1.262 (0.928–1.715) 0.137
Second-line therapy
bDMARDs non-exposure vs
Adalimumab 0.719 (0.468–1.106) 0.134 0.465 (0.302–0.717) <0.001 1.006 (0.797–1.272) 0.957 0.971 (0.766–1.230) 0.806
Etanercept 2.123 (1.488–3.029) <0.001 1.472 (1.029–2.105) 0.034 1.478 (1.224–1.785) <0.001 1.439 (1.188–1.742) <0.001
Golimumab 1.083 (0.581–2.017) 0.802 0.737 (0.395–1.374) 0.337 0.952 (0.669–1.855) 0.785 0.905 (0.635–1.289) 0.581
Infliximab 0.426 (0.160–1.135) 0.088 0.275 (0.103–0.734) 0.010 1.004 (0.757–1.331) 0.977 0.953 (0.717–1.268) 0.743
Secukinumab 1.325 (0.751–2.340) 0.332 0.923 (0.521–1.634) 0.783 1.211 (0.542–2.705) 0.640 1.128 (0.503–2.530) 0.771
Adalimumab vs
Etanercept 2.977 (1.710–5.182) <0.001 3.123 (1.788–5.454) <0.001 1.454 (1.092–1.937) 0.010 1.470 (1.100–1.964) 0.009
Golimumab 1.524 (0.717–3.243) 0.274 1.578 (0.740–3.364) 0.238 0.933 (0.617–1.411) 0.741 0.910 (0.600–1.380) 0.658
Infliximab 0.593 (0.203–1.731) 0.339 0.593 (0.203–1.739) 0.341 0.997 (0.699–1.421) 0.986 0.988 (0.691–1.413) 0.949
Secukinumab 1.891 (0.922–3.878) 0.082 2.139 (1.027–4.454) 0.042 1.145 (0.498–2.636) 0.750 1.001 (0.428–2.341) 0.998
a
Adjusted for age, sex, IBD, psoriasis, MTX, SSZ, glucocorticoids, non-selective NSAIDs and selective cyclooxygenase-2 inhibitors. AAU: acute anterior uveitis; bDMARDs: biological DMARDs; HR: hazard
ratio.

7
8 Oh Chan Kwon et al.
bDMARD non-exposure remained statistically significant.
On the other hand, the favourable effect of golimumab expo-
sure compared with bDMARD non-exposure lost statistical
significance (aHR 0.771, 95% CI 0.620–0.959 for incident
AAU; and aHR 0.874, 95% CI 0.645–1.185 for recurrent
AAU). As in the analysis on risk of incident AAU, infliximab
exposure (aHR 0.891, 95% CI 0.741–1.071 for incident
AAU; and aHR 0.926, 95% CI 0.729–1.177 for recurrent
AAU) and secukinumab exposure (aHR 1.324, 95% CI
0.794–2.209 for incident AAU; and aHR 1.257, 95% CI
0.670–2.359 for recurrent AAU) consistently showed no dif-
ference in risk of recurrent AAU compared with bDMARD
non-exposure. When adalimumab exposure was used as the
comparator, etanercept exposure (aHR 1.793, 95% CI
1.403–2.292) was associated with a higher risk of recurrent
AAU, while no other bDMARDs showed any difference in
risk of recurrent AAU. Collectively, with regard to preventing
recurrent AAU, our data indicate preference for bDMARDs
in the following order: (i) adalimumab, (ii) golimumab, inflix-
imab or secukinumab and (iii) etanercept.
In the sensitivity analysis assessing comparative risk of
second-line bDMARDs, there were some minor differences in
statistical significance compared with the main analysis. That
is, compared with the main analysis, the association between
infliximab exposure (vs bDMARDs non-exposure) and a
lower risk of incident AAU gained statistical significance, and
the association between adalimumab exposure (vs bDMARD
non-exposure) and a lower risk of recurrent AAU lost statisti-
cal significance. Nevertheless, the sensitivity analysis and the
main analysis are consistent in that they both showed trends
toward lower risk (i.e. aHR < 1) of incident AAU with inflixi-
mab exposure (vs bDMARDs non-exposure), and trends to-
ward lower risk of recurrent AAU with adalimumab exposure
(vs bDMARD non-exposure). Moreover, the sensitivity analy-
sis assessing comparative risk of first-line bDMARDs showed
the same results as the main analysis. Therefore, the similar
results of the sensitivity analyses to that of the main analysis
add robustness to our findings.
This study has some limitations that should be noted. First,
although we adjusted for covariates that could affect the
choice of bDMARDs such as IBD and psoriasis [4, 5] in the
multivariable model and performed sensitivity analyses, this
was a retrospective study and confounding by indication
could not be fully excluded. Second, as this was a study using
a claims database, data on detailed disease features of AS,
such as presence of peripheral symptoms of SpA, are not
available. Third, the IL-17is exposure duration was relatively
short. In particular, ixekizumab exposure was only 14.5
person-years, and due to the short exposure duration, ixekizu-
mab was not included in the analysis of comparative risk with
other bDMARDs. Fourth, data on local treatment of AAU
were lacking. The local treatment of AAU could have an im-
pact on AAU recurrence. However, as we applied an interval
of at least 3 months from the first episode in defining the re-
current AAU episode, we presume that the impact of local
treatment of AAU on the AAU recurrence is likely not large.
Fifth, this study included only Korean patients, thereby limit-
ing the generalizability of our results to other ethnic popula-
tions. Further studies with longer IL-17is exposure duration
and various ethnic populations should be conducted.
In conclusion, adalimumab exerted a protective effect
against incident and recurrent AAU, whereas etanercept had
an unfavourable effect on the prevention of incident and
recurrent AAU in patients with AS. Golimumab had a protec-
tive effect against incident AAU and a neutral effect on recur-
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rent AAU. Infliximab and secukinumab had a neutral effect
on incident and recurrent AAU. Compared with adalimumab,
etanercept was associated with a higher risk of incident and
recurrent AAU, and infliximab and secukinumab were associ-
ated with a higher risk of incident AAU, but not recurrent
AAU. Our data provide valuable information on the compar-
ative risk of incident and recurrent AAU across different
bDMARDs, which needs further validation in prospective
studies.
Data availability
The data underlying this article are available in the article.
Funding
The authors declare no funding.
Disclosure statement: The authors declare no conflicts of
interest.
References
1. Stolwijk C, van Tubergen A, Castillo-Ortiz JD, Boonen A.
Prevalence of extra-articular manifestations in patients with anky-
losing spondylitis: a systematic review and meta-analysis. Ann
Rheum Dis 2015;74:65–73.
2. de Winter JJ, van Mens LJ, van der Heijde D, Landewé R, Baeten
DL. Prevalence of peripheral and extra-articular disease in ankylos-
ing spondylitis versus non-radiographic axial spondyloarthritis: a
meta-analysis. Arthritis Res Ther 2016;18:196.
3. Cantini F, Nannini C, Cassarà E, Kaloudi O, Niccoli L. Uveitis in
spondyloarthritis: an overview. J Rheumatol Suppl 2015;93:27–9.
4. Ward MM, Deodhar A, Gensler LS et al. 2019 update of the
American college of rheumatology/Spondylitis association of
America/Spondyloarthritis research and treatment network recom-
mendations for the treatment of ankylosing spondylitis and nonra-
diographic axial spondyloarthritis. Arthritis Rheumatol 2019;71:
1599–613.
5. Ramiro S, Nikiphorou E, Sepriano A et al. ASAS-EULAR recom-
mendations for the management of axial spondyloarthritis: 2022
update. Ann Rheum Dis 2023;82:19–34.
6. Inman RD. Axial spondyloarthritis: current advances, future chal-
lenges. J Rheum Dis 2021;28:55–9.
7. Maxwell LJ, Zochling J, Boonen A et al. TNF-alpha inhibitors for
ankylosing spondylitis. Cochrane Database Syst Rev 2015;
CD005468. doi: 10.1002/14651858.CD005468.pub2.
8. van Denderen JC, Visman IM, Nurmohamed MT, Suttorp-
Schulten MS, van der Horst-Bruinsma IE. Adalimumab signifi-
cantly reduces the recurrence rate of anterior uveitis in patients
with ankylosing spondylitis. J Rheumatol 2014;41:1843–8.
9. van der Horst-Bruinsma I, van Bentum R, Verbraak FD et al. The
impact of certolizumab pegol treatment on the incidence of anterior
uveitis flares in patients with axial spondyloarthritis: 48-week in-
terim results from C-VIEW. RMD Open 2020;6:e001161.
10. van Bentum RE, Heslinga SC, Nurmohamed MT et al. Reduced oc-
currence rate of acute anterior uveitis in ankylosing spondylitis
treated with golimumab—The GO-EASY Study. J Rheumatol
2019;46:153–9.
11. Braun J, Baraliakos X, Listing J, Sieper J. Decreased incidence of
anterior uveitis in patients with ankylosing spondylitis treated with
the anti-tumor necrosis factor agents infliximab and etanercept.
Arthritis Rheum 2005;52:2447–51.
Biologicals and AAU risk in AS
12. Sieper J, Koenig A, Baumgartner S et al. Analysis of uveitis rates
across all etanercept ankylosing spondylitis clinical trials. Ann
Rheum Dis 2010;69:226–9.
13. Lie E, Lindström U, Zverkova-Sandström T et al. Tumour necrosis
factor inhibitor treatment and occurrence of anterior uveitis in an-
kylosing spondylitis: results from the Swedish biologics register.
Ann Rheum Dis 2017;76:1515–21.
14. Baeten D, Sieper J, Braun J et al.; MEASURE 2 Study Group.
Secukinumab, an interleukin-17A inhibitor, in ankylosing spondy-
litis. N Engl J Med 2015;373:2534–48.
15. Deodhar A, Poddubnyy D, Pacheco-Tena C et al.; COAST-W
Study Group. Efficacy and safety of ixekizumab in the treatment of
radiographic axial spondyloarthritis: sixteen-week results from a
phase III randomized, double-blind, placebo-controlled trial in
patients with prior inadequate response to or intolerance of tumor
necrosis factor inhibitors. Arthritis Rheumatol 2019;71:599–611.
16. Lindström U, Bengtsson K, Olofsson T et al. Anterior uveitis in
patients with spondyloarthritis treated with secukinumab or tu-
mour necrosis factor inhibitors in routine care: does the choice of
biological therapy matter? Ann Rheum Dis 2021;80:1445–52.
17. Roche D, Badard M, Boyer L, Lafforgue P, Pham T. Incidence of
anterior uveitis in patients with axial spondyloarthritis treated with
anti-TNF or anti-IL17A: a systematic review, a pairwise and net-
work meta-analysis of randomized controlled trials. Arthritis Res
Ther 2021;23:192.
18. Kim JA, Yoon S, Kim LY, Kim DS. Towards Actualizing the Value
Potential of Korea Health Insurance Review and Assessment
(HIRA) Data as a Resource for Health Research: strengths,
Limitations, Applications, and Strategies for Optimal Use of HIRA
Data. J Korean Med Sci 2017;32:718–28.
9
19. Kwon OC, Han K, Chun J, Gastroenterology, Neurology and
Rheumatology National Data Science Research (GUARANTEE)
Downloaded from https://academic.oup.com/rheumatology/advance-article/doi/10.1093/rheumatology/keae003/7577851 by Fundacion Espanola de Reumatologia user on 25 April 2024
Group et al. Effects of immune-mediated inflammatory diseases on
cardiovascular diseases in patients with type 2 diabetes: a nation-
wide population-based study. Sci Rep 2022;12:11548.
20. Jabs DA, Nussenblatt RB, Rosenbaum JT, Standardization of
Uveitis Nomenclature (SUN) Working GroupStandardization of
uveitis nomenclature for reporting clinical data. Results of the First
International Workshop. Am J Ophthalmol 2005;140:509–16.
21. Khoury G, Morel J, Combe B, Lukas C. Occurrence of anterior
uveitis in patients with spondyloarthritis treated with tumor necro-
sis factor inhibitors: comparing the soluble receptor to monoclonal
antibodies in a large observational cohort. Arthritis Res Ther 2020;
22:94.
22. Zeboulon N, Dougados M, Gossec L. Prevalence and characteris-
tics of uveitis in the spondyloarthropathies: a systematic literature
review. Ann Rheum Dis 2008;67:955–9.
23. Rademacher J, Poddubnyy D, Pleyer U. Uveitis in spondyloarthri-
tis. Ther Adv Musculoskelet Dis 2020;12:1759720x20951733.
24. Atienza-Mateo B, Martın-Varillas JL, Calvo-Rıo V et al.
Comparative Study of Infliximab Versus Adalimumab in
Refractory Uveitis due to Behçet’s Disease: national Multicenter
Study of 177 Cases. Arthritis Rheumatol 2019;71:2081–9.
25. Tai F, Mehraban Far P, Pechlivanoglou P et al. Efficacy and safety
of adalimumab and infliximab for noninfectious uveitis.
Ophthalmology 2022;129:357–9.
26. Wendling D, Joshi A, Reilly P et al. Comparing the risk of develop-
ing uveitis in patients initiating anti-tumor necrosis factor therapy
for ankylosing spondylitis: an analysis of a large US claims data-
base. Curr Med Res Opin 2014;30:2515–21.