https://doi.org/10.53453/ms.2026.7.6
Ocular surface disease in patients with atopic dermatitis treated
with dupilumab: a systematic review and meta-analysis
Mikeila Jazbutytė
1
, Tadas Raudonis²
1
Faculty of Medicine, Medical Academy, Lithuanian University of Health Sciences, Kaunas, Lithuania
²Department of Skin and Venereal Diseases, Vilnius University Hospital Santaros Klinikos, Vilnius, Lithuania
Abstract
Background. Dupilumab has significantly improved outcomes in patients with moderate-to-severe atopic
dermatitis (AD). However, ocular surface disease (OSD), particularly conjunctivitis, has emerged as the most
frequently reported adverse event during treatment, with precise risk estimates from randomized controlled trials
(RCTs) remaining limited.
Aims. To evaluate the incidence and relative risk of conjunctivitis in patients with moderate-to-severe AD treated
with dupilumab compared with placebo.
Methods. A systematic literature review was conducted according to PRISMA guidelines. PubMed was searched
from 2016 to 2025. Thirty-five studies met criteria for qualitative synthesis. For quantitative meta-analysis, three
phase III randomized, double-blind, placebo-controlled trials (SOLO-1, SOLO-2, and LIBERTY AD CAFÉ) were
included. A random-effects model with Restricted Maximum Likelihood estimation was applied. Heterogeneity
was assessed using Cochran’s Q and the I² statistic.
Results. The pooled analysis demonstrated a significantly increased risk of conjunctivitis in patients receiving
dupilumab compared with placebo (RR = 2.90, 95% CI 1.33–6.32), with low heterogeneity (I² = 26.6%). Across
trials, ocular events were predominantly mild to moderate and rarely led to permanent treatment discontinuation.
Qualitative synthesis confirmed baseline ocular vulnerability in AD populations and variability in reported
incidence in real-world settings.
Conclusion. Dupilumab treatment is associated with a nearly threefold increased risk of conjunctivitis compared
with placebo. Although most ocular events are manageable, early recognition and ophthalmologic evaluation
remain important.
Keywords: atopic dermatitis, dupilumab, ocular surface disease, conjunctivitis, meta-analysis
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Medical Sciences 2026 Vol. 14 (5), p. 42-53, https://doi.org/10.53453/ms.2026.7.6
42
1. Introduction
Dupilumab, a monoclonal antibody targeting the
interleukin-4 receptor α subunit and inhibiting
IL-4 and IL-13 signaling, has significantly
improved clinical outcomes in patients with
moderate to severe atopic dermatitis (AD),
particularly in disease control, pruritus
reduction, and quality of life. However, ocular
surface disease (OSD), which is intrinsically
associated with AD due to underlying barrier
dysfunction and chronic inflammation, has
emerged as the most frequently reported adverse
effect during dupilumab therapy. Real-world and
prospective studies report OSD in up to 28–37%
of dupilumab-treated adults, most commonly
presenting as conjunctivitis, blepharoconjunc-
tivitis, or dry eye disease, typically within the
first 6 – 10 weeks of treatment and more
frequently than in non-dupilumab-treated
patients [1–4]. Although the majority of cases
are mild to moderate and manageable with
topical therapy, rare vision-threatening complic-
ations have been described [5]. Despite
increasing clinical awareness, reported incidence
rates vary substantially across studies, and
differences in study design and outcome
reporting limit precise risk estimation in AD
populations. A focused quantitative synthesis of
randomized controlled trial data is therefore
warranted. The aim of this study was to evaluate
the incidence and relative risk of conjunctivitis
and ocular surface disease in patients with
moderate-to-severe AD treated with dupilumab
compared with placebo.
2. Methods
2.1. Study design for systematic literature
review
A systematic literature review was conducted in
accordance with the Preferred Reporting Items
for Systematic Reviews and Meta-Analyses
(PRISMA) statement. The objective was to
evaluate the incidence and relative risk (RR) of
conjunctivitis and ocular surface disease (OSD)
in patients with moderate-to-severe atopic
dermatitis (AD) treated with dupilumab.
Eligibility criteria were defined using the PICOS
framework (Population, Intervention,
Comparator, Outcomes, Study design). The
predefined search period covered publications
from December 2016 to March 2025.
2.2. Search strategy for systematic literature
review
A systematic electronic search was performed in
PubMed using controlled vocabulary (MeSH
terms) and free-text keywords related to atopic
dermatitis, dupilumab, conjunctivitis, and ocular
surface disease. Only English-language full-text
publications were considered. Reference lists of
relevant reviews and eligible studies were
manually screened to identify additional studies.
2.3. Study selection of qualitative synthesis
for systematic literature review
After removal of duplicates, titles and abstracts
were screened. Full-text articles were assessed
against predefined inclusion and exclusion
criteria (Tables 1 and 2). A total of 35 studies met
eligibility criteria and underwent structured
qualitative synthesis for systematic literature
review. These studies were analyzed to
characterize baseline ocular vulnerability in AD,
report OSD incidence ranges, describe clinical
phenotypes, and outline management
approaches across different study designs and
clinical settings.
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Table 1. Identification of studies via databases and registers for qualitative synthesis
Records identified from:
Databases n = 744
Registers n = 0
Records removed before
screening:
Duplicate records removed n
= 186
Records marked as ineligible
by automation tools n = 0
Records removed for other
reasons n = 0
Records screened
n = 558
Records excluded (title/abstract)
n = 471
Reports sought for retrieval
n = 87
Reports not retrieved
n = 4
Reports assessed for eligibility
n = 83
Reports excluded:
Not AD population specific: n
= 18
No extractable ocular
outcome data: n = 14
Non-
randomized/inappropriate
design: n = 9
Review/editorial/case report
only: n = 7
Studies included in review
n = 35
Reports of included studies
n = 35
Identification
Screening
Included
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Table 2. Inclusion and exclusion criteria
Category
Inclusion criteria
Exclusion criteria
Population
• Adolescents or adults with moderate-to-severe
atopic dermatitis (AD)
• Patients treated for AD indication
• Non-AD indications (e.g., asthma)
• Mild AD only
• Animal or preclinical studies
Intervention
• Dupilumab administered according to approved
dosing regimens
• Studies without dupilumab exposure
Comparators
• Placebo (with or without background topical
corticosteroids)
• Any comparator (for qualitative synthesis)
• Studies without a comparator arm
(for meta-analysis eligibility)
Outcomes
• Reported incidence of conjunctivitis
• Ocular surface disease (OSD)
• Keratitis or ocular adverse events
• No extractable ocular safety data
• Outcomes not reported separately for
dupilumab
Study
designs
• Phase III randomized, double-blind, placebo-
controlled trials (for quantitative synthesis)
• Observational and real-world studies (for
qualitative synthesis)
• Case reports or small case series
• Editorials, narrative reviews, letters,
opinions
Timeframe
• Publications from December 2016 to March 2025
• Publications outside predefined
timeframe
Language
• English, full-text available
• Non-English full-text unavailable
Abbreviations: AD: atopic dermatitis; OSD: ocular surface disease; RCT: randomized controlled trial.
2.4. Study selection for quantitative meta-
analysis
A predefined quantitative meta-analysis was
restricted to randomized, double-blind, placebo-
controlled phase III trials that met strict
comparability criteria, including:
placebo comparator
extractable conjunctivitis event data
comparable study duration and outcome
definitions.
Three randomized controlled trials (SOLO-1,
SOLO-2, and LIBERTY AD CAFÉ) fulfilled
these criteria and were included in the
quantitative meta-analysis. The restriction of
quantitative pooling to phase III randomized
trials was predefined to ensure methodological
comparability and minimize clinical and design
heterogeneity.
2.5. Data Extraction for quantitative meta-
analysis
Data were extracted using a predefined structu-
red template and independently verified to
ensure accuracy. Extracted variables included
study design, population characteristics,
dupilumab dosing regimen, comparator details,
and reported ocular outcomes.
For randomized controlled trials included in the
meta-analysis, absolute event counts for
conjuncttivitis in dupilumab and placebo arms
were extracted to calculate risk ratios. For the
remaining studies, reported incidence rates and
effect estimates were recorded for qualitative
synthesis.
2.6. Risk of bias assessment for quantitative
meta-analysis
The risk of bias of randomized controlled trials
included in the meta-analysis was assessed using
the Cochrane Risk of Bias 2 (RoB 2) tool. The
following domains were evaluated: randomi-
zation process, deviations from intended
interventions, missing outcome data, measure-
ment of outcomes, and selective reporting.
Each domain was categorized as low risk, some
concerns, or high risk of bias. Risk-of-bias
assessment was performed, and discrepancies
were resolved (Table 3).
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Table 3. Risk of bias assessment of included randomized controlled trials
Study
Randomization
Deviations
Missing
data
Outcome
measurement
Reporting
Overall
SOLO-1
Low
Low
Low
Low
Low
Low
SOLO-2
Low
Low
Low
Low
Low
Low
LIBERTY
AD CAFÉ
Low
Low
Low
Low
Low
Low
2.7. Quantitative synthesis
Meta-analysis was performed to estimate the
relative risk (RR) of conjunctivitis in dupilumab-
treated patients compared with placebo.
Effect sizes were calculated on the logarithmic
risk ratio scale (logRR), with corresponding
standard errors derived from event count data. A
random-effects model was applied to account for
potential clinical and methodological
heterogeneity. Between-study variance was
estimated using the Restricted Maximum
Likelihood (REML) method.
Statistical heterogeneity was assessed using
Cochran’s Q test and quantified using τ, τ², and
the I² statistic. Results were presented as pooled
risk ratios with 95% confidence intervals and
visualized using forest plots.
All statistical analyses were performed in R
(RStudio) using the “metafor” package.
Statistical significance was defined as p < 0.05.
2.8. Additional analysis
Due to the limited number of eligible
randomized trials, subgroup analyses, network
meta-analysis, or indirect comparisons were not
performed.
3. Results
3.1. Study selection
A total of 744 records were identified through
database searching. After removal of duplicates,
558 records were screened. Of these, 471 were
excluded based on title and abstract. Eighty-
seven full-text articles were assessed for
eligibility, and 35 studies met criteria for
qualitative synthesis.
Three phase III randomized controlled trials
(SOLO-1, SOLO-2, and LIBERTY AD CAFÉ)
were included in the quantitative meta-analysis
3.2. Qualitative synthesis
3.2.1 Epidemiology and baseline ocular
burden
Ocular surface disease (OSD) is a recognized
comorbidity of atopic dermatitis (AD),
encompassing conjunctivitis,
blepharoconjunctivitis, dry eye disease, and
keratitis [6]. Epidemiological studies
demonstrate a substantial baseline ocular burden
in AD irrespective of systemic therapy, with
reported lifetime prevalences of conjunctivitis
ranging from approximately 31.7% to 66.6% and
keratitis from 9% to 10% [7,8]. Clinical
manifestations frequently involve eyelid
inflammation and meibomian gland dysfunction,
reflecting a chronic inflammatory ocular
phenotype of AD [9,10].
3.2.2 Pathophysiology of dupilumab-
associated ocular surface disease
Dupilumab-associated ocular surface disease
(DAOSD) likely reflects pre-existing ocular
surface vulnerability in atopic dermatitis,
amplified by IL-4/IL-13 pathway blockade
[11,12]. Functional goblet cell impairment with
reduced mucin secretion contributes to tear-film
instability, while concomitant meibomian gland
dysfunction promotes evaporative dry eye [13].
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In parallel, cytokine inhibition induces a local
immune shift from Th2-dominant inflammation
toward Th1/Th17 pathways, resulting in an
atopic keratoconjunctivitis-like phenotype [14–
16]. Local ocular exposure to dupilumab may
further disrupt epithelial homeostasis [11,17].
Collectively, these mechanisms suggest that
DAOSD represents an immune-mediated
imbalance of the ocular surface rather than a
purely drug-induced adverse event [18,19].
3.2.3 Clinical characteristics, risk factors, and
management of DAOSD
DAOSD most commonly develops within the
first 4–16 weeks of treatment and presents
predominantly as bilateral conjunctivitis,
although keratitis and mixed ocular surface
phenotypes are also described [20,21]. Typical
symptoms include ocular redness, irritation,
pruritus, tearing, burning, dryness, and photo-
phobia. Slit-lamp findings frequently reveal
bulbar hyperemia, papillary reaction, blepharitis
with meibomian gland dysfunction, and
superficial punctate keratitis [9,22]. While most
cases are mild-to-moderate, chronic or relapsing
courses requiring maintenance topical therapy
have been reported, and rare vision-threatening
complications (e.g., cicatricial changes or
corneal involvement) may occur [5].
Identified risk factors include eyelid eczema,
pre-existing dry eye with superficial punctate
keratitis, high baseline IgE levels, asthma, and
facial or head–neck AD involvement [4,5,23].
Baseline ophthalmologic evaluation may impro-
ve early detection in high-risk individuals [24].
Management is typically stepwise and allows
continuation of dupilumab in most cases. Mild
disease can often be controlled with lubricants
and topical anti-allergic therapy, whereas
moderate-to-severe cases may require topical
corticosteroids with gradual tapering and, in
selected cases, topical calcineurin inhibitors
[9,21-22]. Permanent discontinuation of
treatment due to DAOSD remains uncommon,
and most patients maintain dermatologic benefit
with appropriate ocular treatment [4,21].
3.2.4 Clinical trials and real-world evidence
Randomized clinical trials consistently
demonstrate an increased frequency of DAOSD
with dupilumab in AD, with excess risk largely
confined to the AD indication [25]. Phase III
adult and adolescent AD trials demonstrated
higher conjunctivitis rates while maintaining
rapid and sustained improvement in skin disease
and otherwise comparable safety profiles [26–
28]. In adolescents, conjunctivitis was more
frequent with dupilumab (10.3% vs. 4.7%),
typically mild-to-moderate and rarely leading to
discontinuation [29]. Pediatric randomized
studies reported conjunctivitis in 5% of
dupilumab-treated children, compared with none
on placebo [30]. Integrated safety analyses
across eight phase III trials confirmed conjunct-
tivitis as a recurrent ocular event cluster [31].
Real-world data confirms excess risks of
conjunctivitis and keratitis beyond baseline AD-
associated ocular morbidity [3,32]. In a
clinically meaningful minority, these
manifestations may lead to treatment
interruption [2,5,21]. DAOSD remains
frequently under-recognized and managed
heterogeneously, reflecting gaps in risk
stratification, standardized diagnostic criteria,
and coordinated dermatology–ophthalmology
care pathways [13,25,33–35].
3.3 Quantitative synthesis
Three phase III randomized, double-blind,
placebo-controlled trials (SOLO-1, SOLO-2,
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47
and LIBERTY AD CAFÉ) were included in the
quantitative meta-analysis. The studies were
comparable in terms of design, patient
population, and treatment duration (Table 4).
Across all included trials, conjunctivitis events
were more frequently observed in patients
receiving dupilumab than in those receiving
placebo. Although absolute event numbers
varied between studies, the direction of effect
was consistent (Table 5).
The clinical presentation of ocular events was
generally non-severe, with only occasional
moderate cases and rare need for treatment
discontinuation. Most cases were successfully
managed with supportive or topical ophthalmic
therapy, allowing continuation of dupilumab
treatment in most patients (Table 6).
Table 4. Clinical trial characteristics [36,37]
Study
Design /
Duration
Population
Intervention
Comparato
r
Ocular adverse
event reporting
SOLO-1
(2016)
Phase III,
randomized,
placebo-
controlled
trial / 16
weeks
Adults with moderate-
to-severe atopic
dermatitis
Dupilumab 300
mg
subcutaneously,
weekly or every
other week
Placebo
Conjunctivitis
SOLO-2
(2016)
Phase III,
randomized,
double-blind,
placebo-
controlled trial
/ 16 weeks
Adults with moderate-
to-severe atopic
dermatitis
Dupilumab 300
mg
subcutaneously,
weekly or every
other week
Placebo
Conjunctivitis
LIBERT
Y AD
CAFÉ
(2018)
Phase III,
randomized,
double-blind,
placebo-
controlled trial
/ 16 weeks
Adults with moderate-
to-severe atopic
dermatitis with
inadequate response to,
intolerance of, or
contraindication to
ciclosporin A
Dupilumab 300
mg
subcutaneously,
weekly or every
other week, with
topical
corticosteroids
Placebo with
topical
corticosteroi
ds
Conjunctivitis
Table 5. Ocular events used for meta-analysis [36,37]
Study
Follow-up
Dupilumab (n)
Conjunctivitis
events (n)
Placebo (n)
Conjunctivitis
events (n)
SOLO-1
(2016)
16 weeks
447
18
222
2
SOLO-2
(2016)
16 weeks
473
18
234
1
LIBERTY AD
CAFÉ
(2018)
16 weeks
217
48
108
12
Table 6. Ocular phenotype and management reported in phase III trials [36,37]
Study
Ocular Phenotype
Observed
Severity
Management
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SOLO-1
(2016)
Conjunctivitis
(predominantly allergic)
Mostly mild-to-moderate;
occasional moderate
reactions
Treated with supportive ocular
therapy; rare need for treatment
discontinuation
SOLO-2
(2016)
Conjunctivitis
(predominantly allergic)
Mostly mild-to-moderate;
occasional moderate
reactions
Most events managed
conservatively; discontinuation
uncommon
LIBERTY
AD CAFÉ
(2018)
Conjunctivitis, allergic
conjunctivitis; broader eye
disorders reported
Predominantly mild-to-
moderate; severe events
rare
Managed with topical
ophthalmic therapy; permanent
treatment discontinuation
uncommon
The heterogeneity analysis demonstrated low
between-study variability among the included
randomized controlled trials assessing
conjunctivitis risk in dupilumab-treated patients
(Table 7). Cochran’s Q statistic was not
statistically significant (Q = 2.72, p = 0.256),
indicating no evidence of substantial
heterogeneity across studies. Consistently, the I²
value was 26.6%, suggesting that only a small
proportion of the total variability in effect
estimates could be attributed to true differences
between trials rather than random error. The
estimated between-study variance (τ² = 0.154)
further supports acceptable consistency among
the included studies.
Table 7. Heterogeneity statistics for conjunctivitis risk in dupilumab versus placebo trials
Statistic
Value
Cochran’s Q
2.723
Degrees of freedom (df)
2
p-value (Q test)
0.256
I² (%)
26.55
τ² (between-study variance)
0.154
Abbreviations: Q = Cochran’s heterogeneity statistic; df = degrees of freedom; I² = percentage of variability due
to between-study heterogeneity; τ² = between-study variance.
The pooled analysis using a random-effects
model showed a significantly increased risk of
conjunctivitis in patients receiving dupilumab
compared with placebo (RR = 2.90, 95% CI
1.33–6.32), as illustrated in the forest plot
(Figure 1). At the individual-trial level, all
studies demonstrated an increased risk in the
same direction, although the magnitude of the
effect varied. The SOLO-1 and SOLO-2 trials
reported higher relative risks with wide
confidence intervals, reflecting limited
precision, whereas the LIBERTY AD CAFÉ
trial showed a more moderate but statistically
significant increase in conjunctivitis risk.
However, the precision of effect estimates is
influenced by the limited number of
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conjunctivitis events observed in the placebo
arms, resulting in wider confidence intervals in
some trials.
Figure 1. Forest plot of conjunctivitis risk ratios (RR) in dupilumab-treated patients compared with placebo
across randomized clinical trials (SOLO-1, SOLO-2, and LIBERTY AD CAFÉ). The pooled estimate was
calculated using a random-effects model (REML).
4. Discussion
This systematic review and meta-analysis
demonstrate that dupilumab treatment in
moderate-to-severe atopic dermatitis is
associated with a significantly increased risk of
conjunctivitis compared with placebo (RR =
2.90), with low between-study heterogeneity
supporting the consistency of this association.
These findings indicate that ocular surface
disease represents a reproducible safety signal in
AD populations receiving IL-4/IL-13 pathway
blockade.
The restriction of quantitative synthesis to phase
III randomized, double-blind, placebo-
controlled trials was predefined to ensure
methodological comparability and minimize
clinical and design heterogeneity. Although
these trials share similar structures, their
independent conduct and consistent direction of
effect strengthen the robustness of the observed
association.
Baseline ocular surface vulnerability is common
in AD [6–10], and the increased risk observed
with dupilumab likely reflects interaction
between pre-existing inflammatory
susceptibility and targeted cytokine inhibition
[11–16]. Proposed mechanisms include goblet
cell dysfunction, tear film instability, and
immune pathway shifts rather than direct
pharmacologic toxicity [18,19].
In line with our meta-analytic findings, the
inclusion of a representative real-world case
provides contextual insight into the clinical
relevance of dupilumab-associated ocular
surface disease beyond controlled trial settings.
A 28-year-old male presented to our Centre of
Dermatovenereology with a history of
childhood-onset severe atopic dermatitis
refractory to topical therapy, phototherapy,
cyclosporine, and baricitinib, who was initiated
on dupilumab. The dermatologic response was
rapid and clinically meaningful, with the
SCORAD score decreasing from 64.7 to 29.6
(−35.1 points) and the DLQI score improving
from 23 to 14 (−9 points). However, within the
first months of therapy, the patient developed
ocular surface symptoms characterized by
periocular dryness, irritation, and inflammatory
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changes consistent with mild-to-moderate
conjunctivitis. These manifestations were
managed conservatively with topical ophthalmic
therapy without discontinuation of dupilumab,
while the cutaneous response to dupilumab was
maintained. This clinical course mirrors patterns
reported in randomized trials and observational
cohorts, in which ocular surface disease emerges
despite excellent dermatologic control,
reinforcing the concept of a disease–drug
interaction rather than an isolated adverse event.
These findings underscore the importance of
early recognition and interdisciplinary
management of ocular surface symptoms in
dupilumab-treated patients with atopic
dermatitis.
Importantly, most ocular events reported in
phase III trials were mild to moderate and rarely
led to permanent discontinuation of treatment
[29–31]. Early recognition of symptoms, patient
counseling, and timely ophthalmologic
evaluation may allow continuation of effective
systemic therapy while minimizing ocular
morbidity. Strengths of this study include the
restriction to phase III randomized trials and the
low heterogeneity across the pooled estimates.
Limitations include the small number of eligible
RCTs, limited follow-up duration, investigator-
reported ocular outcomes, and restriction to a
single database.
5. Conclusions
Dupilumab treatment in patients with moderate-
to-severe atopic dermatitis is associated with a
significantly increased risk of conjunctivitis
compared with placebo, with a nearly threefold
higher relative risk observed across phase III
randomized trials and low between-study
heterogeneity. Although most ocular events are
mild to moderate and manageable without
treatment discontinuation, ocular surface disease
is a clinically relevant complication that may
affect patient comfort and adherence. These
findings support the concept of a disease–drug
interaction, in which underlying atopic ocular
susceptibility may be amplified by IL-4/IL-13
pathway blockade rather than reflecting isolated
pharmacologic toxicity. Proactive symptom
recognition and timely ophthalmologic
evaluation may help optimize management
while preserving the dermatologic benefits of
dupilumab therapy.
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