Journal of Dermatological Treatment

ISSN: (Print) (Online) Journal homepage: www.tandfonline.com/journals/ijdt20

Adipose-derived stem cell exosomes for treatment

of dupilumab-related facial redness in patients
with atopic dermatitis

Hye Sung Han, Young Gue Koh, Jun Ki Hong, Yoon Jin Roh, Seong Jun Seo &
Kui Young Park

To cite this article: Hye Sung Han, Young Gue Koh, Jun Ki Hong, Yoon Jin Roh, Seong Jun Seo &
Kui Young Park (2023) Adipose-derived stem cell exosomes for treatment of dupilumab-related
facial redness in patients with atopic dermatitis, Journal of Dermatological Treatment, 34:1,
2220444, DOI: 10.1080/09546634.2023.2220444

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Journal of Dermatological Treatment
2023, VOL. 34, NO. 1, 2220444
https://doi.org/10.1080/09546634.2023.2220444

ARTICLE

Adipose-derived stem cell exosomes for treatment of dupilumab-related facial

redness in patients with atopic dermatitis
Hye Sung Hana , Young Gue Kohb , Jun Ki Hongb , Yoon Jin Rohb, Seong Jun Seob and
Kui Young Park b
a
Department of Dermatology, Chung-Ang University Gwangmyeong Hospital, Chung-Ang University College of Medicine, Gwangmyeong-si, Korea;
b
Department of Dermatology, Chung-Ang University College of Medicine, Chung-Ang University Hospital, Seoul, Korea

ABSTRACT ARTICLE HISTORY

Background: Dupilumab facial redness (DFR) is a side effect of dupilumab treatment that has only Received 28 March 2023
been recently reported. We previously reported on two patients with DFR who were successfully Accepted 18 April 2023
treated with a topical formulation containing human adipose tissue-derived mesenchymal stem KEYWORDS
cell-derived exosomes (ASCEs). Atopic dermatitis; dupilumab;
Objectives: The study aimed to evaluate the efficacy and safety of ASCEs in DFR. dupilumab facial redness;
Participants and methods: We performed 12-week prospective study at single center. Twenty adult exosome; filaggrin;
atopic dermatitis patients diagnosed with DFR were enrolled. They were treated with a topical inflammation
application of the exosome formulation every week for five consecutive weeks.
Results: After exosome treatment, both the average investigator global assessment score and clinical
erythema assessment scale scores decreased. 19 patients (95%) were satisfied with the treatment.
Compared to baseline, erythema index at week 4 were decreased by 31, 27, 13, and 25 units on the
forehead, chin, right and left cheek respectively. The analysis of stratum corneum samples revealed
the expression of IL-1α and human thymic stromal lymphopoietin was suppressed after exosome
treatment, whereas filaggrin and vascular endothelial growth factor expression increased.
Conclusions: This study suggests topical formulation containing ASCEs can alleviate DFR by
downregulating local inflammation and restoring skin barrier function.

Introduction cell (MSC)-derived exosomes (ASCEs) (24). In this study, we aimed

to verify the efficacy of an ASCE topical formulation in treating DFR.
Dupilumab facial redness (DFR) is a recently reported side effect
of dupilumab treatment for atopic dermatitis (AD). Although it
was not reported as an adverse event in phase 3 clinical trials, Materials and methods
recent studies reported DFR occurred in approximately 4–10% of Study design and subjects
patients treated with dupilumab (1–7). Erythema on visible areas
including face and neck leads to a profound psychosocial burden This was a 12-week prospective study, approved by the Chung-Ang
and some patients discontinue dupilumab treatment because of University Hospital Institutional Review Board (IRB no. 2109-014-
this adverse event (1). Unfortunately, the etiology and treatment 477). Twenty Korean patients aged 18 and older, who were on
of this condition remain elusive (8,9). dupilumab for AD and were diagnosed with DFR in Chung-Ang
Exosome treatment is a recently developed cell-free therapeutic University Hospital (Seoul), were recruited in the study. The
strategy in regenerative medicine. Because of their small size patients in this manuscript participated in the study voluntarily
(nanosize), biological origin, lipid bilayer membrane, ability to with good compliance and had given written informed consent
communicate intracellularly, and capacity to modulate the molec- to publication of their clinical data and photographs. The treat-
ular activities of the recipient cell, they are attracting significant ment and examination took 30 min to an hour.
interest among dermatologists (10,11). Exosomes from mesenchy-
mal stem cells (MSCs) are highly immunomodulatory and have Exosome treatment
shown therapeutic effects regarding wound healing, prevention
of scar, skin pigmentation, and wrinkles as well as improving We used the exosome formulation ASCE + SRLV-S (ExoCoBio Inc.,
chronic inflammatory skin disorders such as psoriasis, AD, systemic Seoul, Republic of Korea), which contains 20 mg (970,000 ppm) of
lupus erythematosus, or bullous pemphigoid (11–23). Previously, lyophilized human ASCE. Exosomes in this product were acquired
we reported two successful cases of DFR treated with topical from a human adipose-derived stem cell (ASC)-conditioned
application of human adipose tissue-derived mesenchymal stem medium (CM) developed by ExoSCRT TM technology as described

CONTACT Kui Young Park [email protected] Department of Dermatology, College of Medicine, Chung-Ang University Hospital, 102 Heukseok-ro, Dongjak-Gu,
Seoul 06973, Republic of Korea.
Supplemental data for this article can be accessed online at https://doi.org/10.1080/09546634.2023.2220444.
© 2023 The Author(s). Published with license by Taylor & Francis Group, LLC
This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial License (http://creativecommons.org/licenses/by-nc/4.0/), which permits
unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited. The terms on which this article has been published allow
the posting of the Accepted Manuscript in a repository by the author(s) or with their consent.
2 H. S. HAN ET AL.

previously (ExoCoBio Inc., Seoul, Republic of Korea) (24,25). Briefly, performed by nanoparticle tracking analysis. Characterization of
ASC-CM was collected from ASCs cultured in serum-free Dulbecco’s ASCEs used in this study is described in Supplementary Figure 1.
Modified Eagle’s Medium (Thermo Fischer Scientific, Waltham, MA, One vial of ASCE + SRLV-S was applied to each patient’s entire face
USA), and the non-exosomal particles were removed by a 0.2 μm by dermatologists, and prism sonophoresis (Alummedi, Seoul, Korea)
filter. Next, the exosomes were further purified and concentrated was used to ensure effective drug delivery. This topical application of
through tangential-flow filtration, and quantification was exosomes was performed weekly for five consecutive weeks.

Table 1. Rating grade for investigator global assessment score. Clinical evaluation and measurement of skin parameters
Grade Description
Clinical and objective evaluations were performed at baseline and
0, clear No inflammatory signs of atopic dermatitis
1, almost clear Just perceptible erythema, and just perceptible
every week before the ASCE treatment and then at weeks 8 and
papulation/infiltration 12 (four and eight weeks after the final exosome treatment).
2, mild disease Mild erythema and mild papulation/infiltration Clinical photographs were taken using the Mark-Vu® instrument
3, moderate disease Moderate erythema and moderate papulation/infiltration (PSI plus Co. Ltd.) at each visit. The data from an investigator
4, severe disease Severe erythema and severe papulation/infiltration global assessment (IGA, 0–5, Table 1), a clinical erythema assess-
5, very severe Severe erythema and severe papulation/infiltration with
disease oozing /crusting ment scale (CEA, 0–4, Table 2), and subjective satisfaction (1–5,
Table 3) were recorded. Skin erythema, skin hydration, and
Table 2. Rating grade for clinical erythema assessment scale. trans-epidermal water loss (TEWL) were measured using
Mexameter® MX18, Corneometer® CM825, and Tewamater® TM300
Scale Degree of improvement
(Courage & Khazaka GmbH, Cologne, Germany). Measurements
0 = clear Clear skin with no signs of erythema
1 = almost clear Almost clear, slight redness
were taken in accordance with the manufacturer’s guidelines at
2 = mild Definite redness, very light pink, faintly detectable erythema the forehead, chin, right cheek, and left cheek. During the mea-
3 = moderate Marked redness, dull red, clearly distinguishable erythema surements, the room temperature was maintained at a constant
4 = severe Severe erythema, fiery redness, deep, dark red 20–22 °C and a relative humidity range of 40–60%.

Table 3. Rating grade for patient satisfaction.

Analysis of stratum corneum samples
Scale Degree of satisfaction
1 Very unsatisfied At baseline and week 8 (four weeks after final exosome treatment),
2 Unsatisfied stratum corneum samples were collected using tape stripping
3 Fair (skin D-squame), and subsequently analyzed in order to evaluate
4 Satisfied inflammatory cytokines and skin barrier function. Quantitative
5 Very satisfied
analysis of interleukin-1α (IL-1α), human thymic stromal

Figure 1. Clinical outcomes of patients with dupilumab facial redness treated with adipose-derived stem cell exosome. Change in average investigator global
assessment (IGA), clinical erythema assessment (CEA), and patient satisfaction score over time. The average IGA score decreased from week 2 and continued to
decrease until week 12. The average CEA score decreased significantly from the first week after the first exosome treatment. Overall, 19 out of 20 (95%) patients
had a subjective satisfaction score of 4 (satisfied) at least once during the entire clinical trial period. *p < 0.05, **<0.01, ***<0.001, compared with baseline.
 Journal of Dermatological Treatment 3

lymphopoietin (TSLP), filaggrin (FLG), and vascular endothelial groups were considered to significant at a p value of <0.05.
growth factor (VEGF) was performed through real-time-polymerase Statistical analyses were performed with GraphPad Prism 8.0
chain reaction (RT-PCR) and Western blot techniques. The detailed (GraphPad Software, Inc., CA, USA).
experimental method can be found in Supplementary Material 1.
Results
Statistical analysis Investigator global assessment, clinical erythema assessment
scale, and subjective satisfaction score
We compared the resulting metabolic activities of the treatment
groups and controls using one-way analysis of variance (ANOVA) The average IGA score decreased from week 2 and continued to
and Tukey’s multiple-comparison posttest. Differences between decrease until week 12 (Figure 1). Overall, 12 out of 20 (60%)

Figure 2. Representative clinical photographs of patients. Photographs were taken at baseline, at week 2 (after the first treatment), and week 12 (eight weeks
after final the treatment). After exosome treatment, clinical improvements of erythema on the both cheeks, forehead, and chin were noted.
4 H. S. HAN ET AL.

patients achieved an IGA score of 1 (almost clear) at least once hydration and TEWL were also measured at four different anatom-
during the entire clinical trial period. Similarly, the average CEA ical areas. Although the skin hydration increased and TEWL
score decreased from the first week after the first exosome treat- decreased after exosome treatment, the changes were not statis-
ment. A total of 11 out of 20 (55%) patients achieved a CEA score tically significant. (Supplementary Figures 2 and 3)
of 1 at least once during the entire clinical trial period. The aver-
age subject satisfaction score was highest in week 2 and slowly
decreased over time. However, the average score was above 3 Analysis of stratum corneum samples
(fair) at all times. Altogether, 19 out of 20 (95%) patients had a
To determine the effect of ASCE on proinflammatory cytokine
subjective satisfaction score of 4 (satisfied) at least once during
expression and epidermal proteins, we measured IL-1α, VEGF, TSLP,
the entire clinical trial period. Representative photographs of three
and FLG expression at mRNA and protein levels (Figure 4). The
patients at baseline, after the first treatment, and at week 12 are
mRNA expression of IL-1α decreased in SC samples collected at
shown in Figure 2.
week 8 compared with the baseline. By contrast, the mRNA expres-
sion of FLG and VEGF increased increased at week 8 compared
Skin erythema, hydration, and trans-epidermal water loss with the baseline. TSLP was not detected at the mRNA level.
Regarding protein levels, ASCE upregulated FLG expression and
Skin erythema was measured at the forehead, chin, right cheek, downregulated both IL-1α and TSLP.
and left cheek. Erythema index (EI) decreased in all four areas
after exosome treatment and decreased fastest on the forehead,
where it decreased from week 2. EI on the forehead was 460 at Discussion
baseline, which decreased to 430 at week 2. EI decreased in all
locations from week 4 (Figure 3). Compared to EI measured at The pathogenesis of DFR is still poorly understood, although
baseline, EI at week 4 were decreased by 31, 27, 13, and 25 units several hypotheses exist. For example, it may represent a hyper-
on the forehead, chin, right and left cheek respectively. Skin sensitivity reaction, a site-specific treatment failure, a seborrheic

Figure 3. Changes in the erythema index (EI) were measured at four different anatomical locations on the face (forehead, left and right cheek, and chin). Erythema
index (EI) decreased in all four areas after exosome treatment and decreased fastest on the forehead. *p < 0.05, **<0.01, ***<0.001, compared with baseline
 Journal of Dermatological Treatment 5

dermatitis-like reaction to Malassezia, a rosacea-like reaction asso- applying topical formulation containing ASCE quickly resolves
ciated with Demodex, allergic contact dermatitis, or a combination DFR symptoms. The average IGA and CEA scores decreased from
of multiple mechanisms (26). The etiology of DFR appears to vary the second week of treatment. Notably, CEA decreased faster
by individual because the histologic findings also vary and include than IGA, which may be because erythema improves more than
psoriasiform dermatitis, spongiotic dermatitis with parakeratosis other DFR symptoms such as papulation or infiltration. The clinical
and neutrophil infiltration, or perifollicular and perivascular inflam- improvement in erythema was also supported by the decrease
mation (5,27,28). For the treatment of DFR, various topical for- in EI, which is a more objective measurement. EI decreased on
mulations including corticosteroids, calcineurin inhibitors, and the forehead from week 2, and the cheeks and chin from week
antifungal agents have been attempted, but were generally unsuc- 4. By contrast, patient satisfaction was highest in week 2 and
cessful (28–30). One potential reason for the variable treatment slowly decreased, although a score of at least 3 was maintained.
response could be the heterogeneous pathophysiology of DFR, This may be because ASCE treatment resulted in an immediate
meaning exosomes may be an ideal treatment option for DFR improvement meaning patients were satisfied with the marked
since they are highly immunomodulatory and have a pleiotropic change after the first few treatment sessions but thereafter
effect on the target cells (14,18,23,31). became less sensitive to further improvement in their skin.
Our study investigated the possibility of applying a topical As mentioned above, studies on the successful management
formulation containing ASCE to alleviate local skin inflammation of DFR are very limited. The relatively few case reports of the
seen in dupilumab-treated AD patients. Our results showed successful treatment of DFR include one where oral minocycline,

Figure 4. Results of the analysis of stratum corneum samples. (a) mRNA expression of interleukin-1α (IL-1α). The mRNA expression of IL-1α decreased in SC samples
collected at week 8 compared with the baseline. (b) mRNA expression of vascular endothelial growth factor (VEGF). The mRNA expression of VEGF increased in
SC samples collected at week 8 compared with the baseline. (c) mRNA expression of filaggrin (FLG). The mRNA expression of FLG increased in SC samples collected
at week 8 compared with the baseline. (d) Western blot analysis. (e) Protein expression of filaggrin (FLG). The protein expression of FLG increased in SC samples
collected at week 8 compared with the baseline. (f ) Protein expression of human thymic stromal lymphopoietin (TSLP). The protein expression of TSLP decreased
in SC samples collected at week 8 compared with the baseline. (g) Protein expression of interleukin-1α (IL-1α). The protein expression of IL-1α decreased in SC
samples collected at week 8 compared with the baseline.
6 H. S. HAN ET AL.

topical tacrolimus, and brimonidine tartrate gel improved facial options, as well as to establish a proper therapeutic approach,
redness within a mean of 23 weeks (5). In another case report, treatment dose, and regimen.
topical delgocitinib ointment improved DFR in one month (32).
The only reported clinical study on DFR treatment is a retrospec-
tive review evaluating the efficacy of oral itraconazole. The results Conclusion
showed 11 of 16 (69%) DFR patients had a post-treatment IGA
As the use of dupilumab for patients with AD gradually increases,
result of clear or almost clear (0 or 1) one to six months later,
the incidence of DFR will also increase. The successful manage-
with an average self-reported improvement of 52%. Our study
ment of DFR is important in increasing patient satisfaction with
showed similar results, where 12 of 20 (60%) patients achieved
their dupilumab treatment and improving their quality of life. The
an IGA score of 1 (almost clear), and the average subjective sat-
results of our study demonstrated the potential of a topical for-
isfaction score was 3.6/572). More importantly, previous treatment
mulation containing ASCE in the treatment of DFR. ASCE down-
methods such as oral itraconazole took at least a month or more
regulated inflammation and increased skin barrier-related proteins
to show any therapeutic effect. By contrast, the therapeutic effect
and angiogenesis. Importantly, ASCE resulted in immediate clinical
of ASCE was noticeable after just two treatment sessions.
improvement of DFR, which has not been observed in other treat-
We also observed ASCE alleviated inflammation, upregulated
ment methods. One of the most important advantages of ASCE
skin barrier-related proteins, and balanced the Th1/Th2 immune
is it can result in a therapeutic effect by topical application, which
response by reducing levels of TSLP. These findings were addition-
is important since DFR manifests as localized skin lesions. Thus,
ally supportive of the immunomodulatory and skin barrier-restoring
identifying an effective topical therapy may reduce the risks of
functions of ASCE confirmed in previous murine studies. Previous
adverse systemic effects and improve patient compliance.
studies have reported ASCE treatment relieved AD-like symptoms
and reduced inflammatory cytokines (IL-4, IL-31, IL-23, and TNF-α),
and also improved epidermal barrier functions by facilitating lamel-
Acknowledgment
lar body formation and by de-repressing the synthesis of cera-
mides (14,18). The authors wish to thank all of the dermatologists and collaborators who
In this study, we found ASCE reduced inflammatory cytokine participated in the study.
IL-1α. The IL-1 family cytokines initiate an inflammatory
response. They have also been linked to the pathogenesis of
AD as well as other inflammatory skin disorders (33,34). In Disclosure statement
particular, IL-1α (alarmin) is released from keratinocytes in any
skin condition that involves damage to the epidermis (35). No potential conflict of interest was reported by the author(s).
Also, ASCE upregulated VEGF, which is a principal proangio-
genic factor indicating ASCE can promote angiogenesis, which
is consistent with many previous reports (11,19,36–39). The Funding
repair of eczema lesions not only depends on the control of
inflammation, but also depends on the repair and proliferation This study was funded by ExoCoBio Inc., Seoul, Republic of Korea,
of keratinocytes and angiogenesis (40). Last but not least, our and was supported by the National Research Foundation of
results also demonstrated ASCE improves skin barrier function Korea(NRF) grant funded by the Korea government (MSIT) [No.
by upregulating FLG expression while suppressing TSLP (41). 2022R1A2C2091741].
FLG is a key epidermal protein that contributes to skin barrier
function (41,42). Additionally, TSLP plays a key role in AD
pathogenesis by triggering Th2 cell inflammation and by down- ORCID
regulating FLG expression (43–46). Based on these results, we
Hye Sung Han http://orcid.org/0000-0002-3556-0740
can presume that topical application of ASCE effectively alle-
Young Gue Koh http://orcid.org/0000-0002-6376-0328
viates DFR by suppressing cytokine-mediated inflammation and
Jun Ki Hong http://orcid.org/0000-0002-5277-5823
restoring the skin barrier function.
The major limitation of this study is the small number of
patients and the lack of a control group. Therefore, we cannot
completely rule out the possibility that DFR improved sponta- Data availability statement
neously. However, based on our clinical experience and previous The data used to support the findings of this study are
reports on DFR, the possibility that DFR will improve sponta- available from the corresponding author upon request.
neously, especially within 2 weeks, seems very small. Thus, it can
be assumed that the quick clinical improvement observed in this
study is largely due to the effects of ASCE treatment. Furthermore, References
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