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July 2020 Volume 4 Issue 4

BRIEF ARTICLES

Hypersensitivity Reactions Secondary to Dupilumab in Two
Patients with Moderate to Severe Atopic Dermatitis

Raina Bembry, MD1, Navid Malakouti, MD1, Mary Maiberger, MD1

1Howard University Hospital

Atopic dermatitis (AD) is a chronic
inflammatory disease of the skin with a
complex pathogenesis. It has both genetic
and environmental factors leading to
epidermal barrier defects and immune
system derangements.1,2 AD occurs in
nearly 15-30% of children and 2-10% of
adults.2,3 Conventional treatment for AD
consists of emollients, topical
corticosteroids, and topical calcineurin
inhibitors. Patients with moderate-to-severe
AD not adequately managed by
conventional therapies can be treated with
cyclosporine, azathioprine, methotrexate,
mycophenolate mofetil, and more recently,
dupilumab.3 Dupilumab is a human
monoclonal IgG4 antibody that inhibits the
Th-2 cytokines, interleukin-4 and interleukin-
13, by binding to the interleukin-4 receptor
alpha subunit.4 Dupilumab downregulates
the expression of genes encoding
inflammatory mediators and epidermal
proliferation, and upregulates genes linked

to epidermal barrier, lipid metabolism, and
structure.4,5 Injection site reactions are the
most commonly reported adverse event
associated with the use of dupilumab.7

Hypersensitivity reactions to dupilumab are
rare: less than 1% of trial patients reported
having serum sickness, serum sickness-like,
or urticarial reactions, which were not
reported as adverse effects in phase 3
clinical trials.7,8 We present two cases of
hypersensitivity reactions on second
exposure to dupilumab in two adult-male

Case 1
A 68-year-old Asian man with moderate-to-
severe atopic dermatitis presented with
worsening pruritus and pain, primarily of the
hands, that negatively affected his quality of
life. His disease was only partially managed
with topical clobetasol ointment and oral
methotrexate 12.5 mg, but he still required
oral prednisone intermittently for flares.
Physical examination findings included

INTRODUCTION

CASE PRESENTATION

Dupilumab is a human monoclonal IgG4 antibody that is widely used to treat atopic
dermatitis. Dupilumab was recently FDA approved to treat moderate to severe atopic
dermatitis. Here we decribe two cases of patients with moderate to severe atopic dermatitis
who developed an acute hypersensitivity reaction within hours of their second dose of
dupilumab.

ABSTRACT

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xerotic, lichenified, excoriated firm plaques
on the hands, left foot, buttocks, and
inguinal regions. Additionally,
hyperpigmentation and lichenification of the
buttocks and inguinal region were noted.
Methotrexate was discontinued and he was
injected with a 600 mg loading dose of
dupilumab in clinic which was tolerated well.
He reported improving pruritus on a one-
week telephone follow-up. Within hours of
his second injection, he developed a diffuse
eruption and generalized pruritus. Physical
examination revealed scaly erythematous
patches, plaques and papules involving the
thighs, calves, feet, genitals, arms and
elbows. The shave-biopsy of the right elbow
performed at the time of the reaction
showed spongiotic dermatitis with
superficial, perivascular chronic
inflammation, and rare eosinophils. The
biopsy was consistent with a hypersensitivity
reaction. Dupilumab was discontinued and
he was started on oral prednisone (1mg/kg)
tapered over two weeks which improved the
rash, but pruritus persisted. He was
restarted on his previous dose of
methotrexate which lead to moderate
improvement in pruritus.

Case 2
A 53-year-old Caucasian male presented
with a 10-year history of recalcitrant atopic
dermatitis. He had previously attempted and
failed many treatments including the
following: cyclosporine; mycophenolate
mofetil; methotrexate; apremilast;
narrowband UVB; high potency topical
corticosteroids; topical calcineurin inhibitors;
calcipotriene; and crisoborole. Physical
examination showed several erythematous
papules coalescing into plaques on the
upper extremities, lower extremities, and
trunk, with eczematous patches on the face
and scalp. There were eczematous, slightly
erythematous to tan plaques on the bilateral
lower legs and a thickened scaly plaque on

the left elbow. He demonstrated clinical
dermatographism with associated pruritus.
The patient was initiated on dupilumab and
tolerated the loading dose well. A scheduled
maintenance dose two weeks later resulted
in increased pruritus and worsening
dermatitis within hours of injection. His
physical examination showed eczematous
dermatitis with lichenification, excoriations
and fissures on his legs, back, and arms.
There were erythematous, rough papules on
the vertex scalp on a background of
erythematous, hyperpigmented skin.
Dupilumab was discontinued and he was
initiated on azathioprine, which lead to minor
resolution of his pruritus and dermatitis.

We described two cases of patients with
moderate-to-severe atopic dermatitis (AD)
who developed an acute hypersensitivity
reaction within hours of their second dose of
dupilumab.

Given the temporal relationship between the
second dose of the dupilumab with the
patient’s worsening dermatitis, and the skin
biopsy consistent with a hypersensitivity
reaction, we ascertain these hypersensitivity
reactions were possibly a result of exposure
to dupilumab. 9 We also conclude that the
discontinuation of dupilumab and aggressive
treatment with systemic and topical
immunosuppressants returned both patients
to baseline levels of their disease. It is
unclear why the two patients experienced a
hypersensitivity reaction from dupilumab.
There is documentation of a non-specific
inflammatory response after use of
dupilumab, with resolution after cessation of
the drug. 10

AD can be classified as either acute or
chronic, intrinsic or extrinsic, and can even

DISCUSSION

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be differentiated by ethnicity. Intrinsic AD
affects 20% of the adult population, with
normal levels of IgE.5 In comparison to
extrinsic, there is a higher immune system
activation with increased levels of Th-22 and
Th-17/IL-23 in intrinsic AD.5 Extrinsic AD
affects 80% of the adult population and is
associated with increased levels of IgE and
a predominance of Th-2 activation.4,5

Dupilumab targets cytokines in the extrinsic
pathway, which may lead to a better
response in patients with extrinsic AD.

Acute AD is characterized by an over-
activation of Th-2 and Th-22 immune
profiles, resulting in increased levels of IL-4,
IL-13, IL-31, and IL-22.5 In chronic AD, there
is a switch to a Th-1 mediated pathway and
a decrease in IL-4 activity.

The effective use of Th-2 antagonists has
resulted in new systemic therapies being
investigated for the treatment of AD. The IL-
13 antagonists, tralokinumab and
lebrikizumab, IL-31 antagonist,
Nemolizumab, and other Th-2 antagonists
are currently being evaluated.6 Antagonists
to IgE, Th-22, Th-17/IL-23, PDE-4, Tumor
Necrosis Factor, and JAK are also being
evaluated for their effectiveness in the
systemic treatment of AD.6 AD has a
complex, multifactorial nature. The multitude
of potential targets for pharmacologic
intervention, as well as the variable
response to common treatments warrants
further investigation for the development of
future pharmaceutical therapies.

Conflict of Interest Disclosures: None

Funding: None

Corresponding Author:
Raina Bembry, MD
Howard University Hospital
Department of Dermatology
2041 Georgia Ave NW Suite 4300
Washington, DC 20060
Email: raina.bembry@bison.howard.edu

References:
1. Refs Eichenfield LF, Tom WL, Berger TG, et al.

Guidelines of care for the management of atopic
dermatitis. Journal of the American Academy of
Dermatology. 2014;71(1):116-132.
doi:10.1016/j.jaad.2014.03.023.

2. Bieber T. Atopic Dermatitis. Annals of Dermatology.
2010;22(2):125. doi:10.5021/ad.2010.22.2.125.

3. Sidbury R, Davis DM, Cohen DE, et al. Guidelines of
care for the management of atopic dermatitis. Journal
of the American Academy of Dermatology.
2014;71(2):327-349. doi:10.1016/j.jaad.2014.03.030.

4. Derme AM, Romanelli M, Chiricozzi A. Spotlight on
dupilumab in the treatment of atopic dermatitis: design,
development, and potential place in therapy. Drug
Design, Development and Therapy. 2017;Volume
11:1473-1480. doi:10.2147/dddt.s113192.

5. Mansouri Y, Guttman-Yassky E. Immune Pathways in
Atopic Dermatitis, and Definition of Biomarkers through
Broad and Targeted Therapeutics. Journal of Clinical
Medicine. 2015;4(5):858-873.
doi:10.3390/jcm4050858.

6. Renert-Yuval Y, Guttman-Yassky E. Systemic
therapies in atopic dermatitis: The pipeline. Clinics in
Dermatology. 2017;35(4):387-397.
doi:10.1016/j.clindermatol.2017.03.012.

7. Simpson EL, Bieber T, Guttman-Yassky E, et al. Two
Phase 3 Trials of Dupilumab versus Placebo in Atopic
Dermatitis. New England Journal of Medicine.
2016;375(24):2335-2348.
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8. Dupixent® (dupilumab) [Package Insert]. Sanofi
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9. Zaki S. Adverse drug reaction and causality
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doi:10.4103/0970-2113.80343.

10. Davis JD, Bansal A, Hassman D, et al. Evaluation of
Potential Disease-Mediated Drug-Drug Interaction in
Patients With Moderate-to-Severe Atopic Dermatitis
Receiving Dupilumab. Clinical Pharmacology &
Therapeutics. February 2018. doi:10.1002/cpt.1058.

mailto:raina.bembry@bison.howard.edu