Expert Opinion on Biological Therapy

ISSN: 1471-2598 (Print) 1744-7682 (Online) Journal homepage: www.tandfonline.com/journals/iebt20

Clinical and histopathological characterization of

eczematous eruptions occurring in course of anti
IL-17 treatment: a case series and review of the
literature

G. Caldarola, F. Pirro, A. Di Stefani, M. Talamonti, M. Galluzzo, S. D’Adamio,

M. Magnano, N. Bernardini, P. Malagoli, F. Bardazzi, C. Potenza, L. Bianchi, K.
Peris & C. De Simone

To cite this article: G. Caldarola, F. Pirro, A. Di Stefani, M. Talamonti, M. Galluzzo, S. D’Adamio,

M. Magnano, N. Bernardini, P. Malagoli, F. Bardazzi, C. Potenza, L. Bianchi, K. Peris & C. De
Simone (2020) Clinical and histopathological characterization of eczematous eruptions
occurring in course of anti IL-17 treatment: a case series and review of the literature, Expert
Opinion on Biological Therapy, 20:6, 665-672, DOI: 10.1080/14712598.2020.1727439

To link to this article: https://doi.org/10.1080/14712598.2020.1727439

Published online: 17 Feb 2020.

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EXPERT OPINION ON BIOLOGICAL THERAPY
2020, VOL. 20, NO. 6, 665–672
https://doi.org/10.1080/14712598.2020.1727439

ORIGINAL RESEARCH

Clinical and histopathological characterization of eczematous eruptions occurring in

course of anti IL-17 treatment: a case series and review of the literature
G. Caldarolaa,b, F. Pirro a,b, A. Di Stefania,b, M. Talamonti c, M. Galluzzo c, S. D’Adamioc, M. Magnanod,
N. Bernardinie, P. Malagolif, F. Bardazzid, C. Potenzae, L. Bianchic, K. Perisa,b and C. De Simonea,b
a
Institute of Dermatology, Università Cattolica del Sacro Cuore, Rome, Italy; bDepartment of Dermatology, Fondazione Policlinico Universitario
A. Gemelli IRCCS, Rome, Italy; cDermatology Unit, University of Rome “Tor Vergata”, Rome, Italy; dDivision of Dermatology, Department of
Specialized, Clinical and Experimental Medicine, University of Bologna, Bologna, Italy; eDermatology Unit, Sapienza University of Rome, Polo
Pontino, Terracina, Italy; fDermatology Unit, Azienda Ospedaliera San Donato Milanese, Milan, Italy

ABSTRACT ARTICLE HISTORY

Background: Real-life data often highlight the side effects of certain drugs not previously reported in Received 1 September 2019
randomized controlled trials (RCTs). Accepted 5 February 2020
Objective: To describe cutaneous inflammatory eruptions in psoriatic patients treated with an anti IL- KEYWORDS
17A agent (secukinumab or ixekizumab). Psoriasis; IL17; secukinumab;
Methods: Retrospective analysis of a cohort of patients with chronic plaque psoriasis who started an ixekizumab; anti IL17; side
anti IL-17A agent between September 2016-February 2019 and who developed cutaneous inflamma- effects; eczematous
tory eruptions during treatment. A systematic review of similar events reported in the literature was reactions
performed.
Results: Data of 468 patients were reviewed and 27 cutaneous inflammatory eruptions of 27 (5.8%)
patients were collected. The eruptions appeared after a mean of 16.9 ± 17.0 weeks of therapy showing
a classical acute eczema in 11 patients (40.7%), an atopic dermatitis-like rash in 11 patients (40.7%) and
a psoriasiform eruption in 5 patients (18.5%). Histopathology of 12/27 cases showed epidermal
spongiosis in all these variants.
Conclusion: We described the clinic-pathologic features of some eczematous eruptions occurring in
psoriatic patients, 3–4 months after treatment initiation with an anti IL-17A agent. Further investiga-
tions are needed to explain this phenomenon, that might be defined a paradoxical adverse event,
based upon the role of IL17 in eczema pathogenesis.

1. Introduction alpha agents and ustekinumab, the most frequent adverse

events reported during anti IL-17A therapies are nasopharyn-
Interleukin 17 (IL17) family includes several molecules (IL-17A,
gitis, headache, upper respiratory tract infections, and injec-
IL-17B, IL-17C, IL-17D, IL-17E, and IL-17F) among which IL17A
tion site reactions [4–6]. On the other hand, Candida infections
plays a key role in the pathogenesis of psoriasis [1]. This
seem to be a typical side effect of anti IL-17A therapies, due to
cytokine is produced mainly by T helper 17 (Th-17) lympho-
the pivotal role of IL-17 in the defense against fungal patho-
cytes in response to their stimulation with IL-23 and it has
gens [7]. However, Candida infections occur in a low percen-
a range of effects on different cellular targets in the skin,
tage of cases and do not usually represent a cause of drug
leading mainly to neutrophilic chemotaxis and angiogenesis
withdrawal [7].
[1]. Moreover, IL-17A is critical for the induction of synovial
In the last two years, with the use of anti IL-17A antibodies
inflammation and pathological bone resorption typical of
in the clinical daily practice, several data have been accumu-
psoriatic arthritis through direct activation of osteoclast pre-
lated regarding treatment efficacy in patients who have dif-
cursors [2]. Based on these findings, several new biologic
ferent disease severity, concomitant diseases, previous
agents for the treatment of plaque psoriasis and psoriatic
experience of biological therapy. While confirming their effi-
arthritis, which target IL-17, have been developed. The three
cacy in psoriasis, on the other hand, the use of anti IL-17A
approved IL-17 inhibitors are secukinumab and ixekizumab,
agents in wide populations allows to identify some cutaneous
both IL-17A inhibitors, and brodalumab, a human monoclonal
side effects not previously reported in pivotal clinical trials.
antibody which targets the IL-17-receptor A (IL-17RA) on ker-
Aim of this study is to describe cutaneous inflammatory
atinocytes and immune cells [3].
eruptions in patients with plaque psoriasis and/or psoriatic
The efficacy and tolerability of these drugs have been
arthritis treated with an anti IL-17A agent (secukinumab or
investigated in several randomized controlled trials, showing
ixekizumab) and to review similar reactions reported in the
optimal clinical results and an acceptable safety profile [3]. In
literature.
line with the first available biological therapies, i.e. anti TNF

CONTACT G. Caldarola giacomocaldarola@libero.it Istituto Di Dermatologia, Università Cattolica Del Sacro Cuore, L.go F. Vito 1 00135 Roma
© 2020 Informa UK Limited, trading as Taylor & Francis Group
666 G. CALDAROLA ET AL.
2. Methods
2.1. Retrospective data collection
A retrospective analysis was performed in a cohort of patients with
chronic plaque psoriasis, with or without psoriatic arthritis, who
initiated treatment with secukinumab or ixekizumab during the
period September 2016–February 2019. The study population
consisted of patients attending the outpatient clinics of five parti-
cipating dermatologic centers (Università Cattolica, Rome,
University of Rome ‘Tor Vergata,’ University of Bologna,
University La Sapienza, Polo Pontino, Terracina, and Azienda
Ospedaliera San Donato Milanese, Milan) who developed cuta-
neous inflammatory eruptions during treatment with an anti IL-
17A agent, particularly ixekizumab and secukinumab. Patients
treated with brodalumab were ruled out from this analysis,
because this drug has been just approved in Italy. These events
were considered related to the anti psoriatic treatment according
to two major criteria: a) a Naranjo score [8] ≥4 and b) an agree-
ment of at least 2 out of 3 dermatologists (G.C., F.P., C.D.S.),
evaluating the medical history and the clinical pictures of the
reported cases.
For each patient, demographic and clinical data (age, sex,
ethnicity, height, weight, body mass index [BMI], disease sever-
ity, duration and age of onset of psoriasis, comorbidities, and
previous systemic therapies) at time of starting the anti IL-17A
therapy were collected. In particular, data on concomitant and
personal or family history of atopic diseases were also collected.
Based upon the eruptions previously reported during treatment
with anti TNF alfa, the skin inflammatory reactions occurring
during treatment with secukinumab or ixekizumab were classi-
fied according to the clinical features of the lesions: 1) liche-
noid, 2) eczematous (diffuse erythematous crusted and
excoriated papules isolated and/or merging in plaques), 3) ato-
pic dermatitis-like (in the classical form, with lichenified and
excoriated plaques, mainly at flexures areas, head and neck), 4)
urticarial, 5) psoriasiform, and 6) others. The presence of asso-
ciated symptoms (itching and pain), time of onset, and involved
body site were also collected. Levels of circulating eosinophils
and serum Immunoglobulin E (IgE) were recorded when avail-
able and above the normal range. The management of the skin
reaction (local or systemic therapy, and anti IL-17A agent with-
drawal) was also recorded. Missing data were retrieved from
charts or directly from the patients through phone calls. Only
cases with completed data were collected for the present study.
In order to describe histopathological characteristics of the skin
eruptions, a revision of a lesional skin sample, when available,
was performed by a board-certified dermopathologist (A.D.S.),
blinded for the clinical characteristics of cutaneous lesions.
Microscopic evaluation of hematoxylin-eosin-stained sections
was performed according to established criteria described else-
where [9,10].
The study was conducted following the principles of the
Declaration of Helsinki.
2.2. Literature review
A systematic review was performed to investigate the clinical
characteristics of cutaneous inflammatory eruptions occurring
during the course of treatment with anti IL-17A agents and
reported in the literature. A comprehensive update-search was
carried out in PubMed to cover literature to 28 April 2019.
Keywords ‘psoriasis,’ ‘psoriatic arthritis,’ ‘ixekizumab,’ ‘secukinu-
mab,’ ‘side effects,’ ‘cutaneous,’ ‘eczematous,’ and ‘eczema’ were
used. Search results were restricted to articles written in English.
Reference lists of relevant articles were hand-searched for addi-
tional studies of interest. Case reports and case series were
screened and selected independently by two reviewers (G.C. and
F.P.). Poster abstracts, oral communications, and meeting summa-
ries were excluded. Data extraction was performed and the rele-
vant data were reported into a table.
3. Results
3.1. Patients’ clinical characteristics
Clinical data of 468 patients treated with an anti IL-17A antibody
(325 with secukinumab and 143 with ixekizumab) were reviewed
and 27 cutaneous inflammatory eruptions of 27 (5.8%) patients
were collected (Tables 1 and 2). The 27 patients, 18 (66.7%)
males and 9 (33.3%) females, were of Caucasian ethnicity. At
the time of anti IL-17A treatment initiation, 20 of 27 (74%)
patients have had previous treatment with biologics and, in
particular, 5 patients had been treated with another anti IL-17A
agent without any cutaneous side effect. Only 6 (22.2%) patients
had a personal history of atopy, 11 (40.7%) had a familiar history
of atopy and 13 (48.1%) patients had neither of them.
3.2. Clinical characteristics of the skin eruptions
The cutaneous eruptions appeared after a mean of 16.9 ±
17.0 weeks of therapy. Seventeen (63.0%) skin manifestations
were observed during treatment with secukinumab and 10
(37.0%) during treatment with ixekizumab. Clinical features
were consistent with a classical acute eczematous rash in 11
patients (40.7%) (Figure 1a), an atopic dermatitis-like rash
(Figure 2a) in 11 patients (40.7%) and a psoriasiform eruption
in 5 patients (18.5%) (Figure 3a). No lichenoid or urticarial
lesions were reported. Twenty patients (74.1%) reported that
lesions were associated with itch (mean itch score on
a numerical rating scale: 6/10), 6 patients (22.2%) reported
burning sensations and 1 patient (3.7%) had no symptoms.
The involvement of different body site is reported in Figure 4:
the skin eruption affected mainly the trunk and the flexural
areas in 17 (63.0%) and 12 (44.4%) patients, respectively. At
the time of the eruption, 8 of 11 patients showed high serum
Immunoglobulin E (IgE) levels with a mean value of 313 UI/ml
(normal range: 0–200 UI/ml) while only 1 of 27 patients (3,7%)
showed blood hypereosinophilia with a total eosinophil count
of 1,2 x 10^9/l. No significant differences were found in the
Table 1. Patients’ demographic and clinical characteristics.
Mean age at the time of the eruption (years), mean ± SD 51.0 ± 11.9
Mean BMI (Kg/m2), mean ± SD 26.3 ± 3.8
Mean age at diagnosis (years) of psoriasis, mean ± SD 29.0 ± 16.0
Mean duration of disease (years), mean ± SD 21.2 ± 12.8
Concomitant psoriatic arthritis (PsA), n/tot of pts (%) 6/27 (22.2)
Previous biological therapy, n/tot of pts (%) 20/27 (74)
Abbreviations: BMI, body mass index; SD, standard deviation.
Table 2. Patient and skin eruption characteristics.
Personal and/or Discontinuation of
Age familial Anti IL-17A Duration of therapy Associated treatment
Pt# Sex (yrs) history of atopy agent (weeks) Localization Clinical aspects symptoms (management) Management
1 F 60 No Secukinumab 12 Extensor areas, trunk, folds Eczematous eruption Itch Yes Systemic steroids
2 M 50 Yes Secukinumab 9 Trunk Eczematous eruption Itch Yes Systemic CsA
3 M 20 Yes Secukinumab 9 Trunk Eczematous eruption Itch Yes Systemic CsA
4 M 41 No Secukinumab 52 Extensor areas Eczematous eruption Itch Yes Topical steroids
5 M 54 No Secukinumab 76 Extensor areas Eczematous eruption Burning sensation Yes Topical steroids
6 F 74 No Ixekizumab 6 Flexural areas, palmo-plantar Atopic dermatitis-like Burning sensation Yes Systemic steroids
7 F 55 Yes Secukinumab 4 Extensor areas, trunk Eczematous eruption Itch Yes Systemic steroids
8 M 64 No Secukinumab 24 Extensor areas Eczematous eruption Burning sensation Yes Topical steroids
9 F 58 No Secukinumab 16 Trunk, folds Eczematous eruption Itch No Topical steroids
10 M 49 Yes Secukinumab 4 Flexural areas, face, trunk Atopic dermatitis-like Itch No Topical steroids
11 F 28 Yes Secukinumab 6 Flexural, extensor areas, trunk, folds Eczematous eruption Itch No Topical steroids
12 M 55 No Secukinumab 5 Flexural, extensor areas, face, trunk, folds, Atopic dermatitis-like Itch Yes Topical steroids
palmo-plantar
13 M 63 No Secukinumab 2 Flexural areas, face, trunk, folds Eczematous eruption Itch Yes Topical steroids
14 M 47 No Ixekizumab 10 Flexural areas, trunk Atopic dermatitis-like Itch Yes Systemic steroids
15 M 41 Yes Ixekizumab 8 Extensor areas Eczematous eruption Itch Yes Topical steroids
16 M 53 No Ixekizumab 20 Face, trunk Psoriasiform eruption Itch Yes Topical steroids
17 M 34 No Ixekizumab 8 Extensor areas, trunk Psoriasiform eruption None No Topical steroids
18 M 46 No Ixekizumab 4 Flexural areas, trunk, folds Atopic dermatitis-like Itch No Systemic steroids
19 M 52 No Secukinumab 16 Extensor areas, trunk Psoriasiform eruption Burning sensation Yes Topical steroids
20 F 61 Yes Ixekizumab 4 Eyelids Atopic dermatitis-like Burning sensation No Topical steroids
21 F 47 Yes Ixekizumab 16 Flexural areas, trunk Atopic dermatitis-like Itch Yes Topical steroids
22 M 68 Yes Secukinumab 20 Flexural areas, folds Atopic dermatitis-like Itch Yes Systemic steroids
23 M 59 Yes Secukinumab 16 Flexural areas Atopic dermatitis-like Itch Yes Systemic steroids
24 M 48 Yes Ixekizumab 12 Extensor areas Psoriasiform eruption Burning sensation No Topical steroids
25 F 42 Yes Ixekizumab 26 Extensor areas, trunk Psoriasiform eruption Itch No Topical steroids
26 F 54 No Secukinumab 40 Flexural areas, eyelids, trunk, folds Atopic dermatitis-like Itch Yes Topical steroids
27 M 43 No Secukinumab 32 Flexural areas, trunk Atopic dermatitis-like Itch No Topical steroids
Abbreviations: CsA, cyclosporine.
EXPERT OPINION ON BIOLOGICAL THERAPY
667
668 G. CALDAROLA ET AL.

Figure 1. a. Patient presenting a classical eczematous eruption during treatment with ixekizumab with erythematous crusted and excoriated plaques on the trunk.
b. Histopathology showing full thickness epidermal spongiosis with lymphocytic exocytosis (arrow), spongiotic vesicles (arrowhead), and intracorneal serum crusts
(asterisk) [Hematoxylin and eosin stain, original magnification B: x100, insert: x400].

Figure 2. a. Patient presenting an atopic dermatitis-like eruption during treatment with secukinumab with intensely erythematous flexural plaques.
b. Histopathology exhibiting irregular acanthosis with minimal spongiosis and eosinophils in the dermis (arrow) [Hematoxylin and eosin stain, original magnification
B: x100, insert: x400].

Figure 3. a. Patient presenting a psoriasiform eczema-like eruption during treatment with ixekizumab with erythematous hyperkeratotic excoriated plaque on the
elbows. b. Histopathology demostrating psoriasiform epidermal hyperplasia with mild spongiosis, parakeratosis (arrow), loss of granular layer (arrowhead) and
Munro intracorneal microabscesses (asterisk) [Hematoxylin and eosin stain, original magnification B: x100, insert: x400].
 EXPERT OPINION ON BIOLOGICAL THERAPY 669

Figure 4. Localization of observed cutaneous reactions.

characteristics of the eruptions induced by secukinumab and
ixekizumab (data not reported).
3.3. Histopathological characteristics of the skin
eruptions
In our case series, 12/27 cases (in Table 2, patients nr 4, 5, 6, 7,
12, 14, 15,18, 21, 23, 25, 26) were histopathologically verified
and tissue samples were retrieved for revision. All reviewed
cases exhibited the presence of epidermal spongiosis. In 4 out
of 12 cases, microscopic evaluation showed the prevalence of
full thickness spongiosis with spongiotic vesicles, multiple foci
of parakeratosis with fibrinous exudate, lymphocytic exocytosis
in the epidermis (Figure 1b): these features were consistent
with acute spongiotic dermatitis and were correlated with
a clinical diagnosis of acute eczematous reaction. In 5 of 12
cases, histopathological revision disclosed the presence of irre-
gular acanthosis with minimal spongiosis and focal parakerato-
sis, consistent with atopic dermatitis (Figure 2b): those cases
were clinically classified as atopic dermatitis-like eruption. In 3
of 12, histopathological evaluation disclosed regular epidermal
hyperplasia with papillomatosis, mild spongiosis, loss of gran-
ular layer, parakeratosis with Munro microabscesses and serum
in stratum corneum, edema of papillary dermis with tortuous
and dilated capillary (Figure 3B): these findings were consistent
with a psoriasiform eczema and were clinically classified as
psoriasiform eruption.
3.4. Management of the skin eruptions
In 18 of 27 (66.7%) patients' treatment with the anti IL-17A
inhibitor was suspended and a local (10 patients) or sys-
temic (6 patients) therapy with corticosteroids or cyclospor-
ine (2 patients) was started. In the remaining 9 (33.3%)
patients, the anti IL-17A agent was continued and topical
(8 patients) or systemic (1 patient) steroids were used to
manage the skin reaction.
3.5. Literature review
In literature, four articles have already reported inflammatory skin
eruptions occurring during treatment with anti IL-17 agents (see
Table 3). In particular, Burlando M [11] and Munera-Campos M [12]
reported two single cases, while Teraki Y [13] and Napolitano
M [14] reported a case series of 3 and 4 patients, respectively.
The mean age of patients was 49.4 ± 21.7 years and 5 (55.6%)

Table 3. Clinical and demographic characteristics of the cases reported in the literature.
Age Atopic history Anti IL-17A Treatment duration Discontinuation of
Reference Sex (yrs) (Y/N) agent (weeks) Localization Clinical aspects treatment
[11] F 70 No Secukinumab 24 Eyelids, lips, nostrils Atopic dermatitis-like Yes
[12] M 31 No Ixekizumab 56 Hands, trunk Eczematous eruption No
[13] F 33 No Secukinumab 12 Eyelids Blepharitis Yes
M 52 No Secukinumab 16 Eyelids Blepharitis No
M 89 No Ixekizumab 16 Eyelids Blepharitis No
[14] F 32 Yes Ixekizumab 10 Face, upper and lower Eczematous eruption Yes
extremities, trunk
M 62 No Secukinumab 16 Upper and lower extremities, Eczematous eruption Yes
trunk
M 53 Yes Secukinumab 12 Back, trunk, upper arms, neck Eczematous eruption Yes
F 23 Yes Secukinumab 16 Flexural areas, lips, neck, Atopic dermatitis-like No
extremities, trunk
670 G. CALDAROLA ET AL.
patients were males. The cutaneous eruptions appeared after
a mean of 19.8 ± 14.1 weeks of therapy and were observed during
treatment with secukinumab or ixekizumab in 6 (66.7%) and 3
(33.3%) respectively. In 4 of 9 patients (44.4%), the skin eruptions
had a generalized eczematous appearance and in 2 cases the
lesions had atopic dermatitis-like features. Finally, three patients
had an exclusive palpebral involvement. Only 3 of 9 patients
(33.3%) had a personal history of atopy. In 5 patients (55.6%), it
was necessary to interrupt treatment with anti the IL-17A agent.
4. Discussion
In the present study, we report a case series of eczematous
eruptions occurring during treatment of psoriasis with an anti
IL-17A agent (secukinumab or ixekizumab) and summarized
similar cases reported in the literature.
Based upon the clinical appearance and the site involved, we
defined three possible phenotypes of this cutaneous side effect: 1)
classical acute eczema, 2) atopic dermatitis-like eruption, and 3)
psoriasiform eczema. The histopathological confirmation in our
cases was in line with the distinct clinical profile of each patient. In
fact, although all the eruptions showed a different degree of
spongiosis as a common feature, the different clinical patterns
presented some peculiar histopathological findings. The presence
of severe spongiosis with spongiotic vesicles and lymphocytic
exocytosis was suggestive of an acute eczematous eruption; fea-
tures as irregular acanthosis, thickening of the epidermis with
maintained granular layer and only mild spongiosis were consis-
tent with an atopic dermatitis-like eruption; changes such as
regular epidermal hyperplasia, parakeratosis, neutrophils in the
stratum corneum, and dilated papillar capillaries suggested the
diagnosis of psoriasiform eczema.
This classification seems to be applicable even to the cases
reported in literature, even if the cases of blepharitis described
by Teraky et al. [13] would have needed a histopathological
characterization to be precisely defined in the context of the
patterns that we propose. Based upon the clinical character-
istics (lichenification and fine scaling), the other concomitant
site involved and the associated symptoms, the blepharitis
presented by Burlando et al. [11] and in one of our patients
were classified as atopic dermatitis-like eruptions. However, in
these cases a paradoxical psoriatic involvement of eyelids may
not be definitely ruled out.
In our case series, the skin eruptions occurred 3–4 months
after treatment initiation with an anti IL-17A monoclonal anti-
body and had a high impact on clinical practice since they were
often associated with itching or burning, leading to the interrup-
tion of the biological treatment in almost 60% of patients.
Interestingly, according to our case series, some patients may
experience these eczematous eruptions with an anti IL-17A
agent but not with another one of the same class. Further
investigations are needed to explain this phenomenon.
Personal and/or family history of atopy can not help in predicting
who may experience these eruptions since more than half of the
patients did not report any personal or family concomitant or
past atopic disease. No other risk factors have been identified.
Real-life data often highlight side effects of certain drugs not
previously reported in randomized controlled trials (RCTs). This
could be due to the low frequency of these events or to
a different patient population compared to that included in RCTs.
Eczematous eruptions were not reported in any pivotal
ixekizumab or secukinumab RCTs, but in a single study con-
ducted in Japan (UNCOVER-J) [15]. This was an open-label
study with the aim to evaluate the long-term efficacy and
safety of ixekizumab, in patients with plaque psoriasis, ery-
throdermic psoriasis, and generalized pustular psoriasis. In this
study, the most common adverse events after nasopharyngitis
was eczema, occurring in 11 of 91 (12.1%) patients. Despite
the high prevalence, no further clinical characterization of this
side effect has been reported by the authors.
We believe that eczematous eruptions occurring during anti
IL-17A treatment might represent paradoxical adverse events
(PAEs). This definition is applied to pathological conditions that
appear or worsen during therapy with biological drugs to which
they usually respond (true PAEs). PAEs during biological therapy
also include pathological conditions in which there is a rationale
for the use of the culprit drug even if its effectiveness has not
been demonstrated (borderline PAEs) [16]. In fact, as in psoriasis,
IL17 seems to be involved in the pathogenesis of eczema. IL-17
levels are significantly elevated in the skin of patients with atopic
dermatitis compared with healthy controls and it has been
hypothesized that IL-17 may mediate an immune dysregulation
by amplifying the inflammatory response [17]. Similar results
have also been found in allergic contact dermatitis [18–20]:
based upon these data, anti IL-17 agents have been suggested
for the treatment of both these conditions [21,22].
The mechanisms underlining the onset of these eczematous
PAEs during anti IL-17A treatment are currently unknown. These
agents may block mainly the Th1 pathway, thus inducing an
imbalance in the Th1/Th2 immune response and favoring the
Th2 pathway that is involved in the pathogenesis of eczema [11].
On the other hand, Munera-Campos M. et al. [12] suggested that
an anti IL-17A agent may suppress the expression of keratino-
cyte-derived antimicrobial peptides, which could have a role at
least in atopic dermatitis-like eruptions. Finally, Napolitano
M. et al. [14] speculated that IL-22 may be a key mediator in
the pathogenesis of eczematous PAEs.
In our opinion, these eczematous PAEs occurring during
treatment with secukinumab or ixekizumab may be
a consequence of the selective block of isoform A of IL-17.
Blocking IL17A, in fact, might induce the overexpression of
other isoforms, such as IL-17C. In contrast to IL-17A, which is
produced mainly by Th17 cells, the main source for IL-17C are
epithelial cells and this isoform seems to be involved both in
psoriasis and in atopic dermatitis pathogenesis [23]. In fact, IL-
17C appears to trigger an autocrine loop of stimulation on
keratinocytes, that may be involved in both Th17- and Th2-
driven inflammatory skin inflammation [23], and preliminary
evidence suggests that a IL-17C neutralizing antibody may be
successful in the management of atopic dermatitis [24].
According to this hypothesis, brodalumab, the only anti IL-17
treatment that blocks not only IL-17A and IL-17F, but also IL-
17C, should not be associated with this side effect and it may
be helpful in those patients who experienced this paradoxical
eczematous reaction with anti IL-17A agents. However, to
date, no similar cases have been reported in literature but
a wider clinical experience with this drug is needed.

In the past years, a high number of similar cutaneous man-
ifestations occurring during treatment with anti TNF alfa agents
have been also reported [25]. In particular, psoriasiform or pust-
ular skin manifestations and eczematous reactions as defined by
histological and clinical features have been described in patients
who had or had not a history of psoriasis or eczema. Even in this
case, the detailed interpretation of this undesirable paradoxical
side effect has yet to be elucidated. In our opinion, all these
cutaneous side effects reported in course of anti TNF alfa and
anti IL-17A agents may be an expression of the spectrum of
disease including both atopic dermatitis both psoriasis, recently
described by Kruger et al. [26]. In this spectrum, the different
expression of polar T-cell axes (Th1, Th2, and Th17) and derived
cytokines (IL-17, TNF alfa, IL-22, IL-5) can be variably present and
create some overlapping disease characteristics.
The major limitation of this study is the lack of a control
group including psoriatic patients not treated with anti IL-17A
agents. In fact, it is already known that psoriasis and eczema
may be also spontaneously associated [27]. Moreover, to con-
firm the causative role of the biologic agents in these cases,
a re-challenge test should be needed, but this was not per-
formed. In conclusion, we described the clinic-pathologic fea-
tures of eczematous eruptions occurring in patients with
psoriasis treated with anti IL-17A monoclonal antibodies.
Further studies are needed to understand the mechanisms
underlining the onset of such skin manifestations and to
identify patients who are at risk of developing them. In this
case series, no risk factors have been identified.
Authors' contributions
Conception and design, analysis and interpretation of the data: G. Caldarola,
F. Pirro, A. Di Stefani, K. Peris, C. De Simone. Drafting of the paper or revising it
critically for intellectual content: G. Caldarola, F. Pirro, A. Di Stefani,
M. Talamonti, M. Galluzzo, S. D’Adamio, M. Magnano, N. Bernardini,
P. Malagoli, F. Bardazzi, C. Potenza, L. Bianchi, K. Peris, C. De Simone. Final
approval of the version to be published: G. Caldarola, F. Pirro, A. Di Stefani,
M. Talamonti, M. Galluzzo, S. D’Adamio, M. Magnano, N. Bernardini, P. Malagoli,
F. Bardazzi, C. Potenza, L. Bianchi, K. Peris, C. De Simone. All authors agree to be
accountable for all aspects of the work.
Funding
This paper was not funded.
Declaration of interest
The authors have no relevant affiliations or financial involvement with any
organization or entity with a financial interest in or financial conflict with
the subject matter or materials discussed in the manuscript. This includes
employment, consultancies, honoraria, stock ownership or options, expert
testimony, grants or patents received or pending, or royalties.
Reviewer Disclosures
One of the reviewers on this paper has received grants/research supports
or participation in clinical trials (paid to Institution) Abbvie, Almirall,
Amgen, Boehringer Ingelheim, Celgene, Janssen, Leo-Pharma, Lilly,
Novartis, Pfizer, Regeneron, Roche, Sanofi, UCB.
Receipt of honoraria or consultation fees from Abbvie, Almirall,
Amgen, Baxalta, Biogen, Boehringer Ingelheim, Celgene, Gebro, Janssen,
EXPERT OPINION ON BIOLOGICAL THERAPY 671
Leo-Pharma, Lilly, Merck-Serono, MSD, Mylan, Novartis, Pfizer, Regeneron,
Roche, Sandoz, Samsung-Bioepis, Sanofi, UCB.
Participation in a company-sponsored speaker’s bureau Celgene,
Janssen, Lilly, MSD, Novartis, Pfizer. Another reviewer has received
research, speaking and/or consulting support from a variety of companies
including Galderma, GSK/Stiefel, Almirall, Alvotech, Leo Pharma, BMS,
Boehringer Ingelheim, Mylan, Celgene, Pfizer, Ortho Dermatology,
Abbvie, Samsung, Janssen, Lilly, Menlo, Merck, Novartis, Regeneron,
Sanofi, Novan, Qurient, National Biological Corporation, Caremark,
Advance Medical, Sun Pharma, Suncare Research, Informa, UpToDate
and National Psoriasis Foundation. They also consult for others through
Guidepoint Global, Gerson Lehrman and other consulting organizations
and are a founder and majority owner of www.DrScore.com. The reviewer
is also a part owner of company dedicated to enhancing patients’ adher-
ence to treatment. Other peer reviewers on this manuscript have no
relevant financial relationships or otherwise to disclose.
ORCID
F. Pirro http://orcid.org/0000-0001-6629-9613
M. Talamonti http://orcid.org/0000-0002-3070-4071
M. Galluzzo http://orcid.org/0000-0002-3424-5175
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