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\begin{document}

\title{Epidermolysis Bullosa Pruriginosa Treated with Baricitinib}



\author[1]{Zhe He}%
\author[2]{Rui Zheng}%
\author[1]{Qian Dong}%
\author[1]{Yue Xi}%
\affil[1]{Shanxi Medical University}%
\affil[2]{First Hospital of Shanxi Medical University}%


\vspace{-1em}



  
  \date{May 16, 2024}


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\section*{Epidermolysis Bullosa Pruriginosa Treated with Baricitinib:A
Case
Report}

{\label{epidermolysis-bullosa-pruriginosa-treated-with-baricitiniba-case-report}}

Zhe He\textsuperscript{1}, PhD

Qian Dong\textsuperscript{1}, PhD

Yue Xi \textsuperscript{1}, PhD

Rui Zheng\textsuperscript{2}, PhD

\textsuperscript{1} Shanxi Medical University, Taiyuan, Shanxi, China;
\textsuperscript{2}Department of Dermatology, First Hospital of Shanxi
Medical University, Taiyuan, Shanxi, China.

Correspondence: Rui Zheng, Email:\emph{Zhengr2002@163.com}

EBP: Epidermolysis Bullosa Pruriginosa

JAK-STAT: Janus kinase-signal transducer and activator of transcription

JAK: Janus kinase

DEB: Dystrophic Epidermolysis Bullosa

VAS: The Visual Analogue Scal

\textbf{Abstract} : \textbf{Introduction:} Fewer than 100 cases of
Epidermolysis Bullosa Pruriginosa(EBP) have been reported to date.
Numerous inflammatory dermatoses are driven by soluble inflammatory
mediators, which rely on Janus kinase-signal transducer and activator of
transcription (JAK-STAT) signaling, and inhibition of this pathway using
Janus kinase (JAK) inhibitors might be a useful therapeutic strategy for
these diseases. Chronic inflammation is a hallmark of Dystrophic
Epidermolysis Bullosa (DEB), thus upregulation of inflammatory cytokines
and JAK signaling may play a role in DEB-related pruritus. EBP is a
persistent, recurring disease that seriously affects quality of life.
\textbf{Patient concerns:} A male patient, 28 years of age, was admitted
to our hospital because of recurrent papules, nodules, and intense
itching on the trunk and extremities for 12 years. Repeated large and
intense itching for 12 years has seriously affected the patient's normal
life.\textbf{Diagnosis:} The patient was diagnosed with Epidermolysis
Bullosa Pruriginosa based on examination results.
\textbf{interventions:} Oral baricitinib tablets (2 mg, once a day) +
Oral desloratadine citrate disodium tablets (8.8 mg, once a day)
combined with topical compound flumethasone ointment and Fucidin cream.
\textbf{outcomes:} The patient's skin rashes had subsided and flattened
significantly, and his itching was markedly relieved. The Visual
Analogue Scal (VAS) itching score of the patient had gradually declined
from 8--9 points to 2--3 points. \textbf{Conclusion} : this study
confirms that baricitinib is effective and feasible in treating EBP,
especially in significantly relieving itching, which rendered new ideas
for therapeutic approaches for EBP in the future.

\textbf{Keywords:} Epidermolysis Bullosa, kinase inhibitors, Baricitinib
Treatment



\section*{INTRODUCTION}

{\label{introduction}}

EBP is characterized by recurrent itching and pruritic nodules. In the
case of intense itching, skin becomes fragile, resulting in thickening
and lichenification. In most cases, skin rashes are distributed over
lower extremities, forearms, elbows, dorsum of hands, shoulders, and
lower back, especially the extensor aspect of the extremities.
Baricitinib is a reversible, selective inhibitor of tyrosine protein
kinase, which is capable of modulating the signal transduction of helper
T-cells (Th1, Th2, Th17, and Th22) and might cause many immune-mediated
disorders. EBP is characterized by nodular prurigo-like lichenoid
lesions with intense itching, in addition to the features of DEB, such
as blisters and onychodystrophy.\textsuperscript{1} Currently, EBP is
treated with topical corticosteroids, tacrolimus, and oral thalidomide,
but the outcomes are often
unsatisfactory.\textsuperscript{2-3}Baricitinib is a reversible
selective inhibitor of tyrosine protein kinase, which is capable of
modulating the signal transduction of helper T-cells (Th1, Th2, Th17,
and Th22) and participates in many immune-mediated disorders. Here, one
case of baricitinib in the treatment of EBP is discussed.

\section*{CASE PRESENTATION}

{\label{case-presentation}}

A male patient, 28 years of age, was admitted to our hospital because of
recurrent papules, nodules, and intense itching on the trunk and
extremities for 12 years. The patient had visited another hospital 12
years ago (in 2010). He was diagnosed with EBP based on examination
results from other hospitals (Figure1A) and herpetic autoantibody test
results.

The patient had visited other hospitals several times due to disease
relapse, but the outcomes were often unsatisfactory (Figure2). The
patient came to our hospital on August 2,2021. The physical examinations
revealed multiple reddish-brown hemispherical mung bean-to-soybean-sized
nodules were symmetrically distributed on the trunk and extremities,
densely packed in patches, some of which were anabrotic and crustosus
due to scratching (Figure 1C and 1D). Laboratory test results indicated
routine blood and urine test with normal liver and kidney function,
blood function, blood electrolytes, and blood sedimentation were normal.

\section*{METHODS}

{\label{methods}}

We did a pathology biopsy on him again (Figure1B). He underwent
symptomatic treatment with oral baricitinib tablets (2 mg, once a day) +
oral desloratadine citrate disodium tablets (8.8 mg, once a day)
combined with topical compound flumethasone ointment and Fucidin cream
since August 2, 2021. The Visual Analogue Scale (VAS) scale for the
degree of itching was adopted to assess the severity and control of the
disease. The VAS score of the patient was 7--8 points at the initial
diagnosis.

\section*{CONCLUSION AND RESULTS}

{\label{conclusion-and-results}}

During the 2 years of treatment with baricitinib, the VAS itching score
had steadily decreased (Figure 2), and the patient reported significant
improvement in itching and sleep quality after treatment, without any
adverse effects. After discontinuation of baricitinib for 2 weeks, in
July 2022, the patient returned to the clinic for reexamination, and the
results indicated that the number of skin rashes on the outer side of
both thighs had decreased by half, and the color had become dull,
although some dark brown hyperpigmentation and scars remained on the
extensor aspect of both lower legs. (Figure 1E and 1F). The results of
regular reexaminations showed routine blood and urine with normal liver
and kidney function and electrolytes. Currently, the patient is still
under follow-up.

\section*{DISCUSSION}

{\label{discussion}}

DEB is an autosomal dominant or recessive genodermatosis caused by
variations in COL7A1. Its pathogenesis is not completely understood. EBP
is characterized by nodular prurigo-like lichenoid lesions with intense
itching, in addition to the features of DEB, such as blisters and
onychodystrophy. \textsuperscript{1} Currently, EBP is treated with
topical corticosteroids, tacrolimus, and oral thalidomide, but the
outcomes are often unsatisfactory.\textsuperscript{2-3} Baricitinib is a
reversible selective inhibitor of tyrosine protein kinase, which is
capable of modulating the signal transduction of helper T-cells (Th1,
Th2, Th17, and Th22) and participates in many immune-mediated disorders.
Here, one case of baricitinib in the treatment of EBP was discussed.

This case clinically presented with dense nodular, keratotic papules,
mainly on the extensor side of both lower limbs, which were brownish in
color, with umbilical concavity at the center of some of them, and
subepidermal blisters could be seen by the results of the examination,
while there were no obvious eosinophils in the blisters, and there was
mixed inflammatory cell infiltration in the dermis, so we considered
this to be a case of a specific type, Epidermolysis Bullosa Pruriginosa.
Janus kinase-signal transducer and activator of transcription (JAK-STAT)
is an intracellular signaling pathway upon which many different
proinflammatory signaling pathways converge. Numerous inflammatory
dermatoses are driven by soluble inflammatory mediators, which rely on
JAK-STAT signaling, and inhibition of this pathway using JAK inhibitors
might be a useful therapeutic strategy for these diseases. Evidence
suggests that the dysregulation of helper T-cell (Th1, Th2, and Th17)
signal transduction is implicated in epidermolysis bullosa. Chronic
inflammation is a hallmark of DEB, thus upregulation of inflammatory
cytokines and JAK signaling may play a role in DEB-related pruritus.
Caroppo reported one case of EBP who was successfully treated with
dupilumab. Dupilumab can dually block and inhibit both IL-4 and IL-13
and suppress Th2-mediated inflammatory responses, thus significantly
improving skin lesions and relieving itching.\textsuperscript{4} This
suggests that EBP may be triggered by Th2 immune mechanisms. In
addition, it was reported that baricitinib could alleviate itching
associated with AD, and the significant relief of itching proves the
effectiveness of this strategy, which is the rationale behind the
application of baricitinib in our hospital for targeted treatment
through its downstream JAK-STAT signal. JAK may be a favored target for
EBP-associated symptoms. Moreover, considering the affordability and
durability of the treatment regimen for patients, baricitinib has become
the preferred treatment choice in our clinic instead of dupilumab. Jiang
XY et al. reported one case of EBP in a 40-year-old man without a family
history of DEB and with severe skin lesions and intense itching, which
is significantly improved after treatment with baricitinib.
\textsuperscript{5} He was followed up once every 2 weeks until 16
weeks, and then every 8 weeks. The scores of all three indicators
decreased over time. Joo Kwon retrospectively reviewed the medical
records of DEB patients with refractory pruritus who were treated with
either baricitinib, a JAK1/2 inhibitor, or upadacitinib, a selective
JAK1 inhibitor. A total of 12 DEB patients (six recessive DEB and six
dominant DEB) were included in this study. The mean\selectlanguage{ngerman}±SD baseline pruritus
visual analog scale score was 7.5 ± 1.7. Upadacitinib or baricitinib
treatment resulted in a rapid and sustained decrease in
itch.\textsuperscript{6}

In this paper, one case of EBP was discussed. The patient had a long
history of EBP and a relevant family history of the disease. The typical
skin lesions initially manifested as multiple lichenoid papules and
nodules on both lower extremities, especially their extensor aspect,
with scars forming in the center of the larger nodules, accompanied by
mild scale. Combined with the fact that the results of previous
examinations, the herpetic autoantibody test, and other examinations
were all negative, prurigo nodularis and herpes could be excluded. The
patient had intense itching, which is one of the important
manifestations of EBP. The patient had received traditional treatment
for more than 10 years, and while the progression of the disease had
been controlled to a certain extent, the outcome of itching relief was
unsatisfactory. The patient was treated with baricitinib in our hospital
with the hope of relieving the itching. During the 2 years of treatment
with baricitinib, the patient's skin rashes had subsided and flattened
significantly, and his itching was markedly relieved. The VAS itching
score of the patient was assessed at follow-up, and the point plot
showed that the score had gradually declined from 8--9 points to 2--3
points, indicating a greatly improved quality of life.

EBP is a persistent, recurring disease that seriously affects quality of
life. this study confirms that baricitinib is effective and feasible in
treating EBP, especially in significantly relieving itching, which
rendered new ideas for therapeutic approaches for EBP in the future.
Particularly important for patients suffering from severe itchiness.

\section*{REFERENCES}

{\label{references}}

\begin{enumerate}
\tightlist
\item
  Komatsu K, Yamaguchi S, Utsumi D, Yamamoto I, Takahashi K. A Case of
  Dominant Dystrophic Epidermolysis Bullosa with a G2043R Mutation in
  the Type VII Collagen Gene. Acta Dermatovenerol Croat. 2020
  Dec;28(4):251-252.
\item
  Wang Z, Lin Y, Duan XW, Hang HY, Zhang X, Li LL. Misdiagnosed
  dystrophic epidermolysis bullosa pruriginosa: A case report. World J
  Clin Cases. 2021 May 6;9(13):3090-3094. doi:
  10.12998/wjcc.v9.i13.3090.
\item
  Ferreira S, Azevedo A, Velho GC, Sanches M, Selores M. Epidermolysis
  Bullosa Pruriginosa successfully treated with concomitant topical and
  systemic agents. Australas J Dermatol. 2020 Nov;61(4):355-357. doi:
  10.1111/ajd.13342. Epub 2020 Jun 10.
\item
  Caroppo F, Milan E, Giulioni E, Belloni Fortina A. A case of
  dystrophic epidermolysis bullosa pruriginosa treated with dupilumab. J
  Eur Acad Dermatol Venereol. 2022 May;36(5):e365-e367. doi:
  10.1111/jdv.17887. Epub 2021 Dec 29.
\item
  Jiang X, Wang H, Lee M, Lin Z. Epidermolysis Bullosa Pruriginosa
  Treated With Baricitinib. JAMA Dermatol. 2021 Oct 1;157(10):1243-1244.
  doi: 10.1001/jamadermatol.2021.3174.
\item
  Kwon IJ, Kim SE, Kim SC, Lee SE. Efficacy of oral JAK1 or JAK1/2
  inhibitor for treating refractory pruritus in dystrophic epidermolysis
  bullosa: A retrospective case series. 2023 Dec 20. doi:
  10.1111/1346-8138.17079. Epub ahead of print.
\end{enumerate}

\section*{AUTHOR CONTRIBUTIONS}

{\label{author-contributions}}

\textbf{Zhe He:} Conceptualization; writing -- original draft; writing
-- review and editing. \textbf{Rui Zheng:} Writing -- original draft;
writing -- review and editing. \textbf{Qian Dong:} Writing -- original
draft; writing -- review and editing. \textbf{Yue Xi:} Writing --
original draft; writing -- review and editing.

\section*{FUNDING INFORMATION}

{\label{funding-information}}

None.

\section*{CONFLICT OF INTEREST
STATEMENT}

{\label{conflict-of-interest-statement}}

There are no conflicts of interest to declare.

\section*{ETHICS STATEMENT}

{\label{ethics-statement}}

None.

\section*{CONSENT}

{\label{consent}}

Written informed consent was obtained from the patient to publish this
report in accordance with the journal's patient consent policy.

\section*{DATA AVAILABILITY STATEMENT}

{\label{data-availability-statement}}

All the required information is in the manuscript itself.

\section*{ACKNOWLEDGMENTS}

{\label{acknowledgments}}

I would like to thank Dr. Rui Zheng for her kind guidance on this paper.

\textbf{Figure 1} Hyperkeratosis, epidermal hyperplasia, and fissures
can be seen at the junction of the true epidermis, inflammatory cells,
mainly lymphocytes, were seen around the vessels in the superficial
dermis (A, scale bar: 50\selectlanguage{greek}μ\selectlanguage{english}m). Epidermis showed subepidermal bulla. Dermis
shows mixed inflammatory infiltrate (B, HE\selectlanguage{ngerman}×40). multiple reddish-brown
hemispherical mung bean-to-soybean-sized nodules were symmetrically
distributed on the bilateral calves and right thigh, densely packed in
patches, some of which were anabrotic and crustosus due to the intense
itching (C and D). After 2 years of baricitinib treatment, the results
uncovered that the number of skin rashes on the outer side of both
thighs had decreased by half, and the color had become dull, although
some dark brown hyperpigmentation and scars remained on the extensor
aspect of both lower legs (E and F).

\textbf{Figure 2} Change in VAS after oral baricitinib treatment showed
a gradual downward trend, Patient's past and current treatment plan.\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/Figure1/Figure1}

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\end{figure}\selectlanguage{english}
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\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/Figure2/Figure2}

\end{center}
\end{figure}

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