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\begin{document}

\title{Tyrosine kinase inhibitor-induced severe bullous pemphigoid in a patient
with advanced stage of liver cancer: a case report and literature review}



\author[1]{Yu Li}%
\author[1]{Tingting Wang}%
\author[1]{Mi Wang}%
\affil[1]{West China Hospital of Sichuan University}%


\vspace{-1em}



  
  \date{May 27, 2024}


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\selectlanguage{english}
\begin{abstract}
Apatinib, a novel vascular endothelial growth factor receptor-2 (VEGFR2)
targeted chemotherapy for solid tumors, has revealed promising efficacy
in treating liver cancer in China. Although it has been reported to have
a high incidence of inducing hand-foot skin reactions, other skin
adverse reactions induced by apatinib are rare. Herein, we report a rare
case of apatinib-induced severe bullous dermatosis that was successfully
treated with methylprednisolone and summarize the dermatologic
toxicities of VEGFR tyrosine kinase inhibitor.%
\end{abstract}%



\sloppy


Title page

\textbf{Type of the study:} Case report

\textbf{Title:} Tyrosine kinase inhibitor-induced severe bullous
pemphigoid in a patient with advanced stage of liver cancer: a case
report and literature review

\textbf{Authors:} Li Y\textsuperscript{1,2}, Wang
M\textsuperscript{1,2}, Wang TT\textsuperscript{1,2*}

\textsuperscript{1}Author affiliations Department of Dermatology, West
China Hospital, Sichuan University, Chengdu, 610041, China

\textsuperscript{2}Laboratory of Dermatology, Clinical Institute of
Inflammation and Immunology, Frontiers Science Center for
Disease-related Molecular Network, West China Hospital, Sichuan
University, Chengdu, 610041, China

\textbf{*} Correspondence: Department of Dermatology, West China
Hospital, Sichuan University, Chengdu, 610041, China. Email:
wangtingting817@126.com

\textbf{Ethics statement:} All appropriate informed consent forms were
obtained from the patient's parent. The patient's parent gave written
informed consent for publication of the report details and associated
photographs. Institutional approval was not required to publish the case
details.

\textbf{Conflict of interest:} None.

\textbf{Financial support:} None.

\textbf{Author contributions:} LY and WTT designed the study and
acquired, analyzed, and interpreted the data. LY wrote the manuscript.
WTT and WM critically revised the manuscript for important intellectual
content. All authors have contributed to the manuscript and approved the
submitted version.

Tyrosine kinase inhibitor-induced severe bullous pemphigoid in a patient
with advanced stage of liver cancer: a case report and literature review

Yu Li\textsuperscript{1}, Mi Wang\textsuperscript{1,2}, Tingting
Wang\textsuperscript{1,2}

\textsuperscript{1}Author affiliations Department of Dermatology, West
China Hospital, Sichuan University, Chengdu, 610041, China

\textsuperscript{2}Laboratory of Dermatology, Clinical Institute of
Inflammation and Immunology, Frontiers Science Center for
Disease-related Molecular Network, West China Hospital, Sichuan
University, Chengdu, 610041, China

Correspondence: Tingting Wang

Department of Dermatology, West China Hospital, Sichuan University,
Chengdu, 610041, China. Email: wangtingting817@126.com

\textbf{1 Introduction}

Apatinib, a novel tyrosine kinase inhibitor targeted vascular
endothelial growth factor receptor-2 (VEGFR2) for solid tumors, has
revealed promising efficacy in treating liver cancer in China. Although
it has been reported to have a high incidence of inducing hand-foot skin
reactions, other skin adverse reactions induced by apatinib are rare.
Herein, we report a rare case of apatinib-induced severe bullous
dermatosis that was successfully treated with methylprednisolone and
summarize the dermatologic toxicities of VEGFR tyrosine kinase
inhibitor.

\textbf{Key words:} tyrosine kinase inhibitor, apatinib, drug adverse
reaction, bullous dermatosis

\textbf{2 Case presentation}

A 67-year-old man had a one-month history of erythema and multiple
bullae with itching and pain over the whole body (Figure 1A). Two years
ago, the patient was diagnosed with advanced hepatocellular carcinoma
and underwent chemoembolization and systemic treatment, including
half-year treatment of sorafenib (0.8 g/d) and one-year treatment of
lenvatinib (0.8 mg/d). However, he developed intermittent diarrhea after
the systemic treatment. One month prior, the patient began taking
apatinib mesylate (850 mg/d). After ten days, the patient presented with
patchy erythema, blisters, bullae, and erosion accompanying the oral
mucosa, which was affected by itching and pain. He was admitted to local
hospital and an initial diagnosis of pemphigus was considered, while
discontinuation of apatinib mesylate and symptomatic treatments were
ineffective. Then the patient was admitted to our department. Physical
examination revealed a few vesicles on the trunk, blood blisters on the
hands, and multiple erosions on the trunk, limbs, and scalp, while some
were covered with crust. Skin biopsy and immunofluorescence (IF) were
obtained from the right waist. The skin biopsy demonstrated subepidermal
blisters, individual dyskeratinized cells in the spinous layer,
vacuolized focal basal cells, and sparse lymphocyte infiltration around
the small vessels in the superficial dermis (Figure 2). Direct IF
displayed a basement membrane with linear deposition of IgA, IgG, and
C3, with negative indirect IF (Figure 3). His blood pressure was
120-150mmHg/60-90mmHg while fasting blood glucose fluctuates between 8
and 15mmol/L and postprandial blood glucose fluctuates between 5 and
23mmol/L. Furthermore, laboratory investigations depicted mild anemia,
hypoproteinemia, abnormal liver function, coagulopathy, fecal occult
blood, and urinary tract infection with negative serum autoantibodies
including anti-BP180, anti-Dsg1, anti-Dsg3, and anti-nuclear antibody.
Staphylococcus squirrels and Corynebacterium striatum were cultured from
buttock secretions. Chest CT indicated chronic bronchitis,
pneumonectasis, and mild pulmonary infection.

Based on these findings, the patient was diagnosed with apatinib-induced
bullous dermatosis (BP). The body weight of the patient was 45 kg.
Methylprednisolone (80 mg daily at the initial dose), antibiotics,
symptomatic treatments including albumin, niferex, furosemide, fresh
frozen plasma, insulun and skin care were initiated. Owing to his
multiple underlying diseases, he and his family were discharged after
two weeks of treatment (Figure 1A). Methylprednisolone was replaced with
oral prednisone 30 mg daily, and recombinant human epidermal growth
factor gel was added to promote wound healing. Then the patient took
prednisone 30 mg/d for 2 months by himself, the cutaneous and oral
erosions mostly healed, with a few epithelial islands growing. At the
3-month-follow up visit, the skin lesions of the patient completely
resolved (Figure 1B).

\textbf{3 Discussion}

Liver cancer, one of the fatal cancers worldwide, is often treated with
surgery, chemoembolization and chemotherapy\textsuperscript{1}.
Sorafenib and lenvatinib are first-line chemotherapy agents for the
treatment of hepatocellular carcinoma. However, owing to their
unsatisfactory results and numerous adverse side effects, many other
chemotherapeutic drugs have been investigated to treat this
disease\textsuperscript{2}. Apatinib mesylate is a novel tyrosine kinase
inhibitor (TKI) launched and approved in China in 2014. It can
efficiently and competitively bind to vascular endothelial growth factor
receptor-2 (VEGFR2), which inhibits angiogenesis in tumors and inhibits
tumor growth and progression\textsuperscript{3}.

As previously described, VEGFR TKIs have promising therapeutic efficacy
for multiple tumors. However, a few skin toxicities have also been
elucidated in the literature. In 2015, Massey et al. has revealed that
HFS, rash and pruritis were significantly associated with VEGFR TKIs
with the incidence of 0-37\%, 13-41\% and 14\%,
respetively\textsuperscript{4}. Other cutaneous side effects include
alopecia, pigmentation, depigmentation, xeroderma, ulcer and erythema
multiforme have been reported as well\textsuperscript{4,5}. The
management of these lesions could refer to previous
reviews\textsuperscript{6,7}. In terms of apatinib, commonly reported
side effects of apatinib to include hematologic toxicity, proteinuria,
hypertension, fatigue, nausea, vomiting et al.\textsuperscript{8}.
Regarding cutaneous lesions, the hand-foot syndrome (HFS) is the most
common skin reaction, which may result in a 50.5\%
incidence\textsuperscript{5}. Moreover, some cases have reported skin
pigmentation, rashes, and BP induced by apatinib\textsuperscript{9,10}.

There was only one case reporting that a 62-year-old female patient
developed drug-induced BP (DIBP) after taking apatinib (0.5 g/d) for two
weeks for breast cancer. In the present case, the patient developed
erythema and multiple bullae on the entire body after 10 days of
apatinib treatment. The Naranjo score (a tool used to assess the
possibility of drug-induced adverse reactions) was 7, which indicated a
probable adverse drug reaction of apatinib mesylate. Combined with skin
biopsy and DIF, apatinib-induced BP was diagnosed. The therapeutic
effect of methylprednisolone was significant. Clinical differential
diagnoses at the time of presentation included paraneoplastic pemphigus
(PNP). PNP is a rare, autoimmune disease associated with neoplasm.
Because the clinical features of PNP are polymorphous, it is sometimes
difficult to distinguish it from other bullous diseases.
Histopathological examination demonstrated suprabasal acantholysis and
dyskeratosis, while DIF demonstrated intercellular IgG and/or C3
deposition in the epidermis, with positive IIF\textsuperscript{11}.
However, the clinical and pathohistological findings of this patient
didn't conform to PNP, thus, the diagnosis of BP induced by apatinib was
finally made.

In fact, subepithelial autoimmune bullous dermatosis is a disease
spectrum that includes inherited and acquired bullous skin disorders,
such as BP, linear IgA bullous dermatosis, and lichen planus pemphigoid.
They can be induced either spontaneously or by some
drugs\textsuperscript{12}. In our case, BP was indicated by the
disruption of the basal membrane zone (BMZ) through autoantibodies. The
underlying mechanism may be due to drug ingestion acting as an
immunological trigger, which stimulates the hyperproduction of
autoantibodies, and then the autoantibodies appear to target multiple
antigens within BMZ\textsuperscript{13}. Referring to treating
autoimmune bullous dermatoses, the patient has been prescribed
glucocorticoids as initial therapy and achieved satisfactory
result\textsuperscript{14}.

\textbf{4 Conclusion}

VEGFR TKIs are promising therapeutics for multiple solid cancers.
However, all these molecular targeting agents are associated with a
variety of adverse events that can impact patients' quality of life.
Here, we report a rare and severe case of apatinib-induced BP, which
demonstrated the effectiveness of glucocorticoid therapy for DIBP.

\textbf{Ethics statement}

The patient provided informed consent.

\textbf{Fundings}

None

\textbf{Author contributions}

LY and WTT designed the study and acquired, analyzed, and interpreted
the data. LY wrote the manuscript. WTT and WM critically revised the
manuscript for important intellectual content. All authors have
contributed to the manuscript and approved the submitted version.

\textbf{Reference}

1. Anwanwan D, Singh SK, Singh S, Saikam V, Singh R. Challenges in liver
cancer and possible treatment approaches. Biochim Biophys Acta BBA - Rev
Cancer. 2020;1873(1):188314.

2. Geisler AN, Phillips GS, Barrios DM, et al. Immune checkpoint
inhibitor--related dermatologic adverse events. \emph{J Am Acad
Dermatol} . 2020;83(5):1255-1268.

3. Xie C, Zhou X, Liang C, et al. Apatinib triggers autophagic and
apoptotic cell death via VEGFR2/STAT3/PD-L1 and ROS/Nrf2/p62 signaling
in lung cancer. \emph{J Exp Clin Cancer Res} . 2021;40(1):266.

4. Massey PR, Okman JS, Wilkerson J, Cowen EW. Tyrosine kinase
inhibitors directed against the vascular endothelial growth factor
receptor (VEGFR) have distinct cutaneous toxicity profiles: a
meta-analysis and review of the literature. Support Care Cancer. 2015
Jun;23(6):1827-35.

5. Zheng Q, Ma Y, Shen F, et al. Case of bullous pemphigoid induced by
apatinib mesylate. \emph{Br J Clin Pharmacol} . 2021;87(4):2158-2159.

6. Chu CY, Chen KY, Wen-Cheng Chang J, Wei YF, Lee CH, Wang WM.
Taiwanese Dermatological Association consensus for the prevention and
management of epidermal growth factor receptor tyrosine kinase
inhibitor-related skin toxicities. J Formos Med Assoc. 2017
Jun;116(6):413-423.

7. Geisler AN, Phillips GS, Barrios DM, Wu J, Leung DYM, Moy AP, Kern
JA, Lacouture ME. Immune checkpoint inhibitor-related dermatologic
adverse events. J Am Acad Dermatol. 2020 Nov;83(5):1255-1268.

8. Wang J, Huang D, Yang W, et al. The efficacy and safety of Apatinib
in the treatment of advanced non-small cell lung cancer: A retrospective
trial. \emph{Front Oncol} . 2022;12:1030798.

9. Xia H, Zhou C, Luo Z, Zhang P, Zhu L, Gong Z. Apatinib-Induced
Hand--Foot Skin Reaction in Chinese Patients With Liver
Cancer.\emph{Front Oncol} . 2021;11:624369.

10. Liao Z, Li F, Zhang C, et al. Phase II trial of VEGFR2 inhibitor
apatinib for metastatic sarcoma: focus on efficacy and safety. \emph{Exp
Mol Med} . 2019;51(3):1-11.

11. Paolino G, Didona D, Magliulo G, et al. Paraneoplastic Pemphigus:
Insight into the Autoimmune Pathogenesis, Clinical Features and
Therapy.\emph{Int J Mol Sci} . 2017;18(12):2532.
doi:10.3390/ijms18122532

12. Montagnon CM, Tolkachjov SN, Murrell DF, Camilleri MJ, Lehman JS.
Subepithelial autoimmune blistering dermatoses: Clinical features and
diagnosis. \emph{J Am Acad Dermatol} . 2021;85(1):1-14.

13. Wakelin, Allen, Zhou, Wojnarowska. Drug-induced linear IgA disease
with antibodies to collagen VII. \emph{Br J Dermatol} .
1998;138(2):310-314.

14. Montagnon CM, Lehman JS, Murrell DF, Camilleri MJ, Tolkachjov SN.
Subepithelial autoimmune bullous dermatoses disease activity assessment
and therapy. \emph{J Am Acad Dermatol} . 2021;85(1):18-27.

\textbf{Legends to the figures}

\textbf{Figure 1.} Skin lesions of the patient. (A) Multiple bullae and
erosions appeared on the whole body before treatments and improved after
two weeks later. (B) At the 3-month-follow up, the skin lesions of the
patient completely resolved.\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/image1/image1}

\end{center}
\end{figure}

\textbf{Figure 2.} Histopathological images show subepidermal blisters,
individual dyskeratinized cells in the spinous layer, focal basal cells
vacuolized, and sparse lymphocyte infiltration around small vessels in
the superficial dermis. Hematoxylin-eosin stain: (A)\selectlanguage{ngerman}×40, (B)×100.\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/image2/image2}

\end{center}
\end{figure}

\textbf{Figure 3.} Direct immunofluorescence shows basement membrane
with linear deposition of (A) IgA, (B) IgG and (C) C3. Hematoxylin-eosin
stain:\selectlanguage{ngerman}×40.\selectlanguage{english}
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\includegraphics[width=0.70\columnwidth]{figures/image3/image3}

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\includegraphics[width=0.70\columnwidth]{figures/figure1AB/figure1AB}

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\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/figure2/figure2}

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\includegraphics[width=0.70\columnwidth]{figures/figure3/figure3}

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