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\begin{document}

\title{Successful Treatment of Resistant Plantar Ulcerative Lichen Planus with
Tofacitinib: A Case Report and Comprehensive Review of the Literature}



\author[1]{Afsaneh  Sadeghzadeh-Bazargan}%
\author[1]{Alireza Jafarzadeh}%
\author[1]{Niloufar Najar Nobari}%
\affil[1]{Iran University of Medical Sciences}%


\vspace{-1em}



  
  \date{May 23, 2024}


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\textbf{Introduction:}

Lichen Planus is a skin disease that can also affect the mucous
membranes and nails (1, 2). The skin manifestations of this disease are
multiple purple papules often accompanied by itching (3). The mucosal
involvement of this disease is known as mucosal erosions that often
involve the oral mucosa and genital area (4).

One of the rare types of this skin disease is called ulcerative lichen
planus, which presents as chronic ulcers resistant to treatment,
associated with pain and many disabilities for patients (5, 6). The
involvement of the soles of the feet is one of the most significant
areas affected by ulcerative lichen planus. Despite several treatment
options having been studied in the past, treating plantar ulcerative
lichen planus remains a challenge for dermatologists (4-8).

Tofacitinib, a Janus Kinase inhibitor, has a special place in the
treatment of inflammatory diseases in medicine (9). Recently, studies
have shown its effectiveness in treating various skin diseases such as
psoriasis, alopecia areata, vitiligo, and atopic dermatitis (10). In
recent studies, the effectiveness of this drug in treating certain types
of lichen planus has been mentioned, including lichen planopilaris and
erosions of the oral mucosa (9, 11).

In this article, we presented a case of plantar ulcerative lichen planus
that was initially resistant to treatment but exhibited a remarkable
response upon being treated with oral tofacitinib. In addition, we
conducted a comprehensive review of literature on the efficacy of
tofacitinib in treating various types of lichen planus lesions, while
also discussing other proposed treatments for plantar ulcerative lichen
planus\textbf{.}

\textbf{Case Presentation:}

A 52-year-old woman with a known case of lichen planus was referred to
our clinic with a large ulcerative lesion in the plantar area. Her
lichen planus disease started 9 years ago with skin involvement and
erosion of the oral mucosa. The patient was treated with cyclosporine
tablets 100 mg three times a day and triamcinolone acetonide injection
with a concentration of 5 mg/ml in the mucosal erosion site, which
resulted in improvement of her mucosa and skin condition during the
3-year treatment period. No other diseases were mentioned in the medical
history taken from her, and no drug treatments were mentioned except for
the one prescribed for the treatment of lichen planus. Three years ago,
the patient developed erythema in the sole area, which gradually
progressed over 2 years and eventually led to erosion and ulceration
(Figure 1).

A biopsy sample was taken from the lesion, and the pathologist reported
findings consistent with lichen planus, including hyperkeratosis,
irregular acanthosis, hypergranulosis, basal layer degeneration,
band-like lymphocytic infiltration, civatte body, and melanin
incontinence. Despite the treatment with cyclosporine tablets (100 mg,
three times a day), no satisfactory clinical improvement was observed in
the lesion. Additionally, the patient experienced an increase in blood
pressure following the use of the drug. As a result, the medication was
discontinued, and the patient was referred to our clinic for further
evaluation and treatment.

After obtaining a detailed medical history, a clinical examination was
performed on the patient. The examination revealed an ulcer in the sole
of the foot with an irregular and crusted border. There were no signs of
infection, and the lesion was exuding. No skin lesions were observed in
other areas, and the mucous membranes of the mouth and genitals appeared
to be free of erosions. Upon reviewing the pathology report and
considering the patient's refusal to undergo further sampling, a
diagnosis of ulcerative lichen planus was proposed.

Routine blood tests were ordered for the patient, but no pathological
findings were observed. She was prescribed methotrexate tablets at a
dose of 15 mg per week and triamcinolone acetonide injection with a
concentration of 5 mg/ml at monthly intervals as part of her treatment
plan. After 8 months from the start of the treatment, there was partial
recovery in the lesions, but the patient's ulcer had not completely
healed. Therefore, while re-examining the blood tests, tofacitinib 5 mg
tablets were prescribed twice a day. After completing a one-month course
of the drug, the patient's ulcer completely healed, and no side effects
were reported by the patient (Figure 1).\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/image1/image1}

\end{center}
\end{figure}

\textbf{Fig 1.} Improvement of plantar ulcerative lichen planus after
receiving tofacitinib. \textbf{A:} A patient with lichen planus
presented with a treatment-resistant ulcer on the sole of their
foot.\textbf{B:} There was an improvement in the ulcer after the patient
received one month of tofacitinib treatment.

\textbf{Discussion:}

Plantar Ulcerative Lichen Planus is a rare form of lichen planus that
causes disability and numerous problems for patients (6). Various
treatments have been proposed for this type of disease, which have been
associated with varying degrees of recovery (5-8). In this article, we
present the case of a 52-year-old woman who had a large ulcer on the
sole of her foot that did not heal completely with previous treatments,
including cyclosporine, methotrexate, and triamcinolone acetonide
intralesional injection. She was then prescribed tofacitinib 5 mg
tablets to be taken twice a day, and as a result, the lesion has now
completely healed.

Janus Kinases play an essential role in the transmission of gamma
interferon signals, which are important mediators in the pathogenesis of
lichen planus. Based on this, the drug tofacitinib, which inhibits all
types of Janus kinases, should theoretically be effective in the
treatment of lichen planus (2). In a retrospective review study
published by Plante et al. in 2020, nine previous studies were examined
in which lichen planopilaris patients responded to oral and topical
treatments with tofacitinib. Among the studies reviewed, six studies
investigated oral tofacitinib, and in most cases, a daily dose of 10 mg
was prescribed (9).

It is worth mentioning that another study conducted by Damsky et al. in
2020 reported significant improvement in three patients with
treatment-resistant erosive lichen planus. These patients had not
responded to treatment with cyclosporine, methotrexate, acitretin,
prednisone, and mycophenolate mofetil, but showed a dramatic response to
treatment with tofacitinib at a dose of 5 mg twice a day (11).

Comparing the above study with our study, it is worth noting that our
study involved the plantar surface of the foot, while the other study
involved areas such as oral, penile, ocular, and vaginal mucous
membranes in three patients. The dose used in our study was similar to
the other study, and complete or near-complete treatment responses were
seen in both studies. It is also worth mentioning that the lesions in
both studies were resistant to previous treatments such as cyclosporine
and methotrexate.

In a case report study conducted by Kozlov et al. in 2023, a case of
severe esophageal lichen planus recovery after treatment with
tofacitinib was reported. The study introduced an 89-year-old woman with
lichen planus involving the skin, genital mucosa, mouth, and esophagus.
The patient's esophageal lesions were resistant to treatment with
cyclosporine. While the patient did not respond well to the initial
treatment with tofacitinib at a dose of 5 mg daily, her dysphagia and
weight loss improved after receiving a dose of 5 mg twice a day (12).
The results of this study were consistent with our study, where both
studies showed improvement of the lesion and absence of side effects and
recurrence with a daily dose of 10 mg of tofacitinib. An important point
in this study is the necessity of receiving the appropriate dose of the
drug to control the lesions, as the lesions did not respond to a lower
dose of the drug (5 mg daily).

A case report study by Kilic et al. (2017) documented successful
treatment for erosive lichen planus with cyclosporine tablets in a
65-year-old woman with an erosive plaque on the sole of her foot. After
five months of treatment at a dosage of 3 mg/kg per day, the patient
showed significant improvement (4). However, the outcome of this study
differs from that of your study, as the patient's lesion in Kilic et
al.'s study was erosive, while yours was ulcerative.

This difference in lesion type may explain the varying results observed
with the use of cyclosporine mist. It is possible that cyclosporine mist
could be effective in treating initial forms of erosive lichen planus
lesions in the soles of the feet, but its effectiveness could decrease
as the lesion progresses to the ulcerative form. However, further
comprehensive studies with appropriate sample sizes would be necessary
to confirm this hypothesis.

In the Salavastru study conducted in 2010, a significant improvement in
ulcerative lichen planus lesions on the soles of a 77-year-old woman was
noted after four weeks of treatment with tacrolimus ointment 0.1\% twice
a day (8). However, the use of tacrolimus ointment in ulcerative lesions
presents a challenge of systemic drug absorption, and caution should be
taken in this regard.

Similarly, in the Kandula study conducted in 2018, a 56-year-old woman
presented with a painful ulcer on the metatarsal and plantar level of
the big toe, which responded dramatically to treatment with prednisone
tablets 40 mg daily in combination with clobetasol ointment 0.05\% twice
a day for two weeks (6). However, the use of prednisone, particularly in
older individuals, can have serious side effects.

In addition to the drug treatments discussed in the reviewed studies,
surgical methods have also been reported to improve erosive and
ulcerative lesions of the soles of the feet in lichen planus disease.
For instance, Miotti et al. in 2020 reported successful treatment of
erosive lichen planus in the plantar area with autologous micrografts
and methotrexate tablets. The study involved a 65-year-old woman with a
6-year history of foot sole ulceration caused by erosive lichen planus,
who responded well to treatment with 15 mg of methotrexate tablets per
week and autologous skin grafting from the thigh area (7). However, this
study differs from ours since it combines drug therapy with surgery in
treating ulcerative lesions of lichen planus. It's worth noting that
using invasive and surgical methods in lesion treatment may not be
acceptable to many patients.

If the effectiveness of these treatments is confirmed in wider studies,
each patient's benefit and harm from each treatment method should be
calculated separately. The summary of studies on erosive and ulcerative
lichen planus in the sole area is presented in Table 1.

\textbf{Table 1.} Comparison of studies conducted on erosive and
ulcerative lichen planus in the sole area from 2010 to 2023.\selectlanguage{english}
\begin{longtable}[]{@{}lllllll@{}}
\toprule
\begin{minipage}[b]{0.12\columnwidth}\raggedright\strut
Goucha study (5).\strut
\end{minipage} & \begin{minipage}[b]{0.12\columnwidth}\raggedright\strut
Miotti study (7).\strut
\end{minipage} & \begin{minipage}[b]{0.12\columnwidth}\raggedright\strut
Salavastru study (8).\strut
\end{minipage} & \begin{minipage}[b]{0.12\columnwidth}\raggedright\strut
Kilic study (4).\strut
\end{minipage} & \begin{minipage}[b]{0.12\columnwidth}\raggedright\strut
Kandula study (6).\strut
\end{minipage} & \begin{minipage}[b]{0.12\columnwidth}\raggedright\strut
Our study\strut
\end{minipage} & \begin{minipage}[b]{0.12\columnwidth}\raggedright\strut
Variables\strut
\end{minipage}\tabularnewline
\midrule
\endhead
\begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
Female\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
Female\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
Female\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
female\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
Male\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
Female\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
Gender\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
38\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
65\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
77\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
65\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
56\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
52\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
Age(years)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
None\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
Type 2 diabetes mellitus/ hypertension/dyslipidemia/ obesity/ chronic
renal failure/ anemia/ erosive gastritis\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
Erosion of the oral mucosa/ Skin papules of lichen planus\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
Hashimoto's thyroiditis/ History of cholecystectomy and
hysterectomy\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
Tongue ulcer\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
None\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
Comorbidities\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
Oral prednisone 90 mg/day\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
methotrexate 15 mg tablet once a week and Autologous micrografts\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
Tacrolimus 0.1\% ointment\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
Cyclosporine tablet with a dose of 3 mg/kg/day\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
Oral prednisone 40 mg once daily and clobetasol 0.5\% twice daily\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
Tofacitinib 5mg tablet twice daily p.o.\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
Treatment\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
3 weeks\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
2 weeks\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
4 weeks\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
5 month\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
2 weeks\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
One month\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
The time between starting the drug and complete recovery\strut
\end{minipage}\tabularnewline
\bottomrule
\end{longtable}

\textbf{Conclusion:}

In this study, we report a case of plantar ulcerative lichen planus that
showed a remarkable therapeutic response to treatment with tofacitinib
tablets. We have introduced a suitable treatment option for these
lesions and added another application to the set of tofacitinib's
applications in treating skin diseases. It is recommended to conduct
more extensive studies with a larger sample size in the future to
confirm this therapeutic application.

\textbf{References:}

1. Kozlov M, Levit EK, Silvers DN, Brichkov I. Severe Esophageal Lichen
Planus Treated With Tofacitinib. Cutis. 2023;111(3):155-63.

2. Di Lernia V. Targeting the IFN-\selectlanguage{greek}γ/\selectlanguage{english}CXCL10 pathway in lichen planus.
Medical Hypotheses. 2016;92:60-1.

3. U\selectlanguage{ngerman}çmak D, Azizo\selectlanguage{polish}ğ\selectlanguage{english}lu R, Harman M. Palmoplantar lichen planus: a report
of four cases. J Clin Exp Invest www clinexpinvest org Vol. 2011;2(1).

4. K\selectlanguage{polish}ı\selectlanguage{english}l\selectlanguage{polish}ı\selectlanguage{ngerman}ç FA, Baysak S, Esim AG, Lebe B. A case of erosive lichen planus
with plantar involvement. 2017.

5. Goucha S, Khaled A, Bennani Z, Rammeh S, Zéglaoui F, Zermani R, et
al. Erosive lichen planus of the soles: Effective response to
prednisone. Dermatology and therapy. 2011;1:20-4.

6. Kandula P, Elosiebo R, Mousdicas N. Plantar ulcerative lichen planus:
rapid improvement with a novel triple-therapy approach. Cutis.
2018;102(2):131-5.

7. Miotti G, Zingaretti N, Guarneri G, Manfrè V, Errichetti E, Stinco G,
et al. Autologous micrografts and methotrexate in plantar erosive lichen
planus: healing and pain control. A case report. Case Reports in Plastic
Surgery and Hand Surgery. 2020;7(1):134-8.

8. S\selectlanguage{polish}ă\selectlanguage{english}l\selectlanguage{polish}ă\selectlanguage{english}v\selectlanguage{polish}ă\selectlanguage{english}stru C, Tiplica GS. Therapeutic Hotline: Ulcerative lichen
planus--treatment challenges. Dermatologic Therapy. 2010;23(2):203-5.

9. Plante J, Eason C, Snyder A, Elston D. Tofacitinib in the treatment
of lichen planopilaris: A retrospective review. Journal of the American
Academy of Dermatology. 2020;83(5):1487-9.

10. Tegtmeyer K, Zhao J, Maloney NJ, Atassi G, Beestrum M, Lio PA.
Off-label studies on tofacitinib in dermatology: a review. Journal of
Dermatological Treatment. 2021;32(4):399-409.

11. Damsky W, Wang A, Olamiju B, Peterson D, Galan A, King B. Treatment
of severe lichen planus with the JAK inhibitor tofacitinib. Journal of
Allergy and Clinical Immunology. 2020;145(6):1708-10. e2.

12. Kozlov M, Levit EK, Silvers DN, Brichkov I. Severe Esophageal Lichen
Planus Treated With Tofacitinib. Cutis. 2023;111(3).

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