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\begin{document}

\title{Management of erosive oral lichen planus associated with chronic
hepatitis C}



\author[1]{Taissir Medini}%
\author[1]{emira Besbes}%
\author[1]{wafa nasri}%
\author[2]{nouha abdejlil}%
\author[1]{jamil selmi}%
\affil[1]{University of Monastir Faculty of Dental Medicine of Monastir}%
\affil[2]{Fattouma Bourguiba University Hospital of Monastir}%


\vspace{-1em}



  
  \date{May 18, 2024}


\begingroup
\let\center\flushleft
\let\endcenter\endflushleft
\maketitle
\endgroup





\selectlanguage{english}
\begin{abstract}
Oral Lichen Planus (OLP) and chronic hepatitis C association have been
widely discussed. Here, we presented a case of extensive, erosive OLP in
a hepatitis C virus-positive patient for whom clinical management was
challenging. Full remission was obtained after topical corticosteroid
application and several sessions of oral cavity sanitation.%
\end{abstract}%



\sloppy


\textbf{MANUSCRIPT}

\textbf{Title. Management of erosive oral lichen planus associated with
chronic hepatitis C}

\textbf{Authors\emph{.}}

Taissir MEDINI (DMD)\textsuperscript{\textbf{1,2}}Amira BESBES (DMD,
MSc)\textsuperscript{\textbf{1,2,3}}Wafa NASRI
(DMD)\textsuperscript{1,4,5}Nouha BEN ABDELJELIL (MD)
\textsuperscript{\textbf{6}}

Jamil SELMI (DMD) \textsuperscript{\textbf{1,2,5}}

\textbf{Full contact details of the authors\emph{.}}

1: University of Monastir, Faculty of Dental Medicine, 5019 Monastir,
Tunisia

2: Department of Oral Surgery and Oral Medicine, Dental Medicine
University Clinic of Monastir, Monastir, Tunisia.

3: Research Laboratory of Medical and Molecular Parasitology and
Mycology LR12ES08, Faculty of Pharmacy, University of Monastir, Tunisia

4: Periodontology Department, Dental Medicine University Clinic of
Monastir, Monastir, Tunisia.

5: Research Laboratory of Oral Health and Oral Rehabilitation LR12ES11,
Faculty of Dental Medicine, University of Monastir, Tunisia

6: Department of Cytopathology, Fattouma Bourguiba University Hospital,
University of Monastir, Monastir, Tunisia.

\textbf{Email addresses of all authors (listed by authors' initials).}

\textbf{TM:} \textbf{ORCID}:\emph{https://orcid.org/0000-0001-5254-7241}

\textbf{AB: ORCID:}\emph{https://orcid.org/0000-0003-3742-8687}

\textbf{WN~:}
\textbf{ORCID:}\emph{https://orcid.org/0000-0003-1002-8050}

\textbf{NB~:} \emph{nouhaba@yahoo.fr}

\textbf{JS:}\emph{jamilselmimbcb@gmail.com}



\section*{Authors' contributions.}

{\label{authors-contributions.}}

\textbf{TM} study design, draft, and manuscript editing\textbf{AB}
patient management, study design, draft, and manuscript editing TM and
AB have the same contribution to this paper\textbf{WN} study design,
manuscript editing\textbf{NB} study analysis\textbf{JS} manuscript
editing

All authors read and approved the final manuscript.

\textbf{Corresponding author.}

Taissir Medini. Oral Surgery and Oral Medicine Department, University
Clinic of Dental Medicine,

Avicenne Street 5019

Monastir, Tunisia.

\textbf{Email:}\emph{taissirmedini@gmail.com} .\textbf{Tel:} +216
92989254.

\textbf{Patient's consent}

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

Manuscript words number: 2181

Abstract words number: 49

Number of references: 44

Number of figures:5

Number of tables: 0

Appendix: No



\textbf{Abbreviations list}

\textbf{HVC:} Hepatitis C virus

\textbf{OLP:} Oral lichen planus

\textbf{LP:} Lichen planus

\textbf{EHMs:} Extrahepatic manifestations

\selectlanguage{greek}\textbf{IFN-α:} \selectlanguage{english}Interferon-alpha

\textbf{DAA:} Direct-acting antiviral



\textbf{ABSTRACT}

Oral Lichen Planus (OLP) and chronic hepatitis C association have been
widely discussed. Here, we presented a case of extensive, erosive OLP in
a hepatitis C virus-positive patient for whom clinical management was
challenging. Full remission was obtained after topical corticosteroid
application and several sessions of oral cavity sanitation.

\textbf{Key Clinical Message}

Dentists play a major role in diagnosing and managing Oral Lichen
Planus. They may also contribute to~hepatitis C infection screening.
Thus the importance of regular follow-ups to prevent disease relapses,
exacerbations, or malignant transformations.

\textbf{Keywords}

Oral lichen planus, Hepatitis C virus, viral infection, oral diseases

\textbf{Introduction}

The first histologically confirmed case of Oral Lichen Planus (OLP) in a
patient with chronic hepatitis C was reported in 1991 (1). A
meta-analysis integrating around forty studies showed that the hepatitis
c virus (HCV) -OLP association was significant (2). In addition, the
erosive form of OLP has been reported to be preferentially associated
with HCV infection (1). However, more recent studies have shown
significant variations in the OLP-HCV association according to patients'
age and geographic origin (3). In particular, the presence of the
broad-antigen serotype HLA-DR6 allele would be partly responsible for
variations in the HCV-OLP association depending on the geographical area
(4).

Hepatitis C virus is an enveloped RNA virus with an essentially hepatic
tropism(5). This virus, capable of causing chronic infection in humans,
is responsible for the hepatitis C epidemic, a severe consequence of
which concerns the occurrence of hepatic carcinoma. The recent
development of very effective antiviral molecules makes it possible
today to have very effective treatments to fight against hepatitis C.
However,

some of these antiviral therapies such as interferon-alpha (IFN-\selectlanguage{greek}α\selectlanguage{english}) and
ribavirin therapy

were incriminated in the OLP onset (6).

This paper aims to highlight the importance of dentists' role in
screening HCV infection associated with OLP, and the value of dental
care and follow-ups in relieving the patient and preventing malignant
transformation.

\textbf{Case report}

A 70-year-old female patient consulted the oral medicine and oral
surgery department of the academic dental clinic of Monastir, Monastir,
Tunisia, with a chief complaint of 5 months on defusing oral lesions
causing pain, burning mouth sensation, and discomfort, especially with
chewing and speaking.

The medical history was significant to hypothyroidism, high blood
pressure, Cardiac arrhythmia, and type II diabetes mellitus. Her
medication included Levothyrox\selectlanguage{ngerman}® 125\selectlanguage{greek}µ\selectlanguage{english}g per day, Actopril\selectlanguage{ngerman}®, and insulin
injections.

Extraoral examination showed itchy purplish patches over the arms and
legs, and diffuse crusty ulcerative lesions over her lower lip (Figure
1A). These lesions were painful, bleeding with a tendency to infiltrate
the adjacent skin.

The intraoral examination revealed poor oral hygiene, a deteriorated
metallo-resinous bridge extending from the right mandibular canine to
the second left premolar, and multiple amalgam fillings.

Diffuse erosive areas extending from the premolars region up to the
retromolar area of the buccal mucosa were detected (Figures 1B and 1C).
These erosions were surrounded by white radiating striae from the
periphery of the lesions symmetrically on both sides. Similar lesions
with an erythematous background were noted over the upper and lower,
anterior and posterior vestibular regions, dorsal and ventral surfaces
of the tongue, and the interior surface of the lower lip (Figures 1D and
1E), and posterior maxillary edentulous ridge (Figure 1F). Gingiva
showed marginal erythema with superficial erosion on the attached
gingiva. The lesions were extremely painful and sensitive to touch.\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/image1/image1}

\end{center}
\end{figure}

Although a secondary infection with candidiasis was suspected, the
initial diagnosis was highly suggestive of erosive oral lichen planus.

Oral swabs~were obtained from the above-mentioned locations for
microbiological

examinations which showed numerous pale yellowish dome-shaped colonies
of C.

albicans when cultured in Chromagar\selectlanguage{ngerman}® medium.

An initial prescription of antiseptic mouth wash (chlorhexidine, 0.12\%)
along with a topical antifungal agent (Fungizone®) 3 times a day for 2
weeks was made to treat the fungal infection. She was subjected to a
complete hemogram, hepatitis B and C serology blood test, and Thyroid
blood tests. After 2-week's follow-up, the patient reported a slight
improvement in symptoms (Figures 2A, 2B, 2C, and 2D).\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/image2/image2}

\end{center}
\end{figure}

Sanitation of the oral cavity was initiated with periodontal scaling,
root planning, and the removal of the bridge. Regarding the blood test
results, all the hemogram parameters were found to be within the normal
range. Thyroid blood tests revealed a hypothyroidism FT4: 23,88 pmol/L
(10-22) and TSH\textless{}0,05 \selectlanguage{greek}µ\selectlanguage{english}L/ml (0.27-4,2), and an HCV serology
using ELFA (Enzyme-Linked Fluorescent Assay) was positive.

An incisional biopsy of the lesion was performed under local anesthesia
(Medicaine 2\% with adrenaline 1/100.000\selectlanguage{ngerman}®, Medis, Tunisia) from the left
buccal mucosa. The specimen was divided into two parts, the first was
kept in 10\% formalin and submitted to the anatomopathological
examination and the second was immediately placed in saline~solution and
immediately transported for direct immunofluorescence analysis.

The anatomopathological results revealed a band-like infiltrate made up
of lymphocytes and plasma cells associated
with~liquefaction~degeneration of the~basal cell layer confirming the
diagnosis of erosive OLP (Figure 3).\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/image3/image3}

\end{center}
\end{figure}\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/image4/image4}

\end{center}
\end{figure}

Topical corticosteroids (Solupred\selectlanguage{ngerman}® 20 mg) were prescribed as a mouth
rinse 3 times a day. The patient was subjected to regular follow-ups
(Figures 4A, 4B, 4C, 4D, 4E, 4F) and dose tapering after 6 months when
the erosive lesions and symptoms completely regressed (Figures 5A, 5B,
5C, 5D, 5E).

The patient is followed up with the collaboration of the
gastroenterology and hepatology department.\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/image5/image5}

\end{center}
\end{figure}\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/image6/image6}

\end{center}
\end{figure}

\textbf{Discussion}

Oral lichen planus (OLP) is a chronic inflammatory disease of unknown
etiology that can occur as either a single condition of the oral mucosa
or in association with lesions in genital mucosae,~skin, or nails (7).

This disease is believed to affect around 0.2 to~2.3 percent of the
overall population~and accounts for nearly 0.6 percent of all conditions
discovered by dentists regularly~(7). OLP~is widely distributed~and
affects all racial and ethnic groups, but it is most frequent in
middle-aged female~adults~(8).

The clinical manifestations of OLP are largely polymorphic. Keratotic
lesions, such as papules, reticular, or plaque-like lesions, are
frequently associated~with atrophic, erosive, ulcerative, or bullous
forms~(9). The erosive form is characterized by a variety of symptoms
ranging from moderate discomfort to severe functional disturbances that
affect the~quality of life. Lesions are usually found bilaterally on the
posterior buccal mucosa. The dorsal tongue, labial mucosa, and gingiva
might also be impacted. Gingival mucosa involvement is referred as
desquamative gingivitis (7).

The numerous factors that can trigger a cell-mediated reaction that
results in OLP are discussed elsewhere. (7) Among the exogenous factors,
several infectious agents, including viruses, have been associated with
OLP.

Among the eight recognized human herpesviruses four (\emph{Herpes
simplex 1, Cytomegalovirus, Epstein-Barr virus, Herpesvirus 6} ) have
been implicated in OLP as well as the \emph{human papillomavirus} ,
the\emph{human immunodeficiency virus,} and \emph{hepatitis viruses B}
and mainly \emph{C} (10).

HCV infection is a common illness, with an estimated 71 million people
worldwide chronically afflicted (11). Extrahepatic manifestations (EHMs)
afflict about 74 percent of persons with HCV. (12).

Xerostomia, sialadenitis, Sj\selectlanguage{ngerman}ögren's disease, OLP, oral verrucous and
squamous cell carcinomas (13), bleeding disorders, cheilitis,
gingivitis,~smooth and atrophic tongue, autoimmune bullous diseases such
as Pemphigus Vulgaris and bullous pemphigoid (14, 15) are among the
recorded EHMs in the oral cavity (15). As hepatitis C is most often
asymptomatic, EHMs may be the first symptom of infection.

A recent systematic review and meta\selectlanguage{english}-analysis concluded that the overall
prevalence of HCV in OLP patients was 22.3\% (16). This prevalence
varies according to geographical variations. A possible explanation is
that the high co-occurrence of HCV and OLP in some geographic regions
may be linked to an endemic distribution of HCV in those world
regions(17).

Globally, the prevalence of HCV shows regional variations with an
average of 3\%, which is very likely to be underestimated. According to
the latest World Health Organization global hepatitis Report in 2017
(18), the prevalence is the highest in the Eastern Mediterranean region
(2.3\%), followed by the European region (1.5\%), whereas the South-East
Asia region has the lowest prevalence (0.5\%). Inside these regions, the
difference in prevalence can be important (19).

In North Africa, the prevalence of HCV in the general population is
estimated between 1.2 and 1.9 percent (20). Although, a recent
systematic review showed that the prevalence in Tunisia between 1991 and
2019 did not exceed 1\% in the general population, making it a
low-endemic country (21).

Even though the association between OLP~and chronic HCV infection seems
to be well developed, the pathogenesis raises questions. Several
hypotheses are currently being useful in explaining this association:

\begin{itemize}
\tightlist
\item
  The Hepatitis C virus initiates an auto-immune process, and the
  association of LP~with other auto-immune diseases such as
  diabetes,~vitiligo, or~myasthenia gravis~lends support to this theory
  (22).
\item
  HCV directly affects cellular replication and causes immunological
  changes that lead to the occurrence of LP~(23).
\item
  In chronic HCV immunological alterations~and circulating
  autoantibodies can emerge: ~anti-cardiolipin antibodies, anti-nuclear
  autoantibodies, anti-mitochondrial antibodies, anti-smooth muscle
  antibodies, rheumatoid factor, and anti-thyroperoxidase
  antibodies.~The lymphotropism of HCV~explains~the serological
  auto-immune expressions (24).
\end{itemize}

Several differences were observed when comparing OLP~patients who
have~liver diseases and those who have a normal liver function. Thus,
patients with chronic liver diseases exhibit extensive forms of OLP,
with frequent periods of exacerbation of symptoms~refractory to
treatment, which~is commensurate with the severity of the liver disease
(25).

The acute~erosive form of OLP~is mostly related to chronic~HCV
infection~in a phase that is biologically revealed by elevated serum
levels of~transaminases and increased viral replication.

Although in a recent study published by Arduino et al.~(26) the
automatic screening for HCV in OLP patients must be discussed since the
general prevalence of HBV in the younger population is remarkably
decreased.

However, in our case, it was important to investigate the viral
implication of HCV since the patient was an old female living in a rural
community, where there is a shortage of investigational, preventive, and
educational campaigns on infectious diseases, also to manage the OLP
with the collaboration of infectious disease specialists to balance the
underlying and appropriate therapy.

Another issue is the necessity to test all patients diagnosed with OLP
for the presence of HCV infection, as this liver disease often
progresses asymptomatically for a long period and goes undetected (1).

In determining the~therapeutic approach of OLP, several factors must be
considered; cost-effectiveness, patient's~medical and dental history,
drug interactions, treatment adherence, and psychological conditions.
Early therapy based on a clear diagnosis is crucial (27).

Topical corticosteroids are recommended as first-line therapy for OLP
(28). These drugs control inflammation and immunological response (29).
If topical treatments are ineffective, systemic corticosteroids may be
more useful.

Other Immunomodulatory drugs such as calcineurin inhibitors or retinoids
or systemic immunosuppressives may be beneficial when topical and
systemic corticosteroids are ineffective (28).

Biologic agents ( such as alefacept, efalizumab, basilixima,
polysaccharide nucleic acid fraction of bacillus Calmette--Guerin
(BCG-PSN)\ldots{}) have recently been used (28). However, due to the
high cost, their application in OLP is limited to severe and
refractory~cases (28).

In OLP patients with localized plaques or non-healing erosions, surgical
excision can be indicated (30). Cryosurgery has been used to treat
erosive and drug-resistant OLP, however lesions may turn~into
scars~(31).

Several research explored desquamative gingivitis in OLP patients, where
gingival lesions are chronic and severe. This is caused by plaque
accumulation which is higher in OLP patients, due to a decreased
frequency of tooth brushing, leading to an increased risk of long-term
periodontal disorders(32). Periodontal therapy including biofilm
reduction, scaling, and root planning in association with a decay
treatment and strict oral hygiene must be carried out with topical
corticosteroids prescription for a better result (33).

In severe and refractory cases of erosive OLP, ultraviolet A (PUVA)
therapy and photodynamic therapy have been employed (34).

The effect of laser therapy on erosive forms of OLP was reported in
different studies (Diode laser (35), biostimulation with a pulsed diode
laser (36), carbon dioxide laser evaporation (37), and low dose excimer
laser with ultraviolet B rays (38)). Although promising results were
reported, the effectiveness of this treatment approach is yet to be
proven (34).

For HCV management, interferon-alpha (IFN-\selectlanguage{greek}α\selectlanguage{english}) monotherapy or combined
therapy of IFN-\selectlanguage{greek}α \selectlanguage{english}and ribavirin are typical treatments for chronic HCV.
Several studies investigated the effect of IFN-\selectlanguage{greek}α \selectlanguage{english}therapy on HCV patients
with OLP, finding that IFN-\selectlanguage{greek}α \selectlanguage{english}either improved, triggered, or exacerbated
OLP lesions (6, 34, 39).

This suggests that HCV was not the primary cause of OLP and that other
host-related factors, according to the authors, may have a role in the
pathogenesis of HCV-related OLP (40).

Direct-acting antiviral (DAA) therapy is currently recommended as a
treatment for chronic HCV, based on the degree of liver fibrosis, HCV
genotype, resistance variants, previous treatment failure, and
comorbidities. The advantages of DAA over IFN-\selectlanguage{greek}α \selectlanguage{english}and ribavirin therapy
are an increased response rate and reduced length of therapy (34, 39).

The effectiveness of DAA on OLP lesions was studied, and there are
reports of improvement (41), In contrast, cases of OLP worsening and
development of new cutaneous and genital LP were observed (42).

The studies of Nagao Y. and Tsuji M. (43) highlighted the importance of
dentists in detecting HCV infection in patients with oral mucosal
disorders who have not yet been treated. In the present case, we should
emphasize that HCV infection could be discovered with OLP as a result of
a dentist's demand for a complete investigation of hepatic disease.
Dentists can also play an important role in the improvement of patients'
life quality by providing adequate dental care. Periodic follow-ups are
mandatory to prevent malignant transformation. It has been shown that
oral cancer can be developed on OLP, particularly if associated with
Hepatitis C infection (44).

\textbf{Sources of financial support.} None

\textbf{Acknowledgments.} The authors are grateful to the patient and
her family for their cooperation.

\textbf{Conflict of Interest.} The authors declare that there is no
conflict of interest.

\textbf{Informed consent} was obtained from the patient. The treatment
was conducted following the Helsinki Declaration.

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