Oral Lichen Planus

Introduction

Oral lichen planus (OLP) is a chronic, immune-mediated inflammatory disease that primarily affects the mucous membranes of the mouth. It is considered a T-cell-mediated condition, where specific T cells accumulate and infiltrate the epithelium, leading to inflammation.^[1] OLP is a subgroup of lichen planus (LP), a broader condition that can manifest in various body areas, including the skin, scalp, nails, and other mucous membranes.^[1] While cutaneous LP is often transient, OLP is typically chronic, often causing a burning sensation and sometimes erosion, and can be more resistant to treatment.^[1] It affects approximately 0.1%–3.2% of the adult population and is most common in middle-aged adults, with females accounting for 60%–75% of individuals with OLP.^[1]

Biological Basis

The underlying biological basis of OLP involves a complex interplay of immune responses and genetic factors. It is characterized by the accumulation of CD4+ and CD8+ T cells, with CD8+ T cells infiltrating the epidermis.^[1] While OLP and non-oral LP share many genetic characteristics, recent research indicates some genetic loci have a stronger effect or are exclusively associated with one subgroup. For OLP, genes such as IFIH1, CASP8, CEP43, GRAF2, C12orf42, and ZFP36L1 have been identified.^[1] The Major Histocompatibility Complex (MHC) plays a significant role, with specific HLA alleles like HLA-DRB1*0101, DQB1*0201, DRB1*11, and DQB1*03 being implicated.^[1]OLP also shares genetic risk variants and a common etiology with several autoimmune diseases, including autoimmune hypothyroidism, type 1 diabetes, psoriasis, systemic lupus erythematosus (SLE), Sjögren’s syndrome, dermatomyositis, vitiligo, alopecia areata, inflammatory bowel disease (IBD), ankylosing spondylitis, iridocyclitis, and celiac disease.^[1] Genetic correlations have also been observed with conditions like chronic sinusitis, hallux valgus, and temporomandibular joint disorders (TMD).^[1]

Clinical Relevance

Clinically, OLP can cause significant pain and discomfort, often presenting as a chronic condition that is challenging to manage.^[1] Its strong association with various autoimmune disorders, particularly hypothyroidism, means that individuals with OLP may have an increased risk for these co-morbidities.^[1]A critical aspect of OLP’s clinical relevance is its association with an increased risk for oral cancer, especially tongue cancer.^[1] This malignant transformation risk necessitates careful monitoring and regular examinations. Despite its prevalence and chronic nature, current treatments for OLP are primarily symptomatic, focusing on alleviating discomfort rather than providing a cure.^[1]

Social Importance

The chronic nature of OLP, coupled with the discomfort it causes and the lack of curative treatment, significantly impacts the quality of life for affected individuals. The heightened risk of developing oral cancer underscores the social importance of early detection and continuous surveillance, particularly for lesions on the tongue.^[1] Furthermore, the strong genetic and epidemiological links between OLP and various autoimmune diseases highlight the need for a holistic approach to patient care, considering broader health implications beyond the oral cavity.^[1] Understanding the genetic basis and associations of OLP is crucial for developing targeted therapies and improving diagnostic and prognostic strategies, ultimately aiming to reduce the burden of this condition on individuals and healthcare systems.

Generalizability and Phenotypic Definition Challenges

The study population, primarily drawn from the FinnGen and UK Biobank cohorts, is predominantly of European ancestry, specifically Finnish in FinnGen. This demographic characteristic limits the direct generalizability of the findings to populations of other ethnic backgrounds, as genetic architectures and disease prevalence can vary significantly across diverse ancestries. Consequently, the identified genetic associations and risk factors may not be universally applicable. Furthermore, the cohort exhibits a notable sex bias, with females significantly overrepresented among individuals affected by lichen planus, particularly within the oral lichen planus (OLP) subgroup, which may influence the observed associations and their interpretation.^[2]This demographic skew might not fully reflect the global prevalence or risk factors for oral lichen planus.

A significant challenge arises from the methodology used to define oral lichen planus, which relied on inferring the anatomical location from International Classification of Diseases (ICD) codes associated with oral-related clinics, biopsies, or concomitant oral-related codes, rather than explicit clinical confirmation of oral involvement for all cases.^[1] This indirect phenotyping introduces a potential for misclassification, impacting the precision and reliability of subgroup analyses. Moreover, the UK Biobank data, utilized for replication, could not be subclassified into oral and non-oral forms due to limitations in available clinic data, thereby restricting the ability to validate subgroup-specific genetic findings across independent cohorts.^[1] The observed higher prevalence of lichen planus in FinnGen compared to the UK Biobank further underscores these issues, being largely attributed to the extensive dental clinic information available in Finland which is absent in UK Biobank, highlighting inconsistencies in diagnostic data capture between cohorts.^[1]

Incomplete Etiological Understanding and Environmental Confounders

While the study successfully identified numerous genetic loci associated with oral lichen planus and its subgroups, it provides only a partial understanding of the disease’s complex etiology. The research primarily focuses on genetic associations, leaving a comprehensive exploration of environmental triggers, lifestyle factors, and their interactions with genetic predispositions largely unaddressed. Such gene-environment confounders could play a significant role in disease manifestation and progression, but their specific contributions remain an area for further investigation, representing a notable knowledge gap in the complete etiological picture of oral lichen planus.

Despite leveraging large cohorts, the study’s findings predominantly identify common risk variants, meaning the full spectrum of genetic architecture, including potential contributions from rare variants or more complex polygenic interactions, may not be entirely captured. The presence of both shared genetic characteristics and distinct loci between oral and non-oral lichen planus underscores a complex genetic heterogeneity that still requires deeper mechanistic elucidation. The concept of “missing heritability,” which accounts for the unexplained portion of genetic variance for complex traits, implies that a substantial part of the genetic or environmental influences on oral lichen planus remains unknown, necessitating future research with even greater resolution and diverse methodologies to fully unravel its underlying causes.

Variants

Genetic variations play a significant role in the susceptibility and pathogenesis of oral lichen planus (OLP), a chronic inflammatory disease affecting the mucous membranes of the mouth. The identified variants often reside in genes crucial for immune regulation, cellular integrity, and inflammatory responses, reflecting the complex, immune-mediated nature of OLP. These genetic differences can influence how the immune system responds to environmental triggers or self-antigens, contributing to the development and progression of the condition.

The Major Histocompatibility Complex (MHC) region is a cornerstone of immune function, and variants within this area are strongly associated with OLP. Specifically, the rs28592859 variant, located in the region encompassing HLA-DQA1 and HLA-DQB1 genes, has been identified as a significant genetic factor for lichen planus.^[1] HLA-DQA1 and HLA-DQB1 encode subunits of MHC Class II proteins, which are vital for presenting antigens to T-lymphocytes, thereby initiating adaptive immune responses. Certain HLA-DQB1 alleles, such as DQB1*05:01, are known to confer a substantial risk for both non-oral and oral forms of lichen planus, indicating a shared underlying genetic vulnerability that influences immune recognition and response.^[1] Other variants linked to OLP are involved in immune regulation and programmed cell death. The rs7571586 variant is associated with CASP8 (Caspase-8), a critical enzyme that initiates the extrinsic apoptotic pathway, mediating controlled cell death and regulating inflammatory signaling. Alterations caused by variants in CASP8 may disrupt the normal balance of cell death and survival, contributing to the persistent inflammation and tissue damage characteristic of OLP.^[1] Similarly, the IFIH1 (Interferon Induced With Helicase C Domain 1) locus, where rs2111485 is found, has been specifically linked to OLP. IFIH1 encodes MDA5, an innate immune receptor that detects viral RNA and triggers antiviral responses, suggesting that dysregulated antiviral immunity or responses to specific viral infections might contribute to OLP pathogenesis.^[1] Variants affecting cell structure, adhesion, and RNA processing also contribute to OLP susceptibility. The LPP (LIM Domain And Actin Binding 1) gene, involved in cell adhesion, migration, and signal transduction, contains the rs6780858 variant, which is a significant genetic factor for lichen planus.^[1]This locus also shows associations with other autoimmune conditions like vitiligo and celiac disease, underscoring its broader role in immune-mediated disorders. Thers3825568 variant is located near ZFP36L1(ZFP36 Ring Finger Protein Like 1), an RNA-binding protein that regulates mRNA stability and degradation, influencing cell cycle and inflammatory responses. Its specific association with OLP suggests that altered gene expression or RNA metabolism may contribute to the disease’s chronic nature.^[1] Additionally, the rs748670681 variant in TNRC18(Trinucleotide Repeat Containing 18) is associated with lichen planus, and this gene has broader links to inflammatory bowel disease, psoriasis, and autoimmune hypothyroidism, further supporting an autoimmune basis for LP.^[1] Further insights into OLP genetics come from variants in genes involved in diverse cellular processes. The CEP43 (Centrosomal Protein 43) gene, which plays a role in centrosome organization and cell division, includes the rs9459853 variant, identified as an OLP-specific locus.^[1] This suggests that abnormalities in cell division or structural integrity may be relevant to OLP. The intergenic variant rs10861030 , situated between C12orf42 and LINC02401, is also specifically associated with OLP, implying that regulatory elements or nearby genes within this region impact disease susceptibility.^[1] Similarly, the intergenic variant rs11988402 , found near LINC03093 and GFRA2 (GDNF Family Receptor Alpha 2), represents another genetic factor associated with LP, likely influencing the expression or function of adjacent genes involved in cell signaling or development.^[1]

Key Variants

RS ID	Gene	Related Traits
rs28592859	HLA-DQA1 - HLA-DQB1	oral lichen planus lichen planus
rs9459853	CEP43	oral lichen planus lichen planus
rs10861030	C12orf42 - LINC02401	oral lichen planus lichen planus
rs748670681	TNRC18	ulcerative colitis uveitis iritis psoriasis inflammatory bowel disease
rs7571586	CASP8	oral lichen planus
rs11988402	LINC03093 - GFRA2	oral lichen planus
rs6780858	LPP	Graves disease allergic disease, age at onset allergic disease oral lichen planus lichen planus
rs2111485	FAP - IFIH1	ankylosing spondylitis, psoriasis, ulcerative colitis, Crohn’s disease, sclerosing cholangitis systemic lupus erythematosus Vitiligo inflammatory bowel disease psoriasis
rs2093816	LINC02341	autoimmune disease oral lichen planus lichen planus
rs3825568	ZFP36L1	rheumatoid arthritis systemic juvenile idiopathic arthritis, polyarticular juvenile idiopathic arthritis, rheumatoid factor negative, oligoarticular juvenile idiopathic arthritis oral lichen planus lichen planus

Conceptual and Operational Definition

Oral Lichen Planus (OLP) is precisely defined as a chronic inflammatory and immune-mediated disease that specifically affects the squamous epithelia within the oral cavity.^[1]It is understood as a T-cell-mediated condition, characterized by the accumulation of CD4+ and CD8+ T cells in the underlying connective tissue, with CD8+ T cells infiltrating the epithelial layer, leading to a characteristic interface dermatitis.^[3] Clinically, OLP lesions in non-keratinized areas typically do not cause itching but frequently present with a burning sensation, and unlike cutaneous forms, erosion can be a significant feature in mucosal lichen planus.^[4] Furthermore, OLP tends to be chronic and often shows greater resistance to treatment compared to its cutaneous counterpart.^[4] For large-scale epidemiological and genetic studies, such as the FinnGen study, the operational definition of OLP involves a meticulous approach to identify affected individuals from electronic health records. This process infers OLP diagnosis primarily from International Classification of Diseases (ICD) codes, specifically L43 (with extensions 0,1,3,8,9) in ICD10 and 6970 (with Finnish extensions A,B,C) in ICD8 and ICD9, which are not inherently location-specific.^[1]To refine this, individuals are classified into the oral subgroup if their LP diagnosis was recorded by an oral-related clinic (e.g., dental, orthodontic, oral surgery), if they had a documented oral biopsy (using NOMESCO procedure codes such as EKA10, EJA10, EHA10, ECA20, TEA00, or SXA10) within 56 weeks of the LP code, or if oral-related codes (like oral examination, photography of the mouth, caries, or periodontitis) were present at the same visit as the LP diagnosis.^[1] An additional Finnish-specific oral ICD-10 code, K13.74, is also utilized to further specify oral involvement.^[1]

Classification and Subtypes of Lichen Planus

Lichen planus (LP) is a broad nosological entity encompassing several clinical subtypes based on the affected anatomical site. These include cutaneous LP (affecting the skin), lichen planopilaris (involving the scalp), lichen unguis (affecting the nails), and various forms of mucosal LP, which can manifest in the penile, vulvar, oral, or esophageal regions.^[3]The distinction between oral and non-oral forms of lichen planus represents a significant classificatory challenge, with ongoing research investigating whether they represent a single disease with varied presentations or distinct pathologies.^[1] Although oral and non-oral LP share many genetic characteristics, studies have identified specific genetic loci that demonstrate a stronger association or are exclusively present in one subgroup over the other, supporting the notion of some underlying heterogeneity.^[1] A notable example of this genetic differentiation is the HLA-DQB1*05:01 allele, which, while a significant risk factor for both, confers a substantially higher risk for non-oral LP compared to OLP.^[1] Conversely, loci such as IFIH1, CASP8, CEP43, GRAF2, C12orf42, and ZFP36L1 have been observed to have a stronger or exclusive association with OLP.^[1]This categorical classification into oral and non-oral forms, based on both clinical presentation and genetic underpinnings, signifies an evolving understanding of LP as potentially a spectrum of related conditions rather than a single homogenous disease, thereby influencing diagnostic and therapeutic approaches.

Diagnostic Criteria and Clinical Significance

The diagnostic criteria for OLP rely on a combination of clinical presentation and, often, histopathological confirmation, although specific research criteria may involve broader data integration. Clinically, OLP is characterized by visible lesions in the mouth, which may present with burning sensations and, in some cases, erosions.^[4] In research settings, such as the FinnGen study, diagnostic and measurement criteria leverage comprehensive electronic health data, including clinician-assigned ICD codes, alongside detailed registry information like oral biopsies and co-occurring oral-related medical codes.^[1] This multi-faceted approach is critical for accurately identifying OLP within large cohorts, especially since primary LP ICD codes are not body-location specific, necessitating inferential methods for subgroup classification.^[1]The clinical significance of OLP extends beyond its immediate symptoms, as it is recognized for its potential for malignant transformation, particularly into oral cancer of the lip, tongue, and other oral cavity sites.^[5] Regular examinations are therefore crucial for individuals diagnosed with OLP to facilitate early detection of any malignant changes.^[1]Furthermore, OLP is frequently associated with an increased risk of other autoimmune and inflammatory diseases, including autoimmune hypothyroidism, celiac disease, and Sjögren’s syndrome, highlighting its systemic immune-mediated nature and shared etiologies with other conditions.^[1]

Clinical Manifestations and Subjective Symptoms

Oral lichen planus (OLP) is a chronic inflammatory disease affecting the oral mucosa, often proving more resistant to treatment than its cutaneous counterpart.^[6] Individuals with OLP typically experience a burning sensation in the affected non-keratinized epithelial areas, though these lesions are usually not pruritic.^[1] Clinical examination may reveal erosions on the mucosal surfaces, distinguishing it from the classic skin form which presents as pruritic, purple, polygonal, flat-topped papules with fine white lines.^[3] While the histopathological appearance of lichen planus is similar across different body locations, the specific clinical forms and subjective symptoms vary depending on the affected site.^[1]

Diagnostic Approaches and Phenotypic Diversity

Diagnosis of OLP often relies on International Classification of Diseases (ICD) codes assigned by clinicians, with the oral location inferred from diagnoses made in oral-related clinics.^[1] Objective confirmation can also be achieved through registry data detailing oral biopsies, which are frequently used to verify a presumed OLP diagnosis.^[1] OLP exhibits significant phenotypic diversity and variability, affecting approximately 0.1%–3.2% of the adult population and predominantly occurring in middle-aged adults.^[7] A notable sex difference exists, with 60%–75% of individuals diagnosed with OLP being female.^[8] Furthermore, there is considerable overlap with other forms of lichen planus, as roughly half of all lichen planus patients present with oral lesions, and some individuals experience both oral and cutaneous manifestations.^[4]

Systemic Associations and Prognostic Indicators

OLP carries significant diagnostic and prognostic implications, notably an increased risk for oral cancer, particularly tongue cancer.^[1] Regular examinations are therefore crucial for early detection of any malignant lesions in individuals with OLP.^[1]The condition is also strongly associated with a broader risk of autoimmune and inflammatory diseases, including a somewhat greater risk for autoimmune hypothyroidism, celiac disease, and Sjögren’s syndrome.^[1] Genetic studies reveal correlations with various conditions such as chronic sinusitis, hallux valgus, deviated nasal septum, soft tissue disorders, arthropathies, and temporomandibular joint disorders.^[1] Key genetic loci, such as LPP and CPVL, have been linked to OLP and other autoimmune conditions like vitiligo and celiac disease, whileTNRC18shows associations with inflammatory bowel disease, ankylosing spondylitis, and psoriasis, highlighting shared underlying etiologies.^[1]

Causes of Oral Lichen Planus

Oral lichen planus (OLP) is a chronic inflammatory disease affecting the oral mucosa, characterized by a complex etiology involving genetic predispositions, immune system dysregulation, environmental triggers, and associations with various systemic conditions. It is primarily considered a T-cell-mediated disease, where T cells accumulate and infiltrate epithelial tissues, leading to characteristic lesions.^[1]

Genetic Predisposition and Immune System Dysregulation

Genetic factors play a significant role in an individual’s susceptibility to oral lichen planus, with research identifying numerous inherited variants that contribute to its development. A large-scale genetic study identified 27 genome-wide significant loci associated with lichen planus, with many shared between oral and non-oral forms, while some, likeIFIH1, CASP8, CEP43, GRAF2, C12orf42, and ZFP36L1, showed stronger or exclusive associations with OLP.^[1] The human leukocyte antigen (HLA) complex, particularly alleles such as HLA-A9, HLA-B8, HLA-Bw57, HLA-DR1, HLA-DR6, HLA-DR9, HLA-DRB1*0101, HLA-DRB1*11, HLA-DQB1*0201, and HLA-DQB1*03, is a major genetic contributor, influencing immune responses and increasing risk.^[9]Beyond the MHC, polymorphisms in cytokine genes likeIFNG, IL18, and IL10 have also been implicated, suggesting their role in modulating the immune-mediated inflammatory processes characteristic of OLP.^[10]The immune basis of oral lichen planus is strongly supported by its shared genetic etiology with several autoimmune diseases, indicating a broader immune system dysregulation. Polygenic risk scores for LP show positive correlations with conditions such as hypothyroidism, multiple sclerosis, and psoriasis, highlighting overlapping genetic vulnerabilities.^[1] Specific genetic variants, like those in LPP and CPVL, are associated with OLP and also linked to autoimmune vitiligo, further underscoring a common underlying immune pathology. The involvement of TNRC18, associated with inflammatory bowel disease (IBD) and ankylosing spondylitis, also points to shared genetic pathways impacting immune regulation.^[1]

Comorbidities and Systemic Disease Associations

Oral lichen planus frequently co-occurs with other systemic diseases, suggesting shared pathogenic mechanisms or predisposing factors. A strong association exists between OLP and various autoimmune conditions, including autoimmune hypothyroidism, celiac disease, Sjögren’s syndrome, systemic lupus erythematosus (SLE), dermatomyositis, vitiligo, alopecia areata, and inflammatory bowel disease (IBD).^[11]This overlap indicates that OLP may be a manifestation of a broader autoimmune diathesis, where systemic immune dysregulation affects multiple tissues. Furthermore, OLP has been linked to metabolic disorders such as diabetes mellitus and dyslipidemia, suggesting that metabolic imbalances could also contribute to its pathogenesis or severity.^[12] Beyond autoimmune and metabolic conditions, OLP shows genetic correlations with other health issues, including chronic sinusitis, hallux valgus, deviated nasal septum, soft tissue disorders, arthropathies, and temporomandibular joint disorders.^[1]A critical concern for individuals with OLP is an increased risk for malignant transformation, particularly to oral cancer, especially tongue cancer.^[1] This heightened risk necessitates regular examination for early detection of potentially cancerous lesions, highlighting OLP not only as an inflammatory condition but also as a premalignant one.

Environmental Triggers and Gene-Environment Interactions

Environmental factors can act as triggers or exacerbating agents for oral lichen planus, particularly in genetically predisposed individuals. Infections, notably with the hepatitis C virus (HCV), have been epidemiologically linked to OLP.^[13] This connection is further illuminated by gene-environment interactions, where specific genetic predispositions, such as the HLA-DR6allele, confer a higher risk for OLP in patients with HCV infection.^[13]This interaction underscores how an individual’s genetic makeup can modulate their response to environmental exposures, influencing disease onset and progression.

Other exogenous factors, such as hepatitis B vaccination, have also been reported in association with oral manifestations, suggesting that certain immune-stimulating events can potentially trigger OLP in susceptible individuals.^[14]While specific dietary or socioeconomic factors are not extensively detailed in some studies, the association with cardiovascular risk factors and dyslipidemia implies that broader lifestyle choices or environmental exposures contributing to these conditions might also indirectly influence OLP development or its clinical course.^[12]

Demographic Considerations

While oral lichen planus can occur at any age, it is most commonly diagnosed in middle-aged adults.^[1] This age demographic suggests potential roles for age-related immune changes, cumulative environmental exposures, or hormonal influences in its pathogenesis. Furthermore, OLP exhibits a notable sex bias, with 60%–75% of affected individuals being female.^[1]This contrasts with cutaneous lichen planus, which does not typically show a significant sex bias, indicating that sex-specific biological or hormonal factors may contribute distinctly to the development and presentation of the oral form of the disease.^[1]

Biological Background of Oral Lichen Planus

Oral lichen planus (OLP) is a chronic inflammatory and immune-mediated disease that primarily affects the squamous epithelia of the oral mucosa.^[1] It is characterized by persistent lesions that can cause burning sensations and, in some cases, erosion.^[1] Unlike its cutaneous counterpart, OLP is often chronic and more resistant to treatment.^[6]The disease is considered a T-cell-mediated condition, where specific immune cells play a central role in its development and progression.^[1]

Immune Dysregulation and Cellular Infiltration

The pathogenesis of oral lichen planus is fundamentally driven by immune dysregulation, specifically involving T-lymphocytes. Histopathological examinations reveal an accumulation of CD4+ and CD8+ T cells in the dermis, with CD8+ T cells infiltrating the epidermis, leading to a characteristic interface dermatitis.^[1] This cellular infiltration indicates an ongoing chronic inflammatory response within the oral mucosa. Key biomolecules involved in this process include various cytokines, such as IFNG (interferon-gamma), IL18 (interleukin-18), IL10 (interleukin-10), TGFb1 (transforming growth factor beta 1), IL-1b (interleukin-1 beta), IL-2 (interleukin-2), and IL-4 (interleukin-4), whose polymorphisms and expression patterns are associated with OLP.^[10] These cytokines act as signaling molecules, orchestrating the recruitment and activation of immune cells, contributing to the persistent inflammation and tissue damage observed in OLP.

Genetic Susceptibility and Immune Recognition

Genetic factors play a significant role in predisposing individuals to oral lichen planus, with studies identifying a substantial contribution from the Major Histocompatibility Complex (MHC) region.^[1] Specific HLA (Human Leukocyte Antigen) alleles, such as HLA-DRB1*0101, HLA-DR6, HLA-DR9, and DQB1*0201, have been associated with increased susceptibility to various forms of lichen planus, including OLP, and its specific clinical presentations.^[9]While there is a broadly shared genetic etiology between oral and non-oral lichen planus, certain loci exhibit stronger effects or are exclusively associated with OLP, such asIFIH1, CASP8, CEP43, GRAF2, C12orf42, and ZFP36L1.^[1]These genetic differences underscore a degree of heterogeneity in the underlying molecular pathology between the different forms of the disease.

Molecular Pathways and Cellular Dysfunction

Beyond the MHC, specific molecular pathways contribute to the cellular dysfunction seen in oral lichen planus. The geneIFIH1 (Interferon Induced With Helicase C Domain 1), which is specifically associated with OLP, is crucial in innate immunity, recognizing viral RNA and initiating antiviral responses.^[1] This suggests a potential role for viral triggers or a dysregulation of innate immune pathways in OLP pathogenesis. Another OLP-specific gene, CASP8 (Caspase 8), is a critical component of apoptotic pathways, implying that altered programmed cell death mechanisms in keratinocytes or immune cells may contribute to the characteristic epithelial damage and chronic inflammation.^[1]The interplay of these genes with immune regulatory networks, including the cytokine signaling pathways mentioned previously, dictates the severity and persistence of the disease.

Tissue-Specific Manifestations and Systemic Associations

Oral lichen planus is a distinct manifestation of lichen planus, with unique clinical characteristics in the oral mucosa, such as a burning sensation and the potential for erosion, differentiating it from the typically pruritic skin lesions.^[1] This localized inflammation, however, does not occur in isolation, as OLP is strongly associated with a range of systemic autoimmune diseases, highlighting a shared etiological basis.^[14]Conditions such as autoimmune hypothyroidism, Sjögren’s syndrome, celiac disease, systemic lupus erythematosus (SLE), vitiligo, and alopecia areata show increased prevalence in individuals with OLP.^[1]Furthermore, OLP carries a significant increased risk for oral cancer, particularly tongue cancer, necessitating regular examination to detect malignant transformation early.^[7] This predisposition to malignancy represents a critical long-term consequence of the chronic inflammatory state in the oral mucosa.

Immune Cell-Mediated Inflammatory Signaling

Oral lichen planus (OLP) is primarily characterized as a T-cell-mediated inflammatory disease, involving the accumulation of CD4+ and CD8+ T cells in the dermis and CD8+ T cell infiltration into the epidermis of affected squamous epithelia.^[1]This immune response is orchestrated through complex signaling cascades, where genetic variants influence T-cell activation, differentiation, and cytokine production. Key pathways enriched in OLP involve lymphocyte activation, T-cell activation, and the regulation of immune system processes, including responses to cytokines.^[1] Genes such as IL2RA, ZNF365, RPS3, PLXNC1, TNFSF11, ZFP36L1, IQGAP1, IFIH1, CASP8, FOXP1, and RGS14 are implicated in these processes, modulating receptor activation and downstream intracellular signaling that drives the inflammatory phenotype.^[1]Furthermore, polymorphisms in cytokine genes likeIFNG, IL18, and IL10 have been associated with OLP, suggesting their roles in shaping the immune microenvironment and perpetuating chronic inflammation.^[10]

Genetic Predisposition and Regulatory Mechanisms

Genetic factors play a substantial role in the pathogenesis of oral lichen planus, with a major contribution from the human leukocyte antigen (HLA) system and an overlap with the genetics of other autoimmune diseases.^[1] Specifically, HLA-DQB1 is a significant risk factor, with HLA-DQB1*05:01 showing a stronger association with non-oral LP compared to OLP, although it contributes to both.^[1] Beyond HLA, several specific genetic loci have been identified as risk variants for OLP, including IFIH1, CASP8, CEP43, GRAF2, C12orf42, and ZFP36L1, which may regulate gene expression and protein function through various post-translational modifications or allosteric control mechanisms.^[1]These genetic differences underscore distinct regulatory pathways between oral and non-oral forms of lichen planus, influencing disease susceptibility and progression by affecting gene regulation, protein modification, and overall cellular responses.^[1]

Systemic Crosstalk and Metabolic Associations

Oral lichen planus often exhibits significant pathway crosstalk with other systemic conditions, particularly autoimmune diseases, indicating shared etiologies and network interactions.^[1]There is a documented association between OLP and conditions such as autoimmune hypothyroidism, type 1 diabetes, psoriasis, vitiligo, celiac disease, inflammatory bowel disease, systemic lupus erythematosus, Sjögren’s syndrome, dermatomyositis, and alopecia areata.^[15] Genes like LPP and CPVL, implicated in LP, are also associated with vitiligo and celiac disease, whileTNRC18 variants show connections to IBD, ankylosing spondylitis, and psoriasis.^[1]Furthermore, OLP has been linked to metabolic dysregulation, including associations with dyslipidemia and diabetes mellitus, and infections such as hepatitis C virus and hepatitis B vaccination, suggesting complex systems-level integration where metabolic and infectious pathways can influence or exacerbate the immune-mediated processes in OLP.^[14]

Disease Progression and Malignant Potential

The chronic inflammatory nature of oral lichen planus represents a significant disease-relevant mechanism, where persistent immune activation and tissue damage can lead to cellular dysregulation and increased risk for malignant transformation.^[1]OLP is recognized to have an elevated risk for oral cancer, particularly tongue cancer, highlighting a critical aspect of its pathology involving aberrant cellular growth and uncontrolled proliferation.^[1] This malignant potential suggests dysregulation within pathways that control cell cycle, apoptosis, and tissue repair, where chronic inflammation may overwhelm normal compensatory mechanisms, thereby shifting the cellular environment towards oncogenesis.^[1]Regular examination for malignant lesions is crucial for individuals with OLP, especially those with tongue involvement, reflecting the emergent properties of chronic inflammation leading to cancer.^[1]

Prevalence, Incidence, and Demographic Patterns

Oral lichen planus (OLP) is a chronic inflammatory condition affecting the oral mucosa, with population-level prevalence estimated to range from 0.1% to 3.2% in adults.^[7] For comparison, cutaneous lichen planus (LP) is observed in approximately 0.2% to 1% of the population.^[16] Large-scale biobank studies provide more specific prevalence data, such as the FinnGen study reporting a cohort prevalence of 1.6% for LP, while the UK Biobank (UKBB) reported a lower prevalence of 0.48% for LP.^[1] This disparity in prevalence between the FinnGen and UKBB cohorts is likely due to the extensive inclusion of dental clinic information in the Finnish health registries, which offers a more comprehensive ascertainment of oral conditions.^[1] Analysis of demographic factors reveals distinct patterns for OLP compared to other forms of LP. While all forms of LP can occur at any age, they are most commonly diagnosed in middle-aged adults.^[8] A notable sex bias exists in OLP, with females accounting for 60% to 75% of affected individuals.^[8] In the FinnGen cohort, females were significantly overrepresented among individuals with LP (67.4% of LP-affected individuals versus 56.1% of overall participants), with the oral subgroup showing an even greater female predominance (74.0% of OLP-affected individuals compared to 62.4% of non-OLP-affected individuals).^[1] In contrast, cutaneous LP has not demonstrated a significant sex or ancestry predisposition in prior studies.^[17]

Large-Scale Cohort Investigations and Associated Conditions

Major population cohorts, such as the FinnGen study, have been instrumental in understanding the epidemiological landscape of oral lichen planus. This study leveraged lifelong electronic health records, including diagnoses, procedures, and clinic identities, from 473,580 individuals in Finland to conduct extensive genetic and epidemiological analyses.^[1] Within FinnGen, researchers carefully constructed subgroups of oral LP (n = 3,323) and non-oral LP (n = 4,356) using detailed registry data, including information from oral-related clinics and biopsies.^[1]The study also utilized a time-based analysis, employing the Observational Health Data Sciences and Informatics (OHDSI) common database model, to examine the temporal order of events surrounding the initial lichen planus diagnosis, selecting 50 birth year- and sex-matched controls for each case and analyzing categorical excesses at various time points.^[1]Epidemiological associations derived from these large cohorts highlight significant comorbidities. Oral lichen planus is recognized for its increased risk of oral cancer, particularly tongue cancer, with a reported malignant transformation rate ranging from 0.2% to 2% across the entire FinnGen cohort.^[5] Both oral and non-oral forms of LP demonstrate a broadly increased risk for autoimmune and inflammatory diseases.^[1]Specifically, OLP is associated with a somewhat greater risk for autoimmune hypothyroidism, celiac disease, and Sjo¨gren’s syndrome, while non-oral LP shows a higher risk for discoid lupus erythematosus, psoriasis, and atopic dermatitis.^[11]Both subgroups, however, exhibit similarly increased risks for inflammatory bowel disease, alopecia areata, and vitiligo, and polygenic scores for the overall LP group show strong positive associations with hypothyroidism, multiple sclerosis, and psoriasis.^[1]

Methodological Approaches and Population-Specific Considerations

Population studies on oral lichen planus often rely on robust methodologies involving large-scale health data. In studies like FinnGen, LP diagnoses are identified using International Classification of Diseases (ICD) codes (versions 8, 9, and 10), such as L43 for LP and 6970, which are then refined to distinguish oral from non-oral forms.^[1] This distinction is inferred by identifying diagnoses made in oral-related clinics (e.g., dental, oral surgery), presence of oral biopsies, or co-occurrence of oral-related codes at the same visit.^[1] The validity of this classification strategy is supported by comparing detailed medical characteristics, showing significant excesses of oral indications in the OLP subgroup and topical medications/cutaneous biopsies in the non-OLP group.^[1] Despite these rigorous approaches, methodological limitations and population-specific factors warrant consideration. The primary ICD codes for lichen planus are not inherently specific to body location, making precise subgroup classification challenging, and individuals may present with multiple types of LP over their lifetime.^[1] The FinnGen study’s strict definition of oral LP and exclusionary assignment of non-oral LP means some individuals with OLP diagnosed by general practitioners or those who develop OLP after cutaneous LP might be inadvertently grouped as non-oral.^[1] Furthermore, the ability to create such detailed oral and non-oral LP subgroups is not always feasible across all biobanks; for instance, the UK Biobank could not classify these subgroups due to available clinic data.^[1] While most genetic risk factors are shared between oral and non-oral LP, significant differences in specific genetic loci suggest distinct underlying molecular pathologies, emphasizing the importance of population-level genetic studies using appropriate reference panels, such as Finnish population-specific HLA reference panels.^[1]

Frequently Asked Questions About Oral Lichen Planus

These questions address the most important and specific aspects of oral lichen planus based on current genetic research.

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1. Why do I get these painful mouth sores when my friends don’t?

It’s often due to your unique genetic makeup and how your immune system functions. Oral lichen planus is a T-cell mediated condition, meaning certain immune cells mistakenly attack your mouth lining. Genes likeIFIH1 and CASP8, along with specific HLA alleles, can make you more susceptible, explaining why some people develop it and others don’t.

2. If my mom has OLP, am I more likely to get it too?

Yes, there’s a genetic component to oral lichen planus, so having a close relative like your mother with the condition can increase your risk. This is because certain genetic risk factors, including specificHLA alleles, can be passed down through families. However, it’s not a guarantee, as environmental factors and other genes also play a role.

3. My doctor says I have OLP. Does this mean I might get other health problems?

Yes, having oral lichen planus is linked to an increased risk for several other autoimmune diseases. There are shared genetic risk variants between OLP and conditions like autoimmune hypothyroidism, type 1 diabetes, psoriasis, and systemic lupus erythematosus. It’s important to monitor for these co-morbidities as part of your overall health care.

4. Why does OLP seem to affect more women than men?

Oral lichen planus does show a notable sex bias, with females accounting for 60%–75% of individuals affected. While the exact reasons are still being fully understood, this demographic skew suggests that biological differences, potentially including hormonal influences or specific genetic factors more prevalent in females, contribute to this higher risk.

5. I heard OLP can turn into cancer. Is that a real risk for me?

Unfortunately, yes, oral lichen planus is associated with an increased risk for oral cancer, particularly tongue cancer. This malignant transformation risk is a critical aspect of OLP’s clinical relevance. Regular monitoring and examinations are essential to detect any changes early, especially for lesions on your tongue.

6. My dentist keeps checking my tongue. Why is that so important for OLP?

Your dentist focuses on your tongue because OLP lesions in this area carry a higher risk of malignant transformation into oral cancer. Continuous surveillance is crucial for early detection of any suspicious changes. This proactive monitoring helps manage the increased cancer risk associated with OLP.

7. Could my ancestry affect my risk of getting OLP?

Yes, your ancestry can influence your risk. Much of the current research on OLP genetics has focused on populations of European ancestry, identifying specific genetic associations and risk factors there. Genetic architectures and disease prevalence can vary significantly across diverse ethnic backgrounds, so your specific background might have different risk profiles.

8. Why do treatments only help manage my OLP, not cure it?

OLP is a complex, chronic immune-mediated condition with a significant genetic component, and current treatments are primarily symptomatic. While they can alleviate discomfort, the underlying genetic and immune dysregulation that causes the disease, involving genes likeIFIH1 and CASP8, isn’t fully addressed by current therapies, leading to no definitive cure.

9. My sibling has OLP but I don’t; why the difference?

Even with shared family genetics, there can be individual differences in disease manifestation. While you share some genetic predispositions, factors like specific combinations of genetic variants (some genes likeIFIH1 or HLAalleles might be different), environmental triggers, and lifestyle choices can influence whether OLP develops in one sibling but not another.

10. Do my chronic sinus issues have anything to do with my OLP?

Interestingly, yes, genetic correlations have been observed between oral lichen planus and chronic sinusitis. This suggests that some shared underlying genetic factors or immune pathways might increase susceptibility to both conditions. It highlights how seemingly unrelated health issues can sometimes have common biological roots.

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This FAQ was automatically generated based on current genetic research and may be updated as new information becomes available.

Disclaimer: This information is for educational purposes only and should not be used as a substitute for professional medical advice. Always consult with a healthcare provider for personalized medical guidance.

References

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[3] Boch, K., et al. “Lichen planus.” Front. Med, vol. 8, 2021, p. 737813.

[4] Cassol-Spanemberg, J., Blanco-Carrion, A., Rodriguez-de Rivera-Campillo, M.E., Estrugo-Devesa, A., Jane-Salas, E., and Lopez-Lopez, J. (2018). Cutaneous, genital and oral lichen planus: A descriptive study of 274 patients. Med. Oral Patol. Oral Cir. Bucal 0–0.

[5] Giuliani, M., et al. “Rate of malignant transformation of oral lichen planus: A systematic review.”Oral Dis., vol. 25, 2019, pp. 693–709.

[6] Eisen, D., Carrozzo, M., Bagan Sebastian, J.-V., and Thongprasom, K. (2005). Number V Oral lichen planus: clinical features and management. Oral Dis. 11, 338–349.

[7] Gonza´lez-Moles, M.A´ ., et al. “Malignant transformation risk of oral lichen planus: A systematic review and comprehensive meta-analysis.”Oral Oncol., vol. 96, 2019, pp. 121–130.

[8] Ioannides, D., et al. “European S1 guidelines on the manage- ment of lichen planus: a cooperation of the European Derma- tology Forum with the European Academy of Dermatology and Venereology.” J. Eur. Acad. Dermatol. Venereol., vol. 34, 2020, pp. 1403–1414.

[9] Carcassi, C., et al. “The HLA-DRB1*0101 allele is responsible for HLA susceptibility to lichen ruber planus.” European Journal of Immunogenetics, vol. 21, 1994, pp. 425–429.

[10] Liu, W., et al. “Association of polymorphisms in Th1/Th2-related cytokines (IFN-g, TGFb1, IL-1b, IL-2, IL-4, IL-18) with oral lichen planus: A pooled analysis of case-control studies.”J. Dent. Sci., vol. 18, 2023, pp. 560–566.

[11] De Porras-Carrique, T., et al. “Autoimmune disorders in oral lichen planus: A systematic re- view and meta-analysis.”Oral Dis., vol. 29, 2023, pp. 1382–1394.

[12] Arias-Santiago, S., et al. “Cardiovascular risk factors in patients with lichen planus.”Am. J. Med., vol. 124, 2011, pp. 543–548.

[13] Nagao, Y., et al. “Genome-wide association study identifies risk variants for lichen planus in patients with hepatitis C virus infection.”Clin. Gastroenterol. Hepatol., vol. 15, 2017, pp. 937–944.e5.

[14] Alaizari, N.A., et al. “Hepatitis B vaccination and associated oral manifestations: a non-systematic review of literature and case reports.”Annals of Medical and Health Sciences Research, vol. 4, 2014, pp. 829–836.

[15] Atanaskova Mesinkovska, N., et al. “Association of lichen planopilaris with thyroid disease: a retrospective case-control study.”J. Am. Acad. Dermatol., vol. 70, 2014, pp. 889–892.

[16] Boyd, A.S., and Neldner, K.H. “Lichen planus.” J. Am. Acad. Dermatol., vol. 25, 1991, pp. 593–619.

[17] Alrashdan, M.S., Cirillo, N., and McCullough, M. “Oral lichen planus: a literature review and update.”Arch. Dermatol. Res., vol. 308, 2016, pp. 539–551.