The relationship between clinical symptoms of oral lichen planus and quality of life related to oral health.

INTRODUCTION: Oral Lichen Planus (OLP) is a chronic and relatively common mucocutaneous disease that often affects the oral mucosa. Although, OLP is generally not life-threatening, its consequences can significantly impact the quality of life in physical, psychological, and social aspects. Therefore, the aim of this research is to investigate the relationship between clinical symptoms of OLP and oral health-related quality of life in patients using the OHIP-14 (Oral Health Impact Profile-14) questionnaire. MATERIALS AND METHODS: This descriptive-analytical study has a cross-sectional design, with case-control comparison. In this study, 56 individuals were examined as cases, and 68 individuals were included as controls. After recording demographic characteristics and clinical features by reviewing patients' records, the OHIP-14 questionnaire including clinical severity of lesions assessed using the Thongprasom scoring system, and pain assessed by the Visual Analog Scale (VAS) were completed. The ADD (Additive) and SC (Simple Count) methods were used for scoring, and data analysis was performed using the T-test, Mann-Whitney U test, Chi-Square, Spearman's Correlation Coefficient, and SPSS 24. RESULTS: Nearly all patients (50 individuals, 89.3%) reported having pain, although the average pain intensity was mostly mild. This disease has affected the quality of life in 82% of the patients (46 individuals). The patient group, in comparison to the control group, significantly expressed a lower quality of life in terms of functional limitations and physical disability. There was a statistically significant positive correlation between clinical symptoms of OLP, gender, location (palate), and clinical presentation type (erosive, reticular, and bullous) of OLP lesions with OHIP-14 scores, although the number or bilaterality of lesions and patient age did not have any significant correlation with pain or OHIP scores. CONCLUSION: It appears that certain aspects of oral health-related quality of life decrease in patients with OLP, and that of the OLP patient group is significantly lower in terms of functional limitations and physical disability compared to the control group. Additionally, there was a significant correlation between clinical symptoms of OLP and pain as well as OHIP scores.

The ABO blood group antigens in patients with oral lichenoid reaction.

Evaluating the association of ABO blood group with different delayed hypersensitivity reactions, such as oral lichenoid reaction (OLR), can provide a new perspective for clinical practice. Therefore, this study designed to investigate ABO blood group antigens in OLR patients. In this case-control study, the ABO blood group of 112 OLR patients and 117 individuals without oral lesions were included. Gender, age, characteristics of the lesions, medications and restorative materials recorded. Chi-square test used to compare the frequency of ABO blood groups in OLR patients with controls. The O blood group was significantly higher in OLR patients and all its subtypes. Also, there were significant relation between O blood group, and severity of lesions. The frequency of dysplasia was non-statistically significant higher in OLR patients with O blood group than other blood group. Based on the results of the present study, O blood group was significantly more in patients with lichenoid reaction than control group, and AB blood group was the lowest. Also, O blood group showed a positive association with the more severe form of OLR lesions and frequency of dysplasia.

Dysregulation of TCONS_00006091 contributes to the elevated risk of oral squamous cell carcinoma by upregulating SNAI1, IRS and HMGA2.

In this study, we aimed to study the role of TCONS_00006091 in the pathogenesis of oral squamous cellular carcinoma (OSCC) transformed from oral lichen planus (OLP). This study recruited 108 OSCC patients which transformed from OLP as the OSCC group and 102 OLP patients with no sign of OSCC as the Control group. ROC curves were plotted to measure the diagnostic values of TCONS_00006091, miR-153, miR-370 and let-7g, and the changes in gene expressions were measured by RT-qPCR. Sequence analysis and luciferase assays were performed to analyze the molecular relationships among these genes. Cell proliferation and apoptosis were observed via MTT and FCM. TCONS_00006091 exhibited a better diagnosis value for OSCC transformed from OLP. OSCC group showed increased TCONS_00006091 expression and decreased expressions of miR-153, miR-370 and let-7g. The levels of SNAI1, IRS and HMGA2 was all significantly increased in OSCC patients. And TCONS_00006091 was found to sponge miR-153, miR-370 and let-7g, while these miRNAs were respectively found to targe SNAI1, IRS and HMGA2. The elevated TCONS_00006091 suppressed the expressions of miR-153, miR-370 and let-7g, leading to the increased expression of SNAI1, IRS and HMGA2. Also, promoted cell proliferation and suppressed apoptosis were observed upon the over-expression of TCONS_00006091. This study demonstrated that the expressions of miR-153, miR-370 and let-7g were down-regulated by the highly expressed TCONS_00006091 in OSCC patients, which accordingly up-regulated the expressions of SNAI1, IRS and HMGA2, resulting in the promoted cell proliferation and suppressed cell apoptosis.

What can we learn from treatments of oral lichen planus?

Oral lichen planus (OLP), a T-lymphocyte-mediated disease of the oral mucosa, has a complex pathogenesis that involves a number of factors. The disease is characterized by recurrent episodes and requires continuous follow up, and there is no curative treatment available. Erosive lichen planus, among others, has a risk of malignant transformation and requires standardized treatment to control its progression. Different clinical subtypes of oral lichen planus require appropriate treatment. Pharmacological treatments are the most widely available and have the greatest variety of options and a number of novel pharmacological treatments are presented as highlights, including JAK enzyme inhibitors. The second is photodynamic therapy, which is the leading physiological treatment. In addition, periodontal treatment and psychological treatment should not be neglected. In this review, we briefly discuss the most recent developments in therapies for oral lichen planus after summarizing the most widely used clinical treatments, aiming to provide different proposals for future clinical treatment.

Pigmentary Changes in a Woman With Oral Lichen Planus.

A woman in her 60s presented with oral lichen planus on hands and cheeks since childhood and also present in her parent and sibling. What is your diagnosis?

Clinical value and potential circulating of miR-99a as tumor suppressor biomarker in serum of oral squamous cell carcinoma and erosive atrophic lichen planus.

OBJECTIVES: Oral squamous cell carcinoma (OSCC) is the most common type of oral neoplasms that consist of more over 90% of oral cancers. It was demonstrated that erosive atrophic oral lichen planus (OLP) has potential of malignancy transformation into OSCC. The microRNAs are non-coding regulator sequences involved in cancer process. The miR-99a involve in growth, proliferation, migration, invasion, and metastasis of tumor cells. Therefore, we evaluated miR-99a expression in serum of OSCC and erosive atrophic OLP patients in comparison to healthy control individuals to more investigate about level of miR-99a expression in potential premalignant disorder (erosive atrophic OLP) in comparison to malignant transformation form (OSCC). Gene ontology (GO) and pathway analyses were performed to better understand the importance of miR-99a in OSCC. MATERIALS AND METHODS: In this cross-sectional study, total 90 serum samples from OSCC patients (n = 30), erosive atrophic OLP (n = 30) and healthy control individuals (n = 30) were collected, and then evaluated for miR-99a expression by qPCR. Pathway analysis and protein-protein interaction were done using STRING (v: 12.0), and (GO) terms and related genes were extracted from the GO online search tool. The statistical analysis was evaluated by Kruskal Wallis, Chi-Square, Kruskal Wallis, Spearman and Mann-Whitney tests. The p-value less than 0.05 was considered statistically significant. RESULTS: miR-99a expression down regulated in OSCC in comparison to erosive atrophic OLP and control groups (p < 0.05). The miR-99a up regulated in grade I more than grades II and III (p < 0.05). We showed upregulation of miR-99a in early stage more than advanced stage (p < 0.05). Expression of miR-99a reduced accordance to the increasing of tumor size and lymph involvement levels (p < 0.05). The 165 determined targets were classified into three domains. The most significant enrichment in biological processes, cellular components, and molecular functions was in the cellular nitrogen compound biosynthetic process, cytosolic ribosome, and protein binding, respectively. CONCLUSIONS: We highlighted tumor suppressive role of miR-99a in OSCC patients. It seems that miR-99a can be considered a valuable biomarker for the early diagnosis of erosive atrophic OLP before transformation. CLINICAL RELEVANCE: Our results may help to better understand the prognostic factor for oral squamous cell carcinoma to evaluate survival and subsequent tumor development. And it may also help to understand the pathogenesis of OSCC.

Evaluation of the association between TNF-α-1031 T/C polymorphism with oral lichen planus disease.

BACKGROUND: Oral lichen planus (OLP) is a T-cell-mediated autoimmune disease that affects the epithelial cells of the oral cavity. This study was performed to investigate any possible relationship between - 1031(T/C) polymorphism (rs1799964) of the tumor necrosis factor α (TNF-α) gene with the risk and severity of oral lichen planus (OLP) disease among an Iranian population. METHOD: Saliva samples were collected from 100 patients with OLP and a similar number of healthy controls (age and sex-matched). Then, DNA was extracted from the collected samples for genotyping TNF-α-1031 T/C polymorphism using the PCR-CTPP method. The results were assessed using SPSS software. RESULTS: The findings revealed a significantly higher prevalence of the C allele in OLP patients (53%) compared to healthy controls (36%), suggesting an association between TNF-alpha gene polymorphism and OLP. A multivariate logistic regression analysis supported this finding, as the presence of the C allele was significantly associated with an increased risk of OLP [χ2 = 4.17, p = 0.04, 95% CI = 1.01-2.65, OR = 1.64]. However, our data indicated no significant association between TNF-alpha-1031 T/C gene polymorphism and OLP severity. CONCLUSIONS: These findings provide the first evidence supporting a possible role of TNF-α-1031 T/C gene polymorphism in OLP susceptibility in the Iranian population. The findings of this study demonstrate a positive association between TNF-α-1031 C/T allele distribution and the risk of OLP disease in the Iranian population. Therefore, carrying the C allele may increase the susceptibility to OLP disease.

[Study of the kinetics of accumulation and distribution of the photosensitizer photoditazin in the oral mucosa in patients with lichen planus]. / Izuchenie kinetiki nakopleniya i raspredeleniya fotosensibilizatora fotoditazin v slizistoi obolochke rta u patsientov s krasnym ploskim lishaem.

THE AIM OF THE STUDY: Was to explore the accumulation and distribution of the photosensitizer Photoditazine in the oral mucosa when applied to pathological lesions in patients with severe forms of lichen planus. MATERIAL AND METHODS: A clinical and laboratory examination was carried out in 50 patients with severe forms of lichen planus (bullous and erosive-ulcerative) aged 18 to 70 years, including 6 men and 44 women. For autofluorescent imaging a LED device with a wavelength in the violet region of the spectrum (400±10 nm) was used. Quantitative registration of the kinetics of accumulation and distribution of the photosensitizer was carried out using the method of local fluorescence spectroscopy by measuring the fluorescence spectra. RESULTS: The measurements were made before applying the photosensitizer, 10, 20 and 30 minutes after application. The study showed that in most patients with erosive-ulcerative and bullous forms of lichen planus, the accumulation of the photosensitizer in the lesions on the oral mucosa increased as the exposure time increased from 20 to 30 minutes. The fastest accumulation of the photosensitizer occurred in the areas of mucosal lesions with the most pronounced vascularization, namely, in the area of the tongue and the bottom of the oral cavity. CONCLUSION: Using the method of local fluorescence spectroscopy, the kinetics of accumulation and destruction of photosensitizer in pathological areas of the oral mucosa was determined, and therefore the optimal time of laser exposure to the lesion was determined.

Oral lichen planus and lichenoid lesions - challenges and pitfalls for the general dental practitioner.

Lichen planus is a chronic, mucocutaneous inflammatory condition which, due to its prevalence, will be familiar to the dental profession. However, diverse forms of presentation, important differential diagnosis, potential malignant change and monitoring requirements often result in challenges for those in primary care. This paper looks to examine these challenges and provide information to support those who are involved in recognition and management of patients with lichen planus.

Effects of Curcumin on the treatment of oral lichen planus symptoms: a systematic review and meta-analysis study.

BACKGROUND AND OBJECTIVES: Oral lichen planus (OLP) is a relatively common chronic T-cell-mediated disease that can cause significant pain, particularly in its erosive or ulcerative forms. This study aimed to examine the therapeutic impact of curcumin on symptoms of OLP. MATERIALS AND METHODS: This meta-analysis was performed according to the PRISMA guidelines. All related English documents indexed in electronic databases (including PubMed, Web of Science, Scopus, Embase, Wiley, Cochrane, and ProQuest databases [updated to August 15, 2023]) were retrieved. Data were double-extracted into a predefined worksheet, and quality analysis was performed using the Joanna Briggs Institute (JBI) scale. We carried out meta-analyses, and the random effects model was used to estimate the differences in erythema, lesion size, and pain between the curcumin control groups. RESULTS: The search identified 289 studies, of which 10 were found to meet the inclusion criteria. The overall findings of the meta-analysis revealed that curcumin did not have a significant effect on erythema of OLP (standardized mean difference [SMD] = -0.14; 95% CI, -0.68 to 0.40; P = 0.61; I2 = 57.50%), lesion size of OLP (SMD = -0.15; 95% CI, -0.45 to 0.15; P = 0.33; I2 = 28.42%), and pain of OLP (SMD = -0.38; 95% CI, -0.97 to 0.22; P = 0.22; I2 = 86.60%). However, subgroup analysis based on treatment duration indicated that 2-week treatment duration was significantly associated with a reduction in OLP pain (n = 3; SMD = -1.21; 95% CI, -2.19 to -0.23; P = 0.01). CONCLUSIONS: Curcumin had no significant effect on erythema, lesion size, and pain of OLP compared to the control groups. However, subgroup analysis revealed that curcumin was more effective in reducing pain in non-randomized trials and in trials with a treatment duration of 2 weeks.

Photodynamic therapy for refractory erosive oral lichen planus: a case series study.

Oral lichen planus is a chronic inflammatory disease that occurs on the oral mucosa and is an oral potentially malignant disease. Treatment of oral lichen planus aims to promote healing of the erosion, relieve pain, reduce recurrence of the erosion, and prevent canceration. Corticosteroids are the first line of treatment for oral lichen planus. Refractory oral lichen planus is a clinical classification of oral lichen planus that has not responded to corticosteroid treatment for more than 2 months. Topical 5-aminolevulinic acid-mediated photodynamic therapy is an innovative and effective treatment for potentially malignant oral diseases and has been reported as an alternative treatment to conventional therapies for oral lichen planus. On this basis, we report 3 cases of refractory erosive oral lichen planus in which persistent erosive lesions healed after topical application of 5-aminolevulinic acid-mediated photodynamic therapy without any adverse effects or any signs of recurrence. Topical 5-aminolevulinic acid-mediated photodynamic therapy will become an effective clinical treatment for refractory erosive oral lichen planus.

Oral bacteriome and oral potentially malignant disorders: A systematic review of the associations.

INTRODUCTION: Periodontal bacteria can infiltrate the epithelium, activate signaling pathways, induce inflammation, and block natural killer and cytotoxic cells, all of which contribute to the vicious circle of carcinogenesis. It is unknown whether oral dysbiosis has an impact on the etiology or prognosis of OPMD. AIMS: Within this paradigm, this work systemically investigated and reported on the composition of oral microbiota in patients with oral potentially malignant disorders (OPMD) versus healthy controls. METHODS: Observational studies that reported next generation sequencing analysis of oral tissue or salivary samples and found at least three bacterial species were included. Identification, screening, citation analysis, and graphical synthesis were carried out. RESULTS: For oral lichen planus (OLP), the bacteria with the highest abundance were Fusobacterium, Capnocytophaga, Gemella, Granulicatella, Porphyromonas, and Rothia; for oral leukoplakia (OLK), Prevotella. Streptococci levels in OLK and OLP were lower. The usage of alcohol or smoke had no effect on the outcomes. CONCLUSIONS: An increase in periodontal pathogenic bacteria could promote the development and exacerbation of lichen. Effective bacteriome-based biomarkers are worthy of further investigation and application, as are bacteriome-based treatments.

Prognosis of oral epithelial dysplasia in individuals with and without oral lichen planus.

OBJECTIVES: To investigate the role of oral lichen planus (OLP) on the long-term prognosis of oral epithelial dysplasia (OED). METHODS: Retrospective single-centre cohort study using the 2007-2019 database of the Head and Neck Cancer and Oral Medicine units of University College London Hospital. The exposure of interest was the presence of OLP, and the prognostic outcomes included the development of new primary episodes of OED, progression to malignancy and mortality. Cox proportional hazard and Poisson regression models were performed. RESULTS: A total of 299 patients, of whom 144 had OED arising on the background of OLP (OLP/OED) and 155 had OED without underlying OLP (non-OLP/OED), were included. A pre-existing diagnosis of OLP was significantly associated with a twofold increased risk of subsequent primary OED events (HR = 2.02, p = 0.04), which also developed faster (1.46 vs. 2.96 years, p = 0.04) and with more involvement of non-cancer-prone sites (p = 0.001) than in the non-OLP/OED group. There was no difference between groups in the progression to malignancy or mortality. CONCLUSIONS: Oral lichen planus/OED patients are at higher risk of multiple episodes of primary OED, which can develop faster and at non-cancer-prone sites as compared to non-OLP/OED individuals. Further research is needed to clarify the effects of OLP upon progression to OSCC and mortality.

Assessment of periodontal status in patients with oral lichen planus.

OBJECTIVE: Inflammatory pathogenesis is common to periodontitis and oral lichen planus. This study was conducted to assess and compare the periodontal status of patients with and without oral lichen planus. METHOD AND MATERIALS: 108 patients comprising 54 with oral lichen planus and 54 age-matched systemically healthy participants without oral lichen planus were selected. Periodontal parameters, ie Plaque Index, Gingival Index, bleeding on probing, probing pocket depth, clinical attachment level, and periodontal phenotype were measured. RESULTS: On comparing the test and control groups, statistically significant differences were observed in respect to Plaque Index (P = .00), Gingival Index (P = .00), and bleeding on probing (P = .00). A higher proportion of sites with deeper pockets was observed in the test group (P = .00). On comparison of various oral lichen planus subtypes, significant difference was observed in respect to Gingival Index (P = .00) and bleeding on probing (P = .00). A higher proportion of sites with deeper pockets (P = .01) and greater CAL (P = .00) was observed in the erosive/atrophic subgroup compared to the reticular group. However, the differences between the reticular (a less severe form of oral lichen planus) and control group in terms of Gingival Index (P = .94), Plaque Index (P = .05), bleeding on probing (P = .17), probing pocket depth (P = .56), and clinical attachment level (P = .23) were not statistically significant. Statistically significant differences were observed in terms of Gingival Index (P = .01) and bleeding on probing (P = .00) between thin and thick periodontal phenotypes in the oral lichen planus group. Statistically significant positive correlations in periodontal parameters with increased gingival involvement and severity were observed using Spearman rank correlation coefficient. CONCLUSION: Significantly greater periodontal inflammation in the test group means there is a risk of greater attachment loss in future. Thus, increased attention towards periodontal health in these patients might reduce the rate of disease progression.

Painful refractory erosive tongue lichen planus with malignant transformation.

We present a recent case of long standing erosive tongue lichen planus successfully treated by wide excision and reconstruction with a submental artery island flap. Erosive Lichen Planus is a progressive indolent potentially malignant condition that tends to end up with severe somatic or even neuropathic pain and malignant changes towards its final stages as elaborated in the presented commentary.

Desquamative gingivitis treatment with topical tacrolimus applied to a custom tray: an open trial regarding its efficacy on patients' symptoms.

OBJECTIVE: To evaluate the efficacy of topical tacrolimus offered on a custom tray to treat desquamative gingivitis (DG). STUDY DESIGN: Eighteen patients with symptomatic DG related to oral lichen planus (OLP) or mucous membrane pemphigoid (MMP) were selected, of which 13 completed the study. Periodontal treatment was followed by the fabrication of a custom silicone tray to apply a tacrolimus gel formulation (0.1%). Clinical evaluation (complaint of pain and burning - visual analog scale from 0 to 10; and the presence of erythema, desquamation, vesicle/blister, erosion, ulcer, and bleeding) was performed by the same examiner on day 1, and every 15 days for 90 days. RESULTS: Total remission was found in 4 patients (30.76%). Partial remission was found in 69.24% of the patients, classified with an excellent (30.76%), good (30.76%), and regular (7.69%) recovery, respectively. There was a reduction of about 60% in pain and 65% in burning sensation complaints. Wilcoxon test revealed significant differences between pre- and post-treatment pain and burning sensation symptoms (P < .01). CONCLUSION: Topical application of 0.1% tacrolimus gel was effective in the treatment of DG in controlling pain and burning sensation, leading to the clinical remission of gingival lesions in patients with OLP and MMP.

The expression of p53, ki67 and COX-2 in erosive-type oral lichen planus.

Oral lichen planus is a chronic inflammatory disease that affects the oral mucosa and may undergo malignant changes, which can be reflected in the expression of specific proteins that are responsible for maintaining cellular mitosis and apoptosis. The study aimed to investigate the expression of p53, ki67, and COX-2 in erosive lichen planus using immunohistochemistry to correlate these findings with the histological aspects of the disease. Thirty-three biopsies of erosive lichen planus were collected and diagnosed based on histological and clinical criteria. The blocks were processed for immunohistochemistry to assess p53, ki67, and COX-2 expression in the basal layer, suprabasal, and inflammatory infiltrate respectively. The histological analysis of the samples showed no dysplasia or metastasis. P53 stained positively in 80% of the samples, while ki67 was positive in all the cases, ranging from 5% to 85% positivity. COX-2 expression ranged from 0-50% positivity. The highest expression of p53 was observed in 8 cases (24.2%), with a maximum of 5%, and ki67 exhibited the highest expression of 90% in 3 cases (9.1%). COX-2 was negative in 27 cases (81.8%) and positive in 6 cases (18.1%), with the highest expression at 50% in 1 case and 10 % positivity in 4 cases (12.1%). In our study, the markers p53, ki67, and COX-2 proved to be useful for detecting the proliferative, inflammatory, and physiologic states of the keratinocytes. However, they did not demonstrate utility in detecting any malignant transformation.

Toll-like receptor 9-positive plasmacytoid dendritic cells promote Th17 immune responses in oral lichen planus stimulated by epithelium-derived cathepsin K.

Oral lichen planus (OLP) is a chronic inflammatory disease associated with T cell infiltration. The crosstalk between oral epithelium and mucosal T cells was considered to be crucial in the pathogenesis of OLP. Here, we selectively extracted the normal epithelium (NE) and lesional epithelium (LE) of buccal mucosa specimens from three patients with OLP by laser capture microdissection due to identify the pathogenic factors. Cathepsin K (CTSK) was identified as one of common upregulated genes in the LE by DNA microarray. Immunohistochemically, CTSK was distinctly detected in and around the LE, while it was rarely seen in the NE. Recent studies showed that CTSK enhanced Toll-like receptor 9 (TLR9) signaling in antigen-presenting cells, leading to Th17 cell differentiation. TLR9 expression mainly co-localized with CD123+ plasmacytoid dendritic cells (pDCs). The number of RORγt-positive cells correlated with that of CTSK-positive cells in OLP tissues. CD123+ pDCs induced the production of Th17-related cytokines (IL-6, IL-23, and TGF-ß) upon stimulation with TLR9 agonist CpG DNA. Moreover, single cell RNA-sequencing analysis revealed that TLR9-positive pDCs enhanced in genes associated with Th17 cell differentiation in comparison with TLR9-negative pDCs. CTSK could induce Th17-related production of CD123+ pDCs via TLR9 signaling to promote the pathogenesis of OLP.

ALDH1 immunoexpression in epithelial and stromal cells of oral lichen planus and lesions with lichenoid inflammatory infiltrate

Background: Oral Lichen Planus is a potential malignant disorder and shares clinical and histopathological features with other similar lesions. ALDH1 is a specific biomarker for stem cells identification, however its role in stromal cells of immune inflammatory infiltrate has not been explored. The aim of this study was to investigate the ALDH1 immunoexpression in epithelial and stromal cells of Oral Lichen Planus and other lesions with lichenoid inflammatory infiltrate. Material and Methods: 64 samples of Oral Lichen Planus, Oral Lichenoid Lesions, Oral Leukoplakia and Unspecific Chronic Inflammation were included. ALDH1 was evaluated in both epithelium and stromal cells. ALDH1+ cells ≥ 5% were considered positive in epithelium. Stromal cells were evaluated semi quantitatively. Fields were ranked in scores, according to criteria: 1 (0 to 10%); 2 (11 to 50%) and 3 (>50%). The mean value of the sum of the fields was the final score. Statistical differences among groups were investigated, considering p < 0.05. Results: ALDH1 expression in epithelium was low in all groups without difference among them. ALDH1+ cells in the lamina propria were higher for Lichen Planus [2.0], followed by Leukoplakia [1.3], Lichenoid lesions [1.2] and control [1.1] (p<0.05). Conclusions: ALDH1 immunoexpression in epithelium of lichenoid potential malignant disorders did not show a contributory tool, however ALDH1 in stromal cells of lichen planus might be involved in the complex process of immune regulation associated with the pathogenesis of this disease. (AU)