Interventions for managing oral submucous fibrosis.

BACKGROUND: Oral submucous fibrosis (OSF) is a chronic disease of the oral cavity that causes progressive constriction of the cheeks and mouth accompanied by severe pain and reduced mouth opening. OSF has a significant impact on eating and swallowing, affecting quality of life. There is an increased risk of oral malignancy in people with OSF. The main risk factor for OSF is areca nut chewing, and the mainstay of treatment has been behavioural interventions to support habit cessation. This review is an update of a version last published in 2008. OBJECTIVES: To evaluate the benefits and harms of interventions for the management of oral submucous fibrosis. SEARCH METHODS: We used standard, extensive Cochrane search methods. The latest search date was 5 September 2022. SELECTION CRITERIA: We considered randomised controlled trials (RCTs) of adults with a biopsy-confirmed diagnosis of OSF treated with systemic, locally delivered or topical drugs at any dosage, duration or delivery method compared against placebo or each other. We considered surgical procedures compared against other treatments or no active intervention. We also considered other interventions such as physiotherapy, ultrasound or alternative therapies. DATA COLLECTION AND ANALYSIS: We used standard Cochrane methods. Our primary outcomes were 1. participant-reported resumption of normal eating, chewing and speech; 2. change or improvement in maximal mouth opening (interincisal distance); 3. improvement in range of jaw movement; 4. change in severity of oral/mucosal burning pain/sensation; 5. ADVERSE EFFECTS: Our secondary outcomes were 6. quality of life; 7. postoperative discomfort or pain as a result of the intervention; 8. participant satisfaction; 9. hospital admission; 10. direct costs of medication, hospital bed days and any associated inpatient costs for the surgical interventions. We used GRADE to assess certainty of evidence for each outcome. MAIN RESULTS: We included 30 RCTs (2176 participants) in this updated review. We assessed one study at low risk of bias, five studies at unclear risk of bias and 24 studies at high risk of bias. We found diverse interventions, which we categorised according to putative mechanism of action. We present below our main findings for the comparison 'any intervention compared with placebo or no active treatment' (though most trials included habit cessation for all participants). Results for head-to-head comparisons of active interventions are presented in full in the main review. Any intervention versus placebo or no active treatment Participant-reported resumption of normal eating, chewing and speech No studies reported this outcome. Interincisal distance Antioxidants may increase mouth opening (indicated by interincisal distance (mm)) when measured at less than three months (mean difference (MD) 3.11 mm, 95% confidence interval (CI) 0.46 to 5.77; 2 studies, 520 participants; low-certainty evidence), and probably increase mouth opening slightly at three to six months (MD 8.83 mm, 95% CI 8.22 to 9.45; 3 studies, 620 participants; moderate-certainty evidence). Antioxidants may make no difference to interincisal distance at six-month follow-up or greater (MD -1.41 mm, 95% CI -5.74 to 2.92; 1 study, 90 participants; low-certainty evidence). Pentoxifylline may increase mouth opening slightly (MD 1.80 mm, 95% CI 1.02 to 2.58; 1 study, 106 participants; low-certainty evidence). However, it should be noted that these results are all less than 10 mm, which could be considered the minimal change that is meaningful to someone with oral submucous fibrosis. The evidence was very uncertain for all other interventions compared to placebo or no active treatment (intralesional dexamethasone injections, pentoxifylline, hydrocortisone plus hyaluronidase, physiotherapy). Burning sensation Antioxidants probably reduce burning sensation visual analogue scale (VAS) scores at less than three months (MD -30.92 mm, 95% CI -31.57 to -30.27; 1 study, 400 participants; moderate-certainty evidence), at three to six months (MD -70.82 mm, 95% CI -94.39 to -47.25; 2 studies, 500 participants; moderate-certainty evidence) and at more than six months (MD -27.60 mm, 95% CI -36.21 to -18.99; 1 study, 90 participants; moderate-certainty evidence). The evidence was very uncertain for the other interventions that were compared to placebo and measured burning sensation (intralesional dexamethasone, vasodilators). Adverse effects Fifteen studies reported adverse effects as an outcome. Six of these studies found no adverse effects. One study evaluating abdominal dermal fat graft reported serious adverse effects resulting in prolonged hospital stay for 3/30 participants. There were mild and transient general adverse effects to systemic drugs, such as dyspepsia, abdominal pain and bloating, gastritis and nausea, in studies evaluating vasodilators and antioxidants in particular. AUTHORS' CONCLUSIONS: We found moderate-certainty evidence that antioxidants administered systemically probably improve mouth opening slightly at three to six months and improve burning sensation VAS scores up to and beyond six months. We found only low/very low-certainty evidence for all other comparisons and outcomes. There was insufficient evidence to make an informed judgement about potential adverse effects associated with any of these treatments. There was insufficient evidence to support or refute the effectiveness of the other interventions tested. High-quality, adequately powered intervention trials with a low risk of bias that compare biologically plausible treatments for OSF are needed. It is important that relevant participant-reported outcomes are evaluated.

Exosomes Derived from Human Adipose Mesenchymal Stem Cells Inhibits Fibrosis and Treats Oral Submucous Fibrosis via the miR-181a-5p/Smad2 Axis.

BACKGROUND: Oral submucous fibrosis (OSF) is a chronic disease with carcinogenic tendency that poses a non-negligible threat to human health. Exosomes derived from human adipose mesenchymal stem cells (ADSC-Exo) reduces visceral and cutaneous fibroses, but their role in OSF has received little attention. The aim of this study was to investigate the effects of ADSC-Exo on OSF and elucidate the mechanism. METHODS: In brief, ADSCs were extracted from adipose tissues and subjected to flow cytometry and induction culture. Fibroblasts were isolated from human buccal mucosa and subjected to immunofluorescence. Myofibroblasts were obtained from fibroblasts induced by arecoline and identified. Immunofluorescence assay confirmed that myofibroblasts could take up ADSC-Exo. The effects of ADSC-Exo on the proliferative and migratory capacities of myofibroblasts were examined using the Cell Counting Kit-8 and scratch assay. Real-time quantitative polymerase chain reaction (qPCR) was performed to evaluate mothers against decapentaplegic homolog 2 (Smad2), Smad3, Smad7, collagen type 1 (Col1), Col3, alpha smooth muscle actin (α-SMA), fibronectin, and vimentin. Western blotting was performed to detect phospho (p)-Smad2, Smad2, p-Smad2/3, Smad2/3, Smad7, Col1, Col3, α-SMA, fibronectin, and vimentin. Furthermore, the dual-luciferase reporter assay was performed to prove that miR-181a-5p in ADSC-Exo directly inhibited the expression of Smad2 mRNA to regulate the transforming growth factor beta (TGF-ß) pathway. We also performed qPCR and western blotting to verify the results. RESULTS: ADSC-Exo could promote the proliferation and migration of myofibroblasts, reduce the expressions of p-smad2, Smad2, p-smad2/3, Smad2/3, Col1, αSMA, fibronectin, and vimentin and elevated the levels of Smad7 and Col3. In addition, miR-181a-5p was highly expressed in ADSC-Exo and bound to the 3'-untranslated region of Smad2. ADSC-Exo enriched with miR-181a-5p reduced collagen production in myofibroblasts and modulated the TGF-ß pathway. CONCLUSIONS: ADSC-Exo promoted the proliferative and migratory capacities of myofibroblasts and inhibited collagen deposition and trans-differentiation of myofibroblasts in vitro. miR-181a-5p in exosomes targets Smad2 to regulate the TGF-ß pathway in myofibroblasts. ADSC-Exo perform antifibrotic actions through the miR-181a-5p/Smad2 axis and may be a promising clinical treatment for OSF.

Guideline for the Diagnosis and Clinical Management of Oral Submucous Fibrosis.

Oral submucous fibrosis (OSF) is a chronic, progressive and potentially malignant oral mucosal disease. Patients often have a habit of chewing betel nuts. Areca catechu has been listed as a Class 1 carcinogen by the International Agency for Research on Cancer (IARC), and its main active component, arecoline, is classified as a Group 2B carcinogen by the IARC. The World Health Organization (WHO) categorises OSF as an oral potentially malignant disorder (OPMD). The present guideline describes the risk factors, clinical symptoms and clinical signs of OSF. Clinical staging, auxiliary examination methods, basis for diagnosis and differential diagnosis and the need to improve bad lifestyle habits are proposed and addressed, and local treatment drugs, therapies, dosage and course of treatment, possible adverse reactions, and oral treatment drugs, dosage and course of treatment are proposed. The guideline also addresses the indications for surgical treatment, alternative non-drug treatment methods, selection of treatment plans for different clinical stages, criteria for efficacy evaluation, and preventive measures.

Oral submucous fibrosis in children: an alarming condition and challenges in management.

Oral submucous fibrosis (OSF) is a well-documented potentially malignant condition. It affects most commonly the adult patients of India and Indian subcontinent, only few cases affecting children have been reported in the literature. This paper presents three cases of OSF below the age of 12 years and reviews the aetiology, clinical presentation, treatment modalities in children with improved follow-up results. Clinical features like restricted mouth opening, burning sensation and history of betel nut chewing helps in the diagnosis of the patients, which can be confirmed by histopathological examination. Conservative management and oral physiotherapy in children help in improved mouth opening. Counselling the children, their friends and parents also plays a vital role. The present paper highlights that children on a larger scale are using tobacco products and further studies are required with larger sample size.

A Comparative Study to Evaluate Efficacy of Curcumin and Aloe Vera Gel along with Oral Physiotherapy in the Management of Oral Submucous Fibrosis: A Randomized Clinical Trial.

Rationale (Hypothesis): The antioxidant,anti-inflammatory,immunomodulatory and anti-tumorigenic properties of natural plant's extracts like aloe Vera and curcumin  may produce beneficial therapeutic effects on OSMF patients and may lead to their symptomatic relief. Also, increase in the tissue elasticity with the help of oral physiotherapy excercises , would help in reinforcing increment in  mouth opening. AIM: The aim of the study is to compare the efficacy of Curcumin gel with Aloe Vera gel when both the gel are supplemented along with oral physiotherapy in the management of OSMF. MATERIALS AND METHODS: A study of parallel group trial design, using simple randomization technique, was conducted on confirmed cases of OSMF. Patients were divided into two groups, one group(30 patients) was given curcumin gel(Curenext) and other group (30 patients) aloe Vera gel (Aloe Vera 100% relief) and each group was asked to do same oral physiotherapy excercises supplementally. Follow-up was done for 6 weeks and patients were assessed on the basis of improvement in mouth opening and burning sensation at 2, 4, and 6 weeks. RESULTS: There was an improvement in both the parameters at subsequent visits, but the Aloe Vera gel showed better improvement than curcumin gel in burning sensation after 6 weeks of treatment which was highly statistically significant p < 0.01. CONCLUSION: Curcumin gel and Aloe Vera gel are effective in improving OSMF symptoms, but aloe Vera gel is more efficacious in burning sensation improvement without any side effects. Hence, we can advocate these drugs as adjuvant treatment in addition to the recommended treatment.

Hypothesizing the therapeutic potential of mesenchymal stem cells in oral submucous fibrosis.

Oral submucous fibrosis is the direct consequence of a sustained pro-inflammatory environment characterized by excessive collagen deposition causing tissue fibrosis, and progressive degeneration of vital structures including muscle. The pathogenesis of oral submucous fibrosis is largely mediated by the pro-inflammatory, pro-fibrotic cytokines, excessive oxidative stress, abnormal angiogenesis, and epithelial to mesenchymal transition. Mesenchymal stem cells largely known for their regenerative potential have shown to have an immunomodulatory, anti-fibrotic, anti-oxidative, and angiogenic potential. Thus, mesenchymal stem cells, when introduced in an oral submucous fibrosis micro-environment, could potentially counter the progressive fibrosis. The present hypotheses discuss the various pathogenic aspects of oral submucous fibrosis and the properties of mesenchymal stem cells which could aid in halting the disease progression.

Oral Submucous Fibrosis: A Review on Biomarkers, Pathogenic Mechanisms, and Treatments.

Oral submucous fibrosis (OSF) is a collagen deposition disorder that affects a patient's oral function and quality of life. It may also potentially transform into malignancy. This review summarizes the risk factors, pathogenic mechanisms, and treatments of OSF based on clinical and bio-molecular evidence. Betel nut chewing is a major risk factor that causes OSF in Asia. However, no direct evidence of arecoline-induced carcinogenesis has been found in animal models. Despite identification of numerous biomarkers of OSF lesions and conducting trials with different drug combinations, clinicians still adopt conservative treatments that primarily focus on relieving the symptoms of OSF. Treatments focus on reducing inflammation and improving mouth opening to improve a patient's quality of life. In conclusion, high-quality clinical studies are needed to aid clinicians in developing and applying molecular biomarkers as well as standard treatment guidelines.

Reasons for Initiation of Areca Nut and Related Products in Patients with Oral Submucous Fibrosis within an Endemic Area in Gujarat, India.

Background: While the patterns of consumption of areca nut and its by-products (ANBP) vary across South Asia and the rest of the world, all users share the probable severe outcome of oral submucous fibrosis (OSMF), and this is well reported. The role of psychosocial drivers of habit initiation and addiction is reported less. Objective: To reveal the burden of ANBP abuse, exploring the psychosocial relationship between sex, age at first exposure (AFE), the reason for initiation (RFI) with the type of habit (TOH). Methodology: Data came from the prospective hospital-based study conducted at K.M. Shah Dental College and Hospital covering years 2017 and 2018. Patients with oral lesions were assessed with complete history recording demographics, TOH, AFE, RFI, duration of habit, and clinical diagnosis of any oral and systemic diseases. Patients with a history of scleroderma, facial burns, and oral malignancy were excluded. Results: Of the 13,874 patients, 9.89% reported ANBP. We included 1000 OSMF patients. The mean age of the study cohort was 38.97 ± 14.29 years, with a range of 17-75 years. Males constituted the majority (80.1%). The most common TOH reported was regular use of gutkha (60.1%) followed by mawa (31.4%) with tension and stress (30.3%) being the most common RFI among the cohort. TOH was notably different in relation to AFE. Interestingly, mawa chewing (38.69%) was observed more in females. Importance: This study reveals the burden of ANBP abuse and reports the complex psychosocial relationships between sex, AFE, and RFI with TOH in OSMF patients in this high incidence population.

Photobiomodulation therapy inhibits oral submucous fibrosis in mice.

OBJECTIVES: Oral submucous fibrosis (OSMF) is a chronic inflammatory disease and a potentially malignant oral disorder. However, the best therapeutic treatment for OSMF remains uncertain. Our previous study showed that photobiomodulation (PBM) therapy and forskolin could reduce arecoline-induced fibrosis reactions via the cAMP pathway. The present study aimed to establish an animal model of areca nut extract (ANE)-induced OSMF and to evaluate the therapeutic potential of PBM and forskolin for ANE-induced OSMF. SUBJECTS AND METHODS: The mice were divided into five groups. The buccal tissues were harvested for histomorphological analysis and immunoblotting. RESULTS: Our results showed that PBM significantly reduced the development of ANE-induced OSMF, quantified by changes in submucosal layer thickness and collagen deposition. Additionally, PBM could extensively reduce the protein expression of the fibrotic marker genes alpha-smooth muscle actin (α-SMA) and connective tissue growth factor (CTGF) in buccal submucous lesions. However, forskolin treatment significantly decreased the protein expression of fibrotic marker genes but slightly decreased the observed histomorphological changes. CONCLUSIONS: We established an ANE-induced OSMF mouse model, which also provided a model for the development of a therapeutic treatment for OSMF. The anti-fibrotic effects of PBM and forskolin may be useful for clinical interventions.

Oral submucous fibrosis: a contemporary narrative review with a proposed inter-professional approach for an early diagnosis and clinical management.

Oral Submucous fibrosis (OSMF) has traditionally been described as "a chronic, insidious, scarring disease of the oral cavity, often with involvement of the pharynx and the upper esophagus". Millions of individuals are affected, especially in South and South East Asian countries. The main risk factor is areca nut chewing. Due to its high morbidity and high malignant transformation rate, constant efforts have been made to develop effective management. Despite this, there have been no significant improvements in prognosis for decades. This expert opinion paper updates the literature and provides a critique of diagnostic and therapeutic pitfalls common in developing countries and of deficiencies in management. An inter-professional model is proposed to avoid these pitfalls and to reduce these deficiencies.

Oral submucous fibrosis in Asian countries.

Oral submucous fibrosis (OSF) is a chronic, insidious, and progressive oral mucosal disease that affects entire oral cavity and sometimes pharynx. This oral potentially malignant disorder has a high rate of malignant transformation (7%-30%) to oral squamous cell carcinoma (OSCC), posing global problems for public health. Due to enormous efforts dedicated to this disease in the past decades, there have been significant advances in identification of its etiology and pathogenesis as well as development of corresponding therapeutic approaches, in spite of several challenges. This study reviewed the existing literature concerning OSF in Asian countries, encompassing its etiology, histopathology, pathogenesis, clinical manifestations, diagnosis and differential diagnosis, and treatments. For improving treatment of OSF, the multifactorial etiology analysis, incorporation of effective molecular pathways, cytokines and cells for mechanism illustration, and integration of multidisciplinary modalities were also expounded to guide future research and clinical practice.

Oral Submucous Fibrosis: A Review on Etiopathogenesis, Diagnosis, and Therapy.

Oral submucous fibrosis (OSF) is characterized by abnormal collagen deposition. It is a precancerous disorder and transforms into a malignant tumor in 1.5-15% of all cases. Symptoms include submucous fibrosis, ulceration, xerostomia, a burning sensation, and restricted mouth opening. All of these greatly interfere with patient quality of life. The present review introduces OSF from a molecular perspective and summarizes what is known about its underlying mechanisms, diagnostic biomarkers, and therapeutic interventions. In addition to the aggressive treatment of OSF, its prevention is also important. Future research should, therefore, focus on improving the oral health literacy of the patients susceptible to OSF.

Assessment of oral health-related quality of life instruments for oral submucous fibrosis: A systematic review using the COnsensus-based Standards for the selection of health Measurement Instruments (COSMIN) checklist.

Quality of life (QoL) instruments are becoming increasingly important in research and often used in clinical practice. Various QoL instruments have been developed/ validated for assessment of oral health-related QoL (OHRQoL) in patients with oral submucous fibrosis (OSF). Selection of an adequate instrument is challenging in routine practice due to lack of information on psychometric quality of measurement instruments. This systematic review gives an extensive overview of quality of all the currently available measurement instruments for use in OSF patients. PubMed, Scopus, Web of Science and CINAHL were searched for relevant literature until December 2018 and the information was extracted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. The quality of the identified studies was assessed per measurement property according to the COnsensus-based Standards for the selection of health Measurements Instruments (COSMIN) checklist. Four studies that met the inclusion criteria were included. Three generic and one disease-specific QoL instruments were identified. Information regarding important measurement properties was often incomplete. The evidence for the quality of measurement instruments was found to be variable, none of the instruments performed sufficient on all measurement properties. Based on the available information, OHRQoL-OSF appeared to have adequate COSMIN measurement properties. As recently published, newer QoL instruments have not yet been evaluated in an adequate manner for use in OSF. We suggest future studies should implement OSF-specific OHRQoL-OSF to better understand OSF patients' perspectives and help inform clinicians to propose treatment strategies as per patients' needs.

Oral Submucous Fibrosis in Pediatric Patients: A Systematic Review and Protocol for Management.

AIM: To conduct a systematic review evaluating the cases of oral submucous fibrosis in pediatric patients. MATERIAL AND METHOD: Systematic review was conducted using PRISMA guidelines. The article focused on oral submucous fibrosis in pediatric patients were included. A total of five manuscripts were included in our systematic review. The prevalence of OSMF in pediatric patients, gender distribution, causes, and clinical presentation were reviewed. RESULTS: On systematically reviewing, a total of 10 cases of OSMF in pediatric patients were found. The youngest patient reported to be diagnosed with OSMF was of 2.5 years of age. Female preponderance was noticed. All the patients had the habit of areca nut chewing which subsequently led to fibrosis. CONCLUSION: Such a rapid increase in the rate of OSMF among pediatric population is a potential danger to the society. The habit of areca nut chewing is the major cause for this dreadful condition. Lack of health consciousness and low level of education are the major factors for initiation of this habit among children. Therefore it is imperative for the parents and school as well as government authorities to take serious actions.