Leukoplakia and erythroplakia, palate lesions due to reverse cigar smoking, oral lichen planus, oral submucous fibrosis (OSMF), discoid lupus erythematosus, and hereditary disorders including dyskeratosis congenita and epidermolysis bullosa are among the premalignant conditions listed by the WHO.¹

OSMF is a premalignant disorder that primarily affects people in the Indian subcontinent. It causes the oral soft tissues to become increasingly juxtaepithelial fibrosis-prone, which eventually makes it impossible to open the mouth. The regions of Southeast Asia have a high prevalence of OSMF. Over the previous forty years, the incidence in India rose from 0.03% to 6.42%.^2,3 Five million OSMF sufferers are thought to reside in India, according to data released previously. Typically, guys between the ages of 20 and 40 have OSMF. The soft palate, retromolar pads, buccal mucosa, labial mucosa, and floor of the mouth are the typical locations affected.⁴

Extracellular matrix disruption caused by the use of the Areca nut product is thought to be the cause of OSMF. Diffuse involvement of the pharynx, upper esophagus, and oral cavity is a common clinical manifestation of the disease, showing up as whitish mucosa with reduced flexibility. Seven to twenty-six percent of OSMF tissues have been reported to have epithelial dysplasia; long-term investigations indicate that seven percent of these lesions have a malignant transition rate.⁵

Chewing areca nut and betel quid (or replacement) is the habit that causes the sickness. The burning sensation, trismus, and blanching and stiffness of the oropharynx and oral mucosa are the main clinical presentations of OSMF. In the advanced phases, the vertical fibrous bands in the lips, faucial pillars, and buccal mucosa are also visible. Although a number of theories have been proposed, including areca nut chewing, green chili, dietary deficiencies, genetic predisposition, autoimmune, and collagen problems, the origin and pathogenesis of this entity remain unclear.^5,6

Different therapy approaches have been developed for OSMF, taking into account the level of clinical involvement. While moderate-to-severe OSMF is irreversible, mild OSMF is reversible. The standard treatment consists of oral medications such as carotenoids, alpha lipoic acid, lycopene, vitamins, microelements, and tea pigments, as well as intralesional enzymes such as hyaluronidase, trypsin, chymotrypsin, and placental extracts.^3-6

There is still debate concerning the surgical treatment options for oral submucous fibrosis. The following restrictions apply to surgical treatment: insufficient BFP harvesting in severe cases due to atrophy; aesthetic morbidity regarding the scar after surgery; dysphasia; disarticulation; risk of aspiration after surgery; limited flap reach and coverage; hair growth on flaps; donor site morbidity; secondary debulking procedures; and flap contractures following surgery, among other issues.⁴

Several novel approaches, including gamma-interferon 8, pentoxyfilline (which has anti-inflammatory and vasodialating properties), and spirulina (a blue-green algae rich in carotenoids with antioxidant properties, including high levels of beta-carotene and superoxide dismutase), have been investigated for the effective management of open-ended photosystem failure. The synthetic and natural compounds of vitamin A are called retinoidoids. A class of chemical compounds known as retinoids are either chemically related to or vitamers of vitamin A. In medicine, retinoids are used to control the development of epithelial cells.⁵

Retinoids come in three generations: Retinol, retinal, tretinoin (retinoic acid), isotretinoin, and alitretinoin are examples of the first generation. Etretinate and its metabolite acitretin are examples of second-generation drugs. Adapalene, bexarotene, and tazarotene are examples of third generation.⁶

Retinoids play numerous vital roles in the body, including immune system function, bone tissue formation, regulation of cell proliferation and differentiation, vision, and the activation of tumor suppressor genes. Therefore, the purpose of the study was to assess the effectiveness of a more recent medication called tretinoin, which contains trans retinoic acid (RA).

It was a monocentric single blind study conducted in Department of   Otorhinolaryngology  in Tertiary care centre for a period of 1 year. In order to assess the effectiveness of trans RA in the treatment of OSMF, a premalignant condition in the oral cavity, we have undertaken a study to determine the quality of life in patients with Grade I and Grade II OSMF and to determine the efficacy of tretinoin (a vitamin A supplement) in the form of soft gel capsules containing trans RA.

Patients who complained of having trouble opening their mouths were seen, and their medical history was taken into consideration. Drug allergies and any pertinent medical history were ruled out. A detailed history of the patient's behaviors was recorded, encompassing information on chewing habits, brand, kind, frequency, and duration of chewing, as well as the location and duration of quid storage, as well as whether the quid was eaten or spit out. This was followed by comprehensive clinical examinations.

Clinical confirmation of the lesion led to the patient being instructed to undergo standard blood testing on the first visit for each participant. The ultimate diagnosis of OSMF was reached thanks to the coordinated efforts of an oral pathology diagnostic team and oral and maxillofacial surgeons, as well as the pertinent data that had been gathered. Patients were informed about the nature of the treatment, potential outcomes, potential complications, and the post-therapy outcome. The patients gave their informed consent before beginning the treatment, and over the six months of the therapy, the findings were documented every week, every fifteen days, and every thirty days.

Inclusion Criteria-

In accordance with the 1995 classification by Khanna and Andrade, patients are split into Group I and Group II.

Patients in Group I:Extremely early cases: Common symptoms include burning in the mouth, acute ulceration, and recurring stomatitis; mouth opening limitation is not a factor.

Group II Patients: Early cases: palpable, extensive sheets of fibrosis with an interincisal spacing of 26–35 mm; buccal mucosa appears mottled and marble-like.

In total, 40 patients with OSMF who were classified as Grade I and II by Khanna and Andrade in 1995⁷ were included in the study. Two groups of Twenty patients each, 1 and 2, were randomly selected from among these patients.

Exclusion Criteria-

Those having hypertension, diabetes mellitus, anemic stomatitis, radiation fibrosis, scleroderma, immunosuppressive diseases, peptic ulcer bleeding disorders, cardiac disorders and pregnant women (hazardous to fetus). Patients who have received treatment of oral submucous fibrosis before. Patients who were hypersensitive to the study drugs. Patients falling under the Group III and Group IVA and B of Khanna Andrade group of classification 1995.

Group 1 (test group) received the test drug Tretiome 20 mg. A simple random allocation method had been applied. The drug was given in a concealed packing. Patients in Group 2 (Control group) were given 20 mg/day of lycopene, an antioxidant that is primarily taken as softgels and capsules, twice a day with meals. Following variables were studied likeburning sensation recorded on visual analogous scale visual analog, measurement of maximum mouth opening using Vernier calipers, development of pain and soreness, ulceration, mastication difficulty, speech or swallowing problem and quality of life of patients.

Figure 1- Vernier caliper used for Maximum mouth distance

Figure 2- Mouth Opening measurement using Vernier Calipers

Statistical Analysis-

Patients are advised to report immediately in case of any adverse drug reaction. Each patient was reviewed up to 6 months at specific intervals and the data obtained were assessed by Epi-info 7 was used for analysis. The means were used to express all descriptive data and (SD) as well as frequency (%). Fischer's exact test and the chi-square test were used to evaluate how the two groups' primary and secondary outcome measures differed from one another. In terms of statistics, a p value less than 0.05 was deemed significant.

Table 1- Comparison based on Burning Sensation and Mouth Opening in both groups (N=40)

As per table 1 it was seen the burning sensation in test groups shows a decreasing trends as the efficacy of TRA increases as the time of follow up progresses and it was statistically significant (p<0.05). The result of this study showed an improvement in the mouth opening of the patients of test Group with a significant decrease in the burning sensation as compared to the control group.

Table 2- Comparison based on Size of Fibrous Bands and Interincisal opening in both groups (N=40)

As per table 2 During the follow‑up of each patient, the data collected revealed a significant improvement (p<0.05) in the interincisal opening of the patients in Group I as compared to Group II, suggestive of a decrease in the fibrous bands size on the basis of mean difference (6.10 to 1.6) and increase in the flexibility of cheek mucosa, whereas very mild improvements were visible in the control group patients.

Table 3- Comparison based on difficulty in swallowing, Ulceration in mouth in both groups (N=40)

As per table 3 there was no significant difference seen in pain, soreness but there was a marked reduction in the burning sensation on having spicy food and condiments in the patients on TRA from 70% of patients pre-treatment to 10% of patients post treatment which ultimately decreased the difficulty of swallowing.

Table 4- Side- Effects and Relapse of OSMF of TRA in Test group based on follow up period

As per table 4 the major side effects seen during the follow up period for test group was headache seen in 64% of patients and it was significant (p<0.05), followed by nausea and vomiting in 50%, dizziness and rashes were also seen in patients who were continuously taking the medication for 6 months. Digestive side effects were common from 15 days of treatment in which heart burn was most common. So among the common side effects which were significant was headache, nausea and heart burn. The quality of life significantly improved due to better mouth opening and decrease in burning sensation. None of the patients showed relapse after the discontinuation of the drug.

The patients in this trial were the only ones who were blinded and didn't know what kind of treatment they were getting. There were 40 patients in total during the study period; 20 of them received standard lycopene therapy, while the other 20 received test drug therapy using Tretiome, which is sold as CA ATRA-10 (all-trans RA) and is used to treat Grade I and Grade II OSMF. Reducing the severity of the illness and preventing malignant transformation are the main goals of OSMF treatment. To treat trismus and enhance function, a conservative approach involving a range of medications or their combinations, such as steroids, collagenase, hyaluronidase, placental extracts, and nutritional supplements, as well as surgical procedures like band excision and grafting, has been employed.⁸

A study found that the medical therapy of OSMF is empirical and inadequate, and that vitamin medication did not improve trismus. A further study found that several vitamins and minerals significantly improved symptoms, with 41% of cases exhibiting some improvement in mouth opening. In contrast, a small number of studies found that Vitamin A improved OSMF symptoms but not mouth opening.^9,10,11 Kaugars and Silverman¹² observed that after 10 weeks of treatment with dexamethasone, hyaluronidase, or a combination of hyaluronidase, dexamethasone, and Placentrex, respectively, 66.7%, 83.7%, 91.7%, and 70.8% of patients showed improvement in the stiffness of the oral tissue.

Retinoids are a class of synthetic and naturally occurring vitamin A analogs that suppress carcinogenesis in a variety of epithelial tissues. They have shown promise in clinical trials for the chemoprevention of oral leukoplakia, secondary primary tumors of the aerodigestive tract, and skin tumors in patients with Xeroderma Pigmentosa. Retinol is a substance that the mother gives to the developing embryo and is mostly helpful for the development of the eye.¹³ When the retinol supplement enters the cell membrane in the presence of ADP, it goes through a series of irreversible oxidation events that result in the synthesis of retinaldehyde, which then creates RA, which is able to pass through the membrane without restriction. Not every RA molecule that crosses the cell membrane attaches to the receptor because the nucleus of the cell contains cellular RA-binding proteins, which are limited in number. As a result, the free RA molecule disintegrates and reduces toxicity.^14,15

Other frequently used vitamin A supplements included the Cis-form, while Tretiome, the RA transform used in our study, has the advantage of being less toxic; however, long-term use may be hazardous due to a number of side effects associated with topical application, including erythema, dryness, irritation, and pruritus; when taken systemically, it can cause headache, joint pain, inflammatory back pain, and other conditions.¹⁶

The positive outcomes should incite a larger patient sample size for a clinical trial aimed at expanding the therapeutic utility and applicability of vitamin A, one of our oldest medicinal medicines, for OSMF patients. This baseline study provides opportunities for additional research on the systemic use of all RA forms available for treating OSMF as well as on the use of medication in a formulation that can be injected locally into fibrous bands to validate the above findings.

FUNDING: Vinayaka Missions Research Foundation (DU)

CONFLICT OF INTEREST: None declared

ETHICAL APPROVAL: The study was approved by Institutional Ethical Committee

ACKNOWLEDGEMENTS: The Authors thank Vinayaka Missions Research Foundation (DU) for FUNDING the Research.

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