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A Review of the Effectiveness and Side-Effects of Fluocinolone Acetonide 0.1% in the Treatment of Oral Mucosal Diseases

Topical steroids have been widely used in the treatment of symptomatic oral lesions to reduce pain and inflammation. Potent topical steroids such as clobetasol propionate, fluocinolone acetonide (FA), and fluocinonide have been widely used in the treatment of severe oral mucosal lesions. Many reports have demonstrated that these steroids were effective in treating oral lesions with only minor side-effects. This review describes the effectiveness and side-effects of using FA 0.1% in the treatment of symptomatic oral lichen planus (OLP), oral lichenoid drug reaction (OLDR), oral pemphigus, and herpes associated erythema multiforme (HAEM). FA 0.1% was effective and safe in the treatment of patients with multiple systemic diseases and a pregnant patient with HAEM. Moreover, this topical steroid rapidly reduced pain, inflammation, and enhanced lesion healing with no serious side-effects other than pseudomembranous candidiasis, which is easily treated. In some cases, a long-term treatment with FA 0.1% resulted in hyperpigmentation at the areas of previously healed oral lesions; however, this hyperpigmentation was gradually resolved after discontinuing topical steroid treatment.


Introduction
Over the past decade, various treatments have been used to treat chronic or severe oral lesions, however, a complete cure is difficult to achieve. Topical steroids are considered to be the first-line therapy for oral autoimmune diseases. These drugs have been widely used in the treatment of symptomatic oral lesions, such as recurrent aphthous ulceration (1), oral lichen planus (OLP) (2,3), oral lichenoid drug reaction (OLDR) (4), pemphigus (5-7), mucous membrane pemphigoid (MMP) (8), and Herpes Associated Erythema Multiforme (HAEM) (9). Topical steroids can be used alone or combined with systemic steroids in the treatment of severe oral mucosal diseases. Since topical steroids directly contact and penetrate through the mucous membrane of erosive/ulcerative oral lesions, they can enhance lesion healing.
Oral lesions that were treated using FA 0.1%

Oral lichen planus (OLP)
In 1985, topical steroid-FAS 0.1% was first prepared by the head of the Pharmacology and Oral Medicine Departments, Faculty of Dentistry, Chulalongkorn University, Bangkok, Thailand, and later developed as FAO 0.1% in 1988 (12). FAO 0.1% was effective in the treatment of recalcitrant ulcerative OLP in a 36-year-old female (Figure 2a). Notably, the OLP lesions on her buccal mucosa showed nearly complete remission after 2 weeks of FAO 0.1% treatment ( Figure 2b). Moreover, a 29-year-old female presented to the Oral Medicine Clinic with atrophic OLP on both buccal mucosae and these lesions were unresponsive to previous medications. After treatment with FAO 0.1%, the lesions on her buccal mucosa showed a gradual improvement until complete remission was seen at 22 months (Figure 3a, 3b). In addition, both FAO and FAS use resulted in improved results in the treatment of OLP during a 2 year-follow-up (13). However, in this study, FAO 0.1% was shown to be more effective compared with FAS 0.1%.
Regarding the immunopathogenesis of OLP, we found that the proinflammatory cytokine TNF-α was expressed in every case of OLP in Thai patients, indicating that TNF-α plays an important role in the immunopathogenesis of OLP in Thai patients (14). After treating their OLP lesions with FAO 0.1%, the same lesions were re-biopsied to investigate their TNF-α expression. We found that FAO 0.1% inhibited TNF-α expression in every case. Therefore, FAO 0.1% reduced the OLP inflammatory process by inhibiting the expression of the proinflammatory cytokine TNF-α.
One month after combined treatment with 40-60 mg/day prednisolone and topical FAS 0.1% three times/day on the gingiva, the lesions showed nearly complete remission (Figure 5b). Unfortunately, the patient subsequently developed Cushing syndrome: moon face, steroid acne, and hirsutism ( Figure 6). Her physician gradually reduced the systemic steroid dose and her condition showed improvement. Interestingly, following long-term treatment of a 43-year-old male pemphigus patient with FAS 0.1% combined with 60 mg/ day prednisolone, the oral lesions showed complete remission after 1 year (6). Moreover, his oral pemphigus lesions remained in complete remission during 12 years of follow-up without recurrence or any side-effects.

Herpes Associated Erythema Multiforme (HAEM)
HAEM is an uncommon lesion caused by herpes simplex virus infection and is rarely found in pregnant women (9). FAO and FAS 0.1% were effective in treating severe painful oral ulcerations in a 28-year-old pregnant patient with HAEM (9). Short-term treatment (2 weeks) with this potent topical steroid rapidly reduced pain with nearly complete lesion healing. FAO and FAS 0.1% were effective and safe in the treatment of HAEM in this pregnant patient, who gave birth to a healthy son. Moreover, FAO and FAS 0.1% are low cost and without any side effects in this case.

Side-effects of FAO/FAS
During the treatment of oral lesions such as OLP with FAO/FAS 0.1%, pseudomembranous a candidiasis eruption is common. White plaques that can be wiped off can develop on the buccal mucosa after treatment with FAS 0.1% (Figure 7a). However, pseudomembranous candidiasis is effectively treated with topical antifungal drugs ( Figure 7b) (13,19). In some OLP cases, long-term treatment with topical steroid-FAO 0.1% resulted in hyperpigmentation at the areas of previous oral lesions (Figure 8a). During the follow-up, the mucosal hyperpigmentation gradually resolved within 3 years after discontinuing this topical steroid (Figure 8b).

Discussion
FA 0.1%, both in solution or orabase forms, has been used in the treatment of various recalcitrant oral mucosal diseases. Moreover, only minor side-effects such as pseudomembranous candidiasis or post-inflammatory hyperpigmentation were found with FA use in our long-term observation. FA can be used alone or combined with systemic steroids in the treatment of severe oral lesions in patients with multiple systemic diseases. Carrozzo et al. suggested that the combination of systemic steroids and high potency topical steroids results in good control of these oral lesions (8). This regimen has been found to be safe and effective with only minor side-effects during or after the treatment of oral lesions in both short-term and long-term follow-up. One study showed the transmucosal systemic absorption of potent topical steroids, such as clobetasol (20). Thus, careful monitoring of patients receiving corticosteroid therapy is recommended to avoid adverse local or systemic effects. However, some sideeffects of potent topical steroids, including clobetasol propionate 0.05% and betamethasone, such as Cushing's syndrome, have been reported (21).
In this review, FAS 0.1% in combination with 40-60 mg/day prednisolone for one month in the treatment of severe oral pemphigus resulted in Cushing's syndrome. Therefore, the treatment of severe oral lesions with a systemic steroid should be carefully monitored and these lesions should be treated by an expert.
A report of an HIV patient with OLDR who had very painful erosive lesions involving the lip and buccal mucosa showed that this patient responded to topical FA 0.1% treat-
Prikaz slučaja pacijenta s HIV-om i OLR, koji je imao vrlo bolne erozivne lezije na oralnoj i bukalnoj sluznici, pokazao je da je pacijent dobro odgovorio na lokalnu terapiju FAom 0,1 % (22). Topikalni steroid bio je učinkovit i ublažio je ment (22). This topical steroid was effective, and alleviated the patient's oral pain. Interestingly, a report showed that potent topical steroids such as FA 0.1%, clobetasol propionate 0.05%, and dexamethasone 0.05% were effective in the treatment of severe oral lichenoid drug reaction (OLDR) lesions without serious side-effects in patients with multiple systemic diseases during a 7-year follow-up (4). However, the role of a specific drug in the pathogenesis of OLDR may be important because the drug acts as an antigen, triggering T-cells. Antigen-specific CD8+ cytotoxic T cells then secrete cytokines, such as TNF-α or interferon-α. These cytokines subsequently activate T cells and dendritic cells and trigger basal cell keratinocyte apoptosis, causing an inflammatory immune response (23,24).
Regarding oral mucosal hyperpigmentation, one observation report suggested that mucosal pigmentation could be a secondary effect of topical tacrolimus treatment due to an increase in the number of melanocytes and to an increased melanin production (25). Histopathology from the mucosal pigmentation showed an increase in melanocyte numbers and melanogenesis. However, the hyperpigmentation disappeared when the treatment was stopped, which is similar to the OLP case treated with FA in this review.
In addition to its use on oral lesions, FA may have other applications. A study found that FA strongly potentiated the TGF-β-associated chondrogenesis of bone marrow mesenchymal stem/progenitor cells, increasing the levels of collagen type II more than 100-fold compared with the widely used drug, dexamethasone (26). Thus, FA/TGF-β3 may be clinically used to increase the efficiency of regenerative approaches based on the chondrogenic differentiation of stem cells. The effects of FA on reparative dentin formation and the recovery of injured dental pulp have also been reported (27). The results showed that FA promoted the proliferation of human dental pulp cells (DPCs), especially for the CD146+ subpopulation. CD146+ cells have been shown to be mesenchymal stromal cells capable of multilineage differentiation (28)(29)(30). Thus, in the injured pulp, an increase in CD146+ cells may provide cells that can differentiate into odontoblasts for repairing the dentin defect, as well as reconstituting the dental pulp cell population. Therefore, FA initiates mineralization by DPCs and has a potential role in repairing injured pulp tissues. FA may enhance oral lesion healing by promoting the proliferation and regeneration of oral mucosal cells. Future research on the use of FA in enhancing healing on the oral mucosal cells by inducing the expression of different cytokines that regulate molecules involved in cellular adhesion and extracellular matrix (ECM) formation is recommended for the effective treatment of severe and recalcitrant oral mucosal diseases.