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Vesiculo-erosive Oral Mucosal Disease—Management with Topical Corticosteroids: (2) Protocols, Monitoring of Effects and Adverse Reactions, and the Future
1 Professor of Oral Medicine, Departamento de Medicina Oral, School of Dentistry, Facultad de Odontología, Universidad de Granada, Campus de Cartuja sn, 18071, Granada, Spain; and Correspondence: * corresponding author, magonzal{at}ugr.es
Although topical corticosteroids (TCs) are the most widely used drugs in oral medicine, and specifically in the treatment of vesiculo-erosive oral mucosal disease, there are few evidence-based data for the correct use of these drugs. In this review, we outline the most widely used protocols, the most common reasons for treatment failure, and the adverse effects documented in the literature.
Key Words: erosive lesions • oral mucosa • topical corticosteroids
The clinical judgment of a well-informed professional is crucial in the selection of the appropriate topical corticosteroid (TC) treatment for any particular patient. Some essential clinical parameters must be considered, whose values and evolution reflect the severity of the disease and the success or failure of the treatment.
Pain Lo Muzio et al.(2001) used a 10-cm visual analogue scale, where 7 = worse/more pain, 6 = pain similar to that prior to treatment, 5 = marked pain, 4 = moderate pain, 3 = mild pain, 2 = slight pain, 1 = very slight pain, and 0 = absence of pain. Robinson et al.(1997) used a visual analogue scale with scores ranging from 0 = absence of pain to 10 = severe pain. Silverman et al.(1985) established a disease index (DI) to evaluate the initial presentation and the evolution of pain and other signs of the process throughout the treatment. The DI, a ratio between signs/symptoms at the beginning and end of treatment, was determined by numeric values of 1–4, according to the severity of the disease, assigned before and after the treatment. A ratio greater than 1 was considered beneficial, whereas a ratio below 1 might indicate a worsening of the patient’s condition and call into question the value of the treatment used.
Type of Lesion, Extent, and Location The criteria applied generally relate to the extent of mucosal surface involved. Carbone et al.(1999) and Thongprasom et al.(1992) assessed the severity of lesions and symptoms in patients with lichen planus as: 5 = white striae with erosion > 1 cm; 4 = white striae with erosion < 1 cm; 3 = white striae with atrophy > 1 cm2; 2 = white striae with atrophy < 1 cm; 1 = white striae only; and 0 = no lesion. The intensity of the symptoms was assessed according to a four-point scale: 3 = severe symptoms; 2 = moderate symptoms; 1 = mild symptoms; and 0 = absence of symptoms. Complete resolution was defined as the disappearance of all atrophic-erosive lesions after six months of treatment, with or without persistence of small white striae, and by the presence of only mild clinical symptoms or their complete absence.
Quality of Life
Oral Hygiene
Some patients who are candidates for treatment with TCs fail to respond adequately to this therapy. Before accepting that a patient has not responded to therapy with TCs, the clinician should evaluate some correctable causes of failure in the treatment.
Incorrect Diagnosis
Choice of a TC of Inadequate Potency Another correctable cause of treatment failure is the choice of a TC of inadequate potency for the severity of the disease and/or of an inappropriate vehicle (Lozada-Nur and Miranda, 1997). Severe erosive lesions of the oral mucosa should be treated with a high-potency TC (clobetasol 17-propionate) (Lozada-Nur et al., 1991; González-Moles and Bagan-Sebastian, 2000; Lo Muzio et al., 2001; González-Moles et al., 2002a,b, 2003). In lesions with milder symptoms, control can be attempted with drugs of lower potency. Where there are extensive, deep, or numerous erosive lesions, the best approach is to use aqueous solutions of TC, which allows the drug to access all affected areas and guarantees the prescribed contact time (González-Moles et al., 2002a,b). In the opinion of some (González-Moles and Bagan-Sebastian, 2000; González-Moles et al., 2002a,b, 2003), adherent vehicles are indicated for lesions that are single and accessible or scant and small, such as the use of a tray for application of the drug to lesions in the gingiva or palate. The application of gels or other vehicles that contain alcohol should be avoided, because patient compliance is compromised by the pain caused when the vehicle makes contact with the lesion.
Poor Patient Compliance
It is also important to know which clinical signs and symptoms reveal a failure of the treatment, or a partial response, and which do not. The persistence of pain or ulceration or of interference in the patient’s daily activity provides unequivocal data that the response to treatment is inadequate. However, the persistence (Vincent et al., 1990) or worsening of white keratotic striae in patients with lichen planus does not indicate treatment failure, because TCs have little effect on them, and striae may become even more evident during treatment (González-Moles et al., 1996) (Fig. 2
The development of candidiasis after topical corticosteroid treatment may be incorrectly considered a treatment failure. The appearance of erythematous candidiasis, and the burning sensation it produces, can mimic the symptoms of erosive or atrophic lesions, and may be interpreted by inexperienced clinicians as a treatment failure. Antifungal drugs can resolve this problem. The most frequent adverse effect produced by the use of oral TCs is oral candidiasis, in either erythematous (Vincent et al., 1990; Lozada-Nur et al., 1991, 1994a, Lozada-Nur et al., b; Lozada-Nur and Miranda, 1997) or pseudomembranous (Lo Muzio et al., 2001) forms. Oral candidiasis appears in up to 25–55% of patients using TCs (Vincent et al., 1990; Lozada-Nur et al., 1991, 1994a; Lo Muzio et al., 2001) and can cause considerable discomfort (a burning sensation in the mouth). It can also be a source of confusion for the clinician. According to some authors (Lozada-Nur et al., 1994a; González-Moles et al., 2002a,b, 2003), the predisposing factors for the development of candidiasis are the potency and concentration of the corticosteroid, the vehicle used, and the healthy candida carrier state. Indeed, healthy carriers have a significantly higher risk of developing oral candidiasis after the use of TCs (Lozada-Nur et al., 1994a). Another important risk factor for the onset of candidiasis is the vehicle used to apply the TC (González-Moles et al., 2002a,b). The use of aqueous mouthrinses, compared with adhesive vehicles, appears to be a greater predisposing factor, presumably because all of the oral mucosa is exposed to the drug’s immunosuppressant effect, and because the drug-lesion contact time is likely to be longer, for the same prescribed time, than that achieved with adherent vehicles (González-Moles et al., 2002a,b, 2003). The potency and concentration of the drug also influence the likelihood of candidiasis. Oral candidiasis has been reported to appear in 25–55% of patients treated with clobetasol propionate (Lozada-Nur et al., 1991, 1994a; Lo Muzio et al., 2001), with a lower proportion of patients affected at clobetasol concentrations of 0.025% (Lozada-Nur et al., 1991) compared with 0.05% (Lozada-Nur et al., 1994a; Lo Muzio et al., 2001). The use of high concentrations in aqueous vehicles can even lead to the appearance of candidiasis secondary to the use of low-potency corticosteroids; in one study, 39% of patients treated with 0.1–0.2% triamcinolone acetonide for symptomatic oral lichen planus subsequently developed candidiasis (Vincent et al., 1990). Fortunately, oral candidiasis is easily prevented or treated with antifungals. When a high-potency TC is used in aqueous solution or in a tray, some authors recommend that an antifungal drug be combined with the TC from the start of treatment (González-Moles et al., 2002a,b, 2003). They recommend the addition of 100,000 IU/cc nystatin to the 0.05% clobetasol propionate in aqueous solution or orabase. This procedure is justified by the innocuous nature of nystatin, its low cost, and the high probability that candidiasis will appear in patients treated with this higher concentration of clobetasol propionate. When this approach was applied, excellent outcomes were obtained, with no cases of candidiasis (González-Moles et al., 2002a,b, 2003). Other minor adverse effects associated with the use of TCs in the oral cavity are stomatopyrosis, hypogeusia, and oral hairy leukoplakia (Lozada-Nur et al., 1991, 1994a). Likewise, the use of TCs can, in rare cases, be associated with a hypersensitivity reaction in the oral mucosa (Bircher et al., 1996).
Until recently, most authors considered that, apart from candidiasis, the adverse effects of oral TCs were infrequent, mild, and easily resolved (Lozada, 1980; Lozada-Nur et al., 1991, 1994a, Lozada-Nur et al., b). This idea probably resulted from the use of moderate- or low-potency TCs (Plemons et al., 1990; Lozada-Nur et al., 1991). However, since clobetasol propionate and other potent topical corticosteroids were introduced, there have been increasing reports of adverse effects secondary to the systemic absorption of these drugs (Walsh et al., 1993; Lozada-Nur and Miranda, 1997; González-Moles et al., 2002a,b). Data from studies of the use of TCs on skin have clearly showed that the intact skin acts as a barrier against the systemic absorption of TCs (Feldman and Maibach, 1965; Scheuplein et al., 1969; Squier and Johnson, 1975; Addy, 1980; Carr and Wieland, 1996). In contrast, when the surface layers are altered or removed, the systemic absorption increases considerably (Malkinson, 1958). The absorption of TCs is also greater in diseases that alter the skin, such as psoriasis (Schaefer et al., 1977), and in diseases associated with atrophy and ulcerations of the oral mucosa, especially where these are extensive (González-Moles et al., 2002a,b). The adverse effects that derive from the systemic absorption of corticosteroids include: suppression of the hypothalamus-hypophysis-adrenal (HPA) axis; Cushingoid appearance (moon face); hypertension due to sodium and liquid retention; potassium diuresis; hyperglycemia from glycogen conversion; immunosuppressant effect due to lymphocyte alterations, with the subsequent appearance of opportunistic infectious diseases (oral candidiasis) (Lozada-Nur et al., 1991); mood changes; psychosis; insomnia; capillary fragility with propensity for bruising; gastrointestinal disorders with predisposition for peptic ulcers and bleeding (Ronbeck et al., 1990); weight gain; headaches; and body fat redistribution (buffalo hump). Longer-term effects include cataract formation and osteoporosis from calcium loss (Allenby et al., 1975; Adinoff and Hollister, 1983; Lozada-Nur and Miranda, 1997). Systemic adverse affects have been documented following exposure to TCs. These include an increase in the plasma cortisol and suppression of the HPA axis (Plemons et al., 1990; Lozada-Nur et al., 1991; Walsh et al., 1993; Lozada-Nur and Miranda, 1997; Lo Muzio et al., 2001; González-Moles et al., 2002a,b), which arises due to a negative feed-back mechanism in which a reduction in the adrenocorticotropic hormone suppresses the natural production of cortisol (Holroyd and Wynn, 1983). In this situation, patients may be unable to respond to periods of stress with an adequate production of cortisol (Selye, 1950; Gilman et al., 1985). Previous studies in skin demonstrated that the adrenal suppression starts to become evident 24 hrs after the onset of treatment with topical steroids (Scoggins, 1962; Gill and Baxter, 1964; Kirketerp, 1964) and is most profound over the first seven days (Walsh et al., 1993). Factors that influence adrenal suppression from oral TCs are the type of corticosteroid, the dose, the vehicle, and the individual susceptibility (Lehner and Lyne, 1969, 1970; Williamson et al., 1980). The degree of HPA axis suppression must be assessed in any TC-treated patient who develops a severe adverse effect, by measuring the urinary free cortisol, plasma cortisol levels, response to the administration of systemic ACTH or plasma cortisol levels during insulin-induced hypoglycemia, or by using the CRH stimulation test, among others (Livanou et al., 1967; Editorial, 1975; Schlaghecke et al., 1992). This is especially important if the patient will undergo surgical or other stress. It is prudent to treat these patients in the same way as any patient with secondary adrenaline insufficiency, advising them to wear a medical alert bracelet or necklace and to carry with them an alert card and, probably, a 1-mL syringe containing 4 mg dexamethasone phosphate. In general, minor dental procedures do not require a preventive supplement of systemic corticosteroids unless complications are predicted (Robinson et al., 1997).
Other documented adverse effects associated with TCs include the development of moon face (Fig. 3
Various factors can increase the risk of severe adverse effects: the use of high-potency TCs at elevated concentrations, overdosage, the presence of open blood vessels on the ulcerated surfaces, the presence of large erosive and atrophied areas, and the increased pressure of the solution on the ulcerated surface from rinsing (González-Moles et al., 2002a,b). Note should also be taken of reports (Frey FJ et al. 1981; Frey BM et al., 1982; Lozada et al., 1983) that the release rate of endogenous adrenal cortisol may be related to the risk of adverse effects. In fact, some authors (Lozada-Nur et al., 1991) have recommended that endogenous cortisol levels be monitored when TCs are to be used for a long period, so that this risk can be assessed. The judicious use of TCs diminishes the risk of adverse effects (Carruthers et al., 1975; Westerhof, 1989; Lozada-Nur et al. 1991; Lozada-Nur and Miranda, 1997; Lo Muzio et al., 2001; González-Moles et al., 2003). An unnecessarily high potency or concentration should never be prescribed. Aqueous solutions should be avoided whenever the clinical presentation of the disease permits an alternative vehicle to be used, because they expose the whole mucosa to the corticosteroid. It also appears highly likely, based on the experience with systemic corticosteroids, that the risk of adverse effects diminishes when the applications are reduced to alternate days. Some authors (Lozada-Nur and Miranda, 1997; González-Moles et al., 2002a,b, 2003) recommend changing to alternate-day applications as soon as a substantial improvement of the clinical symptoms is achieved, and progressively reducing the frequency of the therapy for as long as the clinical improvement of the patient is maintained. Once again, we underline the importance of the clinical training and experience of the specialist and the need for a consensus to be reached on the clinical criteria for the assessment of these patients. The potential risk of adverse effects means that patients receiving TC treatment must be very closely monitored, especially when high-potency corticosteroids in aqueous solutions are applied three or more times a day for extensive lesions of the oral mucosa (Lozada-Nur et al., 1991; González-Moles et al., 2002a,b, 2003). Patients should be followed up every two weeks during the induction phase and every month after the disease has been controlled and the frequency of applications has begun to be reduced. In maintenance regimens, when the disease is kept under control with applications on alternate days, the follow-up sessions can be six-monthly (González-Moles et al., 2002a,b, 2003). At each follow-up session, the blood pressure, blood glucose levels, and weight are recorded, an examination is performed for the presence of oral candidiasis, moon face, buffalo hump, hirsutism, and hemorrhagic effusions, and the patient is interviewed about any incidence of mood changes or insomnia (Lozada-Nur et al., 1991; González-Moles et al., 2002a,b, 2003). If adverse effects are present, it is mandatory that the clinician determine the plasma cortisol levels (Pimlott and Walker, 1983) and the degree of HPA axis suppression.
Many issues remain to be addressed regarding the correct use of TCs in oral medicine and regarding newer immunosuppressants such as tacrolimus. One most important question is what should be done with patients after the disease has been controlled by the chronic use of a TC. At present, scientific data are inadequate for us to know how these patients will react if the drug is completely withdrawn (Lozada-Nur et al., 1994a). It is hard to accept that a patient must remain indefinitely under TC treatment after the disease has been perfectly controlled. It therefore seems essential that we investigate how these patients respond after complete withdrawal of the treatment. In this context, it was observed that 65% of patients treated with clobetasol propionate and 55% of patients treated with fluocinonide maintained their clinical improvement 12 months after the cessation of the treatment (Carbone et al., 1999), and that 22% of patients treated for two weeks with fluocinonide remained stable 10 months after stopping the drug (Lozada-Nur and Silverman, 1980). However, lower-potency steroids appear to have a shorter-lived effect after their withdrawal. In one study on lichen planus, where fluocinonide or triamcinolone was used for 24–32 wks, less than 6% of patients were symptom-free 12 months after stopping the drug (Thongprasom et al., 1992). These results appear to indicate that the long-term application of high-potency drugs, especially clobetasol propionate, provides substantially longer disease-free periods after withdrawal of the drug, as well as helping to control the disease (Carbone et al., 1999). Therefore, it seems reasonable to attempt the complete withdrawal of TCs, after a slow reduction of their application, in patients whose disease has been controlled by these drugs. When clobetasol propionate is used, a prolonged period of stability can be expected in a substantial percentage of cases, although both the physician and the patient should be aware of the possibility of a recurrence, which would mean starting the treatment again. One must also define a correct therapeutic approach to patients who develop adverse effects to the TCs before clinical control of the disease has been achieved. The ethical position is to withdraw the drug, which raises the question of what to do with patients whose well-being is severely compromised by the lesions. Comparative data are required before we can determine the responses of patients who are changed to a different or less-potent TC or to a vehicle that limits the area of the mucosa exposed to the drug. It is also necessary to establish the parameters that allow us to predict patient populations at risk of developing adverse effects after TC use. Thus, it should be scientifically determined whether the measurement of endogenous cortisol can identify patients who are predisposed to develop adverse effects (Frey FJ et al., 1981). In conclusion, several questions about the use of TCs in oral medicine remain unanswered and warrant a concerted effort by researchers in this area.
Received for publication April 8, 2004. Accepted for publication September 3, 2004.
Journal of Dental Research, Vol. 84, No. 4,
302-308 (2005)
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ABSTRACT
(I) PARAMETERS USED FOR...
