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Int J Clin Exp Med 2013;6(10):917-921 Original Article Oral lichen planus treated with tacrolimus 0.1% João Paulo Marinho Resende1, Maria das Graças Afonso Miranda Chaves1, Fernando Monteiro Aarestrup1, Beatriz Vieira Aarestrup1, Sergio Olate2,3, Henrique Duque Netto1,4 1Master in Dental Science Program, Universidade Federal de Juis de Fora, Brazil; 2Center for Biomedical Re- search, Universidad Autónoma de Chile, Chile; 3Division of Oral and Maxillofacial Surgery, Universidad de La Frontera, Chile; 4Division of Oral and Maxillofacial Surgery, Universidade Federal de Juiz de Fora, BrazilReceived September 21, 2013; Accepted October 19, 2013; Epub October 25, 2013; Published October 30, 2013 Abstract: Oral lichen planus (OLP) is considered a chronic autoimmune inflammatory disease and its presence may be related to increased emotional stress. The clinical relevance of OLP is the possibility of developing a squamous cell carcinoma, the etiology of which is still unknown. The aim of this study is to treat OLP lesions resistant to con- ventional treatment with corticosteroids, using topical tacrolimus 0.1% (Protopic®) twice a day for a period of eight weeks. Fifteen patients were selected who had filled out a history form and a visual analog scale for pain before and after treatment. All patients underwent an initial biopsy to diagnose the disease and another at the end of the treatment period to evaluate the effect of the medication on the infiltrate. A weekly check was carried out, observing the clinical appearance, pain symptoms and occurrence of side effects which, where present, were mild and tran- sient. The results showed twelve patients (80%) with total or nearly total remission of pain symptoms and lesions, two patients (13.33%) showed clearer lesions and only one patient (6.67%) had no change in clinical symptoms or pain. Histopathological analysis showed OLP had a moderate or strong regression in twelve patients (80%) and an absent or mild regression in three patients (20%). Based on these results, it was concluded that tacrolimus 0.1% (Protopic®) is a safe and effective medication that improves the clinical appearance of the lesion, reduces pain as well as the histopathological features of OLP.
Keywords: Oral lichen planus, tacrolimus, treatment, recalcitrant, corticosteroids Topical tacrolimus is a powerful macrolide imm- unosuppressant to prevent transplant rejetions The prevalence of oral lichen planus (OLP) is of organs such as the kidney, liver and heart [1, relatively low (0.5% to 2.5%), being mainly asso- 3, 5, 9, 11]. It is a topical non-corticosteroidal ciated with adult females at a ratio of 2:1, usu- immunomodulator with a low adverse effect al y emerging in the 4th to 5th decade of life, wh- that presents a rapid response in the control of ere 10% to 15% of the patients with OLP also symptoms compared to traditional corticoste- present cutaneous lesions [1-5].
roids [11-13].
The clinical presentation of OLP is interlaced white lines on an erythroplastic base known as The anti-inflammatory molecular mechanism of "Wickham striae", these being symmetrical in action of tacrolimus is similar to cyclosporine, most patients [3, 4, 6]. It is thought that this which inhibits the production of IL-2 by T lym- reaction is mediated by T lymphocytes, where phocytes [5, 14, 15] by inhibiting calcineurin the cel s of the basal epithelial layer are recog- phosphatase [6, 16], which in turn leads to the nized as foreign due to the change in the anti- inhibition of the nuclear gene transcription of genicity of the surface of the cel s [2, 3, 7-9], IL-2 cytosines and several other pro-inflamma- which is why it is considered to be a disease of tory cytosines such as IL4 and IL5 [17]. As a unknown etiology and pathogeny occurring ma- result, activation and differentiation of inflam- inly in subjects with high stress levels [9, 10]. matory cel s such as T lymphocytes, eosino- Currently OLP lesions are treated with different phils or neutrophils are suppressed, which may pharmacological options, and corticoids in their explain why tacrolimus was also effective in topical or systemic form are used frequently.
subjects with cicatricial pemphigoid.
Treatment of oral lichen planus Table 1. Level of regression of the histopathological The visual analog scale (VAS) was used in all aspects between the first and second biopsy the evaluations; this was completed by the Regression of structural histological aspects (RHS) Level patient, determining the degree of severity Without regression of the pain and the symptomatology. In the eighth week a second biopsy was performed, Moderate regression fol owing the same protocol for col ection, processing and diagnosis as the initial biop- Strong regression sy in order to assess the action of the drug in relation to the histopathological aspects The aim of this investigation is to analyze the characteristic of OLP and also to confirm wheth- behavior of tacrolimus 0.1% in subjects with er the pain symptoms and clinical appearance OLP who have undergone previous convention- were related to the histopathological condi- al treatments without favorable results.
tions. The scar from the first biopsy was used as a reference to perform the new biopsy later- Materials and methods This research protocol was approved by the A quantitative histopathological evaluation was ethics committee of the Universidade Federal made by two different observers to evaluate de Juiz de Fora, Faculty of Dentistry. All the par- the degree of regression or the condition of the ticipants signed the informed consent and were tissue. That analysis was made using a scale informed of the scope of the study.
from 0 to 3, classifying each of the selected 15 patients (11 female and 4 male) aged betw- segments (Table 1). Then the data were sub- een 17 and 78 (age average 55 years) with sym- jected to a descriptive statistical evaluation ptoms associated with the disease were select- through McNemar's test and a paired t-test or a ed from the Department of Oral and Maxil ofacial Wilcoxon test in case the variables did not Surgery of the University Hospital of the UFJF respond to conditions of normality considering and the Neoplasia Diagnosis Support Service a value of p<0.05 to achieve statistical rela- of the UFJF. After the histopathological diagno- sis of OLP, all the patients were treated with 20mg prednisolone for thirty days, and with unfavorable results were incorporated into the All the patients presented symptoms of the dis- ease for at least 1 year of evolution prior to the first therapeutic intervention. The most impor- tant symptoms observed were a burning sensa- One week prior to the start of the study, all tion at the lesion site in 10 patients (3 patients treatments were suspended for all the patients. with burning and pain, 2 patients with itching, An incisional biopsy had been performed previ- and only one patient with burning, itching and ously to confirm the histopathological diagnosis pain at the same time). Three patients had only of OLP. Each patient began the proposed treat- pain and 2 only itching in the area.
ment with tacrolimus 0.1% (Protopic®) for two months (8 weeks) using it in topical form as a The visual analog scale before the treatment cream twice a day (every 12 h). The subjects with tacrolimus 0.1% (Protopic®) presented were instructed to dry the place of application variations from 4 to 9 (average 6.3) in the initial and apply a fine layer using compressed cotton phase. The most detailed analysis of the results and not to eat for 1 h after the application.
showed that the severity of the symptoms in 7 patients was severe pain with levels of 8 (Table During the treatment period, the patients were evaluated weekly, recording the clinical appear- ance of the lesion, the symptoms of the disease After the first week of treatment unwanted and the occurrence of side effects. The treat- effects were described in 6 patients (40%), of ment could be interrupted at any time that which 2 patients had dry mouth, one patient unwanted effects were determined by the dry mouth and palatal changes and one patient research group or when the patients indicated reported burning at the application site; one termination of the study.
patient presented dry mouth and a burning Int J Clin Exp Med 2013;6(10):917-921

Treatment of oral lichen planus Table 2. Responses of the visual analog scale (VAS) in the initial stage (before beginning the treat- ment) and end stage (two months from beginning the treatment) of the 15 patients treated with tacrolimus 0.1% Patients Figure 1. Lesion of erosive OLP in the mucosa; an Figure 2. The same subject after 8 weeks of treat- ulcerated leukoerythroblastic lesion with Wickham ment demonstrating an oral mucosa free of lesions striae in its periphery is observed.
and regression of the pathology.
Figure 3. Histopathological analysis of the lesion Figure 4. In the second biopsy (8 weeks later), a clean where in the stage prior to treatment; epithelium is oral mucosa was observed with regeneration of the observed in serrated teeth, hyperkeratosis, hydropic structural characteristics of the epithelium with the degeneration of the base layer, acanthosis and pre- almost total absence of inflammatory infiltrate (40X).
dominantly lymphocytic inflammatory infiltrate in bundles of connective tissue (40X).
patients (40%) initial y reported a decrease in OLP-associated symptoms, in five patients a sensation and one patient reported only chang- slight improvement was noted (33.3%) and in es in the palatal area.
four patients (26.64%) no change was noted. The clinical analysis showed no change.
It was not necessary to interrupt the treatment for any of the subjects because the side effects The maximum improvement was achieved in were temporary and mild, disappearing com- the 4th and 5th week of treatment, where 12 pletely during the study period; nine patients subjects (79.92%) showed no type of pain or reported no complications. In the first consulta- indicated that the discomfort was less and tion of the clinical study, after one week, six often imperceptible (79.92%) (Figures 1 and 2). Int J Clin Exp Med 2013;6(10):917-921 Treatment of oral lichen planus In the clinical examination of the patients there who had a recurrence of the disease with pain were substantial improvements where the symptoms received new pharmacological treat- lesions disappeared completely or were almost ment for the OLP.
imperceptible. Two patients were observed who, despite indicating an improvement, still presented clearer lesions; in one patient the All the patients included in this study used daily symptoms did not change and no changes in doses of 20 mg prednisolone (once a day) for a the clinical appearance were observed either.
period of at least 4 weeks before the initial When the 8 weeks of the study were complete, biopsy without obtaining satisfactory results or a new VAS was conducted, presenting respons- remission of signs or symptoms. This indication es with a maximum variation between 0 and 4 was proposed by some authors [4, 18] where with an average of 1.1 (Table 2), and when the they reported that 20 mg prednisolone taken initial comparison was set against the final one, oral y may be effective in the treatment of OLP it was observed that there was a significant dif- without needing high doses to obtain a positive ference (p<0.05) between the two scales (p=0.001). Twelve patients presented no pain There is a considerable number of patients who symptoms or these were mild. In one patient do not respond to conventional treatments, who presented with moderate pain, this passed which is why there is a need to find new thera- to mild and in two patients the symptoms peutic modalities to control OLP that have fewer remained constant throughout the treatment. side effects [1, 13, 18, 19].
Additional y, the statistical analysis of the data showed that the improvement in symptoms In this study, the topical application of tacroli- was related to the clinical improvements in the mus 0.1% was indicated due to advantages OLP (p<0.05).
such as the reduction of side effects and fast action in the control of symptoms [1, 12, 13]. Comparison of the biopsies taken towards the The choice of the drug as a second line of treat- end of the treatment with the initial biopsies ment fol ows the direction taken by previously revealed regression in the histopathological published works [10, 11, 16-18, 20] that show structures (RHS) of the OLP. This histopatho- success in treatment with this drug.
logical situation, as with the subject's VAS, pre- sented statistical y significant differences at The dosage used was the manufacturer's rec- the end of the treatment (p<0.05) (Figures 3 ommendation according to some studies [1, 5, 14] that showed this to be an efficient dosage; however, others suggest that application of the In terms of assessing the final clinical appear- drug three times a day [21] or four times a day ance of the lesions, the 12 patients (80.04%) [15] may be more efficient. Additional y, the with RHS of level 2 or 3 presented an almost best results with tacrolimus 0.1% have been total reduction or complete disappearance of between the fourth and fifth week [1, 18, 19], the lesion and with non-existent or mild symp- which is also related positively to our results; toms. In one patient (6.67%) with a RHS 1, the others, however, show greater variation of this clearest lesion was observed and had a sub- time for treatment [10, 11]. Our results present- stantial improvement in the pain symptoms ed the most subjective and objective (clinical) and of the two patients who had a RHS 0, one improvements between the 4th and 5th week. had the best defined lesion with the same After 8 weeks there was an 80% improvement symptoms as at the beginning of the treatment where the lesion was practical y no longer per- and the other had no changes in the clinical pic- ceptible. Even so, two patients presented defi- ture, pain or the histopathological structure.
ciencies in their evolution, similar to that obser- After 5 months of evolution after the end of the ved by other authors [21].
treatment, of the 12 patients who had lesions Using a quantitative analysis, the close relation that had practical y or completely disappeared, between the improvement in clinical character- two patients had a recurrence of the disease, istics, improvement in symptoms and improve- with one of these presenting a new, smal er yet ment in histopathological characteristics was asymptomatic lesion with total surgical resec- observed [22], characterized by a reconstruc- tion of the lesion, whereas the other patient tion of the lining epithelium in the treated areas, Int J Clin Exp Med 2013;6(10):917-921 Treatment of oral lichen planus reducing epithelial hyperplasia and hyperkera- [10] Lozada-Nur FI, Sroussi HY. Tacrolimus powder tosis of the area. in orabase 0.1% for the treatment of oral li- chen planus and oral lichenoid lesions: An Final y, in light of these results, the use of tacro- open clinical trial. Oral Surg Oral Med Oral limus 0.1% is efficient in the control of lesions Pathol Oral Radiol Endod 2006; 102: 744-749.
and the symptoms associated with the OLP [11] Donovan JC, Hayes RC, Burgess K, Leong IT, that does not respond to other therapies with Rosen CF. Refractory erosive oral lichen planus corticosteroids. Studies with a greater number associated with hepatitis C: Response to topi- of subjects must be conducted to be able to cal tacrolimus ointment. J Cutan Med Surg 2005; 38: 1-6.
recommend the use of this drug at different [12] Byrd JA, Davis MD, Bruce AJ, Drage LA, Rogers stages of OLP.
RS 3rd. Response of oral lichen planus to topi- cal tacrolimus in 37 patients. Arch Dermatol Disclosure of conflict of interest 2004; 140: 1508-1512.
[13] Bruce A, Rogers RS 3rd. New and old thera- peutics for oral ulcerations. Arch Dermatol 2007; 143: 519-523.
Address correspondence to: Dr. Sergio Olate, [14] Olivier V, Lacour JP, Mousnier A, Garraffo R, Facultad de Odontología, Universidad de La Monteil RA, Ortonne JP. Treatment of chronic Frontera, Claro Solar 115, 4to Piso, Oficina 20, erosive oral lichen planus with low concentra- Temuco, Chile. E-mail: tions of topical tacrolimus: An open prospec- tive study. Arch Dermatol 2002; 138: 1335- [15] Rozycki TW, Rogers RS 3rd, Pittelkow MR, McE- [1] Vente C, Reich K, Rupprecht R, Neumann C. voy MT, el-Azhary RA, Bruce AJ, Fiore JP, Davis Erosive mucosal lichen planus: response to MD. Topical tacrolimus in the treatment of topical treatment with tacrolimus. Br J Derma- symptomatic oral lichen planus: A series of 13 tol 1999; 140: 338-342.
patients. J Am Acad Dermatol 2002; 46: 27- [2] Ling MR. Topical tacrolimus and pimecrolimus: future directions. Semin Cutan Med Surg [16] Nasr IS. Topical tacrolimus in dermatology. Clin 2001; 20: 268-277.
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[3] Edwards PC, Kelsch R. Oral lichen planus: clin- [17] Fuchs M, Schliemann-Willers S, Heinemann C, ical presentation and management. J Can Elsner P. Tacrolimus enhances irritation in a Dent Assoc 2002; 68: 494-499.
5-day human irritancy in vivo model. Contact [4] Scully C, Eisen D, Carrozzo M. Management of Dermatitis 2002; 46: 290-294.
oral lichen planus. Am J Clin Dermatol 2000; [18] Assmann T, Becker J, Ruzicka T, Megahed M. Topical tacrolimus for oral cicatricial pemphi- [5] Gupta AK, Adamiak A, Chow M. Tacrolimus: a goid. Clin Exp Dermatol 2004; 29: 674-676.
review of its use for the management of der- [19] Shichinohe R, Shibaki A, Nishie W, Tateishi Y, matoses. J Eur Acad Dermatol Venereol 2002; Shimizu H. Successful treatment of severe re- 16: 100-114.
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Int J Clin Exp Med 2013;6(10):917-921


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