Topical Effect of Pimecrolimus Cream in Comparison with Clobetasol Propionate in Patients with Oral Lichen Planus
Abdel Nasser MH Al Refai(1), Atef Ibrahim Al Akhras(2), Ahmed Abd El Aziz Hassan(1) and Abdulrazzaq Ahmed Salem Almaweri(3)
Departments of Oral Medicine and Periodontology, Faculty of Dentistry(1,3), Skin and Venereal Diseases, Faculty of Medicine(2), Suez Canal University(1,2), Egypt and Thamar University(3), Yemen.
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Al Refai et al.
Introduction
Lichen planus is a chronic, immunological, mucocutaneousdisease with a wide range of clinical manifestations. The oral mucosa is commonly involved and may be the only site of involvement.Oral lichen planus (OLP) occurs more frequently than the cutaneous form, it affects 0.5% to 2.0% of general population,tends to be more persistent and more resistant to treatment(1, 2).
Although the cause of lichen planus is unknown, it is generally considered to be an immunologically mediated process that microscopically resembles a hypersensitivity reaction. Current data suggest that OLP is a T cell-mediated autoimmune disease in which auto-cytotoxic CD8+ T cells trigger apoptosis of oral epithelial cells. The etiology involves a cell-mediated immunologically induced degeneration of the basal cell layer of the epithelium(3, 4).
Pimecrolimus (SDZ ASM 981) is one of the new classes of novel ascomycin immunomodulating macrolactams that was developed for treatment of inflammatory skin diseases. Ascomycin, first isolated as a fermentation product of Streptomyces hygroscopicus. In the early 1960s, was initially researched primarily for its antifungal properties. However, more than twenty years later ascomycin was investigated for its structural and immunomodulatory properties(5).
The mechanism of action of pimecrolimus involves its binding to macrophilin 12. The pimecrolimus macrophilin complex then binds to the cytosolic enzyme calcineurin phosphatase. Calcineurin is a Ca /calmodulin dependent protein phosphatase that regulates the translocation of cytosolic components of nuclear factors, which in turn regulate the promoter activities of several mediators during mRNA transcription. (6, 7).Inhibiting the action of calcineurin, the pimecrolimus-macrophilin complex prevents dephosphorylation of the cytoplasmic component of the nuclear factor of activated T cells (NF-AT). NF-AT regulates the mRNA transcription of a number of inflammatory cytokines; therefore, pimecrolimus blocks this transcription, especially Th1 (IL-2, IFN-γ) and Th2 (IL-4, IL-10) type cytokines. Other cytokines, including IL-5, IL-10 and TNFα, are decreased in production by pimecrolimus in a dose-dependent manner. Pimecrolimus also targets mast cells which play an important role to anti-inflammatory activities(6).
Corticosteroid represents the most utilized drug in the treatment of OLP. Among several corticosteroids, clobetasol propionate has been demonstrated to be more active than any other high potency corticosteroid and is now widely used in the management of erosive symptomatic oral diseases, besides fluocinolone acetonide and triamcinolone acetonide. The efficacy of clobetasol in patients with OLP has been confirmed with a complete remission of oral signs in 75% of 25 patients suffering from erosive-atrophic OLP(8).
The present study was designed to compare between the effects of pimecrolimus 1% cream and clobetasol propionate 0.05% cream in treatment of patients with oral lichen planus.
Material and Methods
Patients: Thirty patients with oral lichen planus were selected from the outpatient clinic of the Oral Medicine and Periodontology Department, Faculty of Dentistry, Suez Canal University, as well as from Skin and Venereal Diseases outpatient clinic, Suez Canal University Hospital, between October 2008 and August 2009 Patients with histopathologically proven OLP older than 12 years were included in this study. Diagnosis of the cases was based on the currently accepted clinical criteria of oral lichen planus according to the World Health Organizations definition of OLP(9).
The inclusion criteria of this study were: (1) Presence of painful and atrophic-erosive oral lesions, at the same time with reticular ones. (2) No topical treatment for two weeks and no systemic therapy of OLP for four weeks before study start. (3) Ability to complete the present clinical study.
The exclusion criteria of this study were: (1) Presence of histological signs of dysplasia. (2) Use of lichenoid reaction inducing drugs. (3) Presence of amalgam fillings close to lesions. (4) Pregnant or breast feeding women. (5) Proved or suspected hypersensitivity caused by the tested chemicals.
Study Design: A randomized, controlled study was designed. The study was divided into two phases: Phase I: (Treatment phase) consisted of topical treatment for one month, and phase II: (Follow up phase) was of two month follow-up period intervals.Patients of this study were randomly grouped according to the type of drug given, into two groups:Group 1 consisted of 15 patients in which the patients apply a thin layer (2 ml) of pimecrolimus 1% cream, on the OLP lesion, twice daily for four weeks (Elidel cream, Novartis Pharma GmbH, Nuremberg, Germany). Group 2 consisted of 15 patients in which the patients apply a thin layer of the same amount of 0.05% clobetasol propionate cream, on the OLP lesion, twice daily for four weeks (Dermovate cream, Glaxo, Egypt).After completion of treatment, the lesions were assessed according to the following criteria: (1) Complete remission (CR): No symptoms or very mild symptoms, lesions disappear or mild white striae present. (2) Partial remission (PR): Symptoms reduced, but still mild white striae and mild erythematous area. (3) No response (NR): Symptoms persisted with no improvement or worsening of the lesions(10).
Ethical considerations:Written informed consents were obtained from all the participants in the study.
Statistical analysis: Collected data were analyzed using SPSS version 15. Quantitative data were expressed as means and SD and the significance of the difference between them was tested using Mann-Whitney test and Wilcoxon signed-rank test. Qualitative data were expressed as numbers and percentages, and chi square test was used to test the significance of the difference between them. A probability value (p-value) < 0.05 was considered statistically significant.
Results
Eighteen patients were diagnosed ashaving erosive-atrophic OLP whereas 12 patients disclosed a combined form with reticular, papular or plaque-like lesions mixed with erosive areas. Lesions were most commonly localized at the buccal mucosa (64.1%),tongue (20.51%), gingiva (5.13%), mucobuccal fold (5.13%) and finally lip (5.13%).Thirteen patients were also affected by cutaneous lesions (43.3%). Fifteen patients were randomized for treatment with pimecrolimus 1 % (group 1) and fifteen for clobetasol propionate 0.05 % (group 2).Regarding theage of the patients and the disease duration in both groups of the study, there is no significant difference between two groups.
Analysing the same group, each of the drugs showed statistical differences between signs (lesion severity) and symptoms (pain &burning sensation) at the beginning of the study and at the end of the follow-up periods; whereas, no statistical differences were found comparing signs and symptoms at the end of the treatment with those at the end of the follow-up periods. Comparing the two groups of this study, regarding the clinical improvement (the difference of lesions severity scores) at baseline and at the end of the treatment, no statistical differences were found (p > 0.1). (Table I).Regarding the symptoms improvement (the difference of Burning Sensation Scores) at baseline and at the end of the treatment, no statistical differences were found (p > 1) (Table II).
Like before, the symptoms improvement (the difference of VAS scores for pain) at baseline and at the end of the treatment, no statistical differences were found (p > 0, 7) (Table III).Fourteen of the 15pimecrolimus 1% patients (93%) and 13 of the 15 clobetasol 0.05% patients (87%), had clinical improvement after one month of treatment, no significant difference between both groups (p > 0.05).Similarly, 14 of the 15 pimecrolimus 1% patients (93%), while 13 of the 15 clobetasol 0.05% patients (87%), had symptomatic improvement (burning sensation) after one month of treatment,no significant difference between both groups (p > 0.05).Thirteen of the 15 pimecrolimus 1% patients (87%), while 13 of the 15 clobetasol 0.05% patients (87%), had symptomatic improvement (pain) after one month of treatment, no significant difference between both groups (p > 0.05).
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Topical Effect of Pimecrolimus Cream in Comparison with Clobetasol Propionate in Patients with Oral Lichen Planus
Table (I): Comparison of lesion severity score between the two groups of thestudy at different time points
Parameter / pimecrolimus group / clobetasol group / p-value0 week (baseline) / 3.8 / 3.5 / 0.3 (NS)
1 week / 3.1 / 2.9 / 0.5 (NS)
2 weeks / 2.1 / 1.8 / 0.2 (NS)
1 month (end of treatment) / 0.5 / 0.9 / 0.1 (NS)
2 months / 0.5 / 0.8 / 0.3 (NS)
3 months / 0.5 / 0.8 / 0.3 (NS)
NS: No significant difference (p-value > 0.05) P-value for Mann-Whitney test
Table (II): Comparison of burning sensation score between the two groups of the study at different time points
Parameter / pimecrolimus group / clobetasol group / p-value0 week (baseline) / 2.1 / 2.3 / 0.3 (NS)
1 week / 1.3 / 1.5 / 0.5 (NS)
2 weeks / 0.7 / 0.7 / 0.9 (NS)
1 month (end of treatment) / 0.3 / 0.3 / 1 (NS)
2 months / 0.3 / 0.3 / 1 (NS)
3 months / 0.2 / 0.3 / 1 (NS)
NS: No significant difference (p-value > 0.05) P-value for Mann-Whitney test
Table (III): Comparison of VAS pain score between the two groups of the study at different time points
Parameter / pimecrolimus group / clobetasol group / p-value0 week (baseline) / 6.7 / 5.2 / 0.06 (NS)
1 week / 4.7 / 4 / 0.3 (NS)
2 weeks / 2.8 / 2.5 / 0.7 (NS)
1 month (end of treatment) / 1.2 / 1 / 0.7 (NS)
2 months / 1.1 / 0.9 / 0.8 (NS)
3 months / 1.1 / 0.9 / 0.8 (NS)
NS: No significant difference (p-value > 0.05) P-value for Mann-Whitney test
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Topical Effect of Pimecrolimus Cream in Comparison with Clobetasol Propionate in Patients with Oral Lichen Planus
Discussion
The data of present study were correspondent withSwift et al.(11) who used the same design and method(twice daily for 4 weeks) on twenty patients with OLP (10 pimecrolimus and 10 placebos) and showed that pimecrolimus was superior to placebo.
The results of the present study also were in agreement withTaebunpakulet al.(12)who showed that animprovement in lesion severity occurred in patients treated with topical pimecrolimus 1% cream. Following the administration of pimecrolimus twice daily for four weeks, nearly complete resolution of OLP was documented in all patients. Regarding the same topic,the results of the present study were in agreement with a study done by Volz et al.(13) who investigated the efficacy of pimecrolimus cream 1% (Elidel) compared with vehicle cream in the treatment of erosive OLP. Twenty patients were enrolled to either pimecrolimus or vehicle group with treatment period of 30 days twice daily. Significant reduction of oral erosions was only observed following topical therapy with pimecrolimus cream 1% (p<0.05), whereas patients receiving vehicle cream displayed no reduction of erosive mucosa (p<0.05).
The present study had close clinical results with a study hadthe same design and method done by Passeron et al.(14)who evaluated the efficacy of 1% pimecrolimus cream and assessed its tolerance. Twelve patients with oral lichen planus were enrolled (6 treated with pimecrolimus and 6 took placebo). The drug was applied on lesions twice daily for four weeks. The mean score oflesion severity was (1.67) at base line versus (1.33) at the end of treatment in the placebo group,and (2.17) at base line versus (0.83) at the end of treatment in the pimecrolimus group.
The results of the present study were correspondent withSwift et al.(11)who used the same design and method on 20 patients with OLP (10 pimecrolimus and 10 placebos) and showed that pimecrolimus was superior to placebo. In VAS discomfort scores the base line value at 0 week was (33.30± 26.18) and at the end of the treatment was (20. 75± 22.88),there were statistically significant differences (p<0.05). The differences in the numbers in theirstudy were due to using of visual analog scale that ranged from 0 to 100 mm.
The results of the present study were in agreement withTaebunpakul et al.(12)as well; who showed animprovement in pain symptom occurred in patients treated with topical pimecrolimus 1% cream. Following the administration of pimecrolimus twice daily for four weeks, VAS scores at base line were ( 3.3,4.5 and 9.8) and decreased at the end of treatment to(0.7,1.7 and 1.8) respectively.
The results of the present study were further supported by a study done by Volz et al.(13)who investigated the efficacy of pimecrolimus cream 1% (Elidel) compared with vehicle cream in the treatment of erosive OLP. Twenty patients were enrolled to either pimecrolimus or vehicle group with treatment period of 30 days/ twice daily.A significant decline of meal triggered pain and continuous pain (p<0.05) as detected by VAS was seen in the pimecrolimus group only, whereas vehicle treatment had no significant beneficial effect on either meal-triggered pain or continuous pain (p>0.05).
Results of the present study was in agreementwith Gorouhi et al.(15)who found that the efficacy and safety of pimecrolimus 1% cream and triamcinolone acetonide 0.1% paste were evaluated in treating forty patients with OLP four times daily for a total of two months, with follow-up for another two months. There was no significant difference between changes from baseline median values of pimecrolimus and triamcinolone groups after treatment termination in terms of VAS score (9.8 ±11.3 versus 8.4 ± 18.3, p = 0.70).
In conclusion,the therapeutic effect of pimecrolimus 1% cream and clobetasol propionate 0.05% cream was comparable as no superior efficacy regarding pain controle, lesion size reduction as well as disease severity was superior with one drug than the other according to the protocol used in the present study.
References
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- McCreary CE and McCartan BE. Clinical management of lichen planus. Brit J Oral Maxillofacial Surg; 1999, 37(5):338-343.
- Scully C and El-Kom M. Lichen planus: review and update on Pathogenesis. J Oral Pathol; 1985,14(6):431-458.
- Vincent SD, Fotos PGand Baker KA. Oral lichen planus: the Clinical, historical and therapeutic features of 100 cases. Oral Surg Oral Med Oral Pathol; 1990, 70:165-171.
- Paul C, Graeber M and Stuetz A. Ascomycins: promising agents for the treatment of inflammatory skin diseases. Exp Opin Investig Drugs; 2000,9: 69-77.
- Mrowietz U. Ascomycin macrolactams. J Cutan Med Surg; 2001,5: 22-25.
- Meingassner JG, Grassberger M and Fahrngruber H. A novel anti-inflammatory drug, SDZ ASM 981, for the topical and oral treatment of skin diseases: in vivo pharmacology. Br J Dermatol; 1997, 137: 568-576.
- Lozada-Nur F, Huang MZand Zhou G. Open preliminary clinical trial of clobetasol propionate ointment in adhesive paste for treatment of chronic oral vesiculoerosive diseases. Oral Surg Oral Med Oral Pathol Oral Radiol Endod; 1991,71:283-287.
- WHO Collaborating Centre for Oral Precancerous Lesions: Definition of leukoplakia and related lesions: an aid to studies on oral precancer. Oral Surg Oral Med Oral Pathol; 1978, 46: 518-539.
- Thongprasom P, Luengvisut A, Wongwatanakij C and Boonjatturus K. Clinical evaluation in treatment of oral lichen planus with topical fluocinolone acetonide: a 2-year follow-up.J Oral Pathol Med; 2003,32: 315-322.
- Swift JC, Rees TD, Plemons JM, Hallmon WWand Wright JC. The effectiveness of 1% pimecrolimus cream in the treatment of oral erosive lichen planus. J Periodontol; 2005, 76:627-635.
- Patrayu Taebunpakul, Pantipa Chatchatee, Pornpan Piboonratanakit and Kobkan Thongprasom: Topical pimecrolimus 1% cream in treatment of oral lichen planus. Thai J Pharmacol; 2005, 27: 2-3.
- Volz T, CaroliU, Ludtke H, Bra utigamM, Kohler Spath H, Rocken Mand Biedermann T. Pimecrolimus cream 1 % in erosive oral lichen planus- a prospective randomized double-blind vehicle-controlled study. Bri J Derma; 2008,159: 936-941.
- Passeron T, Lacour JP, Fontas Eand Ortonne JP. Treatment of oral erosive lichen planus with 1% pimecrolimus cream: a doubleblind, randomized, prospective trial with measurement of pimecrolimus levels in the blood. Arch Dermatol; 2007, 143:472-476.
- Gorouhi F, Solhpour A, Beitollahi JM, Afshar S, Davari P, Hashemi P, Nassiri Kashani Mand Firooz A. Randomized trial of pimecrolimus cream versus triamcinolone acetonide paste in the treatment of oral lichen planus. J Am Acad Dermatol; 2007, 57:806-813.
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Topical Effect of Pimecrolimus Cream in Comparison with Clobetasol Propionate in Patients with Oral Lichen Planus
Correspondence to
Abdulrazzaq Ahmed Salem Almaweri
Department of Oral Medicine and Periodontology
Faculty of Dentistry, Suez Canal University
E-mail:
Short cut title: Management of Oral Lichen PlanusAuthor title: Al Refai et al.
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Al Refai et al.
مقارنة التأثيرالموضعي للبيماكروليمص كريم والكلوبيتازول عند مرضى الحزاز المنبسط الفموي
عبد الناصر محمد هاشم الرفاعي(1)، عاطف ابراهيم الاخرس(2)،
احمد عبد العزيز حسن(1)، عبدالرزاق احمد سالم الماوري (3)
قسم طب الفم وعلاج اللثة، كلية طب الأسنان(1)، والجلديه والتناسليه ، كلية الطب البشري(2)،
جامعة قناة السويس، الإسماعيلية، كلية طب الاسنان ، جامعة ذمار (3)
هدف البحث: تهدف هذه الدراسة الى مقارنة فاعلية الكلوبيتازول بروبيونيت٠٥,٠ % كريم مع البيماكروليمص ١% كريم في علاج مرضى الحزاز المنبسط الفموي.
طريقة البحث: اجريت الدراسه على ثلاثين مريضا يعانون من مرض الحزاز المنبسط الفموي من المرضى المترددين على العيادة الخارجية لكلية طب الأسنان – جامعة قناة السويس تراوحت اعمارهم بين ١٣-٦٥ سنة وكذلك المرضى المترددين على العيادة الخارجية بقسم الجلديه والتناسليه بمستشفى جامعة قناة السويس وتم اخذ تاريخ طبي كامل وفحصهم اكلينيكيا واخذ خزعه من كل مريض لتاكيد التشخيص ثم تم اعطائهم العلاج.تم استبعاد المرضى اللذين يتعاطون الادويه التى تسبب الافات الفمويه الشبيهه بالمرض او لديهم الافات الناتجه من حشوات او تركيبات الاسنان.بعد الفحص السريري الأولي تم تقسيم المرضى عشوائيا حسب نوع الدواء المعطى الى مجموعتين:المجموعه الاولى: تكونت من خمسة عشرمريضا كل مريض اعطي بيماكروليمص ١% كريم مرتين يوميا لمدة اربعه اسابيع على المناطق المصابه من الفم.المجموعه الثانيه تكونت من خمسة عشرمريضا كل مريض اعطي كلوبيتازول بروبيونيت٠٥,٠ % كريم مرتين يوميا لمدة اربعه اسابيع على المناطق المصابه من الفم.تم فحص ومعاينة المرضى وتصوير الحالات قبل بدء العلاج ثم خلال الاسبوع الاول والثاني ثم خلال شهروشهرين وثلاثة اشهر بعد نهاية العلاج. في كل زياره تم اخذ المؤشرات التاليه:مؤشر شدة الافه الفمويه.مؤشر شدة الالم.مؤشر الاحساس بالحرقان.وقد ادخلت البيانات التي اخذت من المرضى لعمل الدراسات الاحصائيه في الحاسب الآلي لاظهارالنتائج.
النتائج: ان كلا من بيماكروليمص ١% كريم و كلوبيتازول بروبيونيت٠٥,٠ % كريم اظهرا فعالية واضحة في تخفيض كل المؤشرات السريرية وايضا اظهرا نقصا واضحا في شدةوحجم الافه الفمويه المصاحبه للمرض.
الإستنتاج: ان كلا من بيماكروليمص ١% كريم و كلوبيتازول بروبيونيت٠٥,٠ % كريم يمكن ان يستخدما بشكل فعال في السيطرة على الأعراض الناجمة عن الافات الفمويه المصاحبه لمرض الحزاز المنبسط الفموي أضافة الى خفض شدة وحجم تلك الافات الفمويه.
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