Evaluation Of Clinical Parameters Related To Methotrexate Therapy In Liehen Planus

Background: For better management of lichen planus a clinical trial of oral methotrexate is necessary in our country. Objective: The objective of this study is to evaluate efficacy and safety of methotrexate therapy in the teatment of lichen planus. Methods: It was a prospective randomized controlled clinical trial conducted in the department of Dermatology and Venereology, BSMMU, Dhaka, from January 2009 to December 2010. Forfy four patients of lichen planus were included in the study. Cases (group-A, rr23) were treated with methotrexate (10 mg) single moming dose and control (group-B, n:21) were treated with mini pulse betamethasone (5mg) single morning dose on 2 consecutive days during the period of 12 weeks. Results: Clinical parameters were measured by follow up clinical examination. Morphological lesion of lichen planus improved 95 .7% in group-A and only 28.6% improved in group-B. At the end of study 82.6yo had, no complaints of itching in group-A and,l00%o had no complaints of itching in group-g. 16(69.6%)patients in group-A were completely cured clinically but 10(47.6%) in group-B. Anemia 3(14.2%) and edema 12(57.1%)developed in group-B but none in group-A. In group-B, dyspepsia 15(71.4%), acne 70(47 .6%), mooning face 8(38.1%), striae 8(38.1%) and hypertrichosis 4(19.0%) developed but none in group-A. Intermittent diarhoea, headache, nausea and fatigue complained in both groups of patients but the percentage of complaints was higher amog group-B compared to group-A. Menstrual abnormality developed in group-B 5(71/%) but none in group-A. Conclusion: The overall adverse effects were less in group-A than group-B. Therefore, methohexate can be used as an alternative safer option for the treatment of lichen planus.


Introduction:
Lichen planus is an inflammatory mucocutaneous disease charac tenzed by shiny, vi o lac e ous, p o lygo nal, flat topp e d, firm papules and plaques with Wickham's striae on the surfaces of lesionsl.It is highly pruriticz.T cells become activated via antigen-presenting cells such as Langerhans cells in conjunction with epidermal keratinocytes and co-stimulatory molecules.These activated T lymphocytes play a pivotal role in regulating epidermal cell recogni- tion, the lichenoid response and basal cell damage.Lichen planus is an unpredictable disease that typically persists for 1 to 2 years, but may follow a chronic, relapsing Address for correspondence: : Dr Samaresh chandra Hazra Medical officer, Infectious Diseases Hospital, Mohakhali, Dhaka.E-mail : s amohazr a@y ahoo .com. 90 course over many years'.Lichen planus may cause atrophic cicatricial alopecia and nail dystrophy with the involvement of scalp and nail respectivelya.Skin lesions of lichen planus may be disfiguring.Involvement of the oral and genital mucosa in severe cases may be deb llitatirrg.oral lichen planus may predispose to the develop- ment of squamous cell carcinoma within the lesionsl.Methotrexate is the most commonly dermatologist- prescribed oral immunosuppressive agentss.Methotrexate is mainly related to its effect on epidermal cell proliferation.It has a more significant effect on lymphoid cells.Methotrexate has anti-inflamm atory effects and its anti-inflamm atory effects exerts via inhibition of lympho- cyte proliferation.So methotrexate can be a highly effec- tive treatment alternative to systemic corticosteroid and Topical corticosteroids are widely used as first-line treatment, but response often incompletela.Topical treatment is impractical and patient compliance is poor for patients with generahzedlichen planus" .Oral corticoster- oids result in prompt improvement but relapse is common as the dose is redu cedzs and it is related with many side- effects.These side effects of systemic steroids are unavoi dable26.But methotrexate is well tolerated, convenient dose schedule, easily available, cheap and local made with mild to moderate gastrointestinal, hepatic, renal and hematological side effects that can be deceted by clinical examination and laboratory investiga- tions and take measures to prevent it by adding folic acid and reduce the dose.So, methotrexate can be a highly effective and tolerable treatment alternative to systemic corticosteroid in the treatment of lichen planus6.
Treatment of lichen planus is difficult and a lack of randomized controlled clinical trtal makes evaluation of therapies challengingu.For safer treatment option a prospective, randomrzed controlled clinical trial of oral methotrexate is necessary in our country to find out an alternative safer drug for the treatment of lichen planus.

Methods:
A prospective randomized controlled clinical trial was conducted in the department of Dermatology and Venereology, Bangabandhu Sheikh Mujib Medical University (BSMMU), Dhaka, Bangladesh.The patients of lichen planus attending at the department of Dermatology and Venereology, during the period of January 2009 to December 2010 were enrolled in this study.Total 44 patients were enrolled following inclusion and exclusion criteria.Of them 23 patients in group-A (case) and 2l patients in group-B (control) were selected randomly.A data collection sheet was used for research instrument.
Both male and female patients having 18 years or more, clinically and histopathologically diagnosed lichen planus and baseline investigatios such as CBC, liver and renal functions tests were nonnal and willng to participate in this study were selected as ou.r study patients.After exclu- sion of co-morbidity (acute infection, diabetes mellitus, uncontrolled hypertension, neoplasia, hepatic, renal and haematological diseases), pregnancy and lactation, the selected patients were finally included as our study participants.
Patients reported as lichen planus clinically and histopathologically at BSMMU and followig inclusion and exclusion criteria were selected for study.History clinical examination and baseline haematological and biochemical test of blood (CBC, Liver and renal function tests, Random plasma glucose) were done before intervention.
Group-A patients were given oral methotrexate 10 mg (Tab.Methotrax 10 mg) single morning dose after break- fast once in a week and oral folic acid 5 mg (Tab.Folison 5 mg) single morning dose aftq breakfast on the next day of methotrexate dose for 12 weeks.Group-B patients were given oral betamethasone 5 mg (Tab.Betnelan 0.5 mg, 10 tablets at a time) tn a single morning dose after breakfast on2 consecutive days of every week for 12 weeks.
Patients were followed up for clinical improvement and adverse effects of ther apy at 1", Zno, 6th and l2'h week.Efficacy and adverse effects of drugs were recorded as patient complaints and clinical evaluation.Patients were monitored by physical and dermatological examinations, and laboratory investigations such as CBC and SGPT weekly for first}weeks, then after 6 weeks and 12 weeks.
The treatment with methotrexate was stopped if total 100,000/cu mm of blood or SGPT exceeded 3 times of the upper limit of normal value.When WBC, platelet count and SGPT were refurned to noffinal methotrexate was started at a lower dose.Photographs of lesions at baseline and then after 6 weeks and 12 weeks were taken for subse- quent assessment and compare.
After collection, data was checked for inadequ zcy, irrelevaficy, and inconsistency.A11 data was analyzed with approp rrate statistical tools and SPSS 15 program and presented as text, tables and figure.

Results:
Total 44 patients with complete data were included in the study.The mean age of group-A (n-23) was 34.9 (+13.4) years ranging from 18 to 60 years, whereas the mean age of group-B (n-21) was 32.9 (+11 .4)years ranging from 18 to 61 years, but the mean difference was not statistically significant (p>0.05),though the meanage of group-Awas higher than group-B.No statistically significant sex difference was found between group-A and group-B (p>0.05),though the proportion of male patients were higher in group-A 9 (39.1)compared to group-B 7 (33.3)(Table-I). 9l All the patients had skin lesion, butlg (43.2%) had lesion Data showed that the proportion of macular, popular and in mucous membrane and 10 (22.7%) had nail and 3 plaque was found to be high among group-B 8(38.1%) (6.8%) had lesion in hair follicle.The mean duration of compared to group-A 5(21.7%).On the contrary, popular diseasewasl8.T(+4.0)monthsforthegroup-Aand,l7.5 and plaque was found to be high among group-A (+5.6) months for group-B.But the mean difEerence was 17(73.9%)than group-B 12(57.1%),but the difference not statistically significant (p>0.05)(Table-II).
was not statistically significant (p>0.05) ( During follow up of the patients, it was found tha\95.7% of the lesion became macule treated by oral methotrexate and only 28.6% became macule treated by betamethasone oral minipulse.At the end of follow up, 4.3% had papule and no patient had plaque among the group-A, whereas 61.9% had papule and 4.8% had plaque in group-B and the difference was statistically significant (p<0.05)(Table m).
Considering the color changes, initially 91.3% of the group-A and 90.5% of group-B had violaceous color but no statistically significant difference was found between two groups of patients (p>0.05).But at the end of l2th week follow up, 95.7% in the group-A became post inflammatory hyper pigmentation and it was 85.7% in the group-B and 14.3 % still have erythematous color group-B.Only 4.3% of the group-A had erythematous color.However, analysis did not show any statistically significant difference between two groups of patients (p>0.0s)(Table IV).

Table-III
Comparative studies of patient s improvement by morphological changes 0f lesions during the I 2'h week follow up period Clinical Baseline Presentation Group-A (n-23) Group-B Qr21) P value n (%) n (%) group-Aand no patient had complaints of itching among group-B.But the difference was not statistically signifi- cant (p>0.05)(Table V).Baseline n (%) n (%) Regarding complaints of itching, initially 4.3% of group-A had complaints of mild itching and L4.3% in group-B.However, 65.2% of group-A had severe itching and 71.2% had severe itching group-B.At the end of I2'h week follow up, 82.6% had no complaints of itching in In figure l, it was found that complete remission of the disease was occurred in 69.6% among group-A, whereas it was 47.6% among group-B.The moderate remission was 28.6% in group-B and 21.7% in group-A and parttal remission was 23.8% in group-B and 8.7% in group-A, which were higher among group-B compared to group-A.
However, analysis did not revealed any statistically significant difference between two treatment modalities (p0.05).
Table VI revealed that none of group-A had developed anemia and edema in subsequent follow up.However, 3(L4.2%) patients in group-B developed anemia and 12 (57.L%) of the patients in group-B developed edema during l2th week foltrow up (p<0.05).Analysis revealed that the mean change of body weight was noticed from baseline to l2th week follow up.Body weight increased in group-A from 55.9 (*2.4) to 56.5 (*2.4) and in group-B from 58.7 (+2.6) to 61.5 (+2.5).Mean difference of body weight was found between group-A and group-B (p<0.05)94 indicating mean body weight increased in group-B compared to group-A.
Adverse clinical symptoms like diarrhea, nausea, headache, alopecia and fatigue developed in both groups of patients during follow up period.The percentages of complaints were found to be higher among group-B compared to group-A, but the difference was not statisti- cally significant (p>0.05) between two groups of patients.
Dyspepsia developed in group-A 11 (47 .8o), but in group-B 15 (71.4%).Statistically significant difference was found between two groups ofpatients (p<0.05)(Table VI).during the follow up period.Statistically significant difference was found between two groups of patients (p<0.05).
Among group-A, none developed pu{pura and hypertri- chosis from baseline to follow up period but among group-B pu{pura 2(9.5%) and hypertrichosis 4(19.0%)developed during follow up period.on the contrary mouth ulcer developed in both groups of patients during follow up.However, no statistically significant difference was found between two groups of patients (p>0.05)(Table VI).
Among the female patients, initially none complained of menstrual abnormality among both groups of patients but during follow up period, menstrual abnorm ality devel- oped in group-B 5(7 L.4%) and none developed menstrual abnormality among groip-A(Table VI).Independent sample t test (unpaired student's t test) revealed that no statistically significant mean difference was found between group-A and group-B in terms of pulse rate at the different follow up period (p>0.05).Repeated measure analysis of variance indicated that no statistically significant mean differ- ence was found between baseline to 1", 1" to 2'd , 2nu to 3'd and 3'd to 4'h week follow up (P0.05).Repeated measure ANOVAs analysis indicated that no statistically significant mean differ- ence was found between baseline systolic blood pressure to 1't follow up, 1" to 2"d and2"dto 3'd week follow up within the group (p>0.05),however, statistically significant mean difference was found between 3'd and 4'h and4'h to 5'h week follow up (p<0.05).
But no statistic ally significant mean difference was found between group-A and group:B at different level of follow up $>0.05).Same pattern of diastolic blood pressure was noticed in different phases of follow up.2. a J.
betamethasone.So, methotrexate can be used' as an alternative effective and safe drug therapy for the treatment of lichen planus.
Evaluation of Clinical Pmameter Related to Methohexate Therapv in Lichel Planus Samaxesh Chandra Haza et al other systemic drugs in the treatment of lichen p1anus21.
z Mean pulse rate at dffirent follow up period

Table - II| . Table - I
Distribution of the patients by age and sex in both groups

Table - Il
Distribution of patients by site of involvement and duration of disease.
disease (months) p value reached from unpaired student's t test Evaluation of Clinical Parameter Related to Methotrexate in Lichen P1anus Samaresh Chandra Hazra et al

Table - IV
Comparative studies of patient s improvement by changes of colour of lesions from baseline to I2'h week follow up period

Table
VI also revealed that among group-A, none devel- oped acne, mooning face and striae from baseline to follow up period.But among group-B, acne 10(47.6o/o),

Table - VI
Comparative study of the adverse fficts (symptoms & signs) of the patients during 12 weeks follows up period.