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ORIGINAL ARTICLE
Year : 2017  |  Volume : 10  |  Issue : 2  |  Page : 149-155  

Evaluation of safety and efficacy of low-dose methotrexate as an alternative treatment option to systemic corticosteroids in generalized lichen planus


Department of Dermatology, Smt Kashibai Navale Medical College and General Hospital, Pune, Maharashtra, India

Date of Web Publication14-Mar-2017

Correspondence Address:
Yuvraj Eknath More
Department of Dermatology, Smt Kashibai Navale Medical College and General Hospital, Narhe, Off Mumbai Bypass, Pune-411 041, Maharashtra
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0975-2870.202094

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  Abstract 

Introduction: Lichen planus (LP) is a common, chronic, inflammatory pruritic disorder involving the skin, mucous membranes, nails, and hair follicles. Systemic corticosteroids have long been treatment of choice for generalized LP. However, use of corticosteroids is limited due to multiple side effects. Methotrexate (MTX) can be used as alternative and safe modality in generalized LP. Materials and Methods: Twenty-two cases of generalized LP with comorbidities such as diabetes mellitus and hypertension and steroid-resistant and patients with side effects of long-term corticosteroids were included in this study. MTX was initiated at the dose of 7.5 mg/week. Clinical evaluation for improvement in lesions and pruritus was performed at 2nd, 4th, 8th, and 12th weeks. Results: After 12 weeks, 80% patients had excellent improvement. Patients with an excellent response were followed up. In the 6-month follow-up, four patients showed recurrence while all the remaining 12 showed complete remission. Conclusion: Results of this small study suggest that the use of weekly oral MTX can be highly effective and tolerable treatment alternative for generalized LP.

Keywords: Generalized, lichen planus, methotrexate


How to cite this article:
More YE, Khatu SS, Chavan DC, Mahajan P, Pawar S, Gokhale N. Evaluation of safety and efficacy of low-dose methotrexate as an alternative treatment option to systemic corticosteroids in generalized lichen planus. Med J DY Patil Univ 2017;10:149-55

How to cite this URL:
More YE, Khatu SS, Chavan DC, Mahajan P, Pawar S, Gokhale N. Evaluation of safety and efficacy of low-dose methotrexate as an alternative treatment option to systemic corticosteroids in generalized lichen planus. Med J DY Patil Univ [serial online] 2017 [cited 2017 Mar 30];10:149-55. Available from: http://www.mjdrdypu.org/text.asp?2017/10/2/149/202094


  Introduction Top


Lichen planus (LP) is a common, chronic, inflammatory pruritic disorder involving the skin, mucous membranes, nails, and hair follicles.[1] Topical treatments are associated with good response in limited lesions, but it is impractical and associated with poor compliance in patients suffering from generalized LP. Hence, systemic corticosteroids have long been treatment of choice for generalized LP. However, use of corticosteroids is limited due to multiple side effects such as hypertension, hyperglycemia, osteoporosis, and raised intraocular pressure. In addition, recurrence of LP is quite common after stopping oral steroids and dependency is the usual outcome.[2],[3],[4] Other systemic treatments such as oral retinoids,[5] azathioprine,[6] cyclosporine,[7] mycophenolate mofetil,[8] thalidomide,[9],[10] low molecular weight heparin,[11],[12] PUVA, UVB,[13] and metronidazole [14] have been used in treating generalized LP with variable results. More recently, biological agents have been tried for the similar indication.[15],[16] There are very few reports regarding effectiveness of oral methotrexate (MTX) in treating widespread LP.[2],[17],[18],[19] MTX is a cost-effective drug and oral administration ensures reliable blood levels. Most common side effect of MTX is nausea and vomiting while most notorious side effects are pancytopenia and hepatotoxicity. Pancytopenia typically develops earlier as compared to hepatic fibrosis and cirrhosis which take years to develop. Hence, in case of treatment of LP with MTX, risk of liver damage is low because of short duration of treatment. The treatment with MTX reported good response rate and safety comparable to corticosteroids with lower recurrence rate. MTX was associated with good steroid sparing effect, especially in old ages and patients with systemic diseases.[2],[19] Hence, we decided to study effectiveness of low-dose MTX in patients with LP.


  Materials and Methods Top


A total of 22 patients of generalized LP attending the dermatology outpatient department of SKNMC and GH, Pune, were enrolled in this study. Mainly, fresh cases of generalized LP with comorbidities such as diabetes mellitus and hypertension were included as well as patients with steroid-resistant LP and patients of LP with side effects of long-term corticosteroids were included in this study. The study period was October 2013–October 2014. In all patients diagnosis of LP was proven by detailed clinical and histopathological examination. And it was differentiated from lichenoid reaction by the presence of typical band like infiltrate at dermo epidermal junction and presence of cytoid bodies. Our exclusion criteria were age <18 years and >80 years, pregnancy and lactation, chronic liver and kidney disease, malignancy, alcoholism, and immunocompromised patients.

Before starting treatment, all patients were thoroughly explained about the study protocol and detailed, informed consent forms were signed by everyone. Blood investigations – complete blood count, hemoglobin count, liver and kidney function tests, hepatitis B and enzyme-linked immunosorbent assay for HIV were performed at first visit. Baseline photographs were taken. Test dose of 5 mg MTX was administered to all the patients. One week after administration of test dose, hemoglobin count, complete blood count, and liver function test were repeated. MTX was initiated at the dose of 7.5 mg/week together with 5 mg folic acid, except for the day of administration of MTX. All patients were strongly advised to use only topical emollients and oral antihistamines for symptomatic improvement. Patients of childbearing age group were advised to use contraceptive measures during the administration and 3 months after cessation of the MTX.

The efficacy of the treatment was quantified using a calculated score.[2] Subjective improvement observed by patients and physician on the basis of change of color of lesion from violaceous to postinflammatory hyperpigmentation, remission of itching, disappearance of existing lesions, and appearance of no new lesions.

  • No response ≤25% improvement
  • Mild response = 25%–50% improvement
  • Moderate response = 50%–75% improvement
  • Excellent response ≥75% improvement in lesions with complete resolution of pruritus.


Clinical evaluation for improvement in lesions and pruritus was performed by a single physician at 2nd, 4th, 8th, and 12th weeks and photographs were obtained as well. Adverse events, laboratory abnormalities, and treatment compliance were also noted at each visit. A response rate <75% at 12th week was considered as a treatment failure, and MTX was discontinued and switched to another treatment. All the patients in the study group were followed up at the end of 6 months after stopping treatment with MTX for evaluation of recurrence.


  Results Top


A total of 22 patients with generalized LP [Figure 1],[Figure 2],[Figure 3],[Figure 4] entered the study (males - 9, females - 13). Demographic characteristics of these patients are listed in [Table 1]. Age of the patients ranged from 32 to 65 years (mean - 51.86 years). Age distribution of patients is depicted in [Table 2]. Two patients had hypertrophic variant of LP. Oral mucosal and nail involvement was observed in 4 and 1 patients, respectively, and none of them had scalp or genital involvement [Table 3].
Figure 1: Pretreatment photographs

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Figure 2: Pretreatment photographs

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Figure 3: Pretreatment photographs

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Figure 4: Pretreatment photographs

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Table1: demographic details of cases of generalized LP

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Table2 : Age distribution

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Table3: Area of involvement

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Out of these 22 patients, four patients had diabetes, four had hypertension, and three patients had both diabetes and hypertension. Two out of four diabetic patients, one out of four hypertensives, and one out of three patients with both diabetes and hypertension had developed these comorbidities as a side effect of chronic use of systemic corticosteroids used for treating LP previously. Remaining 11 patients had either no response or recurrence after systemic corticosteroids. The mean duration of the disease was 9 months (range: 2–24 months). Two patients showed side effects such as nausea and vomiting. Two patients were lost to follow-up.

After 2 weeks, eight out of twenty patients (40%) had mild improvement, six patients (30%) had moderate improvement while six (30%) showed no response. Excellent response was not observed at the end of 2 weeks.

After 4 weeks, five out of twenty patients (25%) showed mild improvement, ten patients (50%) had moderate improvement, four patients (20%) had excellent improvement, and one patient (5%) had no improvement [Figure 5],[Figure 6],[Figure 7],[Figure 8].
Figure 5: Follow-up photographs at 4 weeks

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Figure 6: Follow-up photographs at 4 weeks

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Figure 7: Follow-up photographs at 4 weeks

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Figure 8: Follow-up photographs at 4 weeks

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After 8 weeks, three patients (15%) had mild improvement, four patients (20%) had moderate improvement, and eight patients (40%) had excellent improvement.

After 12 weeks, one patient (5%) had mild improvement, three patients (15%) had moderate improvement, and 16 patients (80%) had excellent improvement [Figure 3] and [Figure 4]. Thus, total four patients (20%) showed <75% improvement at the end of 12 weeks and considered as treatment failure and shifted to another treatment modality [Figure 9],[Figure 10],[Figure 11],[Figure 12].
Figure 9: Follow-up photographs at 12 weeks

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Figure 10: Follow-up photographs at 12 weeks

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Figure 11: Follow-up photographs at 12 weeks

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Figure 12: Follow-up photographs at 12 weeks

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Patients with an excellent response were followed up. In the 6-month follow-up, four patients showed recurrence, while all the remaining 12 showed complete remission [Figure 13],[Figure 14],[Figure 15],[Figure 16].
Figure 13: Follow-up photographs at 6 months

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Figure 14: Follow-up photographs at 6 months

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Figure 15: Follow-up photographs at 6 months

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Figure 16: Follow-up photographs at 6 months

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  Discussion Top


This study was done to assess the safety of low-dose oral MTX therapy in the treatment of generalized LP. In the present study, the mean age of all the patients was 51.86 years with a range of 32–65 years. It also showed that 50% of the patients were within 55–65 years age group. This explains the middle-age onset of the disease and it is consistent with the studies conducted by Kachhawa et al., Khondker et al., and Hazra et al.[18],[20],[21]

This study includes nine males (40.90%) and 13 females (59%), which was similar to the report made by Katta that the prevalence of LP was slightly higher in women.[22] In our study, skin involvement was present in all 22 patients (100%), four patients (22.22%) showed mucosal involvement, and one patient (5.55%) showed nail involvement. In a study conducted by Hazra et al., out of 44 patients of LP, all patients had cutaneous lesions (100%),[18] findings being similar to our study; however, 19 (43.2%) showed mucosal involvement, ten (22.7%) patients showed nail involvement, and three (6.8%) of them showed hair involvement, these findings are not consistent with our study. In addition, these findings are not consistent with Daud and Pittlekow, who reported that mucous membrane involvement occurred in approximately 60%–70% of patients with LP.[23] Smaller sample size does not give conclusive epidemiological result. In the present study, smaller sample size is the cause of this dissimilarity. In a study of Turan et al., mucosal involvement is seen in two out of 11 patients, and there are no scalp, genital, and nail involvements,[19] findings being similar to our study.

Although the etiology of LP is unknown, an autoimmune pathogenesis is postulated with activated T-cells directed against basal keratinocytes. On this basis, MTX would be helpful in the treatment of this condition through downregulation of an immunologically mediated response.[19] Its efficacy may also be related to its effect on epidermal cell proliferation. However, in vitro studies demonstrate that MTX has a more significant effect on lymphoid cells. MTX also has an anti-inflammatory effect and it is exerted through inhibition of lymphocyte proliferation. Hence, MTX can be safely used in diabetic, hypertensive, and aged individuals where systemic steroids are relatively contraindicated.

Turan et al. conducted the similar survey in Turkey in 2009 using MTX in 11 patients of generalized LP, in which they started seven patients with 20 mg/week and four patients with 15 mg/week of MTX and complete response was achieved in 10 out of 11 (>90%) patients at the end of four weeks and one case recurrence seen during tapering.[19] Malekzad et al. conducted a study in 18 patients of generalized LP.[2] They initiated MTX at the dose of 7.5 mg in 12 patients and 10 mg in six patients. They reported excellent improvement in 25% of cases at the end of 4th week and 75% of cases at the end of the 8th week. In our study, we started all patients with low-dose MTX (7.5 mg/week). At the end of 4 weeks, only four out of twenty patients (20%) showed excellent response. Moreover, at the end of 8th week and 12th week, 40% and 80% of patients showed excellent improvement, respectively. In Turan et al.'s study,[19] MTX was used at high dose (15–20 mg weekly); thus, they reached higher response rates as compared to Malekzad et al.[2] and our study (>90% complete response after 1 month vs. 75% response at the end of 8 weeks, 80% response at the end of 12 weeks, respectively). Kanwar and De in 2013 treated 24 patients with 15 mg/week dose of MTX, and at the end of 24 weeks, they observed complete remission in 58% of cases.[17] In our study, we reported more than 75% of improvement in 16 (80%) patients.

In Turan et al.'s study, one out of 11 patients discontinued MTX due to intolerable adverse effects at the end of 4 weeks and one patient had recurrence after 2.5 months during follow-up of 6 months.[19] Malekzad et al. reported one nonresponsive patient and two patients with adverse laboratory findings.[2] They also reported no recurrence in 12 patients in 6-month follow-up. In our study, we have noticed no adverse effects and recurrence in four out of 16 patients in follow-up of 6 months. In our study, low dose in the beginning gave good compliance and lesser side effects with an advantage of low cumulative dose and most of the patients showed excellent response at the end of 8–12 weeks. This late response and higher recurrence rate in our study are due to low dose of MTX.

A study conducted by Nylander Lundqvist et al. consists of MTX supplemented with steroid ointments for the treatment of severe erosive lichen ruber.[24] MTX was used in a dose of 10–15 mg/week for a period of 17 months and they all got remarkably better. This explains that erosive lesions need long-term treatment. In our patients with mucosal involvement, response was noted at the end of 8 weeks, and as the lesions were not very severe or erosive in nature, moderate to excellent response was noted at the end of 12 weeks.

Thus, MTX can be a very reliable treatment for generalized LP. It has some superiority over corticosteroids such as safety in diabetic, hypertensive, or old patients. Moreover, MTX may be associated with lower recurrence rates. Its major disadvantage is its delayed onset of action that is unacceptable for some patients.


  Conclusion Top


Results of this small study suggest that the use of weekly oral MTX can be highly effective and tolerable treatment alternative for generalized LP, especially when there is concern regarding use of systemic corticosteroids due to side effects and resistant disease. Larger prospective controlled trials are needed to establish the optimal dosage and duration of MTX therapy in generalized LP.

Limitation of study

There was smaller number of subjects and the control group was not included in the study.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

 
  References Top

1.
Breathnach SM, Black MM. Lichen planus and lichenoid disorders. In: Burns T, Cox N, Griffiths C, editors. Rook's Textbook of Dermatology. 8th ed., Vol. 2. USA: Blackwell Publishing Company; 2010. p. 41.6-41.11.  Back to cited text no. 1
    
2.
Malekzad F, Saeedi M, Ayatollahi A. Low dose methotrexate for the treatment of generalized lichen planus. Iran J Dermatol 2012;14:131-5.  Back to cited text no. 2
    
3.
Verma KK, Mittal R, Manchanda Y. Lichen planus treated with betamethasone oral mini-pulse therapy. Indian J Dermatol Venereol Leprol 2000;66:34-5.  Back to cited text no. 3
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Ramesh M, Balachandran C, Shenoi SD, Rai VM. Efficacy of steroid oral mini-pulse therapy in lichen planus: An open trial in 35 patients. Indian J Dermatol Venereol Leprol 2006;72:156-7.  Back to cited text no. 4
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Laurberg G, Geiger JM, Hjorth N, Holm P, Hou-Jensen K, Jacobsen KU, et al. Treatment of lichen planus with acitretin. A double-blind, placebo-controlled study in 65 patients. J Am Acad Dermatol 1991;24:434-7.  Back to cited text no. 5
    
6.
Verma KK, Mittal R, Manchanda Y. Azathioprine for the treatment of severe erosive oral and generalized lichen planus. Acta Derm Venereol 2001;81:378-9.  Back to cited text no. 6
    
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Level NJ, Munro CS, Marks JM. Severe lichen planus clears with very low-dose cyclosporine. Clin Exp Dermatol 1992;17:66-7.  Back to cited text no. 7
    
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Dalmau J, Puig L, Roé E, Peramiquel L, Campos M, Alomar A. Successful treatment of oral erosive lichen planus with mycophenolate mofetil. J Eur Acad Dermatol Venereol 2007;21:259-60.  Back to cited text no. 8
    
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Boyd AS, King LE Jr. Thalidomide-induced remission of lichen planopilaris. J Am Acad Dermatol 2002;47:967-8.  Back to cited text no. 9
    
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Doherty SD, Hsu S. A case series of 48 patients treated with thalidomide. J Drugs Dermatol 2008;7:769-73.  Back to cited text no. 10
    
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Pacheco H, Kerdel F. Successful treatment of lichen planus with low-molecular-weight heparin: A case series of seven patients. J Dermatolog Treat 2001;12:123-6.  Back to cited text no. 11
    
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Rai R, Kaur I, Kumar B. Low-dose low-molecular-weight heparin in lichen planus. J Am Acad Dermatol 2002;46:141-3.  Back to cited text no. 12
    
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Taneja A, Taylor CR. Narrow-band UVB for lichen planus treatment. Int J Dermatol 2002;41:282-3.  Back to cited text no. 13
    
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Büyük AY, Kavala M. Oral metronidazole treatment of lichen planus. J Am Acad Dermatol 2000;43(2 Pt 1):260-2.  Back to cited text no. 14
    
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Fivenson DP, Mathes B. Treatment of generalized lichen planus with alefacept. Arch Dermatol 2006;142:151-2.  Back to cited text no. 15
    
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Asch S, Goldenberg G. Systemic treatment of cutaneous lichen planus: An update. Cutis 2011;87:129-34.  Back to cited text no. 16
    
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Kanwar AJ, De D. Methotrexate for treatment of lichen planus: Old drug, new indication. J Eur Acad Dermatol Venereol 2013;27:e410-3.  Back to cited text no. 17
    
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Hazra SC, Choudhury AM, Asaduzzaman AT, Paul HK. Adverse outcome of methotrexate and mini pulse betamethasone in the treatment of lichen planus. Bangladesh Med Res Counc Bull 2013;39:22-7.  Back to cited text no. 18
    
19.
Turan H, Baskan EB, Tunali S, Yazici S, Saricaoglu H. Methotrexate for the treatment of generalized lichen planus. J Am Acad Dermatol 2009;60:164-6.  Back to cited text no. 19
    
20.
Kachhawa D, Kachhawa V, Kalla G, Gupta LP. A clinico-aetiological profile of 375 cases of lichen planus. Indian J Dermatol Venereol Leprol 1995;61:276-9.  Back to cited text no. 20
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21.
Khondker L, Wahab MA, Khan SI. Profile of lichen planus in Bangladesh. Mymensingh Med J 2010;19:250-3.  Back to cited text no. 21
    
22.
Katta R. Lichen planus. Am Fam Physician 2000;61:3319-24, 3327-8.  Back to cited text no. 22
    
23.
Daud MS, Pittlekow MR. Lichen planus. In: Wolff K, Goldsmith LA, Katz SI, Gilchrest BA, Paller AS, Leffell DJ, editors. Fitzpatriks Dermatology in General Medicine. 7th ed. New York: McGraw-Hill Medical Publishing Division; 2008. p. 244-54.  Back to cited text no. 23
    
24.
Nylander Lundqvist E, Wahlin YB, Hofer PA. Methotrexate supplemented with steroid ointments for the treatment of severe erosive lichen ruber. Acta Derm Venereol 2002;82:63-4.  Back to cited text no. 24
    


    Figures

  [Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5], [Figure 6], [Figure 7], [Figure 8], [Figure 9], [Figure 10], [Figure 11], [Figure 12], [Figure 13], [Figure 14], [Figure 15], [Figure 16]
 
 
    Tables

  [Table 1], [Table 2], [Table 3]



 

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