Methotrexate Versus Methotrexate Plus Folic Acid in the Treatment of Moderate to Severe Plaque Psoriasis: A Randomized Clinical-Trial

Background: Psoriasis is a chronic, recurring inflammatory disease affecting the skin, joints and nails that has a significant negative impact on the quality of life. Efficacy of methotrexate versus combination of methotrexate plus folic acid in the treatment of psoriasis has been rarely assessed. Objectives: To compare the efficacy of methotrexate versus methotrexate plus folic acid in the treatment of moderate to severe chronic plaque psoriasis Material and Methods: Eighty patients with moderate to severe chronic plaque psoriasis were randomized to receive either methotrexate (group A) or methotrexate plus folic acid (group B). End point of treatment was 75% reduction in Psoriasis Area and Severity Index (PASI 75) score or upto 3 months, whichever was earlier. Patients were then followed up for a period of 12 weeks for assessment of relapse, DLQI and adverse effects. Results: Of 80 patients, 71 completed the treatment and follow up period (33 in group A, and 38 in group B). PASI 75 was achieved in 34/40(85%) patients in group A and 32/40(80%) patients in group B (P < 0.142). There was statistically significant number of patients who had greater adverse effect in methotrexate than in methotrexate plus folic acid (p=0.020). There was significant difference in the number of patients who relapsed during the follow-up period (P = 0.013) with more relapse in group B. Conclusion: Combination of methotrexate and folic acid developed lesser adverse effect and greater relapse in comparison to methotrexate alone.


Introduction
P soriasis is a common, chronic, disfi guring, infl ammatory and prolifera ve condi on of the skin and has remi ng and relapsing course.The characteris c lesion consists of red, scaly, sharply demarcated, indurated plaque, presents par cularly over the extensor surface of the extremi es and scalp.The disease is variable in dura on, periodicity of fl ares and extent.Morphological variants are common. 1he prevalence of psoriasis varies from 1.5 to 3% and incidence indicated to 60 individuals per 100 000 per year. 2 The prevalence of psoriasis is 2% in a study conducted in eastern Nepal to iden fy the pa ents profi le and belief regarding the disease psoriasis.3 Psoriasis may have a major impact on quality of life and self-esteem.It can lead to limita ons with daily ac vi es, occupa onal func oning and rela onship.4 The severity of the disease determines the therapeu c approach. 5Monotherapy with systemic agents may be insuffi ciently eff ec ve or produce many side-eff ects.In these cases, combina on, rota onal or sequen al treatment strategies may be u lized for be er results.3 Methotrexate a folic acid antagonist though eff ec ve produces many side eff ects associated with liver toxicity in long-term and gastrointes nal intolerance in short-term use.Folic acid supplementa on found to reduce its side eff ects but in a recent small study, sugges ons are made that supplementary folic acid might reduce the eff ec veness of methotrexate.Therefore, we had planned to undertake the study to compare the therapeu c effi cacy of methotrexate versus methotrexate plus folic acid in the treatment of moderate to severe plaque psoriasis and iden fy the adverse eff ects, Dermatology life quality index (DLQI), and relapse associated with these regimes.

Material and methods
Pa ents with plaque psoriasis a ending the outpa ent department (OPD) of Dermatology department, BPKIHS, Dharan with more than 2% BSA involvement were included and pa ents with less than 2% BSA, pregnant and lacta ng women, pa ents with systemic diseases and those who received systemic treatment for psoriasis within the past 4 weeks and topical treatment within the past 2 weeks, those with history of skin cancer and immunosuppression due to disease or drugs were excluded in the study.This study is an observer blinded, randomized, clinical trial and was approved by the Ins tu onal Ethical Commi ee.
The sample size of 40 pa ents were recruited in each arm of the study, considering 80% power, 5% alpha error, two sided and percentage of PASI 75 reduc on at 12 weeks in methotrexate group 50%.

Subject enrollment
A prior informed and wri en consent was taken from all pa ents.Par culars of an individual pa ent and detailed history with respect to the chief complaints, dura on of illness, associated symptoms and site of involvement were documented in a preset proforma for each pa ent.Seasonal varia on, precipita ng factors, joint involvement, family history and past treatment taken were also recorded.A complete clinical examina on was done in all pa ents.The sites involved and the morphology of the lesion were documented in the proforma.Body surface area (BSA) was measured using the rule of nine as in burn.Severity of the disease was assessed using PASI (Psoriasis Area and Severity Index).
Baseline inves ga ons of rou ne blood counts (Hb, TLC, DLC, platelets), liver func on test (total bilirubin/ conjugated, SGOT, SGPT, ALP) and renal func on test (S.Urea, S. Crea nine), Urine R/M, and X-ray chest PA view were done to rule out any systemic involvement.A HIV test was done a er sending the pa ent for the pretest counseling only in high risk pa ents.All females of reproduc ve age group underwent the pregnancy test and were also advice to use contracep ves during the treatment period.
A wash off period of 2-4 weeks was given to pa ents on any kind of past treatment (i.e. 2 weeks for topical and 4 weeks for any systemic treatment).
No concomitant therapy was allowed except for emollients and an -histamines during treatment and follow-up period.
Two parallel groups (1:1) generated with the help of Ralloc so ware and were randomized into two interven on group.Group A (Methotrexate(MTX)) and Group B (Methotrexate plus folic acid(MTX+FA).

Methotrexate (Group A)
Oral MTX was given in the dose of 0.4mg/kg/week with maximum of 25 mg/week for a period of 12 weeks.No changes were permi ed in the dose of MTX used during the study.

Methotrexate plus folic acid (Group B)
Oral MTX was given in the dose of 0.4mg/kg/week with maximum of 25 mg/week for a period of 12 weeks similar to group A, in addi on single dose of 5 mg folic acid was administered 24 hours a er.

Assessment
Assessment was done by calcula ng PASI and TBSA (%) during follow-up.DLQI were assessed at 12 and 24 weeks using Nepali version.Relapse assessed at 16, 20 and 24 weeks of follow-up.TLC, DLC, Hb, platelets, LFT repeated twice weekly for fi rst 4 weeks and every 4 weekly for remaining 8 weeks.Cumula ve dose of methotrexate was calculated.The primary end point was change in PASI at 12week and secondary end point was adverse eff ect, DLQI, and Relapse.Level of outcome measured as: 1. Excellent/good : clearance/minimal residual disease, or PASI 90 2. Sa sfactory: PASI 75 3. Improvement: PASI 50 4. Mild improvement: PASI 1-<50 5.No improvement: PASI 0 6.Relapse: PASI >25 from baseline Treatment discon nua on was done if there were any serious adverse eff ect and if there were any abnormal laboratory fi ndings.

Statistical analysis
Data from all randomized pa ents were included on intent-to treat basis.T-test was used where equal variance was demonstrated.Chi square test was used in the ini al explora on of the data.Otherwise, equivalent nonparametric sta s cs (Wilcoxon rank sum test) was used.Kaplan-Meir test used to assess the relapse a er comple on of the treatment period.

Results
Of 116 pa ents, 36 pa ents were excluded from the study and 80 pa ents were randomized.
Among 80 randomized pa ents (40 in each group), a total of 71 (33 in Group A and 38 in Group B) completed the treatment and follow-up (Figure 1).
A baseline demographic comparison of the 2 groups (Group A and B) of pa ents is shown in Table 1.The pa ents of both groups were not sta s cally diff erent in regards to age (p=0.475),dura on (p=0.867),PASI (p=0.432),TBSA (p=0.263), and DLQI (p=0,137).

Psoriasis area severity index (PASI)
There was marked reduc on in percentage score of PASI between the two treatment groups, however there was no sta s cal signifi cance (p=0.682)(Table 2).During the follow-up period of 12 weeks carried at 4 weekly interval, the mean PASI reduc on at 24 weeks was also sta s cally not signifi cant (P=0.260)(Table3).PASI 75 was achieved at 8 th week in Group A, whereas it was at 9 th week in group B (p=0.058) and the total cumula ve dose of methotrexate was slightly lower in Group A than Group B (p=0.050).Both were sta s cally insignifi cant (Table 4).

Total body surface area (TBSA)
Reduc on in percentage of total body surface area was marked in both the groups but was sta s cally insignifi cant (P=0.732), at 12 weeks (Table 5) and during follow-up period of 12 weeks a er comple on of treatment (i.e. at 24 weeks) (p=0.174)(Table 6).

Dermatology life quality index (DLQI)
Marked reduc on in DLQI was present both at 12 weeks and at 24 weeks, however sta s cally signifi cant reduc on was at 12 weeks (P=0.041)and favored Group A over Group B (Table 7).

Adverse effects (ADRS)
In methotrexate group, 11(27.5%),pa ents developed the side eff ects, in methotrexate plus folic acid 5(12.5%).There was sta s cally signifi cant diff erence in side eff ects at the end of study among the two treatment group (P=0.020)(Table 8).However the side eff ects were not serious.

Relapse
There was signifi cant diff erence in number of pa ents who relapsed at the end of study among the two groups (p=0.013)(Table 9).Higher number of pa ents relapsed during follow-up period of 12 weeks in methotrexate plus folic acid group compared to methotrexate alone (36.8% vs 21%)

Discussion
Many therapeu c agents are used for the treatment of psoriasis vulgaris with variable effi cacy but none is a defi nite treatment.Methorexate has been in use for more than fi ve decades as monotherapy and in combina on with other agents in the treatment of psoriasis, despite its poten al short-term and longterm side-eff ects. 6 our study, there was no sta s cal signifi cant diff erence in the number of pa ents who achieved marked improvement in PASI between the two groups (methotrexate and methotrexate plus folic acid) at 12 weeks (P =0.682).The mean total cumula ve dose of methotrexate (140.75±60.5 mg in methotrexate, and 170.75±40.5 mg in methotrexate plus folic acid) received by the pa ents in the two groups to achieve marked improvement was sta s cally not signifi cant (P=0.050).The diff erence in the me (8.5±4.5 weeks in Group A and 9.5±4.In the present study, reduc on in percentage of total body surface area was sta s cally insignifi cant (P=0.732), at 12 weeks of treatment and follow-up period (P=0.174).
In the present study, the median reduc on in DLQI between methotrexate and methotrexate plus folic acid was marked and sta s cally signifi cant at comple on of treatment at 12 weeks (P=0.041)favouring methotrexate alone.This similar reduc on in PASI, TBSA and DLQI between the two groups shows folic acid do not aff ect the mechanism of ac on of methotrexate and its effi cacy.
Total of 16 (20%) pa ents developed various side eff ects during treatment and follow up period among all pa ents in both group.In methotrexate 11 (27.5%)pa ents developed the side eff ects; in methotrexate plus folic acid 5(12.5%)pa ents developed the diff erent side eff ects.There was sta s cally signifi cant diff erence in side eff ects at the end of study among the two treatment group (P=0.020).These side eff ects were graded in a 4 point scale (from 0-no side eff ect to 3-severe) to know the severity of side eff ect.Majority of pa ents experienced grade 1 (mild) and few developed moderate degree of symptoms only and which disappeared on con nua on of treatment.Majority of side eff ects were gastrointes nal intolerance, like anorexia, nausea, and vomi ng, followed by fa gue and malaise and pruritus.Folic acid supplementa on decreases the side eff ects of methotrexate without aff ec ng its effi cacy.Gastrointes nal side eff ects are predominantly due to deple on of folic acid by the ac on of methotrexate (Folate antagonist).
Relapse in any pa ents were said to be present when there was more than 25% increase in PASI score from that of PASI score at the end of treatment.There were signifi cant number of pa ents who relapsed at the end of follow-up (24 weeks) in methotrexate plus folic acid group (14) compared to methotrexate alone (7) (p=0.013).This higher relapse rate in folic acid supplementa on group could be due to faster loss of eff ect of methotrexate by folic acid.
The study concludes that the supplementa on of folic acid with methotrexate do not aff ect its effi cacy and decreases the adverse eff ect of methotrexate both gastrointes nal and hepatotoxicity.The gastrointes nal adverse eff ect par cularly the nausea and vomi ng decreases the compliance of oral methotrexate and hampers its effi cacy thereby increasing the morbidity of psoriasis.In addi on decrease in hepatotoxicity will prevent the mortality associated with the psoriasis.However folic acid supplementa on group have higher relapse, it could be because of faster loss of eff ect of methotrexate due to folic acid.Further randomized studies with longer follow-up are required to support these fi ndings.

Figure 3 :
Figure 3: Change in Total Body Surface Area during treatment and follow-up

Figure 4 :
Figure 4: Change in Dermatology Life Quality Index during treatment and follow-up (0.3-0.5 mg/kg/week) from 1981 to 2000 and found marked improvement to occur in 88% of pa ents in 8.5 ± 5.1 weeks.7These fi ndings are similar to our fi ndings in effi cacy, dose and dura on required for achieving PASI 75.

Table : 1
: Baseline characteris cs of study popula ons

Table 2 :
Change in PASI during treatment

Table 3 :
Change in PASI during follow-up a er treatment

Table 4 :
PASI 75 response to treatment

Table 5 :
Change in Total Body Surface Area during treatment

Table 6 :
Change in Total Body Surface Area during follow-up a er treatment

Table 7 :
Change in Dermatology Life Quality Index