2014.2-3.Evaluation

                                                                                                                            article in PDF  
Our Dermatol Online.  2014; 5(2): 118-123
DOI:.  10.7241/ourd.20142.29
Date of submission:  29.11.2013 / acceptance: 06.02.2014
Conflicts of interest: None
 

EVALUATION OF THERAPEUTIC RESPONSE OF METHOTREXATE AND CALCIPOTRIOL COMBINATION COMPARED WITH METHOTREXATE ALONE IN PLAQUE PSORIASIS

Deepthi Vasanthada1, Vasanth Kumar PM2, Krishna Rao Pasagadagula3, Ramesh Tatapudi4, Ramesh Malothu4

1UCEV-JNTUK, Vizianagaram Campus, A.P, India
2Department of Pharmacy, UCEV-JNTUK, Vizianagaram Campus, A.P, India
3Department of Dermatology Venerology and Leprosy, Andhra Medical College, Visakhapatnam, A.P, India
4Department of Biotechnology, UCEV-JNTUK, Vizianagaram campus, A.P, India
 

Corresponding author:  Dr. Vasanth Kumar PM    e-mail: vasanthpharma@gmail.com


 

Abstract
Introduction: Psoriasis is a common chronic, non-contagious, immune mediated disease. Plaque psoriasis is characterized by thick, white, silvery or red patches on the skin. Plaque psoriasis mainly affects scalp, and palms of hands and soles of feet. T-cells are a type of immune system cells which protect the body from foreign substances. But during psoriasis T-cells activated at a great rate than normal, in turn release of cytokines increases as a result skin cells growing too quickly, moving to the surface to the skin and appear on the skin as dead cells.
Materials and Methods: Plaque psoriasis is common form of psoriasis, which mainly affects palms of hands and soles of feet and scalp. Out of 76 patients with plaque psoriasis we selected 50 patients based on PASI scores. Within the 50 patients, 32 patients with Palmoplantar psoriasis and 18 patients with scalp psoriasis. All 50 patients were subjected to randomized control trail, so each type of psoriasis is divided into two groups i.e. A and B. All A group patients were treated with MTX, whereas all B group patients were treated with combination of MTX and Calcipotriol. All necessary investigations like complete blood count, liver enzyme,creatinine, urea, alkaline phosphate, PASI were measured at 0, 2,4 6,8 weeks interval.
Results: We observed that, a significant reduction in PASI is observed with combination of MTX and Calcipotriol as compared to Methotrexate alone.
Conclusion: From the above study we concluded that, combination of MTX and Calcipotriolis more effective than MTX alone in plaque psoriasis.
 
Key words:  Plaque psoriasis; Methotrexate; Calcipotriol; PASI

 

Introduction
Psoriasis is a common chronic, non-contagious, immune mediated disease. Psoriasis is mainly five types; they are plaque, guttate, inverse, pustular, erythrodermic. The most common form, plaque psoriasis, is characterized by thick, white, silvery or red patches on the skin. Plaque psoriasis mainly affects the scalp, and the palms of the hands and the soles of the feet. T-cells are a type of immune system cells which protect the body from foreign substances. But during psoriasis T-cells activates at a great rate than normal, in turn releases cytokines, which increases rapidly [1,2]. These cytokines stimulate skin cells to reproduce and mature at a faster rate, as a result skin cells growing too quickly, moving to the surface of the skin and appear on the skin as dead cells. Methotrexate is an anti folate, anti-metabolite drug, used in the treatment of auto immune diseases Methotrexate inhibits enzyme Dihydrofolatereductaseenzyme that involves in the production of tetrahydrofolate from dihydrofolate. As a result folic acid synthesis is inhibited, it is essential for DNA, RNA, and Thymidine synthesis. DNA, RNA, Thymidine are required for new cell growth and multiplication [3-5]. Methotrexate also inhibits T-cells activation.Calcipotriol is a vitamin D analogue, upon topical administration which binds with vitamin D receptor (VDR). Vitamin D receptor is found on the cells of many different tissues of thyroid, Bone, kidney and T-cells of immune system. T-cells play a major role in psoriasis; calcipotriol binds with vitamin D receptors of T-cells, and modulate T- cells cell growth and differentiation. Psoriasis is a complex disease, so combination therapy is beneficial that minimize risks [6-9]. Calcipotriol have anti-inflammatory, anti-proliferative, immunomodulatory properties. By using topical calcipotriol along with methotrexate reduces toxicities that associates with use of methotrexate as monotherapy, as well as calcipotriol also increases safety and efficacy of Methotrexate.
 
Material and Methods
I. Patient’s information
In this study, 76 patients with plaque psoriasis attended to the skin O.P. department K.G.H. Visakhapatnam. We selected 50 patients based on the psoriasis area severity index (PASI) and all necessary laboratory investigations were performed for present study. Out of 50 patients, 33 (66%) were males and 17 (34%) were females, and patients age ranged between 20 to 65 years (Tabl. I). Among the 50 patients, 32 patients with Palmoplantar psoriasis, 18 patients with scalp psoriasis. The extent of psoriasis was measured by using PASI scores (Tabl. II).
 
Sex
Male
33 (66%)

Female
17 (34%)
Age
Minimum
25 years

Maximum
60 years

                  Table I. Sex and Age incidence in psoriasis.

Type of psoriasis
No. of patients
Measuring scale
Palmoplantar psoriasis
32
PASI
Scalp psoriasis
18
PASI

                  Table II. Type of plaque psoriasis.

 
II. Grouping of patients
Grouping of patients is very essential, where each type of psoriasis is divided into two groups, based on Randomized control trail (RCT). By using Randomized control we can achieve equal groups and minimize errors. In this present study we selected Block type of randomized control trail (Tabl. III).
 
Palmoplantar psoriasis
Group-A
16

Group-B
16
Scalp psoriasis
Group-A
9

Group-B
9

                  Table III. Grouping of patients.

 
III. Drug and Dosage information
Methotrexate is administered orally to the patients with plaque psoriasis involving >10 psoriasis area severity index (PASI). Methotrexate has some adverse effects like nausea, abdominal pain, fatigue, fever, and 7.5mg of MTX given once in a week for palmoplantar and scalp psoriasis. Calcipotriol is vitamin-D analogue, applied topically to the affected areas. It is available as ointment form as well as solution form. For treatment of palmoplantar psoriasis, calcipotriol 50 μg/g ointment is applied twice daily topically, whereas for treatment of scalp psoriasis, calcipotriol 50 μg/ml scalp solution is applied twice daily topically. Information about drugs and dosage information was mentioned in the following table (Tabl. IV).
 
Drug
Dose and Route
of administration
Type of dosage form
Nature of
application
Plaque psoriasis
Methotrexate
7.5mg Oral
Tablet
Once weekly
Palmoplantar
Scalp psoriasis
Calcipotriol
50 μg/g Topical
Ointment
Twice daily
Palmoplantar
Psoriasis

50 μg/ml Topical
Solution
Twice daily
Scalp psoriasis

                  Table IV. Drug and dosage information.

 
IV. Experimental Design
In this present study, 50 patients were subjected to all necessary investigations before and during administration of drugs. The investigations include PASI, Complete blood count and liver enzymes, creatinine, urea, alkaline phosphate. They are conducted every two weeks up to eight weeks. Here all group-A patients are treated with methotrexate, whereas all group-B patients were treated with combination of methotrexate and calcipotriol. The Complete information about PASI scores before drug administration are mentioned in the following table (Tabl. V).
 



Mean PASI score
Drugs
Palmoplantar Psoriasis
Group-A
16
24.40
MTX

Group-B
16
23.28
MTX+ Calcipotriol
Scalp psoriasis
Group-A
9
22.42
MTX

Group-B
9
24.13
MTX+Calcipotriol

                  Table V. Experimental design.

 
V. PASI scores
The extent of psoriasis disease is measured by using PASI scales, PASI is used to measure palmoplantar and scalp psoriasis. PASI scale is considered as gold standards for measurement of psoriasis, here total body is divided into four parts, and these are head, upper extremities, trunk, and lower extremities. The extent of erythema, thickness, and scales is measured for each organ and given scores range from 0-4. Area score is given for each organ based on the percentage of body organ affected with psoriasis and scores ranges from 0-6. The scale mentioned is as below (Tabl. VI).
Redness, thickness, scale were given score range from 0-4.
 

Head
Upper
Extremities
Trunk
Lower Extremities
Redness




Thickness




Scale




Sum
A1=
A2=
A3=
A4=
Area score
B1=
B2=
B3=
B4=
Multiply
A1×B1×0.1=C1
A2×B2×0.2=C2
A3×B3×0.3=C3
A4×B4×0.4=C4
Total
C1=
C2=
C3=
C4=

                  Table VI. PASI scores.

Area score:
Score 1:<10%
Score 2: 10-<30%
Score 3: 30-<50%
Score 4: 50-<70%
Score 5: 70-<90%
Score 6: 90-<100%
PASI score: C1+ C2+ C3+ C4=

VI. Inclusion and Exclusion criteria
Inclusion criteria:
1. Patients with plaque psoriasis i.e. >10 PASI score
2. Patients must be suitable for systemic therapy and calcipotriol
3. Age of patients between 20 to 65 years
Exclusion criteria:
1. Patients with hypercalcemia.
2. Patients with previous history of liver diseases.
3. Patients with guttate, erythrodermic, inverse and pustular psoriasis.
4. Pregnancy and lactating women.
 
Results
Before starting the treatment each patient was evaluated with complete blood count, creatinine, urea, alkaline phosphatase, serum albumin, SGOT, SGPT and PASI score. During the treatment also these parameters were well monitored at 2, 4, 6, 8, week’s interval. The entire information was mentioned in the following Table VII.
 

Groups
Before drug
treatmen, Mean
values
Drug treatment
At 2
weeks
At 4
weeks
At 6
weeks
At 8
weeks
% reductionin
PASIScores
Palmo plantar
psoriasis
G-A
24.40
MTX
23.93
20.54
17.36
13.86
PASI 50

G-B
23.28
MTX+ Calcipotriol
20.79
15.32
11.58
5.36
PASI 75
Scalp psoriasis
G-A
22.42
MTX
21.32
18.48
16.27
12.58
PASI 50

G-B
24.13
MTX+ Calcipotriol
20.83
16.51
12.86
5.42
PASI 75

                  Table VII. Reduction in PASI score in palmoplantar and scalp psoriasis.

From the above table, we have observed that 75% reduction in PASI score is achieved with combination of methotrexate and calcipotriol, whereas 50% reduction in PASI score is achieved with methotrexate alone. 75% improvement in PASI score was considered as endpoint for clinical trials. Methotrexate is considered as well known drug for treating psoriasis. Psoriasis is a complex disease, so combination therapy was preferred to treat psoriasis. Methotrexate may combine with UVB, retinoids, PUVA, Vitamin D analogues for improving its efficiency, limiting side effects, reducing doses. In this study methotrexate was combined with Vitamin D analogue, Calcipotriol. Methotrexate alone and its combination with calcipotriol were given for 8 weeks for palmoplantar and scalp psoriasis. Calcipotriol 50 μg/g ointment is applied topically twice daily for palmoplantarpsoriasis, whereas 50 μg/ ml solution is applied topically twice daily for scalp psoriasis. 7.5mg of Methotrexate is administered once weekly alone to group A patients of palmoplantar, and scalp psoriasis, achieving PASI score between 50-75 % is 8 (32%) patients and < 50% is achieved in 13 (52%) patients, 4 (16%) patients were poor responders to methotrexate. Whereas combination of methotrexate and calcipotriol given for group B patients of palmoplantar and scalp psoriasis, achieving PASI scores, > 75% was achieved in 18 (72%) patients, between 50-75 % was achieved in 7 (28%) patients (Tabl. VIII). We observed that an increased efficiency in patients who used the combination (MTX+ Calcipotriol) therapy than the methotrexate monotherapy. After treatment with methotrexate, investigations showed that no changes in complete blood count, SGOT, SGPT, alkaline phosphatase, creatinine, and serum albumin. In the present study we used low dose methotrexate, thereby side effects were minor, they were found in four patients, consisting of headache, nausea, skin itching and fever, whereas calcipotriol also produces some adverse effects in two patients, they are erythema, pruritus and burning.
 
PASI scores
Group-AMTX alone
Group-BMTX+ Calcipotriol
>75
0 (0%)
18 (72%)
50-75
8 (32%)
7 (28%)
<50
13 (52%)
0 (0%)

                  Table VIII. Number of patients within the PASI score range.

 
Discussion
Psoriasis is a complex disease; it is very difficult to treat with conventional therapy, in such case combination therapy is preferable to treat the disease (Fig. 1 and 2). During psoriasis skin cells grows too quickly and moves to the surface of the skin appears as dead cells. Psoriasis mainly occur due to cold weather, stress, alcohol drinking, smoking, hormones, cuts, tattoos, allergies, medication for high blood pressure, heart disease and psychiatric disorders. In summer psoriasis undergoes remission and winter comes then relapse of psoriasis occur. Because sunlight having Ultra violet-A and Ultra violet-B rays. It may act as therapy for psoriasis. Some people suffering from psoriasis in summer more. Because sunlight acts as precipitating agent it may damage the skin. M. Frincu et al. [10] Explained that, Combination of methotrexate and phototherapy has positive role as methotrexate doses are reduced, the administration time is reduced and the risk of occurrence of severe side effects, both blood and liver is low. A drawback of treatment with phototherapy was that the patient had to come almost every day to perform clinical cure with UV, with duration of at least one hour per day. Treatment with methotrexate for four weeks cure psoriasis plaques, the same was explained by BL. Masuria et.al, [11] prior to the therapy, average involvement was 47.5% which after four weeks methotrexate therapy reduced to 8.3%. A complete clearing of psoriasis occurred in 40% of patients after methotrexate therapy. The clinical response started as early as 1 sore throat week in most of the patients. PASI score was considered as more reliable tool for measurement of extent of psoriasis plaques. According to NeerajaPuri et al, [12] PASI score remains the most accepted and widely used measure in clinical trials. Reduction in PASI score indicates decrease in severity of psoriasis. PASI 75 means 75% reduction in symptoms of psoriasis, whereas PASI 50 means 50% reduction in symptoms of psoriasis. PASI 75 considered as meaningful end point for clinical trials. Combination therapy is more effective than methotrexate alone; methotrexate was combined with various topical agents, oral agents and phototherapy. According to de Jong et al. [13], Menter MA et al [14]. Combination treatment minimizes the side effects associated with methotrexate and also reduces dose of methotrexate. This combination therapy also minimizes time of exposure of drug. According to PVS Prasad et al [15] thirty five patients admitted with psoriasis were analyzed. Sixteen patients received 20% crude coal tar and 19 patients received 20% crude coal tar along with Methotrexare in a weekly oral schedule (15mg/wk). After 4 weeks of therapy there was total clearance in 52.6% of the patients with combination therapy, whereas only 12.5% of the patients with conventional therapy achieved this. Chronic plaque psoriasis shows a high clearance rate if coal tar application is combined with oral methotrexate, than with the conventional coal tar alone. According to Lin YK et al. [16] jerry Bajel et al. [17] topical vitamin D serves as a foundation, it increases safety and efficacy of all medications. There by topical vitamin D used in combination therapy with systemic agents and phototherapy. Vitamin D has immunomodulatory properties that decrease anti-microbial peptides in keratinocytes, which promotes inflammation process. It has anti-inflammatory and anti-proliferative properties. Vitamin D decreases toxicity associated with these drugs used as monotherapy. Methotrexate is known as gold standard drug for treatment of psoriasis, Leung WY et al. [18] and Talwar S et al. [19] stated that; methotrexate is one of the well-established drugs for the treatment of moderate to severe psoriasis. Careful selection of patients, pretreatment evaluation and post treatment monitoring of methotrexate is essential because of its serious adverse effects of methotrexate. Folate is usually added to reduce the adverse effects of methotrexate. Liver biopsy remains the gold standard to detect the methotrexate related hepatic fibrosis and it is recommended in patients who have received a cumulative dose of 1.0-1.5 g.
 
 
Figure 1A and B. The above picture shows the patient with psoriasis of palms of hands psoriasis.
Figure 2A and B. The above picture shows the patients with psoriasis of soles of feet.
Conclusion
From the above study, we concluded that combination therapy is more effective in treating psoriasis compared to methotrexate as monotherapy. Combination therapy increases efficacy, reduce side effects and decreases chances of relapse. PASI 75 is achieved with combination therapy (Methotrexate + Calcipotriol) whereas PASI 50 is achieved with methotrexate monotherapy. PASI 75 was considered as end point for clinical trials. So combination therapy is more effective in treating psoriasis compared to methotrexate as monotherapy. Hence combination (Methotrexate + Calcipotriol) therapy plays a major role in treating palmoplantar and scalp psoriasis.
 
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