Lajevardi Et Al-2015-International Journal of Dermatology

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Clinical trial

The efficacy of methotrexate plus pioglitazone vs.

methotrexate alone in the management of patients

with plaque-type psoriasis: a single-blinded randomized

controlled trial

Vahide Lajevardi, MD, Zahra Hallaji, MD, Soroush Daklan, MD, Robabeh Abedini, MD,Azadeh Goodarzi, MD, and Mona Abdolreza, MD

Department of Dermatology, Razi Hospital,

Tehran University of Medical Sciences,

Tehran, Iran

Correspondence

Soroush Daklan, MD

Razi Hospital

Vahdat-e-Eslami Square, 11996 Tehran

Iran

E-mail: [email protected]

Conflicts of interest: None.

Abstract

Recently, thiazolidinediones have shown to be efficacious with a favorable safety profile

when used in the treatment of chronic plaque-type psoriasis. The aim of this study was to

evaluate and compare the efficacy and safety of a combination of methotrexate plus

pioglitazone and methotrexate alone in plaque-type psoriasis. A total of 44 adult patients

with plaque-type psoriasis were included in the study. Patients were randomized to

treatment with methotrexate alone (group A) or methotrexate plus pioglitazone (group B)

for 16 weeks. The primary efficacy outcome measure was psoriasis area and severity

index (PASI) score change between the study groups at week 16 relative to baseline. The

secondary efficacy outcome measure was dermatology life quality index (DLQI) score

change between the two groups at week 16 relative to baseline. The PASI 75 score was

also measured. After 16 weeks of therapy, the percentage of reduction in the mean PASI

score was 70.3% in group B and 60.2% in group A. PASI 75 was achieved in 14 patients

(63.6%) in group B compared with two patients (9.1%) in group A within 16 weeks, which

was significant (P < 0.001). At 16 weeks from the baseline, a 63.6% decrease in the mean

DLQI score of group B was seen, while the decrease for group A was 56.9%. Pioglitazone

enhances the therapeutic effect of methotrexate in plaque-type psoriasis, as demonstratedby a reduction in the mean PASI scores. In terms of DLQI, there was no extra benefit by

the addition of pioglitazone to methotrexate therapy.

Introduction

Psoriasis is a common inflammatory cutaneous disease.

The pathogenesis of psoriasis is known to involve T lym-

phocytes, with subsequent keratinocyte hyperproliferation

in the epidermis.1 The epidermis is now regarded as an

active component in innate immune responses and capa-

ble of inducing adaptive immunity, therefore psoriasis

could be considered a disorder of both innate and adap-

tive immune systems.2 Whatever the etiology and patho-genesis of psoriasis, the outcome is inflammation,

hyperproliferation, and aberrant differentiation of the

keratinocytes, which are hallmarks of psoriasis.3

The most recent studies have shown that treatment

strategies must be individualized, and the role of guide-

lines is only an aid in decision-making processes4; there-

fore, whether to use topical or systemic agents depends

on the situation and should be personalized for each

patient. The current well-established systemic treatments

include phototherapy, which is not always feasible, meth-

otrexate (MTX), cyclosporine, and oral retinoids, all with

significant potential for toxicity, or in the case of the biol-

ogics, with a high cost of treatment. To conquer this, the

search for new low price drugs with a better side effect

profile is justified. Furthermore, because psoriasis is a life-

long disorder, special considerations about long-term

systemic drugs are necessary. Therefore, combination

therapy using a conventional agent plus a safe, non-

expensive drug may be a rational method to overcomeboth above-mentioned limitations and at the same time

increasing efficacy.

Thiazolidinediones (TZDs) are insulin-sensitizing drugs

that proved to be effective in diabetes.5,6 It has been

demonstrated that TZDs may be effective in many enti-

ties other than diabetes, including dermatologic

diseases7,8 and more specifically in psoriasis.3,9 – 14 The

observations suggest that TZDs take their effects by

inhibiting epidermal growth, promoting terminal

ª 2014 The International Society of Dermatology International Journal of Dermatology 2015, 54, 95–101

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differentiation of keratinocytes, and reducing inflamma-

tory responses.15 The rationale behind using pioglitazone

(among other TZDs, which consist of pioglitazone, ros-

iglitazone, and troglitazone) in our study was that piog-

litazone is probably more effective in decreasing

triglycerides than rosiglitazone,7

and troglitazone hasbeen withdrawn for its potential severe hepatotoxicity.

However, the other two members of this family proved to

be safe and with a favorable side effect profile. Among

the adverse effects of pioglitazone, one could point out to

a moderate increase in hepatic transaminase levels, weight

gain due to fluid retention, hematuria, and proteinuria.6

Moreover, the newer studies on psoriasis used pioglitaz-

one in their research.11 – 14

MTX is an effective, conventional, well-established

systemic agent long approved by the US Food and Drug

Administration for psoriasis.16 MTX acts mainly through

the inhibition of immunologically active cells, and it has

been shown that it is 10 –

100 times more effective at

decreasing the number of lymphocytes than keratino-

cytes.17 Considering the fact that the effect of TZDs is

largely through inhibition of epidermal cells and MTX by

suppression of lymphoid cells, and regarding the patho-

genesis of psoriasis as a disease of both epidermal and

lymphoid cells, one could postulate the synergic effects of

a combination therapy with these two agents. Then we

hypothesized that the combination of pioglitazone plus

MTX may come into use and make us capable of increas-

ing the efficacy of lower doses of MTX in the manage-

ment of plaque-type psoriasis.

Materials and methods

Study design and patients

This randomized controlled, assessor-blinded, parallel-group

study of 16 weeks’ duration was done at the Department of

Dermatology, Razi Hospital, Tehran University of Medical

Sciences, Tehran, Iran, between May 2012 and October 2012.

Approval by the Ethics Committees was obtained, and all

patients provided informed consent. Before study set-up, we

registered it in the Iranian Registry of Clinical Trials, available at

http://www.irct.ir/ (Identifier: IRCT201202279149N1).

Patients with chronic plaque-type psoriasis, who had

indications for systemic therapy, enrolled in this prospective,

randomized, comparative clinical trial. Moreover, the inclusion

criteria for this study demanded that patients were not

systemically treated with medications or had undergone

phototherapy for their disease in the last six months, and all

topical treatments had to be withheld for at least one month

before the beginning of the study. Patients were not allowed to

enter the study if they had a history of congestive heart failure,

renal, hepatic, or pulmonary disease, or if they had abnormal

hepatic enzymes (aminotransferases more than 1.5 times the

upper limit of normal), diabetes, and any other major systemic

diseases. Women of child-bearing potential were also excluded.

Patients were withdrawn from the study if a severe adverse

effect occurred that warranted withdrawal of the medication,

these include: severe weight gain due to fluid retention and

edema, a significant change in blood cells (i.e., leukopenia,thrombocytopenia, anemia), a significant increase in hepatic

enzymes (more than 2.5 times of the baseline), nausea and

vomiting unresponsive to countermeasures, or any persistent

change in blood biochemistry results and urinalysis (e.g.,

hematuria or proteinuria).

Pretreatment evaluation

A complete physical examination and evaluation of psoriasis

area and severity index (PASI) scores were carried out in all

patients. The quality of life was assessed by the dermatology

life quality index (DLQI) questionnaire. Purified protein

derivative skin tests were performed on all cases and chest

x-ray in those with a previous history of pulmonary disease. If

there was any evidence of latent tuberculosis, patients were

required to start anti-tuberculosis prophylaxis. In all patients,

complete blood cell count, blood glucose, lipid profile, hepatitis

B and C serology, renal and liver function tests, and urinalysis

were also performed.

Treatments and follow-up

Subjects were randomized to either the MTX group (group A) or

MTX plus pioglitazone group (group B). In both groups oral

MTX was initiated at a dose of 7.5 mg weekly and titrated to a

maximum fixed dose of 10, 12.5, or 15 mg for patients with a

body mass index (BMI) of 35, respectively, byincrements of 2.5 mg weekly at intervals of 1 – 2 weeks. To

prevent the adverse effects of MTX, folic acid 1 mg was

administered daily for all patients, except the days they were

receiving MTX. In prescribing MTX, we used divided oral dose

schedule for all subjects, 2.5 – 5.0 mg at 12-hour intervals for

three doses each week. Patients in group B also received

pioglitazone 30 mg/day given orally. Duration of the study

period was based on the observation that maximum effect of

pioglitazone may emerge after several weeks. To secure a

sufficient period to see the effects of the trial drugs especially

pioglitazone, we allotted 16 weeks to this study. Subjects were

followed at weeks 1, 2, 4, 6, 10, and 16 after the start of the

study. During the study period, no concurrent antipsoriatic drug,

topical or systemic, was permitted, with the exception of bland

emollients.

Efficacy and safety assessments

During each visit, patients were evaluated in terms of adverse

effects by a detailed history taking, weight monitoring, direct

questions about side effects, and by the following laboratory

investigations: complete blood cell count, liver tests, and

urinalysis. In addition to the above-mentioned evaluations, lipid

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Clinical trial Pioglitazone and methotrexate in psoriasis Lajevardi et al.96


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profile, blood glucose, and renal function tests were also

recorded at weeks 4, 6, 10, and 16 of the baseline.

PASI and DLQI scores reassessed at 6, 10, and 16 weeks

after baseline for efficacy measurements. The primary efficacy

outcome measure was PASI score change between the study

groups at week 16 relative to baseline (week 0). The secondaryefficacy outcome measure was the DLQI score change

between the two groups at week 16 relative to baseline. To

make our study comparable with previous trials, at weeks 10

and 16, we also calculated PASI 75, defined as the proportion

of patients who achieved at least a 75% decrease in PASI

score. PASI and DLQI score measurements were calculated by

a person not involved in any processes of the patient

management, i.e., who did not know which patient under PASI

or DLQI calculation belongs to which group.

Statistical analysis

Subjects were assigned in two parallel groups by block

randomization, consisting of blocks of four patients. All analyses

were intention-to-treat, defined as all enrolled patients who

received at least one treatment dose of each drug. A sample

size of 18 patients for each parallel group would have a power

of 80% at a = 0.05, assuming a standard deviation of 10 and a

difference of 10 in the PASI score between the intervention and

the control arms at 16 weeks. Because of a long follow-up

period and the possible loss of patients, we decided to add four

cases to each group. Statistical differences of efficacy were

calculated using the Mann – Whitney U test for continuous

variables and the Fisher exact test for categorical variables,

with statistical significance at P < 0.05. Data were analyzed by

SPSS software (version 13.0; SPSS, Chicago, IL, USA).

Results

The total study enrollment was 44 patients (22 cases ran-

domly assigned to each group) ranging in age from 20 to

75 years, all with plaque-type psoriasis (Fig. 1). Of these,

39 (88.6%) were males and five (11.4%) were females.

The MTX treatment group (n = 22) and the MTX plus

pioglitazone group (n = 22) were comparable at baseline,

in terms of demographics and disease characteristics

(Table 1).

The reduction in PASI scores within the groups by

weeks 10 and 16 was remarkable (P < 0.05 for both

groups). The difference in the mean PASI scores between

the groups was statistically significant at week 16

(P = 0.021) (Table 2), with 70.3% reduction in group B

mean PASI scores as compared with a 60.2% reduction

in group A. The same measurement in groups A and B at

week 10 was 42.5% and 54.8%, respectively, again sta-

tistically significant (P = 0.029).

Four patients (18.2%) in group B achieved PASI 75 by

week 10, while no one in group A could obtain a PASI

75 at the same interval (P < 0.001). PASI 75 was

achieved in 14 patients (63.6%) in the intervention group

compared with two patients (9.1%) in the control group

within the 16 weeks, and this was significant (P < 0.001).

Furthermore, at week 16, complete clearance of the dis-

ease (PASI 100) was obtained in four patients (18.2%) of

Table 1 Baseline demographic details and disease

characteristics

Methotrexate alone

group

Methotrexate +

pioglitazone group

Number of patients 22 22Age, mean (SD),

years

42.5 (1 6.09) 36.18 (12.79 )

Male/female 20/2 19/3

PASI baseline,

mean (SD)

18.61 (8) 17.63 (6.99)

Weight, mean

(range), kg

78 (48 – 115) 76 (52 – 122)

BMI (%), kg/m2

35 1 (4.5) 0 (0)

BMI, body mass index; PASI, psoriasis area and severity

index.

44 randomized

22 assigned to methotrexate

alone group

Disconnuaon treatment

(n = 1)

- Side effects (n = 1)

22 ITT analysis

22 assigned to methotrexate

plus

pioglitazone group

Disconnuaon treatment

(n = 3)

- Consent withdrawal (n = 1)

- Side effects (n = 2)

22 ITT analysis

Figure 1 Flow diagram of participants through trial. ITT,

intention to treat.


Lajevardi et al. Pioglitazone and methotrexate in psoriasis Clinical trial 97


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group B, while one subject 1 (4.5%) in group A achieved

this result (P = 0.345).

The efficacy of treatment was also evaluated by the

DLQI score using the relevant questionnaire. As expected,

the quality of life in our patients was remarkably

improved in both groups from week 6 onward

(P < 0.05), but the difference between the two groups in

terms of the mean DLQI scores was not significant. At 16weeks, a 63.6% decrease in the DLQI score of group B

was seen, while the decrease for group A was 56.9%,

then, statistically not significant (P = 0.708). The percent-

age of improvement in the DLQI score was also calcu-

lated at week 10, once more we did not observe a

significant difference between the two groups (a 39.6%

reduction for control and 44.3% for case and P = 0.391)

(Table 3), showing that patients in the intervention group

were not more satisfied with the treatment than controls.

There was also no significant difference between the two

groups in terms of reduction in the mean DLQI scores

before week 16 (P values are shown in Table 3). It is

notable that all percentages have been calculated relative

to baseline.

The discontinuation rate was 9.1% (four of 44). Four

were lost to follow-up during the study period. Three

patients assigned to group B were excluded from the

study, of these one for abnormal elevations in serum trans-

aminases, one for leukopenia, and one due to consent

withdrawal. One patient randomized to group A withdrew

due to leukopenia. No other major side effect occurred

during the trial period. Only two patients received

prophylactic antituberculosis treatment (isoniazid) during

the study period. A detailed profile of adverse effects in

the two treatment groups of the study is shown in

Table 4.

Discussion

We conducted this 16-week, single-center, randomized,

assessor-blinded trial to evaluate the effects of a combina-

tion of MTX and pioglitazone in the management of

plaque-type psoriasis. To our knowledge, this combina-

tion has not been previously used for psoriasis, and to

date our study is the first to consider the effect of pioglit-

azone on DLQI scores. According to our study results,

the combination therapy with these agents has a signifi-

cant effect on the severity of the disease but not on

patient’s quality of life, as demonstrated by PASI and

DLQI scores, respectively.

First introduced in the late 1990s, TZDs are now

widely used to treat patients with type 2 diabetes. TZDs

are ligands for the peroxisome proliferator activator

receptor (PPAR)-c, which are expressed in many tissues,

including epidermal keratinocytes.8 PPARs have three

members (a, b, and c), all transcription factors that

belong to the nuclear hormone receptors superfamily, of

which steroid, retinoic acid, vitamin D3, and thyroid hor-

mone receptors are members.18 Three well-known anti-

psoriatic agents, i.e., corticosteroids, calcipotriol, and

acitretin, act through these receptors, then it will be of no

surprise that pharmacological ligands for one other mem-

ber of this superfamily of receptors is a relevant therapeu-tic modality.

Table 2 Psoriasis area and severity index (PASI) scores in the

two treatment groups: PASI score, mean (SD)

Week

Methotrexate alone

group (n = 22)

Methotrexate +

pioglitazone group

(n = 22)

P

values

0 18.61 (8) 17.63 (6.99) 0.769

6 13.91 (8.28) 11.78 (4.62) 0.438

10 11.16 (6.78) 7.21 (3.48) 0.030

16 7.72 (6.21) 4.46 (2.91) 0.021

Table 3 Dermatology life quality index (DLQI) scores in the

two treatment groups: DLQI score, mean (SD)

Week

Methotrexate alone

group (n = 22)

Methotrexate+

pioglitazone group

(n = 22)

P

values

0 19.82 (2.86) 19.77 (4.47) 0.9256 15.91 (3.74) 15.5 (5.75) 0.869

10 11.77 (3.35) 10.73 (4.55) 0.370

16 8.45 (2.72) 6.64 (4.68) 0.055

Table 4 Number of patients reporting AEs

Methotrexate alone

group (n = 22) (%)

Methotrexate +

pioglitazone group

(n = 22) (%)

Total AEs 8 (36.36) 10 (45.45)

Weakness/fatigue 2 (9) 3 (13.63)

Nausea/vomiting 3 (13.63) 2 (9)

Headache 4 (18.18) 4 (18.18)

Weight gain 0 (0) 1 (4.5)Edema 0 (0) 0 (0)

Thrombocytopenia 0 (0) 0 (0)

Anemia 0 (0) 0 (0)

Leukopenia 1 (4.5) 1 (4.5)

Elevated liver

enzymes

0 (0) 1 (4.5)

AEs, adverse events.

The percentages were calculated for all patients within the

respective group. P values calculated with Fisher’s exact test

were insignificant for all AEs.




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In addition to their critical role in a variety of intracel-

lular functions, PPARs are involved in cutaneous

homeostasis influencing skin tissue by epidermal growth

suppression, promoting terminal differentiation of kerati-

nocytes, and regulating inflammatory responses. As a

result, ligands for these receptors (e.g., TZDs) may haveclinical implications in dermatologic diseases whose

mechanism of action involve hyperproliferation and aber-

rant differentiation of the keratinocytes, like psoriasis. In

2004, an in vitro study by Bhagavathula et al.19 showed

that rosiglitazone (a potent TZD) has inhibitory effects

on proliferation and motility of keratinocytes, pointing to

a possible successful role for TZDs in psoriasis.

PPARs are widely distributed in the body, and their

activations have various advantages, including a decrease

in blood pressure, an improvement in lipid profile (lower-

ing triglycerides and increasing high-density lipoprotein),

induction of apoptosis, fibrinolysis, lowering blood glu-

cose, anti-inflammatory properties, etc.5,15; therefore,

TZDs may be beneficial to risk factors of atherosclerosis

such as hyperlipidemia and endothelial dysfunction. It is

of interest that there is an association between psoriasis,

obesity, metabolic syndrome, and atherosclerotic

events20 – 22 and that treating patients with psoriasis with

TZDs may have an additional benefit.

The application of TZDs as a treatment in psoriasis

for the first time was described by Pershadsingh et al.9 in

1998. There were also several other case reports10,14,23

and one population-based study24 indicating that TZDs

may be efficacious in this regard, but of interest are two

randomized, placebo-controlled, double-blind studies.The first was published by Shafiq et al. in 200511; they

used pioglitazone at doses of 15 and 30 mg and explored

a dose-dependent efficacy by this drug. The second and

more recent one performed by Mittal et al. in 200912

demonstrated the efficacy of a combination of acitretin

plus pioglitazone in plaque-type psoriasis. At week 12,

they found a reduction in the mean PASI scores of

51.7% and 64.2% in the acitretin plus placebo group

and in the acitretin plus pioglitazone group, respectively.

Nevertheless, there are also some evidences against the

usefulness of TZDs in psoriasis. Two large-scale studies

with a total number of 2595 patients observed no more

than a placebo effect for rosiglitazone,25 although it

could be due to a large placebo response, concomitant

use of topical corticosteroids, and an insufficient dose of

rosiglitazone.

MTX, a folic acid antagonist, was the first systemic

agent used effectively for psoriasis.26 Although previous

investigations allowed doses of MTX up to 25 mg weekly

for psoriasis,27 for two reasons we adopted the aforemen-

tioned low doses of MTX according to the BMI of our

patients. First to see whether pioglitazone could exert an

additional effect on the disease or not, because higher

doses of MTX might have concealed benefits obtained by

pioglitazone. The second was to avoid the confounding

effect of different doses of the drug on the measures of

disease improvement (PASI and DLQI) between the two

groups (in our study, only one patient had a BMI >

35and received 15 mg/week of MTX, and patients receiving

12.5 mg MTX weekly had a roughly similar distribution

across the two groups, i.e., four subjects in group A and

three subjects in group B).

In our study, PASI 100 in the MTX alone group was

obtained in 4.5% of patients after 16 weeks, which is in

accordance with a reported study by Saurat et al.,28

which observed a PASI 100 in 7.3% of their MTX-trea-

ted patients at week 16. When evaluating the results in

terms of PASI 100 at week 16, we noticed an extra bene-

fit by adding pioglitazone to the therapeutic regimen, i.e.,

a complete clearance of 18.2%, although it was not sta-

tistically significant (P = 0.345). However, at week 16,

the reduction in the mean PASI scores in groups A and B

were 60.2% and 70.3%, respectively, which showed a

significant difference (P = 0.021).

Heydendael et al.29 compared the efficacy of MTX to

cyclosporine in chronic plaque psoriasis. At 16 weeks,

they observed a PASI 75 in 60% of their patients treated

with MTX, which has a remarkable discrepancy with our

9.1% in MTX alone group; however, it could be attribut-

able to the higher doses of MTX (up to 22.5 mg) they

used. It is noteworthy that we achieved a similar success

(a PASI 75 in 63.6% at 16 weeks) with our MTX plus

pioglitazone group and at the same time using a lowerdose of MTX. When comparing our results with studies

using lower doses of MTX, the difference is much lower.

Flystrom et al.30 also compared MTX to cyclosporine,

but they did not increase the dose beyond 15 mg/week in

the MTX arm of their study. The percentage of patients

achieving PASI 75 at week 12 was only 24%, which is

closer to the 9.1% achieved by us in controls, keeping in

mind that we still applied a lower dose (most patients in

our study received MTX 10 mg/week). Moreover, the

mean PASI change from baseline at 12 weeks was 58%

in their study, which is in accordance with our 60.2% at

16 weeks in controls.

Subjects were closely monitored in terms of adverse

effects by regular laboratory tests, direct questions, and

weight measurement. Although adverse events occurred in

about 41% of all patients (Table 4), they were temporary

and mild in severity, with the overall frequency of them

similar across treatment groups. One (4.5%) patient in

group A and two (9.1%) in group B experienced side

effects leading to discontinuation of treatment, with an

overall exclusion rate of 6.81% (three of 44) due to side

effects, one in each group for leukopenia and one for




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hepatic enzyme rises in group B. All changes reverted to

normal after some weeks of discontinuation. In the MTX

arm of a study by Heydendael et al., 27.9% of patients

left the treatment because of elevations in transaminases

compared to 6.81% of our study, again the discrepancy

could be attributable to differences in MTX doses usedby us.

Our study had two important advantages. It had a

longer duration in comparison with previous studies

considering the effect of pioglitazone on plaque-type

psoriasis. It was also the first randomized controlled study

to evaluate the influence of pioglitazone on DLQI scores

of patients with psoriasis. Our study also had some limi-

tations. The female participants were heavily outnum-

bered by males, because we excluded all women with

child-bearing potential. It also was not placebo-con-

trolled, although the objective evaluation of PASI scores

was performed by a blinded dermatologist.

In conclusion, in terms of the mean PASI scores, the

treatment effects of pioglitazone offer additional thera-

peutic benefit compared with MTX therapy alone in

patients with plaque-type psoriasis. No significant differ-

ence between the groups was found for DLQI. Moreover,

we observed that this combination led to the same results

in disease improvement with a lower dose of MTX,

thereby reducing the risk of serious adverse events experi-

enced by higher doses of MTX. Nevertheless, studies on

the subject are yet scarce, and to prove the results

obtained by us, future placebo-controlled trials of longer

duration are needed.

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