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: soroush.daklan@gmail.com
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 demonstrated
by 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 lymphocytes, with subsequent keratinocyte hyperproliferation
in the epidermis.1 The epidermis is now regarded as an
active component in innate immune responses and capable of inducing adaptive immunity, therefore psoriasis
could be considered a disorder of both innate and adaptive immune systems.2 Whatever the etiology and pathogenesis 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 guidelines is only an aid in decision-making processes4; therefore, whether to use topical or systemic agents depends
on the situation and should be personalized for each
patient. The current well-established systemic treatments
2014 The International Society of Dermatology

include phototherapy, which is not always feasible, methotrexate (MTX), cyclosporine, and oral retinoids, all with
significant potential for toxicity, or in the case of the biologics, 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 lifelong disorder, special considerations about long-term
systemic drugs are necessary. Therefore, combination
therapy using a conventional agent plus a safe, nonexpensive drug may be a rational method to overcome
both 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 entities other than diabetes, including dermatologic
diseases7,8 and more specifically in psoriasis.3,914 The
observations suggest that TZDs take their effects by
inhibiting epidermal growth, promoting terminal
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Pioglitazone and methotrexate in psoriasis

differentiation of keratinocytes, and reducing inflammatory responses.15 The rationale behind using pioglitazone
(among other TZDs, which consist of pioglitazone, rosiglitazone, and troglitazone) in our study was that pioglitazone is probably more effective in decreasing
triglycerides than rosiglitazone,7 and troglitazone has
been 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 pioglitazone in their research.1114
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 10100 times more effective at
decreasing the number of lymphocytes than keratinocytes.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 pathogenesis 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 increasing the efficacy of lower doses of MTX in the management 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
International Journal of Dermatology 2015, 54, 95101

Lajevardi et al.

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 <30, 3035, and >35, respectively, by
increments of 2.5 mg weekly at intervals of 12 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, 2.55.0 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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Lajevardi et al.

profile, blood glucose, and renal function tests were also

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

Pioglitazone and methotrexate in psoriasis

Table 1 Baseline
characteristics

demographic

details

Clinical trial

and

disease

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 secondary
efficacy 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 MannWhitney 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 randomly 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 statistically 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
2014 The International Society of Dermatology

Number of patients
Age, mean (SD),
years
Male/female
PASI baseline,
mean (SD)
Weight, mean
(range), kg
BMI (%), kg/m2
<30
3035
>35

Methotrexate alone
group

Methotrexate +
pioglitazone group

22
42.5 (16.09)

22
36.18 (12.79)

20/2
18.61 (8)

19/3
17.63 (6.99)

78 (48115)

76 (52122)

17 (77.27)
4 (18.18)
1 (4.5)

19 (86.37)
3 (13.63)
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 eects (n = 1)

22 ITT analysis

22 assigned to methotrexate
plus
pioglitazone group

Disconnuaon treatment
(n = 3)
- Consent withdrawal (n = 1)
- Side eects (n = 2)

22 ITT analysis

Figure 1 Flow diagram of participants through trial. ITT,

intention to treat.

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 disease (PASI 100) was obtained in four patients (18.2%) of
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Lajevardi et al.

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
6
10
16

18.61
13.91
11.16
7.72

17.63
11.78
7.21
4.46

0.769
0.438
0.030
0.021

(8)
(8.28)
(6.78)
(6.21)

(6.99)
(4.62)
(3.48)
(2.91)

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
6
10
16

19.82
15.91
11.77
8.45

19.77
15.5
10.73
6.64

0.925
0.869
0.370
0.055

(2.86)
(3.74)
(3.35)
(2.72)

(4.47)
(5.75)
(4.55)
(4.68)

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 16
weeks, 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 percentage of improvement in the DLQI score was also calculated 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 transaminases, 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
International Journal of Dermatology 2015, 54, 95101

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 combination of MTX and pioglitazone in the management of
plaque-type psoriasis. To our knowledge, this combination has not been previously used for psoriasis, and to
date our study is the first to consider the effect of pioglitazone on DLQI scores. According to our study results,
the combination therapy with these agents has a significant effect on the severity of the disease but not on
patients 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 hormone receptors are members.18 Three well-known antipsoriatic agents, i.e., corticosteroids, calcipotriol, and
acitretin, act through these receptors, then it will be of no
surprise that pharmacological ligands for one other member of this superfamily of receptors is a relevant therapeutic modality.

Table 4 Number of patients reporting AEs

Total AEs
Weakness/fatigue
Nausea/vomiting
Headache
Weight gain
Edema
Thrombocytopenia
Anemia
Leukopenia
Elevated liver
enzymes

Methotrexate alone
group (n = 22) (%)

Methotrexate +
pioglitazone group
(n = 22) (%)

8
2
3
4
0
0
0
0
1
0

10
3
2
4
1
0
0
0
1
1

(36.36)
(9)
(13.63)
(18.18)
(0)
(0)
(0)
(0)
(4.5)
(0)

(45.45)
(13.63)
(9)
(18.18)
(4.5)
(0)
(0)
(0)
(4.5)
(4.5)

AEs, adverse events.

The percentages were calculated for all patients within the
respective group. P values calculated with Fishers exact test
were insignificant for all AEs.
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Lajevardi et al.

In addition to their critical role in a variety of intracellular functions, PPARs are involved in cutaneous
homeostasis influencing skin tissue by epidermal growth
suppression, promoting terminal differentiation of keratinocytes, and regulating inflammatory responses. As a
result, ligands for these receptors (e.g., TZDs) may have
clinical implications in dermatologic diseases whose
mechanism of action involve hyperproliferation and aberrant 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 (lowering triglycerides and increasing high-density lipoprotein),
induction of apoptosis, fibrinolysis, lowering blood glucose, 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
events2022 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 aforementioned low doses of MTX according to the BMI of our
patients. First to see whether pioglitazone could exert an
2014 The International Society of Dermatology

Pioglitazone and methotrexate in psoriasis

Clinical trial

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 >35
and 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-treated patients at week 16. When evaluating the results in
terms of PASI 100 at week 16, we noticed an extra benefit by adding pioglitazone to the therapeutic regimen, i.e.,
a complete clearance of 18.2%, although it was not statistically 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 attributable 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 lower
dose 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 used
by 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 limitations. The female participants were heavily outnumbered by males, because we excluded all women with
child-bearing potential. It also was not placebo-controlled, 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 therapeutic benefit compared with MTX therapy alone in
patients with plaque-type psoriasis. No significant difference 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 experienced 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.
References
1 Gupta AK, Langley R, Poulin Y, et al. Pathogenesis of
psoriasis and current challenges. J Cutan Med Surg 2004;
8(Suppl.): 37.
2 Bos JD, De Rie MA, Teunissen MB, et al. Psoriasis:
dysregulation of innate immunity. Br J Dermatol 2005;
152: 10981107.
3 Kuenzli S, Saurat JH. Peroxisome proliferator-activated
receptors as new molecular targets in psoriasis. Curr
Drug Targets Inflamm Allergy 2004; 3: 205211.
4 Mrowietz U. Implementing treatment goals for successful
long-term management of psoriasis. J Eur Acad Dermatol
Venereol 2012; 26(Suppl. 2): 1220.
5 Parulkar AA, Pendetgrass ML, Granda-Ayala R, et al.
Nonhypoglycemic effects of thiazolidinediones. Ann
Intern Med 2001; 134: 6171.
6 Jermendy G. PPARg agonists-Antidiabetic drugs with a
potential role in the treatment of diseases other than
diabetes. Diabetes Res Clin Pract 2007; 78S: S29S39.
7 Boyd AS. Thiazolidinediones in dermatology. Int
J Dermatol 2007; 46: 557563.

International Journal of Dermatology 2015, 54, 95101

Lajevardi et al.

8 Friedmann PS, Cooper HL, Healy E. Peroxisome

proliferator-activated receptors and their relevance to
dermatology. Acta Derm Venereol 2005; 85: 194202.
9 Pershadsingh HA, Sproul JA, Benjamin E, et al.
Treatment of psoriasis with troglitazone therapy. Arch
Dermatol 1998; 134: 13041305.
10 Ellis CN, Varani J, Fisher GJ, et al. Troglitazone
improves psoriasis and normalizes models of proliferative
skin disease: ligands for peroxisome proliferator-activated
receptor-gamma inhibit keratinocyte proliferation. Arch
Dermatol 2000; 136: 609616.
11 Shafiq N, Malhotra S, Pandhi P, et al. Pilot trial:
Pioglitazone vs. placebo in patients with plaque psoriasis.
Int J Dermatol 2005; 44: 328333.
12 Mittal R, Malhotra S, Pandhi P, et al. Efficacy and safety
of combination Acitretin and Pioglitazone therapy in
patients with moderate to severe chronic plaque-type
psoriasis: a randomized, double-blind, placebo-controlled
clinical trial. Arch Dermatol 2009; 145: 387393.
13 Bongartz T, Coras B, Vogt T, et al. Treatment of active
psoriatic arthritis with the PPARgamma ligand
pioglitazone: an open-label pilot study. Rheumatology
(Oxford) 2005; 44: 126129.
14 Robertshaw H, Friedmann PS. Pioglitazone: a promising
new therapy for psoriasis. Br J Dermatol 2005; 152:
189191.
15 Kuenzli S, Saurat JH. Peroxisome proliferator-activated
receptors in cutaneous biology. Br J Dermatol 2003; 149:
229236.
16 Bolognia JL, Jorizzo JL, Rapini RP. Bolognias Textbook
of Dermatology, Vol 1, 3rd edn. New York: Elsevier
Saunders, 2012: 135156.
17 Jeffes EWB, McCullough JL, Pittelkow MR, et al.
Methotrexate therapy of psoriasis: differential sensitivity
of proliferating lymphoid and epithelial cells to the
cytotoxic and growth-inhibitory effects of methotrexate.
J Invest Dermatol 1995; 104: 183184.
18 Mossner R, Schulz U, Kruger U, et al. Agonists of
peroxisome proliferators-activated receptor-c inhibit cell
growth in malignant melanoma. J Invest Dermatol 2002;
119: 576582.
19 Bhagavathula N, Nerusu KC, Lal A, et al. Rosiglitazone
inhibits proliferation, motility, and matrix
metalloproteinase production in keratinocytes. J Invest
Dermatol 2004; 122: 130139.
20 Hercogova J, Ricceri F, Tripo L, et al. Psoriasis and body
mass index. Dermatol Ther 2010; 23: 152154.
21 Alsufyani MA, Golant AK, Lebwohl M. Psoriasis and the
metabolic syndrome. Dermatol Ther 2010; 23: 137143.
22 Prodanovich S, Kirsner RS, Kravetz JD, et al. Association
of psoriasis with coronary artery, cerebrovascular, and
peripheral vascular diseases and mortality. Arch
Dermatol 2009; 145: 700703.
23 Pershadsingh HA, Benson SC, Ellis CN. Improvement in
psoriasis with rosiglitazone in a diabetic and a
nondiabetic patient. Skinmed 2005; 4: 386390.

2014 The International Society of Dermatology

Lajevardi et al.

24 Brauchli YB, Jick SS, Curtin F, et al. Association between

use of thiazolidinediones or other oral antidiabetics and
psoriasis: a population based case control study. J Am
Acad Dermatol 2008; 58: 421429.
25 Ellis CN, Barker JN, Haig AE, et al. Placebo response in
two long-term randomized psoriasis studies that were
negative for rosiglitazone. Am J Clin Dermatol 2007; 8:
93102.
26 Roenigk HH Jr, Auerbach R, Maibach H, et al.
Methotrexate in psoriasis: consensus conference. J Am
Acad Dermatol 1998; 38: 478485.
27 Montaudie A, Spidian E, Paul C, et al. Methotrexate in
psoriasis: a systematic review of treatment modalities,
incidence, risk factors and monitoring of liver toxicity.
J Eur Acad Dermatol Venereol 2011; 25(Suppl. 2): 1218.

2014 The International Society of Dermatology

Pioglitazone and methotrexate in psoriasis

Clinical trial

28 Saurat JH, Stingl G, Dubertret L, et al. Efficacy and

safety results from the randomized controlled
comparative study of adalimumab vs. methotrexate vs.
placebo in patients with psoriasis. Br J Dermatol 2008;
158: 558566.
29 Heydendael VM, Spuls PI, Opmeer BC, et al.
Methotrexate vs. cyclosporine in moderate-to-severe
chronic plaque psoriasis. N Engl J Med 2003; 349:
658665.
30 Flytstrom I, Stenberg B, Svensson A, et al. Methotrexate
vs. ciclosporin in psoriasis: effectiveness, quality of life
and safety; a randomized controlled trial. Br J Dermatol
2008; 158: 11612.

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