STUDY

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
Rajan Mittal, MD; Samir Malhotra, MD, DM; Promila Pandhi, MD, DM; Inderjeet Kaur, MD; Sunil Dogra, MD, DNB

Objective: To evaluate the efficacy and safety of com-
bination therapy with acitretin and pioglitazone hydro-
chloride in patients with moderate to severe chronic
plaque-type psoriasis.
Design: Randomized, double-blind, placebo-controlled
clinical trial.
Setting: A tertiary care referral hospital.
Patients: The study included patients of either sex (age
range, 18-65 years) with moderate to severe chronic
plaque-type psoriasis. Patients were excluded if they were
of child-bearing potential or if they had impaired liver
or renal function, hyperlipidemia, diabetes mellitus, coro-
nary artery disease, or a body mass index greater than
30 (calculated as weight in kilograms divided by height
in meters squared). Of the 62 patients screened, 41 were
randomly assigned to 2 groups: 22 to an acitretin (25 mg)
plus placebo group and 19 to an acitretin (25 mg) plus
pioglitazone hydrochloride (15 mg) group.
Main Outcome Measure: Change in Psoriasis Area
and Severity Index score between the 2 groups from base-
line to 12 weeks.
Results: After 12 weeks of therapy, the percentage of re-
duction in the Psoriasis Area and Severity Index score was
64.2% in the acitretin plus pioglitazone group and 51.7%
in the acitretin plus placebo group. The majority of the ad-
verse events were mild to moderate except for 1 possibly
unrelated episode of acute myocardial infarction in a
49-year-old woman in the acitretin plus placebo group.
Conclusions: Pioglitazone has a potential beneficial an-
tipsoriatic effect and may provide a convenient, effica-
cious, and relatively safe option to combine with acitre-
tin, although further studies are needed.
Trial Registration: clinicaltrials.gov Identifier:
NCT00395941
Arch Dermatol. 2009;145(4):387-393

Authors Affiliations:
Departments of Pharmacology
(Drs Mittal, Malhotra, and
Pandhi) and Dermatology and
Venereology (Drs Kaur and
Dogra), Postgraduate Institute
of Medical Education and
Research, Chandigarh, India.
P
SORIASIS IS A CHRONIC,
inflammatory, immune-
mediated skin disorder that
can cause considerable mor-
bidity and have an adverse
impact on quality of life.1-3 It affects 2% to
3% of the world’s population, with chronic
plaque-type psoriasis accounting for ap-
proximately 90% of the cases.4 The course
of the disease is unpredictable, with pa-
tients generally having multiple remis-
sions and relapses that require repeated
and prolonged courses of therapy through-
out life. However, potential serious toxic
effects, eg, end-organ damage, which are
associated with long-term use of cur-
rently available therapeutic modalities such
as methotrexate, cyclosporine, and pho-
totherapy, limit the use of most drugs as
monotherapy. Therefore, one way to over-
come these limitations is by the use of com-
bination therapy to provide safe and ef-
fective care and to minimize cumulative
toxic effects.5
For editorial comment
see page ded90001
Acitretin, a synthetic retinoid, is a
widely used systemic antipsoriatic drug.
It acts by decreasing proliferation, by nor-
malizing the differentiation of epidermal
keratinocytes, and by exerting anti-
inflammatory effects.6 Although acitretin
is largely devoid of serious and irrevers-
ible toxic effects, which have been ob-
served with other antipsoriatic drugs, its
use as monotherapy in patients with
chronic plaque-type psoriasis is associ-
ated with a slow and often incomplete re-
sponse.7-10 Also, the toxicity of acitretin is
dose-related, thereby limiting the use of

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higher, more efficacious doses.11 Therefore, acitretin is
often used in combination with other topical or sys-
temic agents, such as calcipotriol, phototherapy, and cy-
closporine. Such combination treatment strategies al-
low the use of lower doses of acitretin and thereby decrease
adverse effects and enhance efficacy.12-14
Thiazolidinediones (TZDs), which are peroxisome pro-
liferator-activated receptor (PPAR)-␥ agonists, have po-
tential beneficial therapeutic effects in psoriasis. Pio-
glitazone hydrochloride is a TZD that is used as insulin
sensitizer in patients with type 2 diabetes mellitus.15 Thia-
zolidinediones have been shown to inhibit proliferation
and to induce differentiation in various in vitro and mu-
rine models of psoriasis.16,17 Also, it has been suggested
that the anti-inflammatory and antiangiogenic proper-
ties of TZDs underlie their beneficial effects in psoria-
sis.18-20 A number of recent clinical studies, including 3
open-label studies and 1 randomized, double-blind, pla-
cebo-controlled, prospective study, have provided evi-
dence of some therapeutic benefit of TZDs in psoria-
sis.16,21-23 Further evidence in support of a role for TZDs
in psoriasis was provided in a recently published popu-
lation-based case-control study involving 36 702 pa-
tients with a first-time diagnosis of psoriasis. In that study,
Brauchli et al24 found that there was a statistically sig-
nificant decrease in the risk for the development of pso-
riasis in long-term users of TZDs compared with non-
users (adjusted odds ratio, 0.33; 95% confidence interval
(CI), 0.16-0.66).
Because both acitretin and pioglitazone act by nor-
malizing cellular proliferation and differentiation,
by inhibiting angiogenesis, and by exerting anti-inflam-
matory actions in psoriatic skin through different
mechanisms at the nuclear level,7,25 we hypothesized
that pioglitazone and acitretin therapy might lead to ad-
ditive efficacy in patients with psoriasis. Therefore, we
conducted this study to evaluate the safety and efficacy
of combination therapy with pioglitazone and acitretin
in patients with moderate to severe chronic plaque-type
psoriasis.
METHODS
We conducted this study at the Postgraduate Institute of Medi-
cal Education and Research, Chandigarh, India, between Janu-
ary 2007 and December 2007 after obtaining approval from the
institutional ethics committee. The study was an investigator-
initiated, prospective, randomized, double-blind, placebo-
controlled, parallel-group, fixed-dose clinical trial of 12 weeks’
duration.
PATIENTS
Patients of either sex, 18 to 65 years of age, with moderate to
severe chronic plaque-type psoriasis (body surface area in-
volvement ⬎20%) who were attending the psoriasis clinic were
screened regarding their eligibility for inclusion in the study.
Only women who had completed their family and had under-
gone a tubectomy or were postmenopausal were eligible for the
study. Patients were excluded from the study if they were of
child-bearing potential or if they had (1) a history of hyper-
sensitivity to acitretin or pioglitazone; (2) impaired hepatic func-
tion (serum bilirubin level ⬎50% of the normal value and as-
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partate aminotransferase, alanine aminotransferase, and alkaline
phosphatase levels ⬎1.5 times the upper limit of normal); im-
paired renal function (serum creatinine ⬎1.5 mg/dL [to con-
vert to micromoles per liter, multiply by 88.4] in men and ⬎1.4
mg/dL in women); (3) hyperlipidemia requiring systemic
therapy; (4) a body mass index greater than 30 (calculated as
weight in kilograms divided by height in meters squared);
(5) a history of excessive alcohol use; (6) diabetes mellitus;
(7) congestive heart failure; or (8) ischemic heart disease.
Written informed consent was obtained from the patients
before inclusion in the trial. A detailed clinical examination and
evaluation of Psoriasis Area and Severity Index (PASI) scores26
were performed for all patients. Laboratory investigations, in-
cluding a complete blood cell count, serum electrolyte levels,
liver function tests (LFTs), renal function tests (RFTs), fast-
ing serum lipid profile, fasting blood glucose levels, urinaly-
sis, electrocardiography, and radiography of the patients’ right
ankle joints and lumbosacral spines, were also performed.
THERAPY AND FOLLOW-UP
Following a washout period of 2 weeks’ duration for topical
therapy and 4 weeks’ duration for systemic therapy, the eli-
gible patients were randomized to either of the treatment arms:
acitretin plus placebo or acitretin plus pioglitazone. A random-
ization list was generated using a random numbers table, and
the code was kept with an investigator who was not directly
involved in the assessment of end points. Acitretin was admin-
istered at a dosage of 25 mg/d in both groups. Pioglitazone hy-
drochloride was administered at a dosage of 15 mg/d to one
group, while the other group received a matching placebo. The
drugs or placebo were supplied in sealed containers bearing the
code for each patient according to the randomization list. All
participants were advised to take the drugs once a day after break-
fast. The treatment was continued until the patient achieved
complete clearance of lesions or for 12 weeks, whichever came
first. No concomitant antipsoriatic therapy was allowed, ex-
cept for emollients and anithistamines. Patients were advised
against unsupervised exposure to excessive sunlight or sun-
lamps.
The patients were followed up at 2, 4, 8, and 12 weeks after
randomization. At each visit, efficacy, safety, and compliance
were checked. Compliance was assessed at each follow-up visit
by direct questioning of the patients about any missed doses
and by pill count. Consumption of more than 80% of study medi-
cations was taken as a measure of adequate compliance.
EFFICACY AND SAFETY ASSESSMENT
The primary efficacy parameter was a change in PASI score be-
tween the 2 groups from baseline to 12 weeks. The secondary
efficacy parameter was the proportion of subjects who achieved
marked improvement, ie, at least 75% decrease in PASI score
(PASI 75) by week 2, 4, 8, or 12.
Adverse events were elicited at each follow-up visit by open
method, by asking leading questions, and by detailed physical
examination. Laboratory investigations, including complete
blood cell counts, LFTs, RFTs, fasting lipid profiles, fasting blood
glucose levels, and serum electrolyte levels, were repeated at 4
weekly intervals; x-ray films of the lumbosacral spines and right
ankle joints were repeated at the end of the study period to as-
sess any adverse effects of the use of acitretin on the bones.
STATISTICAL ANALYSIS
Assuming an SD of 10 in PASI scores and a difference of 10 in
the PASI score between the drug and the placebo arms at 12
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 Table 1. Baseline Characteristics in the 2 Study Groups
62 Assessed for eligibility

Acitretin (25 mg)

21 Excluded ⴙ Pioglitazone
15 Did not meet entry criteria Acitretin (25 mg) Hydrochloride
6 Refused to participate
ⴙ Placebo Group (15 mg) Group
Variable (n = 22) (n = 19)
41 Randomized Age, mean (SD), y 38.1 (11.5) 42.2 (10.6)
Sex, No. (%)
Males 21 (96) 19 (100)
22 Assigned to acitretin + 19 Assigned to acitretin + Females 1 (4) 0 (0)
placebo pioglitazone Weight, mean (SD), kg 66.6 (12.4) 67.6 (9.2)
Height, mean (SD), m 1.7 (0.8) 1.7 (0.5)
BMI, mean (SD) 23.9 (4.0) 24.0 (3.0)
2 Withdrawn 2 Withdrawn
1 Disease exacerbation 1 Disease exacerbation Duration of disease, mean 9.8 (6.1) 11.6 (6.0)
1 Adverse event 1 Withdrew consent (SD), y
BSA involved, mean (SD), % 39.1 (12.5) 36.5 (10.2)
PASI baseline 19.7 (5.8) 17.5 (4.6)
22 ITT analysis 19 ITT analysis Prior therapies used, No. (%) a
Topical therapy 22 (100) 19 (100)
20 Per-protocol analysis 17 Per-protocol analysis Systemic therapy 15 (68) 14 (74)
Phototherapy 10 (46) 9 (47)

Figure 1. Flow diagram of patients in the 2 groups. ITT indicates Abbreviations: BMI body mass index (calculated as weight in kilograms
intent-to-treat. divided by height in meters squared); BSA, body surface area;
PASI, Psoriasis Area and Severity Index.
a Topical therapies included coal tar, corticosteroids, and calcipotriol;

weeks to be clinically significant at ␣ = 0.05, with 80% power, systemic therapies included methotrexate, cyclosporine, and hydroxyurea;
and phototherapy included psoralen plus UV-A and narrow-band UV-B.
a sample size of 16 patients per group was calculated. Keeping
in mind a dropout rate of 25%, we decided to randomize 20
patients per group.
Data are presented as mean (SD) or median (range) or pro- Table 2. Psoriasis Area and Severity Index (PASI)
portions. All data analysis was intention to treat. Continuous Scores in the 2 Treatment Groups
variables were analyzed using the Mann-Whitney U test, while
categorical variables were analyzed using ␹2 or Fisher exact test. PASI Score, Mean (SD)
A 2-sided P value of less than .05 was considered statistically
significant. Acitretin (25 mg)
Acitretin (25 mg) ⴙ Pioglitazone
ⴙ Placebo Group Hydrochloride (15 mg)
RESULTS Week (n = 22) (n = 19)
0 19.7 (5.8) 17.5 (4.6)
Sixty-two patients with moderate to severe chronic plaque- 2 19.3 (5.9) 17.0 (4.8)
4 17.4 (7.3) 14.8 (5.1)
type psoriasis were screened for eligibility. Forty-one pa-
8 14.5 (7.8) 11.5 (5.4)
tients satisfied the entry criteria and were randomly as- 12 10.0 (8.5) 6.0 (5.6) a
signed to the 2 treatment arms: 22 to the acitretin (25
mg) plus placebo group and 19 to the acitretin (25 mg) aP = .04 compared with the acitretin plus placebo group.
plus pioglitazone hydrochloride (15 mg) group
(Figure 1). The 2 treatment groups were similar with
respect to majority of the baseline parameters, includ- CI, 49.2%-79.3%) in the acitretin plus pioglitazone group
ing duration of disease, body surface area involved, PASI compared with 51.7% (95% CI, 38.7%-64.7%) in the ac-
score, and laboratory indices (Table 1). itretin plus placebo group. Overall, the lesions cleared
or almost cleared in 7 patients (37%) in the acitretin plus
EFFICACY pioglitazone group compared with 2 patients (9%) in the
acitretin plus placebo group (P =.06).
There was clinical improvement in both groups, as shown Furthermore, at 12 weeks, PASI 75 was achieved in 8
by a decrease in the PASI score from week 0 to week 12 patients (42%) in the acitretin plus pioglitazone group com-
(P⬍.05 for both groups). An initial worsening of the dis- pared with 5 patients (23%) in the acitretin plus placebo
ease, observed as an increase in the PASI score at 2 weeks, group(P=.31).Also,PASI75wasattainedearlier,ie,byweek
was seen in 7 patients (37%) in the acitretin plus pio- 8 in 2 patients (11%) in the acitretin plus pioglitazone group
glitazone group vs 11 patients (50%) in the acitretin plus compared with 1 patient (4%) in the acitretin plus placebo
placebo group (P = .53). At the end of 12 weeks, the re- group (P=.59). Compliance with study medication, as de-
duction in the mean PASI score was significantly greater termined by direct questioning and pill count, was greater
in the acitretin plus pioglitazone group than in the ac- than 95% for all patients included in the trial.
itretin plus placebo group (P = .04) ( Table 2 and Clinically, improvement was seen as a decrease in ery-
Figure 2). The percentage of reduction in the PASI score thema, scaling, induration, and the body surface area in-
from baseline to 12 weeks of treatment was 64.2% (95% volved (Figures 3, 4, and 5). Scaling was the first pa-

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Acitretin (25 mg) + placebo
Acitretin (25 mg) + pioglitazone hydrochloride (15 mg)
25
20
15
PASI Score
10
5 weeks of acitretin therapy.
0 ported findings that treatment with retinoids results in con-
0 2 4 8
Weeks
Figure 2. Median Psoriasis Area and Severity Index (PASI) score in the 2
treatment groups at 0, 2, 4, 8, and 12 weeks. Asterisk indicates P= .04 when
the acitretin plus pioglitazone hydrochloride group was compared with the
acitretin plus placebo group.
rameter to improve, followed by erythema and induration.
Thinner plaques tended to respond earlier than thicker
plaques. Also, smaller lesions responded earlier than larger
ones. Lesions over the extensor aspects of the elbows and
knees were the last to respond. Characteristically, larger
plaques cleared from the center outward (Figure 3).
SAFETY
Adverse events were seen in 15 patients in each group.
Most were mild, although 1 patient (a 49-year-old wom-
an) had an episode of acute myocardial infarction (AMI)
after just 5 days of therapy. Commonly observed ad-
verse effects were increased erythema, dry skin, dry
mouth, thirst, increased pruritus, cheilitis, myalgia, ar-
thralgia, and weight gain (Table 3).
There was no consistent trend in triglyceride levels
among either group at various time intervals, although an
increase of 10% to 41% was seen in 10 patients (46%) in
the acitretin plus placebo group and an increase of 14% to
39% was seen in 5 patients (26%) in the acitretin plus pio-
glitazone group (P=.33). No significant change was noted
in the results of the other laboratory investigations, includ-
ing LFTs or fasting blood glucose levels, throughout the
study period in the 2 groups (P⬎.05). Comparison of the
baseline and end-of-study x-ray films of the lumbosacral
spines and right ankle joints also did not reveal any evi-
dence of skeletal changes in either treatment group.
COMMENT
This investigator-initiated, randomized, double-blind, pla-
cebo-controlled, parallel group, fixed-dose clinical trial
for evaluating the efficacy and safety of combination
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therapy with acitretin plus pioglitazone in patients with
moderate to severe plaque-type psoriasis shows that the
use of acitretin and pioglitazone combined led to a sig-
nificantly greater reduction in PASI score at 12 weeks than
the use of acitretin plus placebo. To the best of our knowl-
edge, this is the first such study in patients with chronic
plaque-type psoriasis.
The frequency of complete to almost complete remis-
sion with acitretin plus placebo (9%) observed in our study
is comparable to that reported by Kragballe et al,9 who
observed complete remissions with acitretin mono-
therapy in 11% of patients. Furthermore, the approxi-
mately 50% reduction in the PASI score observed in the
acitretin plus placebo group is in agreement with a pre-
vious study by Olsen et al,10 who observed a similar im-
∗ provement in erythema, scaling, and induration after 20
There was gradual clinical improvement during the
study period, which is in agreement with previously re-
12
siderable improvement in psoriasis over 6 to 12 weeks.27
We also observed that the addition of pioglitazone to the
regimen led to a decrease in the initial flare-up of disease,
as fewer patients in the acitretin plus pioglitazone group
(37%) than in the acitretin plus placebo group (50%) had
an increase in their PASI scores at 2 weeks of therapy. Since
the baseline demographics and the disease parameters were
comparable in the 2 groups in our study, the observed dif-
ferences could be ascribed to the additive effect of acitre-
tin and pioglitazone.
From a mechanistic viewpoint, the combination of reti-
noids and PPAR-␥ agonists is particularly appealing as
both groups of drugs have antiproliferative, prodifferen-
tiating, anti-inflammatory, and antiangiogenic activ-
ity7,25 and thus may provide additive efficacy in patients
with psoriasis. Furthermore, both retinoic acid recep-
tors and PPARs act on DNA as heterodimers with reti-
noid X receptors.15,27 Such cooperativeness at the recep-
tor level due to heterodimerization of PPAR and retinoid
receptors may be involved in the additive effects of ac-
itretin and pioglitazone, although this speculation needs
further elucidation.
In our study, most of the adverse events observed were
mild and tolerable. Common adverse events involved mu-
cocutaneous and musculoskeletal complaints, which are
frequent and known side effects of acitretin therapy.7,28,29
We did not observe any remarkable abnormalities in labo-
ratory parameters, including serum lipid levels, LFT re-
sults, and fasting blood glucose levels, in either group.
However, there was an episode of AMI in a 49-year-old
woman in the acitretin plus placebo group after just 5
days of therapy. It is unlikely, however, that the event
was related to the drug therapy. Furthermore, in com-
parison to the general population, patients with psoria-
sis have been shown to be at a higher risk for myocar-
dial infarction (hazard ratio, 1.21; 95% CI, 1.10-1.32).30
Although, to our knowledge, there are no published re-
ports of acitretin therapy being associated with AMI, the
prescription information leaflet for Soriatane (acitretin,
Connectics Corporation, Palo Alto, California) reports
the development of AMI in a few patients, but causality
has not been established.31 Because of the seriousness of
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 A B C

Figure 3. Photographs of a patient in the acitretin plus placebo group. A, Plaque-type psoriasis lesions over the back and arms at baseline. B, Initial disease
exacerbation at 2 weeks. C, Characteristic central clearing of lesions at 12 weeks.

A B

Figure 4. Photographs of a patient in the acitretin plus plus pioglitazone hydrochloride group. A, Extensive psoriasis lesions over the arms and trunk at baseline.
B, Complete clearance of lesions at 12 weeks.

the event, however, the patient was withdrawn from our
study.
Acitretin is an established antipsoriatic drug, and there
is growing evidence of a potential therapeutic role of TZDs
in psoriasis.16,21-23 In a randomized, double-blind, placebo-
controlled, prospective study, Shafiq et al23 demon-
strated the efficacy and safety of pioglitazone therapy in
patients with moderate to severe chronic plaque-type pso-
riasis. The percentages of reduction in the mean PASI
scores observed in the study were 21.5%, 41.1%, and
47.5% in the placebo, 15-mg pioglitazone hydrochlo-
ride, and 30-mg pioglitazone hydrochloride groups, re-
spectively.23 Furthermore, a trend toward greater anti-
psoriatic response with the use of rosiglitazone was seen
in 2 clinical trials, although the observed difference for
the primary end point (PASI 75) was not statistically sig-
nificant when compared with placebo (P=.44 and P=.27
for rosiglitazone 2-mg and 4-mg groups, respectively).32
The lack of statistical significance in these trials could
be attributable to a large placebo response (in about one-
third of the patients) and to the use of topical cortico-
steroids that could diminish the difference between the
2 groups. Also, as suggested by Ellis et al,32 there is the
possibility that an optimal dose of rosiglitazone for an-
tipsoriatic activity was not achieved.
According to our study results, the addition of pio-
glitazone to acitretin therapy can enhance antipsoriatic
efficacy. In comparison to other antipsoriatic drugs that
have been used in combination with acitretin, pio-
glitazone may offer a safer alternative as it has been used
in patients with diabetes mellitus for several years, and
most of the placebo-controlled trials have shown the in-
cidence of adverse effects due to pioglitazone therapy to
be approximately equal to that found with placebo.33 Fur-
thermore, PPAR-␥ agonists are known to possess an ar-
ray of beneficial effects, including a decrease in blood pres-
sure, an increase in high-density lipoprotein levels, and
an improvement of fibrinolysis.34 Moreover, the occur-
rence of diabetes, hypertension, and metabolic syn-
drome in patients with psoriasis is not uncommon, and
these conditions may coexist more often than is typi-
cally predicted from the prevalence of either disorder
alone.35 Pioglitazone therapy may be particularly useful
in these subsets of patients.
Our study has several important advantages. Its ran-
domized, double-blind, placebo-controlled design al-

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 A B

Figure 5. Photographs of a patient in the acitretin plus plus pioglitazone hydrochloride group. A, Plaque-type psoriasis lesions coalescing together over the trunk
and arms at baseline. B, Complete clearance of lesions at 12 weeks.

The study also has some limitations. The lowest dose

Table 3. Adverse Events Observed During the Study of pioglitazone (15 mg/d) was used. It would be inter-
in the 2 Treatment Groups esting to evaluate 30- and 45-mg doses of pioglitazone
with acitretin to clarify any dose-response relationship.
Total No. (%)
Also, there was an underrepresentation of females in
Acitretin (25 mg) our study, probably because of the strict entry criteria,
Acitretin (25 mg) ⴙ Pioglitazone as acitretin is a pregnancy category X drug, not suitable
ⴙ Placebo Hydrochloride for females of child-bearing potential. The study was
Group (15 mg) Group
Adverse Event a (n=22) (n=19)
also underpowered to detect smaller differences in
response.
Dry mouth 15 (68) 11 (58)
Thirst 15 (68) 11 (58)
In conclusion, the present study provides important
Dry skin 14 (64) 13 (68) insights into the beneficial effect of pioglitazone in com-
Increased erythema 14 (64) 8 (42) bination with acitretin for therapy of moderate to severe
Cheilitis 12 (54) 3 (16) b chronic plaque-type psoriasis. Pioglitazone may offer a
Increased pruritus 6 (27) 4 (21) convenient, efficacious, and relatively safer alternative for
Myalgia 6 (27) 2 (10) combining with acitretin than currently available immu-
Weight gain of ⬎1 kg 5 (23) 4 (21)
nosuppressive agents, although this theory needs to be
Gastritis 5 (23) 2 (10)
Arthralgia 4 (18) 5 (26) proved by further studies. Also, the long-term safety of
Rhinitis 4 (18) 4 (21) pioglitazone therapy in patients with chronic plaque-
Blurred night vision 2 (9) 4 (21) type psoriasis needs to be established.
Acute myocardial infarction 1 (4) 0 (0)

a Other adverse events included somnolence, insomnia, sun burns, skin
fissuring, low back pain, dyspepsia, fatigue, xerophthalmia, laryngitis,
pharyngitis, malaise, headache, pedal edema, and abdominal pain in 1 or 2
patients each in the 2 groups.
b P ⬍.05 compared with the acitretin (25 mg) plus placebo group.
lowed proper characterization of the therapeutic effi-
cacy of the combination of acitretin and pioglitazone. The
duration of study was also sufficient to study the re-
sponse to treatment. Also, since the recruitment contin-
ued for the major part of the year, the effect of seasonal
variations in the disease could be ruled out. Further-
more, the study was an investigator-initiated study, and
the pharmaceutical companies supplying the drugs had
no role in protocol design, data collection, or analysis of
results.
Accepted for Publication: August 21, 2008.
Correspondence: Samir Malhotra, MD, DM, Depart-
ment of Pharmacology, Postgraduate Institute of Medi-
cal Education and Research, Chandigarh 160012, India
(samirmalhotra345@yahoo.com).
Author Contributions: Dr Mittal had full access to the
data in the study and takes responsibility for the integ-
rity of the data and the accuracy of the data analysis. Study
concept and design: Mittal, Malhotra, Pandhi, Kaur, and
Dogra. Acquisition of data: Mittal and Kaur. Analysis and
interpretation of data: Mittal, Malhotra, Pandhi, and Dogra.
Drafting of the manuscript: Mittal, Malhotra, and Kaur.
Critical revision of the manuscript for important intellec-
tual content: Mittal, Malhotra, Pandhi, and Dogra. Sta-
tistical analysis: Malhotra. Obtained funding: Mittal, Mal-
hotra, and Pandhi. Administrative, technical, and material

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support: Mittal, Malhotra, Pandhi, Kaur, and Dogra. Study
supervision: Malhotra, Pandhi, Kaur, and Dogra.
Financial Disclosure: None reported.
Funding/Support: Acitretin (25 mg) was donated by In-
nova, a division of Ipca Laboratories Ltd, Mumbai, In-
dia, and pioglitazone (15 mg) was donated by Ind-Swift
Ltd, Chandigarh.
Role of the Sponsor: The pharmaceutical companies had
no role in the design and conduct of the study; in the col-
lection, analysis, and interpretation of the data; or in the
preparation, review, or approval of the manuscript.
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