Background: Psoriasis has been viewed recently as a multisystemdisease with several important comorbidities such as metabolicsyndrome, insulin resistance and increased cardiovascular risk. All sharecommon inflammatory pathogenic mechanisms. Pioglitazone, aperoxisome proliferator activated receptor-gamma (PPAR-gamma) agonist, is aninsulin-sensitizing drug that, in addition to its metabolic role in control ofdiabetes and dyslipidemia, has a pro-differentiating and an antiproliferativeaction on keratinocytes and also a regulatory effect on theinflammatory response.Objectives: First: To clinically evaluate the therapeutic efficacy ofpioglitazone in comparison to placebo in the treatment of adult patientswith moderate-to-severe psoriasis vulgaris, whether diabetic ornormoglycemic, as regards their cutaneous lesions. Second: To evaluatethe possible effects of pioglitazone on psoriasis comorbidities: metabolicsyndrome, insulin resistance, cardiovascular risk and the relatedunderlying systemic inflammation. Third: To evaluate whether themolecular action of pioglitazone on its nuclear receptors, PPARγ, in thelesional psoriatic skin, is responsible for its possible clinical effect oncutaneous manifestations of the disease.Methods: A randomized double blind placebo-controlled trial (RCT)was performed for 10 weeks. Forty eight adult patients were randomizedto one of the two arms of the study: pioglitazone 30 mg daily oral tabletor matching placebo. The primary outcome was defined as treatmentsuccess if psoriasis area and severity index (PASI-50) was achieved.Secondary outcomes included assessment of changes in metabolicsyndrome, insulin resistance and cardiovascular risk. Clinical andlaboratory measurements included: body mass index (BMI), erythrocytesedimentation rate (ESR), high sensitivity-C reactive protein (hs-CRP),waist circumference, arterial blood pressure, serum triglycerides, highdensity lipoprotein-C, fasting blood sugar (FBS) and fasting seruminsulin. Both HOMA-IR and HOMA beta cell index were calculated.Lesional skin expression of PPARγ1 and PPARγ2 mRNA was measuredusing PCR. Data analysis in the RCT included total group analysis and subgroup analysis. Further data analysis and correlations were performedwithin pioglitazone group only.Results: Pioglitazone resulted in significantly higher treatment success incomparison to placebo (58.3% versus 25% respectively, p= 0.019) as wellas higher percent reduction of PASI from baseline {-56.8% ± 32.0 (95%CI, -71.8 to -41.8) versus -5.1% ± 105.4 (95% CI, -61.3% to 51.0%)(p= 0.009)}. Although hs-CRP showed significant reduction frombaseline within pioglitazone group, this effect was not superior to placeboin the between-group comparison. In all analyses, pioglitazone showed noefficacy in management of components of metabolic syndrome or insulinresistance after 10 weeks. The percent reduction of HOMA-IR inpioglitazone group showed a significant inverse correlation with bothbaseline patient’s age and BMI {(r= -0.492); (r= -0.621)}. Although bothPPARγ1 and PPARγ2 showed significant elevation from baseline withinpioglitazone group, a significant difference from placebo was noticedonly in PPARγ2 as regards both the percent changes {37.5% ± 26.2 (95%CI, 24.8 to 50.1) versus 14.8% ± 18.9 (95% CI, 4.7 to 24.9)} and themeans. PPARγ1 upregulation was directly correlated with hs-CRPpercent reduction (r= 0.470). Incidence of transient lower limb edemawas significantly higher in pioglitazone group. Other adverse eventsincluded transient headache and elevation of arterial blood pressure.Conclusions: oral pioglitazone 30 mg daily has a potential beneficial rolein adult patients with moderate-to-severe psoriasis vulgaris as regards theimprovement of cutaneous manifestations. The cutaneous effect ofpioglitazone in psoriasis is partly mediated through PPARγ2upregulation, however there is likely a PPARγ-independent mechanismthat awaits for investigation. Cardio-protective role through reduction ofhs-CRP appears to be a rapid effect, but seems related to improvement ofpsoriasis rather than a specific pioglitazone effect. Significant effects onmetabolic syndrome and insulin resistance were not achievable in a 10-week duration and further multicentric long term RCTs with escalatingdoses are recommended to further investigate these effects.