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Troglitazone Improves Psoriasis and Normalizes Models of Proliferative Skin Disease
Ligands for Peroxisome Proliferator-Activated Receptor- Inhibit Keratinocyte Proliferation
Charles N. Ellis, MD;
James Varani, PhD;
Gary J. Fisher, PhD;
Mary E. Zeigler, PhD;
Harrihar A. Pershadsingh, MD, PhD;
Stephen C. Benson, PhD;
Yiqing Chi, MD;
Theodore W. Kurtz, MD
Arch Dermatol. 2000;136:609-616.
Background Psoriasis is often treated with agents that activate nuclear hormone receptors for glucocorticoids, retinoids, and vitamin D. The peroxisome proliferator-activated receptor- (PPAR) is a related nuclear hormone receptor that can be activated by its ligands, including the thiazolidinediones.
Objective To assess whether treatment with troglitazone, a currently available thiazolidinedione used to treat diabetes mellitus, has an effect on psoriasis in normoglycemic patients and whether ligands for PPAR have an effect on models of psoriasis.
Design Open-label administration of troglitazone in patients with psoriasis and evaluation of drug actions in cellular, organ, and transplant models of psoriasis.
Setting University and community hospital outpatient departments and university laboratories.
Patients Patients with chronic, stable plaque psoriasis and control subjects. Five patients with psoriasis received troglitazone (none withdrew); 10 different untreated patients and 10 controls provided tissue samples.
Interventions Oral troglitazone therapy at various dosages in patients with psoriasis; also, use of troglitazone, ciglitazone, and 15-deoxy- -12,14-prostaglandin J2 in psoriasis models.
Main Outcome Measures Investigator-determined clinical results in patients and cell counts and histological evidence in models.
Results All patients' psoriasis improved substantially during troglitazone therapy. Peroxisome proliferator-activated receptor- was expressed in human keratinocytes; ligands for PPAR inhibited the proliferation of normal and psoriatic human keratinocytes in culture. Troglitazone treatment normalized the histological features of psoriatic skin in organ culture and reduced the epidermal hyperplasia of psoriasis in the severe combined immunodeficient mouse and human skin transplant model of psoriasis (P<.05 compared with untreated controls).
Conclusions Peroxisome proliferator-activated receptor- might be a useful intracellular target for the treatment of psoriasis; further study is needed to assess the clinical value of ligands for PPAR, including troglitazone.
From the Departments of Dermatology (Drs Ellis and Fisher) and Pathology (Drs Varani, Zeigler, and Chi), University of Michigan Medical School, Ann Arbor; the Department of Family Medicine, University of California, Irvine, and Kern Medical Center, Bakersfield, Calif (Dr Pershadsingh); the Department of Biological Sciences, California State University, Hayward (Dr Benson); and the Department of Laboratory Medicine, University of California, San Francisco (Dr Kurtz). Drs Ellis and Benson have served as ad hoc consultants for Bethesda Pharmaceuticals, Mill Valley, Calif. Drs Pershadsingh and Kurtz own stock in and are principals in Bethesda Pharmaceuticals.
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