Primary cicatricial alopecias are rare disorders that are poorly understood, difficult to treat, and lead to permanent hair loss.7
The various types of cicatricial alopecias are provisionally classified based on the predominant cellular infiltrate in active disease (lymphocytic, neutrophilic, mixed).8
Lichen planopilaris is a prototypic lymphocytic cicatricial alopecia, with patients often presenting with sudden-onset hair loss and clinically significant symptoms of itching, burning, and pain of the scalp.
We have performed gene expression profiling studies that have shown that the expression of genes required for lipid metabolism and peroxisome biogenesis are decreased in LPP.6
Specifically, the expression of PPAR-γ, a transcription factor that regulates both inflammatory and lipid metabolic genes, was dramatically downregulated in LPP.6
Peroxisome proliferator–activated receptor γ belongs to the nuclear receptor superfamily and initiates gene transcription by forming a heterodimer with the retinoid receptor RXR. Targeted deletion of PPAR-γ in the follicular stem cells in mice causes a skin and hair phenotype closely resembling scarring alopecia.6
In addition, targeted deletion of maternal hematopoetic PPAR-γ in mice results in transient alopecia in the nursing neonates.9
These data support the concept that PPAR-γ is essential for healthy pilosebaceous units. Thus, a new model for the pathogenesis of cicatricial alopecia has emerged in which a loss of PPAR-γ function leads to decreased peroxisome biogenesis and lipid homeostasis, causing tissue damage (lipotoxic effects) of the pilosebaceous unit. This tissue damage then triggers chemokine and cytokine expression in the form of leukotrienes and prostaglandins that recruit lymphocytes and macrophages and activate a lipid-mediated programmed cell death (lipoapoptosis), contributing to permanent hair loss. One may speculate that a combination of genetic factors (such as peroxisomal polymorphisms) or environmental triggers (toxins) may lead to this localized and acquired PPAR-γ dysfunction. Based on these new data, it was proposed that PPAR-γ agonist therapy represents a new strategy in the treatment of cicatricial alopecias.6
Thiazolidinediones or glitazones are medications widely used for the treatment of type 2 diabetes mellitus (DM) and were originally identified as regulators of adipogenesis and glucose homeostasis. They exert their action by increasing the activity of the nuclear receptor PPAR-γ. Thiazolidinediones have been shown to have anti-inflammatory, antiproliferative, and immunomodulatory effects, including downregulation of proinflammatory nuclear transcription factors (nuclear factor-κβ, nuclear factor of activated T-lymphocytes), proteolytic enzymes (matrix metalloproteinase-9), and inflammatory interleukins (interleukin 1β [IL-1β], IL-2, and IL-6) and other inflammatory molecules (TNF).10,11
Because thiazolidinediones can affect signaling pathways involved in lipid homeostasis in sebocytes, regulation of the epidermal barrier, and inflammatory pathways, their use has been advocated in various inflammatory skin disorders, including atopic dermatitis, psoriasis, and acne.12
In this patient, a number of anti-inflammatory medications had failed to arrest the ongoing symptoms, signs, and perifollicular lymphocytic infiltration seen on histologic findings. In contrast, after initiation of pioglitazone therapy, the patient experienced rapid resolution of his symptoms and a decrease in inflammation on biopsy, suggesting that pioglitazone was responsible for his improvement, even though this cannot be definitively concluded from this single case report.
Rosiglitazone maleate and pioglitazone are the thiazolidinediones currently available in the United States. Because these medications lower blood glucose levels by improving insulin sensitivity, circulating insulin concentrations are not affected, and they can be safely used in patients without DM. The thiazolidinediones can cause dosage-dependent weight gain owing to fat accumulation and fluid retention or peripheral edema as a result of renal sodium reabsorption.13
The rate of peripheral edema is reported to be 5% in patients not prescribed insulin. This fluid retention, however, may pose a cardiovascular risk in patients predisposed to congestive heart failure.14
Recent data suggest an increase in relative risk of myocardial infarction among patients with type 2DM treated with rosiglitazone.15
Although the myocardial risk patients without DM is unknown, the use of thiazolidinediones in patients with cardiac risk factors should proceed with caution. It has also been suggested that liver function tests should be obtained before initiating therapy with these medications and periodically thereafter because they are similar in structure to another thiazolidinedione, troglitazone, which was removed from the market owing to severe idiosyncratic hepatotoxic effects. Pioglitazone also induces cytochrome P450 isoform CYP3A4, raising the possibility of drug interactions, for example, with oral contraceptives.16
When compared with other oral medications used for treatment of LPP and other cicatricial alopecias, the thiazolidinediones have an acceptable adverse effect and safety profile. Another consideration for drug delivery is the topical administration of thiazolidinediones. Of interest, new proprietary PPAR-γ agonists optimized for topical administration are reportedly under development.17
A recent publication18
showed the relative rarity of LPP, which has an incidence rate of only 1.15% to 7.59% in all new patients with hair loss seen annually in 4 tertiary hair research centers in the United States. Thus, any drug having an indication for LPP would be eligible for orphan drug status by the US Food and Drug Administration. Given the experimental evidence for the role of PPAR-γ in LPP and the positive clinical and histologic effects of pioglitazone in this patient, studies evaluating the efficacy of thiazolidinediones, either orally or topically, may be advocated for LPP.