Vulvodynia: Identification of Potential Relevant Biomarkers

Overview

Vulvodynia is a syndrome of unexplained vulvar pain that is frequently accompanied by physical disabilities, limitation of daily activities (such as sitting and walking), sexual dysfunction and psychologic disability. Originally suggested by McKay, the term "vulvodynia" has also been suggested by the International Society for the Study of Vulvar Disease Task Force to describe any vulvar pain. The incidence and prevalence of vulvodynia have not been well studied. Age distribution for the condition may range from the 20s to the 60s, and it is limited almost exclusively to white women. Obstetric and gynecologic history is usually unremarkable. Risk-taking sexual behavior is rare, and few patients have a history of sexually transmitted diseases. Vulvar pain usually has an acute onset, at times associated with episodes of vaginitis or certain therapeutic procedures of the vulva (cryotherapy or laser therapy). In most cases, vulvodynia becomes a chronic problem lasting months to years. Vulvar pain is frequently described as burning or stinging, or a feeling of rawness or irritation. Most patients consult several physicians before being diagnosed. Many are treated with multiple topical or systemic medications, with minimal relief. In some cases, inappropriate therapy may even make the symptoms worse. Since physical findings are few and cultures and biopsies are frequently negative, patients may be told that the problem is primarily psychologic, thus invalidating their pain and adding to their distress.

Sphingosine-1-phosphate (S1P) is a potent anti-apoptotic sphingolipid with potent pro-inflammatory actions which are driven in most part by activation of the S1P receptor subtype S1PR158. Biologically active S1P is generated by the phosphorylation of sphingosine, catalyzed by two sphingosine kinases (SphK1, SphK2). S1P levels are further regulated by its dephosphorylation by two phosphatases (SGPP1 and SGPP2) and through degradation by one lyase (SGPL1). Once released S1P initiates signaling through a family of five cognate G protein-coupled receptors (S1PR1-5), leading to various cellular responses9. S1P signaling has important roles in inflammation and cancer. S1P acting via the S1PR1 has been implicated in the development of pain of several etiologies as discovered by Salvemini and coworkers and subsequently extended by others. FTY720 (fingolimod/Gilenya®) is the first orally available agent approved by the FDA for the treatment of relapsing-remitting multiple sclerosis (MS). The work by Salvemini's group in providing a mechanistic basis for understanding chronic pain through the S1P/S1PR1 axis, provides a promising therapeutic target for the use of agents like FTY720 as a novel treatment for pain. Ongoing work by the Salvemini's lab suggests that increased expression of S1PR1 in circulating peripheral blood leukocytes (PBLs) may provide a relevant biomarker to predict severity and pain induction outcomes as well as predict patient responses to anti-S1PR1 approaches.