Identification of Transient Receptor Potential (TRP) Channels as New Potential Therapeutic Targets in Primary and Secondary Raynaud's Phenomenon.

Raynaud's phenomenon (RP) is a clinical syndrome that results from an excessive vascular reactivity of the microcirculation of the fingers and/or other extremities of the body in response to a stress, mostly cold.

Primary RP affects 4 to 6% of the general population and displays important geographic variations. Most secondary RP are linked to systemic scleroderma, a rare condition affecting mainly women. The systemic scleroderma is characterized by a cutaneous and visceral fibrosis and is associated with micro vascular damages and the production of self antibodies directed against specific cellular antigenes. The American College of Rheumatology in association with the European League Against Rheumatism has recently set diagnostic criteria that define this disease more precisely. Besides, clinical forms without cutaneous infringment have been described as limited scleroderma. Cutaneous limited forms are characterized by cutaneous fibrosis affecting mainly hands, arms and face.

RP is the first clinical sign of these forms ; anti-centromer antibodies are found in 50 to 90% patients. Diffuse cutaneous scleroderma is a fast progressing disease that affects most parts of the skin and internal organs and displays the presence of anti topoisomerase antibodies in 30% of the patients.

Whether it is primary or secondary, severe forms of RP can result in an important functional disability. Besides that, iterative ischemic episodes contribute to the onset of trophic disorders that are associated with a higher morbidity. These trophic disorders are mainly encountered in the most severe forms, especially those that are secondary to systemic scleroderma ; a third of which will turn into gangrene or amputation, leading to an important disability for these patients. Up to now, no curative treatment of these ulcers has displayed a convincing efficacy.

Despite its frequency and the potential seriousness of its complications, therapeutic care options for RP remain limited. Conservative measures are recommended in the first place, especially avoiding cold exposure and wearing warm clothes. When those measures do not suffice, pharmacological treatment can be introduced. Only calcic inhibitors are authorized for this indication but their effect on the frequency of the crises is modest (reduction of 2.8 crises per week on average). In scleroderma secondary RP, the effect appears to be modest as well according to the severity of the affection and displays a reduction of 4 crises per week on average. Besides that, this kind of treatment, when taken continuously, exposes the patients to side effects (inferior limb edema in particular). Other vasodilators such as type 5 phosphodiesterase have a significant effect, but the latter remains low in secondary RPs. Finally, intravenous injections of Iloprost on a sequential scheme have displayed a superior effect compared to Nifedipine, but result in intense and frequent side effects that limit considerably the use of this medication for a common practice.