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

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.

Therefore, there is a real need for new therapeutic targets in RP and this requires a better knowledge of the physiopathology of this phenomenon.

Whether it is primary or secondary, microvascular dysfunction is now considered as a key element in the physiopathogeny of RP. Some ionic channels from the Transient Receptor Potential Channels' family react to temperature variations and are therefore involved in the microvascular response. In the cutaneous tissue, multiple TRP channels are present on the afferent neurons and are involved in the response to hot temperatures (especially TRPV1, TRPV3 and TRPV4) or to environmental cold (TRPM8) or hyper algic cold (TRPA1). Although they were initially reduced to an afferent role towards thermic or chemical stimuli, TRP channels have been lately recognized as having more complex functions, especially in the cutaneous homeostasis sustainibility, the growth and cellular differentiation and even the inflammatory response. Thus, the recent identification of numerous TRP channels (TRPV1, TRPV3, TRPV4, TRPM8, TRPA1, TRPC1, TRPC4, TRPV6) on the surface of keratinocytes suggests their involvement in the differenciation of these cells. Although their precise role and barrier function in the skin remain unknown, anomalies of the expression of some TRP channels have been associated with specific dermatologic diseases, and have recently being the issue of a review. Nevertheless, TRP expression in Raynaud's phenomenon has been investigated only few times in human skin .

Considering the major role of the micro vascular dysfunction in RP and the involvement of specific TRP channels in the regulation of the cutaneous microvascular tone, the investigators put forward the hypothesis that the expression of some of these channels could be modified in primary and scleroderma secondary RP forms. This hypothesis is supported by an experimental trial (on mouse model of systemic cutaneous scleroderma), in which the activation of TRPV1 has been associated to the release of vasodilator peptides that displayed a protective effect against fibrosis and thus suggesting a plausible role of TRPV1 in the physiopathology of cutaneous systemic scleroderma.

Although RP strikes different parts of the body (hands, feet, ears...), the essential topography of Raynaud's crises remains hands. In scleroderma secondary RP, the microcirculatory damages that are the easiest to reach are the areas surrounding nails. The latters can be examined using a non-invasive technique that is capillaroscopy and sometimes even to the naked eye. Histology by cutaneous biopsy can be made as well.

The investigators propose here to sample cutaneous biopsies in these areas, that are on the one hand the most pathognomonic to display the microvascular damages and on the other hand, concerned by the Raynaud's crises.

Now studied as potential therapeutic targets for many disorders, TRP channels could represent a very interesting track in severe RP forms. The current development of numerous agonists and inhibitors of TRP channels could allow to foresee a clinical trial in Raynaud's phenomenon. On a physiopathological point of view, a better knowledge of the potential role of TRP channels in this disease could also explain the differences that have been observed between primary and secondary Raynaud's phenomenons.