The key role of aquaporin 3 and aquaporin 10 in the pathogenesis of pompholyx☆
Introduction
Pompholyx, or dyshidrotic eczema, is a chronic vesicobullous disorder of the palms and solest characterized by many deep-seated pruritic, painful, clear vesicles [1] (Fig. 1A). The small vesicles can fuse and may then create scaling and painful fissures which ultimately incapacitate the patient for work and activities of daily living. Many factors are suspected to trigger pompholyx, including allergens, stress or seasonal changes but the exact immunological mechanism(s) remains elusive. The condition has been associated with allergies to metals, foods or drugs or left undiagnosed as “idiopathic” [1], [2]. Importantly, the factors that maintain the disease once it has become chronic are even more elusive. As pompholyx becomes increasingly recurrent and resistant, patient quality of life is generally compromised.
The exact prevalence of pompholyx has been difficult to establish due to a lack of specific biomarkers. Current studies estimate its prevalence between 0.05–10.6% in the adult population [3], [4]. The large range may be due to its inclusion as a form of Atopic Dermatitis (AD) by some clinicians. Pompholyx has a particularly high incidence in nursing [4], where hand washing is frequent. Interestingly, the prevalence of this disease seems to decrease with age [5].
There are several treatments that have been reported to manage pompholyx. Topical emollition and corticosteroids constitute the first line of treatment. Other topical treatments include calcineurin inhibitors [6] and retinoids, including bexarotene [7]. Interestingly, bexarotene is a synthetic retinoid specifically selective for the retinoid X receptors (RXR) [8], similar to alitretinoin’s specificity (see below). For treatment-resistant disease, systemic corticosteroids [9], immunosuppressants [10], [11], selective UVB phototherapy [12], Botulinum toxin A [13], anti-histaminics [14] biologics [15], radiotherapy [16] and tap water iontophoresis [17] have been used to treat refractory hand eczemas with varying degrees of success [18].
Currently, one new therapeutic for pompholyx has reached the market: alitretinoin or 9-cis retinoic acid. This treatment has been efficacious in double-blind randomized studies, leading to 75% improvement in patients with recalcitrant chronic hand eczemas, with an impressive 50% remission rate [19]. Alitretinoin differs from other retinoic acids such all-trans retinoic acid (ATRA) or isotretinoin because it acts through RXR receptors in addition to retinoic acid receptors (RAR). The RXR/RAR dual specificity is also shared by bexarotene, another retinoic acid that is able to improve pompholyx [8]. This dual specificity may account for the unique beneficial effects of alitretinoin and bexarotene regarding pompholyx compared to other retinoic acid isomers such as ATRA or Isotretinoin. However, like all retinoids, alitretinoin is teratogenic, and strict pregnancy prevention measures must be observed before, during and after treatment. Alitretinoin is currently approved only in the UK, Europe and Canada, and in addition, it is generally cost-prohibitive at this point.
Alitretinoin however does not provide an irreversible cure, since recurrence of the disease following discontinuation of therapy has been described [20], although tachyphylaxis in subsequent treatments is not observed [20]. Side-effects associated with alitretinoin treatment are considerable, including benign intracranial hypertension prompting headaches and nausea among other adverse reactions, in which cases patients must discontinue treatment immediately [21]. Alitretinoin has also been described to induce dryness of the mucosa, increase plasma cholesterol and triglyceride levels in patients [19], [21], necessitating the need for serum monitoring on a regular basis.
Section snippets
Aquaporins
Aquaporins are channel proteins that increase the permeability of cell membranes to the bi-directional, osmotically-driven passage of small uncharged molecules, including water, glycerol and urea [22]. Currently, thirteen members have been identified in mammals and they are subdivided into three categories: aquaporins, aquaglyceroporins and super-aquaporins for their ability to transport strictly water, water and glycerol or their restricted intracellular expression respectively. Interestingly,
Hypothesis
We hypothesize that AQP3 and APQ10 are overexpressed across all layers of the epidermis thereby facilitating dehydration of the affected palms and soles of pompholyx patients. Therefore, minimizing wet to dry cycles concomitantly with the usage of AQP3 and AQP10 topical or systemic inhibitors might be the key to successful treatment of pompholyx.
Evidence that AQP3 and AQP10 are over-expressed in the hands of pompholyx patients
Immunohistochemical staining was used to demonstrate the expression of AQP3 and AQP10 in hand skin biopsies obtained from three individuals diagnosed with pompholyx (Fig. 1). AQP3 and AQP10 expression can be observed across all layers of the epidermis in the palm lesions of pompholyx patients (Figs. 2A and 3A, respectively). However, in non-lesional skin from pompholyx patients, AQP3 and AQP10 expression remained confined to the stratum basale although expression appeared to still be higher
Stratum corneum hydration decreases following exposure to water
One of the puzzling characteristics of skin is that the stratum corneum (SC) tends to become dehydrated after water exposure [29]. This is a known phenomenon, and it happens in a matter of seconds after water exposure, with skin dehydration being one of the main mechanisms increasing the extent of pompholyx blisters [30]. However, why does exposure to water lead to a net decrease in the ability of the skin to retain water? Should not the opposite be the case, since the skin tissue has received
Evaluation of the hypothesis
If the hypothesis put forward in this paper is valid, the therapeutic power of alitretinoin resides in its unique ability to down regulate AQP3 and AQP10 expression on keratinocytes in the skin of pompholyx patients. The episodes where the disease is recurrent might be due to the residual presence of AQP3 and AQP10 or an incomplete return to their basal expression levels across the very same layers where it was once over-expressed. This residual AQP presence might be enough to initiate the
Clinical implications
If the hypothesis is correct, water exposure should be regarded as the primary factor responsible for maintaining pompholyx. Therefore, patients should avoid prolonged water exposure to afflicted areas of the skin as often as possible. Patients may benefit from wearing double gloves whenever taking showers. The double glove should consist of an inner cotton glove within a water-proof glove made tight using a rubber band around the wrist. There is a strong rationale behind this approach [39].
Discussion
Although several treatments are available, pompholyx remains a chronic skin condition that if left unchecked can seriously impact the quality of life of those suffering. The condition is never fatal, but is a serious ailment mediating depression or social isolation. In this prospectus we wished to put forward a compelling hypothesis to explain the underlying pathophysiology of this disease and preliminary data to support the hypothesis. We hypothesize that over-expression of AQP3 and AQP10
Human skin biopsies
All studies involving human subjects were approved by the Institutional Review Boards of Case Western Reserve University and University Hospitals Case Medical Center. 3-mm punch biopsies were obtained from two pompholyx patients diagnosed by a certified dermatologist and one healthy adult volunteer following informed consent. The biopsies were immediately snap frozen in liquid nitrogen and stored at −80 °C until further use.
Immunohistochemistry
For IHC analysis, 7 μm sections were prepared and stored at −80 °C until
Conflict of interest
All authors state that they don’t have any conflict of interest.
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