Primary Aquagenic Pruritus Successfully Treated by β-Alanine: A Case Report Open Access

Here, we present a case of an adult male with treatment-refractory primary aquagenic pruritus (AP) who was successfully managed with β-alanine. The CARE Checklist was completed and attached as online supplementary material (for all online suppl. material, see https://doi.org/10.1159/000545842).

A 33-year-old adult male was referred for a second opinion due to a 5-year history of a chronic recalcitrant itchy skin induced by showering, exercise-sweat, rainwater, and bathing in seawater. The symptoms initiated 5–10 min after a shower and lasted for 30–45 min. While there were no visible skin changes, the patient reported an excruciating itch, mainly on the extensor sides of the legs, with a worst itch numeric rating scale (WiNRS) = 10 during each episode. His past medical record was unremarkable and there was no history of AP or hematological diseases in his family. Laboratory tests including complete blood cell counts, total IgE, blood glucose, thyroid, and kidney function parameters were normal and no genetic variants of JAK2-, CALR-, or MPL-genes were identified. The patient had been treated unsuccessfully with moisturizers, potent topical corticosteroids, high-dose peroral nonsedating antihistamines (fexofenadine 360 mg × 2) and subcutaneous omalizumab (300 mg Q4W) for 3 months. On an experimental basis, oral treatment with 4–5 g β-alanine powder suspended in water 5–15 min before showering was initiated and a marked improvement of post shower pruritus (WiNRS = 1) was reported. No side effects, except a transient tingling sensation in the skin following intake of β-alanine was reported. Treatment efficacy was maintained at 20-week follow-up.

This case suggests that β-alanine might present a safe and efficient treatment option in primary AP. Paradoxically, β-alanine has been recognized as a weak pruritogen evoking nonhistaminergic itch by activation of mechanosensitive sensory afferents expressing mas-related G-protein coupled receptor D (MrgprD) [1]. Although histamine-independent sensory afferents expressing MrgprD may transmit β-alanine induced itch, the pathophysiology of primary AP remains largely unknown [2]. Since a delay between water exposure and initiation of pruritus was reported, a disturbed neuroimmune interaction between histamine-independent cutaneous sensory afferents and epidermal-, dermal-, or immune cells such as keratinocytes, basophils, or mast cells (MC) is possible. A recent mouse study (2019) corroborated a regulatory role for MrgprD-expressing afferents, maintaining cutaneous homeostasis by glutamate-induced suppression of MC hyperresponsiveness [3]. MC activation through murine MrgprB2 or human MrgprX2 resulted in a different secretory release pattern – less monoamines and more tryptase – than the well-known FcεRl-mediated pathway [4, 5]. Interestingly, FcεRl-independent MC stimulation through MrgprB2 agonism resulted in activation of both specialized MrgprA3-expressing pruriceptors and mixed nociceptive/pruriceptive afferents expressing MrgprD – the latter possibly in a regulatory role [4]. The insufficient effect of high-dose antihistamines and omalizumab in our patient supports the notion of a mainly FcεRl-independent nonhistaminergic pathway in primary AP which is further supported by the lack of a wheal and flare reaction in our patient. While speculative, decreased steady-state activity of MrgprD-expressing neurons in epidermis, decreased glutaminergic tonus and hyperresponsive MC might constitute important factors in the pathophysiology of primary AP. β-alanine induced glutamate release might lead to an autocrine and/or paracrine effect locally via glutamate receptors expressed on sensory afferents [6, 7]. More research is warranted, especially exploring the role of MrgprD agonism in pruritic skin conditions.

Currently, there is no report of β-alanine efficacy on pruritus in patients with secondary AP, especially those diagnosed with a myeloproliferative neoplasia (MPN). While AP might occur in the context of an underlying MPN, often preceding the latter by years, most AP cases are not linked to MPN [8]. In support of a role of MCs and basophils in AP, Pieri et al. [9], intriguingly, reported a higher number of hyperresponsive circulating basophils in patients with MPN and AP as compared to those without AP. In conclusion, this study adds to the body of evidence supporting a role for β-alanine as an efficient and safe treatment option in patients with AP.

The patient in this manuscript has given written informed consent to publication of his case details. Ethical approval is not required for this study in accordance with local guidelines.

The authors have no conflicts of interest to declare.

No funding was received for this study.

Farzad Alinaghi: writing – original draft; investigation; data curation; and project administration. Jesper Elberling: writing – review and editing; conceptualization; methodology; and supervision.

All data generated or analyzed during this study are included in this article and its online supplementary material files. Further inquiries can be directed to the corresponding author.