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Aquagenic pruritus and polycythemia vera: Still valid (and mysterious) after all these years

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By Warren R. Heymann, MD, FAAD
Dec. 6, 2023
Vol. 5, No. 48

Dr. Warren Heymann photo
It was thrilling to deliver the introductory dermatology lecture to our first-year medical students this year because most of the class was in person and fully engaged with the material. I am approaching the half-century mark when I was in their place — I recall so many ingrained dictums that affected my practice (whether valid or not). One caveat that has stood the test of time is to “think of polycythemia vera (PV) if your patient complains of itching after bathing.”

It is difficult to ascertain the origin of that axiom, however the term “aquagenic pruritus” (AP) is attributed to Walter Shelley in a question-and-answer column from JAMA in 1970, responding to a query as to why a 17-year-old male developed pruritus after his skin became wet and then dried, without any apparent skin lesions. Dr. Shelley responded:

On the basis of history and laboratory findings, it would appear that this young man is suffering from what we have termed “aquagenic pruritus.” This is a diminutive form of aquagenic urticaria (JAMA 189:895,1964). The cause is not known, although it has been assumed that the water leads to the formation or absorption of some pruritogenic compound. The condition is usually prolonged over a period of many years. Some symptomatic amelioration may be achieved by the application of a bland oil topically. Although generally it is unrelated to systemic disease, aquagenic pruritus may occur in association with polycythemia vera or as an early sign of Hodgkin's disease. Hence, periodic observation should be made for the possible clinical appearance of these entities as well as mastocytosis, should the symptoms persist. (1)

AP is defined as a prickling, stinging sensation occurring within 30 minutes of contact with water, independent of water temperature or salinity, without any apparent skin changes. Episodes may last up to two hours. (2) Most cases of AP are idiopathic. The major associations are lymphoproliferative disorders (PV, Hodgkin lymphoma, non-Hodgkin lymphoma, myelodysplastic syndrome, essential thrombocythemia, lymphoblastic leukemia, hypereosinophilic syndrome); less likely are other malignancies (squamous cell carcinoma, pancreatic cancer), iron deficiency, sarcoidosis, juvenile xanthogranuloma, hepatitis C, and drugs (bupropion, antimalarials). (1,2,3) In idiopathic cases, AP has been observed in families, suggesting a genetic predisposition. Another intriguing association is lactose intolerance — this was observed in 10 of 39 patients with AP (25.6%), which is higher than the overall prevalence of lactose intolerance in Germany (15-20%). (4) (Could changes in the gut microbiome observed in lactose intolerant patients be at play?) (5)

This commentary will focus on AP with myeloproliferative neoplasms (MPN), particularly PV.

Le Gall-Ianotto et al collected 1444 self-report questionnaires (Myeloproliferative Neoplasm-Symptom Assessment Form Total Symptom Score) from 504 patients with MPN — 54.4% essential thrombocythemia (ET) patients, 37.7% PV patients, and 7.9% primary myelofibrosis (PMF) patients. Pruritus was reported by 49.8% of the patients regardless of type of MPN or driver mutations. Patients suffering from pruritus were more symptomatic and had a higher rate of evolution into myelofibrosis/acute myeloid leukemia (19.5% vs. 9.1%, OR = 2.42, p = 0.0009) than MPN patients without pruritus. Patients with AP had the highest pruritus intensity values (p = 0.008) and a higher rate of evolution (25.9% vs. 14.4%, p = 0.025, OR = 2.07) than patients with non-AP. The authors concluded that pruritus, especially AP, which is a major constitutional symptom observed in MPN, should be assessed in all MPN patients due to a higher symptom burden and a higher risk of evolution. (6) In another study of 394 ET patients, Le Gall-Ianotto reported AP in 42 cases (10.6%); they presented increased risk of thromboses (30.9 versus 17%, P = .03; OR = 2.2) and aggressive disease (33.3 versus 13.3%, P = .0007; OR = 3.2), during follow-up. Identifying these patients is crucial for therapeutic management decisions. (7)

AP adversely affects quality of life. Based on a patient-directed questionnaire, Siegel et al reported that 301 of 441 PV patients suffered from AP. In 64.8%, AP occurred on average 2.9 years before the diagnosis of polycythemia vera. Only in 15.4% did this lead to a hematological investigation. AP occurs primarily on the trunk and proximal parts of the extremities. Most patients complain about itching (71.8%), the remainder about tickling, stinging, or burning sensations. Forty-four patients (14.6%) classified the pruritus as “unbearable.” (8) AP predominantly affects the ventral extremities and upper trunk while rarely afflicting the face, feet, and hands. (9) The Janus kinase-2 (JAK2) gene involved with intracellular signaling is mutated in 90% of cases of PV. (10) AP is not restricted to JAK2-positive cases. (6)

The pathomechanism(s) of PV-associated AP is poorly understood. The interplay of JAK mutations (notably JAK2V617F), mast cells, basophils, eosinophils, cytokines (IL-31) and acetylcholinesterase activity in nerve fibers have been implicated. (2)

Image for DWII on aquagenic pruritus
Image from JAAD 2022; 86(1):17-34.

Therapeutically, mixed results have been reported with adding sodium bicarbonate to bath water, topical capsaicin, antihistamines, pregabalin, naltrexone, paroxetine, beta-blockers, and phototherapy. (2, 4, 11) Studies are underway assessing the substance P inhibitor aprepitant for AP in MPN. (12) Perhaps some of the emerging treatments for atopic dermatitis (tapinarof, roflumilast, JAK inhibitors, lebrikizumab [anti-IL-13], nemolizumab [anti-IL-31], and others) as reviewed by Labib et al (13) could be effective in AP. Further research should increase our knowledge of AP. I have the inkling that if Shelley were still alive, he would have figured this out by now.

Point to Remember: Although most often idiopathic, aquagenic pruritus should trigger a work-up for myeloproliferative neoplasms (MPN), particularly polycythemia vera.

Our expert’s viewpoint

Gil Yosipovitch, MD, FAAD
Professor, Stiefel Chair of Medical Dermatology
Director Miami Itch Center
Dr. Phillip Frost Department of Dermatology and Cutaneous Surgery
Miller School of Medicine, University of Miami

Aquagenic pruritus (AP) is a skin condition characterized by the development of itching in contact with water without an observable skin rash (which differs from aquagenic urticaria). AP has been associated with polycythemia vera and with many myeloproliferative skin disorders as Dr. Heymann beautifully reviewed the historical perspective and every medical student is supposed to know. Of note, in my practice the majority of patients are idiopathic. There are several familial cases of this condition with no relation to polycythemia vera or myeloproliferative disorders, suggesting a hereditary component in these cases.

Interestingly, in recent years patients with AP reported that β-alanine, a nonessential amino acid, commonly used as a nutritional supplement, especially for bodybuilders, has reduced AP. Only an anecdotal case report has reported the use of this supplement in AP. (14)

Recently, we conducted a large web-based survey with a support group for AP in which β-alanine was found to be the most commonly used effective treatment. To make things more complicated, β-alanine has also been reported to induce itch by activating MRGPRD a G-coupled protein involved in itch in sensory neurons. (15) Several patients reported that indeed β-alanine also induces itch that is different in quality and less severe than the itch of AP and it was a short-lived effect. These important patient observations will clearly require further research on the mechanism of action and clinical benefits of β-alanine in the context of AP before we will start prescribing β-alanine regularly for our AP patients.

  1. Shelley WB.Post-wetness (aquagenic) pruritus. JAMA; 1970: 1385.

  2. Hamie L, Abou-Rahal J. Water-related dermatoses. Int J Dermatol. 2019 May;58(5):515-529. doi: 10.1111/ijd.14316. Epub 2018 Dec 2. PMID: 30506676.

  3. Negrão C, Machado M, Mourato M, Sismeiro R, Jonet M. Paraneoplastic Aquagenic Pruritus: A Case of Pancreatic Cancer. Cureus. 2023 Feb 28;15(2):e35566. doi: 10.7759/cureus.35566. PMID: 37007428; PMCID: PMC10061241.

  4. Heitkemper T, Hofmann T, Phan NQ, Ständer S. Aquagenic pruritus: associated diseases and clinical pruritus characteristics. J Dtsch Dermatol Ges. 2010 Oct;8(10):797-804. English, German. doi: 10.1111/j.1610-0387.2010.07463.x. Epub 2010 Jun 8. PMID: 20546386.

  5. Brandao Gois MF, Sinha T, Spreckels JE, Vich Vila A, Bolte LA, Weersma RK, Wijmenga C, Fu J, Zhernakova A, Kurilshikov A. Role of the gut microbiome in mediating lactose intolerance symptoms. Gut. 2022 Jan;71(1):215-217. doi: 10.1136/gutjnl-2020-323911. Epub 2021 Mar 18. PMID: 34086598; PMCID: PMC8666824.

  6. Le Gall-Ianotto C, Ficheux AS, Lippert E, Herbreteau L, Rio L, Pan-Petesch B, Misery L, Ianotto JC. Differences between aquagenic and non-aquagenic pruritus in myeloproliferative neoplasms: An observational study of 500 patients. J Eur Acad Dermatol Venereol. 2023 Jun;37(6):1175-1183. doi: 10.1111/jdv.18990. Epub 2023 Mar 9. PMID:36808754.

  7. Le Gall-Ianotto C, Le Calloch R, Couturier MA, Chauveau A, Lippert E, Carré JL, Misery L, Ianotto JC. Aquagenic pruritus in essential thrombocythemia is associated with a higher risk of thrombosis. J Thromb Haemost. 2019 Nov;17(11):1950-1955. doi: 10.1111/jth.14588. Epub 2019 Sep 8. PMID: 31344312.

  8. Siegel FP, Tauscher J, Petrides PE. Aquagenic pruritus in polycythemia vera: characteristics and influence on quality of life in 441 patients. Am J Hematol. 2013 Aug;88(8):665-9. doi: 10.1002/ajh.23474. Epub 2013 Jul 8. Erratum in: Am J Hematol. 2013 Oct;88(10):925. PMID: 23657863.

  9. Legat FJ. Aquagenic pruritus indicates increased risks in patients with myeloproliferative neoplasms. J Eur Acad Dermatol Venereol. 2023 Jun;37(6):1095-1096. doi: 10.1111/jdv.19107. PMID: 37171288.

  10. Lu X, Chang R. Polycythemia Vera. 2022 Apr 28. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2023 Jan–. PMID: 32491592.

  11. Morgado-Carrasco D, Riera-Monroig J, Feola H, Aguilera P. Treatment of 2 Patients With Aquagenic Pruritus With UVA/Narrow Band UVB Combined Therapy Once a Year. Actas Dermosifiliogr (Engl Ed). 2020 Dec;111(10):889-892. English, Spanish. doi: 10.1016/j.ad.2019.02.026. Epub 2020 Jul 15. PMID: 32679119.

  12. Le Gall-Ianotto C, Verdet R, Nowak E, Le Roux L, Gasse A, Fiedler A, Carlhant-Kowalski D, Marcorelles P, Misery L, Ianotto JC. Rationale and design of the multicentric, double-blind, double-placebo, randomized trial APrepitant versus HYdroxyzine in association with cytoreductive treatments for patients with myeloproliferative neoplasia suffering from Persistent Aquagenic Pruritus. Trial acronym: APHYPAP. Trials. 2021 Dec 19;22(1):938. doi: 10.1186/s13063-021-05864-8. PMID: 34923994; PMCID: PMC8686668.

  13. Labib A, Ju T, Yosipovitch G. Emerging Treatments for Itch in Atopic Dermatitis: A Review. J Am Acad Dermatol. 2023 May 6:S0190-9622(23)00761-2. doi: 10.1016/j.jaad.2023.04.057. Epub ahead of print. PMID: 37156337.

  14. Friedlander MS, Admani S. Aquagenic pruritus in an adolescent effectively managed with β‐alanine supplementation. Pediatric Dermatology. 2021;38(1):320-321

  15. Liu Q, Sikand P, Ma C, Tang Z, Han L, Li Z, Sun S, LaMotte RH, Dong X. Mechanisms of itch evoked by β-alanine. J Neurosci. 2012 Oct 17;32(42):14532-7. doi: 10.1523/JNEUROSCI.3509-12.2012. PMID: 23077038; PMCID: PMC3491570.

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