October 2026 digest

From Rajka’s itch experiments to sodium-channel biology

What a rare inherited pain disorder may teach us about the itch–pain continuum in atopic dermatitis
Alain Taïeb  |  International Society of Atopic Dermatitis

More than 50 years ago, Georg Rajka asked a question that still matters: why does the skin of a patient with atopic dermatitis (AD) itch so readily, even when it looks normal? In his 1975 book, he summarized experiments showing that people with AD experienced unusually long-lasting itch after a standard stimulus [1]. The stimulus was trypsin, a proteolytic enzyme, injected into the skin. In visibly affected skin, itch lasted longer than two minutes in 92% of patients with AD, compared with just 4% of patients with other forms of eczema or psoriasis (Table 1).

TABLE 1  /  Duration of trypsin-induced itch in affected skin

Itch duration	AD (n=25)	Other eczema (n=25)	Psoriasis (n=25)
>2 min	23 (92%)	1 (4%)	1 (4%)
1–2 min	2 (8%)	20 (80%)	17 (68%)
<1 min	0	4 (16%)	7 (28%)

Counts (percentages); original Table 3.2 in Rajka [1], p. 39. The book reports P<0.1% for the AD–other eczema comparison.

The finding was not restricted to eczema lesions. In skin that appeared unaffected, 65% of patients with AD still reported itch lasting more than two minutes; the corresponding figure was 5% in other eczemas and zero in psoriasis (Table 2). The group with allergic rhinitis and a previous history of AD also showed prolonged responses, although it comprised only five participants.

TABLE 2  /  Duration of trypsin-induced itch in clinically unaffected skin

Itch duration	AD (n=40)	Other eczema (n=20)	Psoriasis (n=20)	Atopic rhinitis (n=20)	Rhinitis + past AD (n=5)
>2 min	26 (65%)	1 (5%)	0	2 (10%)	5 (100%)
<2 min	14 (35%)	19 (95%)	20 (100%)	18 (90%)	0

Counts (percentages); original Table 3.3 in Rajka [1], p. 39. The past-AD/rhinitis group was small (n=5).

Rajka distinguished an episode of itch triggered by a stimulus from what he called “itchy skin”—a lasting tendency to itch [1]. Today we would ask whether this heightened response reflects changes in the skin, in sensory nerves, or in both.

What inherited pain can tell us about sensory nerves

That question recalls a French family with primary erythermalgia whom I followed. Their disabling attacks of burning pain, red skin and heat sensitivity contributed to our 2005 study with Joost Drenth and colleagues linking this inherited disorder to mutations in SCN9A, the gene for the NaV1.7 sodium channel [2]. These channels help sensory nerves generate electrical signals. The family carried the F216S variant. Later laboratory work showed that it makes NaV1.7 easier to activate [3]. In 2026, the same variant was reported in a separate Japanese family, including one carrier who had no symptoms [4]. The contrast reminds us that carrying a disease-associated variant does not guarantee an identical illness.

Two new papers add different perspectives. In a randomized trial published in the New England Journal of Medicine, a drug blocking another sodium channel, NaV1.8, relieved acute pain after surgery and reduced the need for rescue opioids [5]. In Brain Communications, Newton and colleagues examined sodium-channel variants in roughly half a million UK Biobank participants. Several variants previously described as disease-causing were too common, and too weakly associated with pain, to support that interpretation [6]. Our family’s F216S variant was not found in UK Biobank and was listed as having laboratory evidence of increased channel activity [6]. Its rarity and the evidence from families make a stronger case than a laboratory result alone. Nevertheless, the unaffected carrier in Japan shows why the precise relationship between gene, nerve activity and symptoms remains important.

Why this matters for itch in AD

Pain and itch use some of the same sensory-nerve machinery, but they are not the same sensation. In one family, a variant of SCN9A caused bouts of itch followed by burning pain [7]. Work in humans and mice also links NaV1.9 to itch [8]. Mouse experiments show that NaV1.7, NaV1.8 and NaV1.9 contribute differently depending on what triggers the itch; interestingly, trypsin was among the substances tested [9]. In AD, patients may have severe itch with relatively few visible lesions. Others report stinging, burning or pain, sometimes even after the rash has improved. These symptoms may involve ongoing inflammation, greater sensitivity of skin nerves, or both. Rajka’s experiments remind us that visible inflammation and sensory experience need not move together.

The recent NaV1.8 trial shows that blocking a peripheral sodium channel can relieve acute pain. It does not show that the same drug treats chronic atopic itch. Persistent itch involves several signalling pathways, and success against one type of pain does not ensure success against another sensation. The possibility is worth testing, not assuming. Translating these findings into clinical research will require longitudinal assessment of sensory symptoms alongside inflammatory disease activity. Measuring itch, pain, burning and sleep disturbance, together with experimentally evoked sensory responses, may help identify distinct patterns of neuronal hypersensitivity and, potentially, new treatment targets. Rare human sodium-channel disorders provide valuable models for understanding these mechanisms. An important next step would be to investigate whether genetic variation in NaV channels contributes to differences in itch and pain sensitivity in patients with AD compared with individuals without AD, while also exploring how inflammation modifies channel function independently of genetic variation. Existing and emerging selective sodium-channel inhibitors could provide a direct way to test the therapeutic relevance of these pathways, although their efficacy against chronic atopic itch remains to be demonstrated in clinical proof-of-concept studies.

More than 50 years after Georg Rajka described the distinctive responsiveness of atopic skin, we still need to understand what makes this skin intrinsically prone to itch, beyond the effects of visible inflammation.

References

1. Rajka G. Atopic Dermatitis. London: WB Saunders; 1975. Chapter 3, Itch in Atopic Dermatitis:36–40.
2. Drenth JPH, te Morsche RHM, Guillet G, et al. SCN9A mutations define primary erythermalgia as a neuropathic disorder of voltage gated sodium channels. J Invest Dermatol. 2005;124:1333–1338. doi:10.1111/j.0022-202X.2005.23737.x
3. Choi JS, Dib-Hajj SD, Waxman SG. Inherited erythermalgia: limb pain from an S4 charge-neutral Na channelopathy. Neurology. 2006;67:1563–1567. doi:10.1212/01.wnl.0000231514.33603.1e
4. Kida M, Ueda-Hayakawa I, Morisaka H, et al. Identification of the SCN9A variant c.647T>C (p.Phe216Ser) in a patient with primary erythromelalgia. J Dermatol. 2026;53:e610–e611. doi:10.1111/1346-8138.70318
5. Singla N, Katz NP, Vaughn B, et al. Phase 2b trial of a NaV1.8 inhibitor for acute pain. N Engl J Med. 2026;395:454–464. doi:10.1056/NEJMoa2602910
6. Newton GWT, Charman C, Nickerson AP, et al. NaV1.7, 1.8 and 1.9 mutations linked to painful channelopathies have no pain phenotype in UK Biobank. Brain Commun. 2026. doi:10.1093/braincomms/fcag374
7. Devigili G, Eleopra R, Pierro T, et al. Paroxysmal itch caused by gain-of-function Nav1.7 mutation. Pain. 2014;155:1702–1707. doi:10.1016/j.pain.2014.05.006
8. Salvatierra J, Diaz-Bustamante M, Meixiong J, et al. A disease mutation reveals a role for NaV1.9 in acute itch. J Clin Invest. 2018;128:5434–5447. doi:10.1172/JCI122481

ISAD Beijing 2026

What an Incredible 16th Georg Rajka ISAD Symposium!

We extend a huge and heartfelt thank you to Professor Lin MA and her entire local organizing team for hosting a truly memorable and impactful 16th Georg Rajka International Symposium on Atopic Dermatitis.

The attention to detail, the warm hospitality, and the flawless execution of this large-scale international event were exceptional. The blend of cutting-edge science and a shared patient-centric approach perfectly embodied the event’s theme: “Science and Empathy in AD.”

A big thanks to our industry sponsors, to the ISAD board of Directors, to our CEO Laurent X. ELGARD, to our ~1000 worldwide colleagues from over 55 countries and our new Chinese friends for the wonderful interactions and to everyone who contributed to making this 2026 symposium so special. Augsburg, Germany will host us next year under the leadership of Andreas WOLLENBERG.

Next steps:

• The ActaDV abstract book is under preparation.
• The recordings and the presentations will be available this month of November on the platform to all participants.

Amy Paller to Be Honored by the Women’s Dermatologic Society in 2027