Mast cell mediators other than histamine induced pruritus in atopic dermatitis patients – a dermal microdialysis study

Atopic dermatitis is a genetically determined chronic inflammatory skin disease in which persistent itching, especially severe at night, 1 is the dominant symptom. Two types of itch occur in atopic dermatitis: an itch evoked by pharmacological mediators, and ‘itchy skin’2 (allokinesis). This term is used to describe an altered state of skin sensitivity in which any mechanical stimulus applied to the skin causes an itchy sensation, and it explains why wool fibres cause such intense itching in atopic eczema patients. Scratching relieves itching by causing ‘surround inhibition’ through activation of inhibitory neuronal circuits in the substantia gelatinosa of the dorsal horn of the spinal chord. 3 Interestingly, two‐point discrimination of itch is significantly better in atopics than controls, 4 probably due to increased excitation of dorsal horn neurones, leading to changes in sensitivity of the receptive field. The recent identification of dedicated nonmyelinated slow‐conducting C‐fibres for itch in normal human skin 5 should prompt further research in this field. Histamine is probably not always an important mediator of itch in atopic dermatitis, since it induces reduced subjective and vascular responses (at least in chronic atopic dermatitis patients 6). Recent studies 7 indicate that a distinction can be drawn between TH2‐ (early, more acute) and TH1‐ (late and more chronic) driven atopic dermatitis. 7 It can be anticipated that histamine‐induced itching could play a greater part in the former than the latter. Antihistamines may prove more effective antipruritics in the TH2‐driven disease. In chronic (TH1‐driven) atopic eczema, not only direct histamine responses, but also histamine‐evoked allokinesis is diminished in atopic skin. 8 In this issue, Schmelz and colleagues from Erlangen use dermal microdialysis to demonstrate reduced extravasation of protein from the microcirculation of the skin in atopic dermatitis patients in response to intradermal delivery of histamine and the chemical histamine liberator, compound 48/80. 9 These vasoactive agents also induced reduced itching in atopic patients compared with control subjects. Co‐administration of the H1‐antihistamine cetirizine in the perfusate reduced 48/80‐induced pruritus in controls but not in patients with atopic dermatitis, raising the possibility of involvement of other non‐histaminic mediators. If histamine is not a major culprit, then what candidate molecular mediators are under suspicion? Circumstantial evidence strongly favours neuropeptides, including substance P and other neurokinins. 3 Itching is manifestly exacerbated by stress in atopics, leading to antidromic release of neuropeptides via peripheral neurones.10,11 Substance P is a potent mediator of itch in skin. 12 Interleukin‐2 (IL‐2) is a potent pruritogen in human skin. 13 In a double‐blind study, IL‐2 caused itching in both healthy and atopic dermatitis subjects following intradermal injection. Furthermore, administration of cyclosporin, which downregulates transcription of IL‐2, leads to rapid relief of itch in atopic dermatitis patients. Other candidate mediators include mast cell‐derived proteases, eicosanoids, eosinophil granule proteins and platelet activating factor. However, there is no conclusive evidence of the involvement of any of the above pro‐inflammatory mediators in the itch of atopic dermatitis. Could the itch of atopics be at least partially central in origin? 3 Indirect evidence that at least in some patients the itch derives from the central nervous system comes from studies utilizing antipruritic drugs. Krause and Shuster 14 showed that the sedative antihistamine trimeprazine and the non‐antihistamine hypnotic nirazepam, but not the low‐sedation antihistamines astemizole and terfenadine, suppresses itching, measured as nocturnal scratching, in atopic eczema patients. They concluded that antipruritic drugs act centrally in atopic dermatitis to relieve itch. The opioid peptide system, located in the central nervous system also deserves consideration. It has been known for years that spinal administration of morphine for analgesic purposes induces pruritus 15 which can be relieved by the µ‐receptor opioid antagonist naloxone. There have also been recent reports of the value of nalmefene, an oral opioid µ‐receptor antagonist in the relief of pruritus of atopic eczema.16,17 Although the existence of ‘central itch’ still awaits confirmation, clinical experience supports its relevance. We have all seen patients with atopic dermatitis in whom ‘itch‐scratch‐itch’ seems substantially out of proportion to the degree of skin involvement. Despite the prevalence and severity of itching in atopics, treatment options remain limited. Dry skin is common in these patients and vigorous emollient treatment usually helps. Avoidance of wool, soaps, detergents and extreme climatic variations all help. House‐dust mite avoidance also helps in specifically sensitive patients. Sedative antihistamines may reduce the distressing nocturnal itch‐scratch‐itch cycle. Topical corticosteroids are not inherently antipruritic although their anti‐inflammatory and immunosuppressive actions may lead indirectly to reduction of itch. Recently topical doxepin 5% cream has been proposed for relief of pruritus in atopic dermatitis. 18 It is, however, absorbed percutaneously to a substantial degree, which limits its value. Immunosuppressive treatment by azathioprine or cyclosporin may be of value in severely afflicted patients unresponsive to more conservative measures. Tacrolimus, a topical immunosuppressive with an action resembling that of cyclosporin, shows some promise in the relief of itching of atopic eczema. 19