Top

Clinical Reviews in Allergy & Immunology

Published in:

01-12-2016

Mediators of Chronic Pruritus in Atopic Dermatitis: Getting the Itch Out?

Authors: Nicholas K. Mollanazar, Peter K. Smith, Gil Yosipovitch

Published in: Clinical Reviews in Allergy & Immunology | Issue 3/2016

Abstract

For centuries, itch was categorized as a submodality of pain. Recent research over the last decade has led to the realization that itch is in fact a separate and distinct, albeit closely related, sensation. Chronic itch is a common complaint and has numerous etiologies. Various receptors (TRPA1, TRPV1, PAR2, gastrin-releasing peptide receptor (GRPR), Mas-related G proteins), secreted molecules (histamine, nerve growth factor (NGF), substance P (SP), proteases), and cytokines/chemokines (thymic stromal lymphopoietin (TSLP), IL-2, IL-4, IL-13, and IL-31) are implicated as mediators of chronic pruritus. While much remains unknown regarding the mechanisms of chronic itch, this much is certain: there is no singular cause of itch. Rather, itch is caused by a complex interface between skin, keratinocytes, cutaneous nerve fibers, pruritogenic molecules, and the peripheral and central nervous systems. Atopic dermatitis is one of the most itchy skin dermatoses and affects millions worldwide. The sensation of atopic itch is mediated by the interplay between epidermal barrier dysfunction, upregulated immune cascades, and the activation of structures in the central nervous system. Clinicians are in possession of an arsenal of different treatment options ranging from moisturizers, topical immunomodulators, topical anesthetic ion channel inhibitors, systemic immunomodulators, as well as oral drugs capable of reducing neural hypersensitization. Emerging targeted therapies on the horizon, such as dupilumab, promise to usher in a new era of highly specific and efficacious treatments. Alternative medicine, stress reduction techniques, and patient education are also important treatment modalities. This review will focus on the mediators of chronic pruritus mainly associated with atopic dermatitis (atopic itch), as well as numerous different therapeutic options.

While MrgprA3 mediates CQ-induced itch in mice, a separate receptor, MrgprC11, is activated by BAM8-22. This is in direct contrast to that in humans, wherein MrgprX1 activation is responsible for both mechanisms.

Dalgard F, Svensson A, Holm JO, Sundby J (2004) Self-reported skin morbidity among adults: associations with quality of life and general health in a Norwegian survey. J Investig Dermatol Symp Proc 9:120–125PubMedCrossRef

Matterne U, Strassner T, Apfelbacher CJ, Diepgen TL, Weisshaar E (2009) Measuring the prevalence of chronic itch in the general population: development and validation of a questionnaire for use in large-scale studies. Acta Derm Venereol 89:250–256PubMedCrossRef

Mollanazar NK, Koch SD, Yosipovitch G (2015) Epidemiology of chronic pruritus: where have we been and where are we going? Curr Dermatol Rep 4(1):20–29CrossRef

Boguniewicz M (2005) Atopic dermatitis: beyond the itch that rashes. Immunol Allergy Clin North Am 25:333–351PubMedCrossRef

Dawn A, Papoiu AD, Chan YH, Rapp SR, Rassette N, Yosipovitch G (2009) Itch characteristics in atopic dermatitis: results of a web-based questionnaire. Br J Dermatol 160:642–644PubMedCrossRef

Yosipovitch G, Ansari N, Goon A, Chan YH, Goh CL (2002) Clinical characteristics of pruritus in chronic idiopathic urticaria. Br J Dermatol 147:32–36PubMedCrossRef

Yosipovitch G, Papoiu AD (2008) What causes itch in atopic dermatitis? Curr Allergy Asthma Rep 8:306–311PubMedCrossRef

Papoiu AD, Coghill RC, Kraft RA, Wang H, Yosipovitch G (2012) A tale of two itches. Common features and notable differences in brain activation evoked by cowhage and histamine induced itch. Neuroimage 59:3611–3623PubMedCrossRef

Davidson S, Zhang X, Yoon CH, Khasabov SG, Simone DA, Giesler GJ Jr (2007) The itch-producing agents histamine and cowhage activate separate populations of primate spinothalamic tract neurons. J Neurosci 27:10007–10014PubMedPubMedCentralCrossRef

10.

Davidson S, Zhang X, Khasabov SG, Simone DA, Giesler GJ Jr (2009) Relief of itch by scratching: state-dependent inhibition of primate spinothalamic tract neurons. Nat Neurosci 12:544–546PubMedPubMedCentralCrossRef

11.

Han L, Dong X (2014) Itch mechanisms and circuits. Annu Rev Biophys 43:331–355PubMedPubMedCentralCrossRef

12.

Reilly DM, Ferdinando D, Johnston C (1997) The epidermal nerve fibre network: characterization of nerve fibres in human skin by confocal microscopy and assessment of racial variations. Br J Dermatol 137:163–170PubMedCrossRef

13.

Hendrix S, Picker B, Liezmann C (2008) Skin and hair follicle innervation in experimental models: a guide for the exact and reproducible evaluation of neuronal plasticity. Exp Dermatol 17:214–227PubMedCrossRef

14.

Hilarp NA (1959) The construction and functional organization of the autonomic innervation apparatus. Acta Physiol Scand Suppl 46:1–21

15.

Hosoi J, Murphy GF, Egan CL (1993) Regulation of Langerhans cell function by nerves containing calcitonin gene-related peptide. Nature 363:159–163PubMedCrossRef

16.

Botchkarev VA, Eichmuller S, Peters EM (1997) A simple immunofluorescence technique for simultaneous visualization of mast cells and nerve fibers reveals selectivity and hair cycle-dependent changes in mast cell–nerve fiber contacts in murine skin. Arch Dermatol Res 289:292–302PubMedCrossRef

17.

Peters EM, Ericson ME, Hosoi J (2006) Neuropeptide control mechanisms in cutaneous biology: physiological and clinical significance. J Invest Dermatol 126:1937–1947PubMedCrossRef

18.

Simone DA, Zhang X, Li J, Zhang JM, Honda CN, LaMotte RH et al (2004) Comparison of responses of primate spinothalamic tract neurons to pruritic and algogenic stimuli. J Neurophysiol 91:213–222PubMedCrossRef

19.

Andrew D, Craig AD (2001) Spinothalamic lamina I neurons selectively sensitive to histamine: a central neural pathway for itch. Nat Neurosci 4:72–77PubMedCrossRef

20.

Sweet WH, White JC, Hawkins R, Nilges RG (1950) Anterolateral cordotomy: results, complications and causes of failure. Brain 73:346–367PubMedCrossRef

21.

Nathan PW (1990) Touch and surgical division of the anterior quadrant of the spinal cord. J Neurol Neurosurg Psychiatry 53:935–939PubMedPubMedCentralCrossRef

22.

Potenzieri C, Undem BJ (2012) Basic mechanisms of itch. Clin Exp Allergy 42:8–19PubMedCrossRef

23.

Papoiu AD, Kraft RA, Coghill RC, Yosipovitch G (2015) Butorphanol suppression of histamine itch is mediated by nucleus accumbens and septal nuclei: a pharmacological fMRI study. J Invest Dermatol 135(2):560–568PubMedCrossRef

24.

Papoiu AD, Emerson NM, Patel TS, Kraft RA, Valdes-Rodriguez R, Nattkemper LA et al (2014) Voxel-based morphometry and arterial spin labeling fMRI reveal neuropathic and neuroplastic features of brain processing of itch in end-stage renal disease. J Neurophysiol 112:1729–1738PubMedPubMedCentralCrossRef

25.

Namer B, Carr R, Johanek LM, Schmelz M, Handwerker HO, Ringkamp M (2008) Separate peripheral pathways for pruritus in man. J Neurophysiol 100:2062–2069PubMedPubMedCentralCrossRef

26.

Orn P (1998) A currently developed method of measurement. A discovery of specific nerve fibers explains the way of itching through the body. Lakartidningen 95:2666–2667PubMed

27.

Schmelz M, Schmidt R, Bickel A, Handwerker HO, Torebjork HE (1997) Specific C-receptors for itch in human skin. J Neurosci 17:8003–8008PubMed

28.

Schmelz M, Schmidt R, Weidner C, Hilliges M, Torebjork HE, Handwerker HO (2003) Chemical response pattern of different classes of C-nociceptors to pruritogens and algogens. J Neurophysiol 89:2441–2448PubMedCrossRef

29.

Palmer CN, Irvine AD, Terron-Kwiatkowski A, Zhao Y, Liao H, Lee SP et al (2006) Common loss-of-function variants of the epidermal barrier protein filaggrin are a major predisposing factor for atopic dermatitis. Nat Genet 38:441–446PubMedCrossRef

30.

Loden M (2003) Role of topical emollients and moisturizers in the treatment of dry skin barrier disorders. Am J Clin Dermatol 4:771–788PubMedCrossRef

31.

Loden M (2012) Effect of moisturizers on epidermal barrier function. Clin Dermatol 30:286–296PubMedCrossRef

32.

Lee CH, Chuang HY, Shih CC, Jong SB, Chang CH, Yu HS (2006) Transepidermal water loss, serum IgE and beta-endorphin as important and independent biological markers for development of itch intensity in atopic dermatitis. Br J Dermatol 154:1100–1107PubMedCrossRef

33.

Yosipovitch G, Xiong GL, Haus E, Sackett-Lundeen L, Ashkenazi I, Maibach HI (1998) Time-dependent variations of the skin barrier function in humans: transepidermal water loss, stratum corneum hydration, skin surface pH, and skin temperature. J Invest Dermatol 110:20–23PubMedCrossRef

34.

Ny A, Egelrud T (2004) Epidermal hyperproliferation and decreased skin barrier function in mice overexpressing stratum corneum chymotryptic enzyme. Acta Dermatol Venereol 84:18–22CrossRef

35.

Wavrin S, Bernard H, Wal JM, Adel-Patient K (2014) Cutaneous or respiratory exposures to peanut allergens in mice and their impacts on subsequent oral exposure. Int Arch Allergy Immunol 164:189–199PubMedCrossRef

36.

Brough HA, Liu AH, Sicherer S, Makinson K, Douiri A, Brown SJ et al (2015) Atopic dermatitis increases the effect of exposure to peanut antigen in dust on peanut sensitization and likely peanut allergy. J Allergy Clin Immunol 135(1):164–170PubMedPubMedCentralCrossRef

37.

Noti M, Kim BS, Siracusa MC, Rak GD, Kubo M, Moghaddam AE et al (2014) Exposure to food allergens through inflamed skin promotes intestinal food allergy through the thymic stromal lymphopoietin-basophil axis. J Allergy Clin Immunol 133:1390–9–1399.e1-6CrossRef

38.

Yosipovitch G (2007) The pruritus receptor unit: a target for novel therapies. J Invest Dermatol 127:1857–1859PubMedCrossRef

39.

McNeil B, Dong X (2014) Mrgprs as itch receptors. In: Carstens E, Akiyama T (eds) Itch: mechanisms and treatment. Taylor & Francis Group, Boca Raton

40.

Dong X, Han S, Zylka MJ, Simon MI, Anderson DJ (2001) A diverse family of GPCRs expressed in specific subsets of nociceptive sensory neurons. Cell 106:619–632PubMedCrossRef

41.

McNeil B, Dong X (2012) Peripheral mechanisms of itch. Neurosci Bull 28:100–110PubMedCrossRef

42.

Zylka MJ, Dong X, Southwell AL, Anderson DJ (2003) Atypical expansion in mice of the sensory neuron-specific Mrg G protein-coupled receptor family. Proc Natl Acad Sci U S A 100:10043–10048PubMedPubMedCentralCrossRef

43.

Liu Q, Tang Z, Surdenikova L, Kim S, Patel KN, Kim A et al (2009) Sensory neuron-specific GPCR Mrgprs are itch receptors mediating chloroquine-induced pruritus. Cell 139:1353–1365PubMedPubMedCentralCrossRef

44.

Lembo PM, Grazzini E, Groblewski T, O’Donnell D, Roy MO, Zhang J et al (2002) Proenkephalin A gene products activate a new family of sensory neuron-specific GPCRs. Nat Neurosci 5:201–209PubMedCrossRef

45.

Sikand P, Dong X, LaMotte RH (2011) BAM8-22 peptide produces itch and nociceptive sensations in humans independent of histamine release. J Neurosci 31:7563–7567PubMedPubMedCentralCrossRef

46.

Han L, Ma C, Liu Q, Weng HJ, Cui Y, Tang Z et al (2013) A subpopulation of nociceptors specifically linked to itch. Nat Neurosci 16:174–182PubMedCrossRef

47.

Finger S, Wade NJ (2002) The neuroscience of Helmholtz and the theories of Johannes Muller. Part 2: sensation and perception. J Hist Neurosci 11:234–254PubMedCrossRef

48.

Vergnolle N, Ferazzini M, D’Andrea MR, Buddenkotte J, Steinhoff M (2003) Proteinase-activated receptors: novel signals for peripheral nerves. Trends Neurosci 26:496–500PubMedCrossRef

49.

Reddy VB, Iuga AO, Shimada SG, LaMotte RH, Lerner EA (2008) Cowhage-evoked itch is mediated by a novel cysteine protease: a ligand of protease-activated receptors. J Neurosci 28:4331–4335PubMedPubMedCentralCrossRef

50.

Reddy VB, Shimada SG, Sikand P, Lamotte RH, Lerner EA (2010) Cathepsin S elicits itch and signals via protease-activated receptors. J Invest Dermatol 130:1468–1470PubMedPubMedCentralCrossRef

51.

Soh UJ, Dores MR, Chen B, Trejo J (2010) Signal transduction by protease-activated receptors. Br J Pharmacol 160:191–203PubMedPubMedCentralCrossRef

52.

Steinhoff M, Bienenstock J, Schmelz M, Maurer M, Wei E, Biro T (2006) Neurophysiological, neuroimmunological, and neuroendocrine basis of pruritus. J Invest Dermatol 126:1705–1718PubMedCrossRef

53.

Steinhoff M, Neisius U, Ikoma A, Fartasch M, Heyer G, Skov PS (2003) Proteinase-activated receptor-2 mediates itch: a novel pathway for pruritus in human skin. J Neurosci 23:6176–6180PubMed

54.

Buddenkotte J, Stroh C, Engels IH, Moormann C, Shpacovitch VM, Seeliger S (2005) Agonists of proteinase-activated receptor-2 stimulate upregulation of intercellular cell adhesion molecule-1 in primary human keratinocytes via activation of NF-kappa B. J Invest Dermatol 124:38–45PubMedCrossRef

55.

Minke B, Cook B (2002) TRP channel proteins and signal transduction. Physiol Rev 82:429–472PubMedCrossRef

56.

Moran MM, McAlexander MA, Biro T, Szallasi A (2011) Transient receptor potential channels as therapeutic targets. Nat Rev Drug Discov 10:601–620PubMedCrossRef

57.

Valdes-Rodriguez R, Kaushik SB, Yosipovitch G (2013) Transient receptor potential channels and dermatological disorders. Curr Top Med Chem 13:335–343PubMedCrossRef

58.

Stander S, Moormann C, Schumacher M, Buddenkotte J, Artuc M, Shpacovitch V et al (2004) Expression of vanilloid receptor subtype 1 in cutaneous sensory nerve fibers, mast cells, and epithelial cells of appendage structures. Exp Dermatol 13:129–139PubMedCrossRef

59.

Shim WS, Tak MH, Lee MH, Kim M, Kim M, Koo JY et al (2007) TRPV1 mediates histamine-induced itching via the activation of phospholipase A2 and 12-lipoxygenase. J Neurosci 27:2331–2337PubMedCrossRef

60.

Wilson SR, Gerhold KA, Bifolck-Fisher A, Liu Q, Patel KN, Dong X et al (2011) TRPA1 is required for histamine-independent, Mas-related G protein-coupled receptor-mediated itch. Nat Neurosci 14:595–602PubMedPubMedCentralCrossRef

61.

Smart D, Gunthorpe MJ, Jerman JC, Nasir S, Gray J, Muir AI et al (2000) The endogenous lipid anandamide is a full agonist at the human vanilloid receptor (hVR1). Br J Pharmacol 129:227–230PubMedPubMedCentralCrossRef

62.

Caterina MJ, Julius D (2001) The vanilloid receptor: a molecular gateway to the pain pathway. Annu Rev Neurosci 24:487–517PubMedCrossRef

63.

Sulk M, Seeliger S, Aubert J, Schwab VD, Cevikbas F, Rivier M et al (2012) Distribution and expression of non-neuronal transient receptor potential (TRPV) ion channels in rosacea. J Invest Dermatol 132:1253–1262PubMedCrossRef

64.

Xiao B, Patapoutian A (2011) Scratching the surface: a role of pain-sensing TRPA1 in itch. Nat Neurosci 14:540–542PubMedCrossRef

65.

Aubdool AA, Brain SD (2011) Neurovascular aspects of skin neurogenic inflammation. J Invest Derm Symp P 15:33–39CrossRef

66.

Hutter MM, Wick EC, Day AL, Maa J, Zerega EC, Richmond AC et al (2005) Transient receptor potential vanilloid (TRPV-1) promotes neurogenic inflammation in the pancreas via activation of the neurokinin-1 receptor (NK-1R). Pancreas 30:260–265PubMedCrossRef

67.

Gibson RA, Robertson J, Mistry H, McCallum S, Fernando D, Wyres M et al (2014) A randomised trial evaluating the effects of the TRPV1 antagonist SB705498 on pruritus induced by histamine, and cowhage challenge in healthy volunteers. PLoS One 9, e100610PubMedPubMedCentralCrossRef

68.

Atoyan R, Shander D, Botchkareva NV (2009) Non-neuronal expression of transient receptor potential type A1 (TRPA1) in human skin. J Invest Dermatol 129:2312–2315PubMedCrossRef

69.

Kwan KY, Glazer JM, Corey DP, Rice FL, Stucky CL (2009) TRPA1 modulates mechanotransduction in cutaneous sensory neurons. J Neurosci 29:4808–4819PubMedPubMedCentralCrossRef

70.

Toth BI, Olah A, Szollosi AG, Biro T (2014) TRP channels in the skin. Br J Pharmacol 171:2568–2581PubMedPubMedCentralCrossRef

71.

Oh MH, Oh SY, Lu J, Lou H, Myers AC, Zhu Z et al (2013) TRPA1-dependent pruritus in IL-13-induced chronic atopic dermatitis. J Immunol 191:5371–5382PubMedPubMedCentralCrossRef

72.

Costa R, Marotta DM, Manjavachi MN, Fernandes ES, Lima-Garcia JF, Paszcuk AF et al (2008) Evidence for the role of neurogenic inflammation components in trypsin-elicited scratching behaviour in mice. Br J Pharmacol 154:1094–1103PubMedPubMedCentralCrossRef

73.

Wilson SR, Nelson AM, Batia L, Morita T, Estandian D, Owens DM et al (2013) The ion channel TRPA1 is required for chronic itch. J Neurosci 33:9283–9294PubMedPubMedCentralCrossRef

74.

Denda M, Tsutsumi M, Goto M, Ikeyama K, Denda S (2010) Topical application of TRPA1 agonists and brief cold exposure accelerate skin permeability barrier recovery. J Invest Dermatol 130:1942–1945PubMedCrossRef

75.

McCoy DD, Knowlton WM, McKemy DD (2011) Scraping through the ice: uncovering the role of TRPM8 in cold transduction. Am J Physiol Regul Integr Comp Physiol 300:R1278–R1287PubMedPubMedCentralCrossRef

76.

Denda M, Tsutsumi M (2011) Roles of transient receptor potential proteins (TRPs) in epidermal keratinocytes. Adv Exp Med Biol 704:847–860PubMedCrossRef

77.

Patel T, Ishiuji Y, Yosipovitch G (2007) Menthol: a refreshing look at this ancient compound. J Am Acad Dermatol 57:873–878PubMedCrossRef

78.

Frolich M, Enk A, Diepgen TL, Weisshaar E (2009) Successful treatment of therapy-resistant pruritus in lichen amyloidosis with menthol. Acta Derm Venereol 89:524–526PubMedCrossRef

79.

Han JH, Choi HK, Kim SJ (2012) Topical TRPM8 agonist (icilin) relieved vulva pruritus originating from lichen sclerosus et atrophicus. Acta Derm Venereol 92:561–562PubMedCrossRef

80.

Denda M, Tsutsumi M, Denda S (2010) Topical application of TRPM8 agonists accelerates skin permeability barrier recovery and reduces epidermal proliferation induced by barrier insult: role of cold-sensitive TRP receptors in epidermal permeability barrier homoeostasis. Exp Dermatol 19:791–795PubMedCrossRef

81.

Kobayashi K, Fukuoka T, Obata K, Yamanaka H, Dai Y, Tokunaga A et al (2005) Distinct expression of TRPM8, TRPA1, and TRPV1 mRNAs in rat primary afferent neurons with adelta/c-fibers and colocalization with trk receptors. J Comp Neurol 493:596–606PubMedCrossRef

82.

Ringkamp M, Schepers RJ, Shimada SG, Johanek LM, Hartke TV, Borzan J et al (2011) A role for nociceptive, myelinated nerve fibers in itch sensation. J Neurosci 31:14841–14849PubMedPubMedCentralCrossRef

83.

Obreja O, Ringkamp M, Namer B (2010) Patterns of activity-dependent conduction velocity changes differentiate classes of unmyelinated mechano-insensitive afferents including cold nociceptors, in pig and in human. Pain 148:59–69PubMedCrossRef

84.

Ikoma A, Steinhoff M, Stander S, Yosipovitch G, Schmelz M (2006) The neurobiology of itch. Nat Rev Neurosci 7:535–547PubMedCrossRef

85.

Tominaga M, Ozawa S, Tengara S, Ogawa H, Takamori K (2007) Intraepidermal nerve fibers increase in dry skin of acetone-treated mice. J Dermatol Sci 48:103–111PubMedCrossRef

86.

Tominaga M, Tengara S, Kamo A, Ogawa H, Takamori K (2011) Matrix metalloproteinase-8 is involved in dermal nerve growth: implications for possible application to pruritus from in vitro models. J Invest Dermatol 131:2105–2112PubMedCrossRef

87.

Kamo A, Tominaga M, Negi O, Tengara S, Ogawa H, Takamori K (2011) Topical application of emollients prevents dry skin-inducible intraepidermal nerve growth in acetone-treated mice. J Dermatol Sci 62:64–66PubMed

88.

Kinkelin I, Motzing S, Koltenzenburg M, Brocker EB (2000) Increase in NGF content and nerve fiber sprouting in human allergic contact eczema. Cell Tissue Res 302:31–37PubMedCrossRef

89.

Ishiuji Y, Coghill RC, Patel TS, Oshiro Y, Kraft RA, Yosipovitch G (2009) Distinct patterns of brain activity evoked by histamine-induced itch reveal an association with itch intensity and disease severity in atopic dermatitis. Br J Dermatol 161:1072–1080PubMedPubMedCentralCrossRef

90.

Wahlgren CF, Hagermark O, Bergstrom R (1991) Patients’ perception of itch induced by histamine, compound 48/80 and wool fibres in atopic dermatitis. Acta Derm Venereol 71:488–494PubMed

91.

Urashima R, Mihara M (1998) Cutaneous nerves in atopic dermatitis. A histological, immunohistochemical and electron microscopic study. Virchows Arch 432:363–370PubMedCrossRef

92.

Sugiura H, Omoto M, Hirota Y, Danno K, Uehara M (1997) Density and fine structure of peripheral nerves in various skin lesions of atopic dermatitis. Arch Dermatol Res 289:125–131PubMedCrossRef

93.

Darsow U, Raap U, Stander S (2014) Atopic dermatitis. In: Carstens E, Akiyama T (eds) Itch: mechanisms and treatment. Taylor & Francis Group, Boca Raton

94.

Liu T, Berta T, Xu ZZ, Park CK, Zhang L, Lu N et al (2012) TLR3 deficiency impairs spinal cord synaptic transmission, central sensitization, and pruritus in mice. J Clin Invest 122:2195–2207PubMedPubMedCentralCrossRef

95.

Dou YC, Hagstromer L, Emtestam L, Johansson O (2006) Increased nerve growth factor and its receptors in atopic dermatitis: an immunohistochemical study. Arch Dermatol Res 298:31–37PubMedCrossRef

96.

Chen PS, Chen LS, Cao JM, Sharifi B, Karagueuzian HS, Fishbein MC (2001) Sympathetic nerve sprouting, electrical remodeling and the mechanisms of sudden cardiac death. Cardiovasc Res 50:409–416PubMedCrossRef

97.

Huang EJ, Reichardt LF (2003) Trk receptors: roles in neuronal signal transduction. Annu Rev Biochem 72:609–642PubMedCrossRef

98.

Rukwied RR, Main M, Weinkauf B, Schmelz M (2013) NGF sensitizes nociceptors for cowhage- but not histamine-induced itch in human skin. J Invest Dermatol 133:268–270PubMedCrossRef

99.

Lee J, Noh G, Lee S, Youn Y, Rhim J (2012) Atopic dermatitis and cytokines: recent patents in immunoregulatory and therapeutic implications of cytokines in atopic dermatitis—part I: cytokines in atopic dermatitis. Recent Pat Inflamm Allergy Drug Discov 6:222–247PubMedCrossRef

100.

Auriemma M, Vianale G, Amerio P, Reale M (2013) Cytokines and T cells in atopic dermatitis. Eur Cytokine Netw 24:37–44PubMed

101.

Wilson SR, The L, Batia LM, Beattie K, Katibah GE, McClain SP et al (2013) The epithelial cell-derived atopic dermatitis cytokine TSLP activates neurons to induce itch. Cell 155:285–295PubMedPubMedCentralCrossRef

102.

Ziegler SF, Roan F, Bell BD, Stoklasek TA, Kitajima M, Han H (2013) The biology of thymic stromal lymphopoietin (TSLP). Adv Pharmacol 66:129–155PubMedPubMedCentralCrossRef

103.

Moniaga CS, Jeong SK, Egawa G, Nakajima S, Hara-Chikuma M, Jeon JE et al (2013) Protease activity enhances production of thymic stromal lymphopoietin and basophil accumulation in flaky tail mice. Am J Pathol 182:841–851PubMedCrossRef

104.

He R, Geha RS (2010) Thymic stromal lymphopoietin. Ann N Y Acad Sci 1183:13–24PubMedPubMedCentralCrossRef

105.

Locksley RM (2010) Asthma and allergic inflammation. Cell 140:777–783PubMedPubMedCentralCrossRef

106.

Spergel JM, Paller AS (2003) Atopic dermatitis and the atopic march. J Allergy Clin Immunol 112:S118–S127PubMedCrossRef

107.

Jariwala SP, Abrams E, Benson A, Fodeman J, Zheng T (2011) The role of thymic stromal lymphopoietin in the immunopathogenesis of atopic dermatitis. Clin Exp Allergy 41:1515–1520PubMedCrossRef

108.

Li M, Messaddeq N, Teletin M, Pasquali JL, Metzger D, Chambon P (2005) Retinoid X receptor ablation in adult mouse keratinocytes generates an atopic dermatitis triggered by thymic stromal lymphopoietin. Proc Natl Acad Sci U S A 102:14795–14800PubMedPubMedCentralCrossRef

109.

Ying S, O’Connor B, Ratoff J, Meng Q, Mallett K, Cousins D et al (2005) Thymic stromal lymphopoietin expression is increased in asthmatic airways and correlates with expression of Th2-attracting chemokines and disease severity. J Immunol 174:8183–8190PubMedCrossRef

110.

Briot A, Deraison C, Lacroix M, Bonnart C, Robin A, Besson C et al (2009) Kallikrein 5 induces atopic dermatitis-like lesions through PAR2-mediated thymic stromal lymphopoietin expression in Netherton syndrome. J Exp Med 206:1135–1147PubMedPubMedCentralCrossRef

111.

Briot A, Lacroix M, Robin A, Steinhoff M, Deraison C, Hovnanian A (2010) Par2 inactivation inhibits early production of TSLP, but not cutaneous inflammation, in Netherton syndrome adult mouse model. J Invest Dermatol 130:2736–2742PubMedCrossRef

112.

Hovnanian A (2013) Netherton syndrome: skin inflammation and allergy by loss of protease inhibition. Cell Tissue Res 351:289–300PubMedCrossRef

113.

Kouzaki H, O’Grady SM, Lawrence CB, Kita H (2009) Proteases induce production of thymic stromal lymphopoietin by airway epithelial cells through protease-activated receptor-2. J Immunol 183:1427–1434PubMedPubMedCentralCrossRef

114.

Gaspari AA, Lotze MT, Rosenberg SA, Stern JB, Katz SI (1987) Dermatologic changes associated with interleukin 2 administration. JAMA 258:1624–1629PubMedCrossRef

115.

Lee RE, Gaspari AA, Lotze MT, Chang AE, Rosenberg SA (1988) Interleukin 2 and psoriasis. Arch Dermatol 124:1811–1815PubMedCrossRef

116.

Kremer AE, Feramisco J, Reeh PW, Beuers U, Oude Elferink RP (1842) Receptors, cells and circuits involved in pruritus of systemic disorders. Biochim Biophys Acta 2014:869–892

117.

Wahlgren CF, Tengvall Linder M, Hagermark O, Scheynius A (1995) Itch and inflammation induced by intradermally injected interleukin-2 in atopic dermatitis patients and healthy subjects. Arch Dermatol Res 287:572–580PubMedCrossRef

118.

Wahlgren CF, Scheynius A, Hagermark O (1990) Antipruritic effect of oral cyclosporin A in atopic dermatitis. Acta Derm Venereol 70:323–329PubMed

119.

Totterman TH, Scheynius A, Killander A, Danersund A, Alm GV (1985) Treatment of therapy-resistant Sezary syndrome with cyclosporin-A: suppression of pruritus, leukaemic T cell activation markers and tumour mass. Scand J Haematol 34:196–203PubMedCrossRef

120.

Sonkoly E, Muller A, Lauerma AI, Pivarcsi A, Soto H, Kemeny L (2006) IL-31: a new link between T cells and pruritus in atopic skin inflammation. J Allergy Clin Immunol 117:411–417PubMedCrossRef

121.

Dillon SR, Sprecher C, Hammond A, Bilsborough J, Rosenfeld-Franklin M, Presnell SR (2004) Interleukin 31, a cytokine produced by activated T cells, induces dermatitis in mice. Nat Immunol 5:752–760PubMedCrossRef

122.

Heise R, Neis MM, Marquardt Y, Joussen S, Heinrich PC, Merk HF et al (2009) IL-31 receptor alpha expression in epidermal keratinocytes is modulated by cell differentiation and interferon gamma. J Invest Dermatol 129:240–243PubMedCrossRef

123.

Cornelissen C, Marquardt Y, Czaja K (2012) IL-31 regulates differentiation and filaggrin expression in human organotypic skin models. J Allergy Clin Immunol 129:426–433PubMedCrossRef

124.

Kasraie S, Niebuhr M, Werfel T (2013) Interleukin (IL)-31 activates signal transducer and activator of transcription (STAT)-1, STAT-5 and extracellular signal-regulated kinase 1/2 and down-regulates IL-12p40 production in activated human macrophages. Allergy 68:739–747PubMedCrossRef

125.

Raap U, Wichmann K, Bruder M, Stander S, Wedi B, Kapp A et al (2008) Correlation of IL-31 serum levels with severity of atopic dermatitis. J Allergy Clin Immunol 122:421–423PubMedCrossRef

126.

Singer EM, Shin DB, Nattkemper LA, Benoit BM, Klein RS, Didigu CA et al (2013) IL-31 is produced by the malignant T-cell population in cutaneous T-cell lymphoma and correlates with CTCL pruritus. J Invest Dermatol 133(12):2783–2785PubMedCrossRef

127.

Miyagaki T, Sugaya M, Suga H (2012) Increased CCL18 expression in patients with cutaneous T-cell lymphoma: association with disease severity and prognosis. J Eur Acad Dermatol Venereol 27:e60–e67PubMedCrossRef

128.

Ohmatsu H, Sugaya M, Suga H (2012) Serum IL-31 levels are increased in patients with cutaneous T-cell lymphoma. Acta Derm Venereol 92:282–283PubMedCrossRef

129.

Raap U, Wieczorek D, Gehring M, Pauls I, Stander S, Kapp A et al (2010) Increased levels of serum IL-31 in chronic spontaneous urticaria. Exp Dermatol 19:464–466PubMedCrossRef

130.

Cevikbas F, Wang X, Akiyama T, Kempkes C, Savinko T, Antal A et al (2014) A sensory neuron-expressed IL-31 receptor mediates T helper cell-dependent itch: involvement of TRPV1 and TRPA1. J Allergy Clin Immunol 133:448–460PubMedCrossRef

131.

Hawro T, Saluja R, Weller K, Altrichter S, Metz M, Maurer M (2014) Interleukin-31 does not induce immediate itch in atopic dermatitis patients and healthy controls after skin challenge. Allergy 69:113–117PubMedCrossRef

132.

Kato A, Fujii E, Watanabe T, Takashima Y, Matsushita H, Furuhashi T et al (2014) Distribution of IL-31 and its receptor expressing cells in skin of atopic dermatitis. J Dermatol Sci 74:229–235PubMedCrossRef

133.

Wittmann M, McGonagle D, Werfel T (2014) Cytokines as therapeutic targets in skin inflammation. Cytokine Growth Factor Rev 25:443–451PubMedCrossRef

134.

Leung DY, Boguniewicz M, Howell MD, Nomura I, Hamid QA (2004) New insights into atopic dermatitis. J Clin Invest 113:651–657PubMedPubMedCentralCrossRef

135.

Hamid Q, Boguniewicz M, Leung DY (1994) Differential in situ cytokine gene expression in acute versus chronic atopic dermatitis. J Clin Invest 94:870–876PubMedPubMedCentralCrossRef

136.

Simon D, Braathen LR, Simon HU (2004) Eosinophils and atopic dermatitis. Allergy 59:561–570PubMedCrossRef

137.

Chan LS, Robinson N, Xu L (2001) Expression of interleukin-4 in the epidermis of transgenic mice results in a pruritic inflammatory skin disease: an experimental animal model to study atopic dermatitis. J Invest Dermatol 117:977–983PubMedCrossRef

138.

Zheng T, Oh MH, Oh SY, Schroeder JT, Glick AB, Zhu Z (2009) Transgenic expression of interleukin-13 in the skin induces a pruritic dermatitis and skin remodeling. J Invest Dermatol 129:742–751PubMedCrossRef

139.

Jeong CW, Ahn KS, Rho NK, Park YD, Lee DY, Lee JH et al (2003) Differential in vivo cytokine mRNA expression in lesional skin of intrinsic vs. extrinsic atopic dermatitis patients using semiquantitative RT-PCR. Clin Exp Allergy 33:1717–1724PubMedCrossRef

140.

Hamid Q, Naseer T, Minshall E, Song Y, Boguniewicz M, Leung D (1996) In vivo expression of IL-12 and IL-13 in atopic dermatitis. J Allergy Clin Immunol 98:225–231PubMedCrossRef

141.

Brandt EB, Sivaprasad U (2011) Th2 cytokines and atopic dermatitis. J Clin Cell Immunol 2(3):110PubMedPubMedCentralCrossRef

142.

Metwally SS, Mosaad YM, Abdel-Samee ER, El-Gayyar MA, Abdel-Aziz AM, El-Chennawi FA (2004) IL-13 gene expression in patients with atopic dermatitis: relation to IgE level and to disease severity. Egypt J Immunol 11:171–177PubMed

143.

Beck LA, Thaci D, Hamilton JD, Graham NM, Bieber T, Rocklin R et al (2014) Dupilumab treatment in adults with moderate-to-severe atopic dermatitis. N Engl J Med 371:130–139PubMedCrossRef

144.

Savinko T, Matikainen S, Saarialho-Kere U, Lehto M, Wang G, Lehtimaki S et al (2012) IL-33 and ST2 in atopic dermatitis: expression profiles and modulation by triggering factors. J Invest Dermatol 132:1392–1400PubMedCrossRef

145.

Pushparaj PN, Tay HK, H’ng SC, Pitman N, Xu D, McKenzie A et al (2009) The cytokine interleukin-33 mediates anaphylactic shock. Proc Natl Acad Sci U S A 106:9773–9778PubMedPubMedCentralCrossRef

146.

Kroeger KM, Sullivan BM, Locksley RM (2009) IL-18 and IL-33 elicit Th2 cytokines from basophils via a MyD88- and p38alpha-dependent pathway. J Leukoc Biol 86:769–778PubMedPubMedCentralCrossRef

147.

Rankin AL, Mumm JB, Murphy E, Turner S, Yu N, McClanahan TK et al (2010) IL-33 induces IL-13-dependent cutaneous fibrosis. J Immunol 184:1526–1535PubMedCrossRef

148.

Tamagawa-Mineoka R, Okuzawa Y, Masuda K, Katoh N (2014) Increased serum levels of interleukin 33 in patients with atopic dermatitis. J Am Acad Dermatol 70:882–888PubMedCrossRef

149.

Massi D, Panelos J (2012) Notch signaling and the developing skin epidermis. Adv Exp Med Biol 727:131–141PubMedCrossRef

150.

Kwon SM, Alev C, Lee SH, Asahara T (2012) The molecular basis of Notch signaling: a brief overview. Adv Exp Med Biol 727:1–14PubMedCrossRef

151.

Artavanis-Tsakonas S, Rand MD, Lake RJ (1999) Notch signaling: cell fate control and signal integration in development. Science 284:770–776PubMedCrossRef

152.

Leung DY (2013) New insights into atopic dermatitis: role of skin barrier and immune dysregulation. Allergol Int 62:151–161PubMedCrossRef

153.

Melnik BC (2015) The potential role of impaired notch signalling in atopic dermatitis. Acta Derm Venereol 95:5–11PubMedCrossRef

154.

Dumortier A, Durham AD, Di Piazza M, Vauclair S, Koch U, Ferrand G et al (2010) Atopic dermatitis-like disease and associated lethal myeloproliferative disorder arise from loss of Notch signaling in the murine skin. PLoS One 5, e9258PubMedPubMedCentralCrossRef

155.

Yoo J, Omori M, Gyarmati D, Zhou B, Aye T, Brewer A et al (2005) Spontaneous atopic dermatitis in mice expressing an inducible thymic stromal lymphopoietin transgene specifically in the skin. J Exp Med 202:541–549PubMedPubMedCentralCrossRef

156.

Liu YJ (2006) Thymic stromal lymphopoietin: master switch for allergic inflammation. J Exp Med 203:269–273PubMedPubMedCentralCrossRef

157.

Ziegler SF, Artis D (2010) Sensing the outside world: TSLP regulates barrier immunity. Nat Immunol 11:289–293PubMedPubMedCentralCrossRef

158.

Ziegler SF (2010) The role of thymic stromal lymphopoietin (TSLP) in allergic disorders. Curr Opin Immunol 22:795–799PubMedPubMedCentralCrossRef

159.

Benditt EP, Bader S, Lam KB (1955) Studies of the mechanism of acute vascular reactions to injury. I. The relationship of mast cells and histamine to the production of edema by ovomucoid in rats. AMA Arch Pathol 60:104–115PubMed

160.

Simons FE, Simons KJ (2011) Histamine and H1-antihistamines: celebrating a century of progress. J Allergy Clin Immunol 128:1139–1150.e4PubMedCrossRef

161.

Han S, Mancino V, Simon MI (2006) Phospholipase Cbeta 3 mediates the scratching response activated by the histamine H1 receptor on C-fiber nociceptive neurons. Neuron 52:691–703PubMedCrossRef

162.

Rossbach K, Wendorff S, Sander K, Stark H, Gutzmer R, Werfel T et al (2009) Histamine H4 receptor antagonism reduces hapten-induced scratching behaviour but not inflammation. Exp Dermatol 18:57–63PubMedCrossRef

163.

Cowden JM, Zhang M, Dunford PJ, Thurmond RL (2010) The histamine H4 receptor mediates inflammation and pruritus in Th2-dependent dermal inflammation. J Invest Dermatol 130:1023–1033PubMedCrossRef

164.

Kollmeier A, Francke K, Chen B, Dunford PJ, Greenspan AJ, Xia Y et al (2014) The histamine H(4) receptor antagonist, JNJ 39758979, is effective in reducing histamine-induced pruritus in a randomized clinical study in healthy subjects. J Pharmacol Exp Ther 350:181–187PubMedCrossRef

165.

De Felipe C, Herrero JF, O’Brien JA, Palmer JA, Doyle CA, Smith AJ et al (1998) Altered nociception, analgesia and aggression in mice lacking the receptor for substance P. Nature 392:394–397PubMedCrossRef

166.

Church MK, Okayama Y, el-Lati S (1991) Mediator secretion from human skin mast cells provoked by immunological and non-immunological stimulation. Skin Pharmacol 4(Suppl 1):15–24PubMed

167.

Hagermark O, Hokfelt T, Pernow B (1978) Flare and itch induced by substance P in human skin. J Invest Dermatol 71:233–235PubMedCrossRef

168.

Fjellner B, Hagermark O (1981) Studies on pruritogenic and histamine-releasing effects of some putative peptide neurotransmitters. Acta Derm Venereol 61:245–250PubMed

169.

Jorizzo JL, Coutts AA, Eady RA, Greaves MW (1983) Vascular responses of human skin to injection of substance P and mechanism of action. Eur J Pharmacol 87:67–76PubMedCrossRef

170.

van der Kleij HP, Ma D, Redegeld FA, Kraneveld AD, Nijkamp FP, Bienenstock J (2003) Functional expression of neurokinin 1 receptors on mast cells induced by IL-4 and stem cell factor. J Immunol 171:2074–2079PubMedCrossRef

171.

Luger TA (2002) Neuromediators—a crucial component of the skin immune system. J Dermatol Sci 30:87–93PubMedCrossRef

172.

Steinhoff M, Stander S, Seeliger S, Ansel JC, Schmelz M, Luger T (2003) Modern aspects of cutaneous neurogenic inflammation. Arch Dermatol 139:1479–1488PubMedCrossRef

173.

Paus R, Theoharides TC, Arck PC (2006) Neuroimmune endocrine circuitry of the ldquo [brain-skin connection rdquo]. Trends Immunol 15:1–13

174.

Furutani K, Koro O, Hide M, Yamamoto S (1999) Substance P- and antigen-induced release of leukotriene B4, prostaglandin D2 and histamine from guinea pig skin by different mechanisms in vitro. Arch Dermatol Res 291:466–473PubMedCrossRef

175.

Biro T, Toth BI, Marincsak R, Dobrosi N, Geczy T, Paus R (2007) TRP channels as novel players in the pathogenesis and therapy of itch. Biochim Biophys Acta 1772:1004–1021PubMedCrossRef

176.

Kulka M, Sheen CH, Tancowny BP, Grammer LC, Schleimer RP (2008) Neuropeptides activate human mast cell degranulation and chemokine production. Immunology 123:398–410PubMedPubMedCentralCrossRef

177.

Salomon J, Baran E (2008) The role of selected neuropeptides in pathogenesis of atopic dermatitis. J Eur Acad Dermatol Venereol 22:223–228PubMed

178.

Abadia Molina F, Burrows NP, Jones RR, Terenghi G, Polak JM (1992) Increased sensory neuropeptides in nodular prurigo: a quantitative immunohistochemical analysis. Br J Dermatol 127:344–351PubMedCrossRef

179.

Jarvikallio A, Harvima IT, Naukkarinen A (2003) Mast cells, nerves and neuropeptides in atopic dermatitis and nummular eczema. Arch Dermatol Res 295:2–7PubMed

180.

Stander S, Siepmann D, Herrgott I, Sunderkotter C, Luger TA (2010) Targeting the neurokinin receptor 1 with aprepitant: a novel antipruritic strategy. PLoS One 5, e10968PubMedPubMedCentralCrossRef

181.

Duval A, Dubertret L (2009) Aprepitant as an antipruritic agent? N Engl J Med 361:1415–1416PubMedCrossRef

182.

Vincenzi B, Fratto ME, Santini D, Tonini G (2010) Aprepitant against pruritus in patients with solid tumours. Support Care Cancer 18:1229–1230PubMedCrossRef

183.

Vincenzi B, Tonini G, Santini D (2010) Aprepitant for erlotinib-induced pruritus. N Engl J Med 363:397–398PubMedCrossRef

184.

Yamamoto M, Haruna T, Yasui K, Takahashi H, Iduhara M, Takaki S et al (2007) A novel atopic dermatitis model induced by topical application with dermatophagoides farinae extract in NC/Nga mice. Allergol Int 56:139–148PubMedCrossRef

185.

Papoiu AD, Wang H, Nattkemper L, Tey HL, Ishiuji Y, Chan YH et al (2011) A study of serum concentrations and dermal levels of NGF in atopic dermatitis and healthy subjects. Neuropeptides 45:417–422PubMedPubMedCentralCrossRef

186.

Nockher WA, Renz H (2006) Neurotrophins in allergic diseases: from neuronal growth factors to intercellular signaling molecules. J Allergy Clin Immunol 117:583–589PubMedCrossRef

187.

Verge VM, Richardson PM, Wiesenfeld-Hallin Z, Hokfelt T (1995) Differential influence of nerve growth factor on neuropeptide expression in vivo: a novel role in peptide suppression in adult sensory neurons. J Neurosci 15:2081–2096PubMed

188.

Kanda N, Watanabe S (2003) Histamine enhances the production of nerve growth factor in human keratinocytes. J Invest Dermatol 121:570–577PubMedCrossRef

189.

Andoh T, Kuwazono T, Lee JB, Kuraishi Y (2011) Gastrin-releasing peptide induces itch-related responses through mast cell degranulation in mice. Peptides 32:2098–2103PubMedCrossRef

190.

Liu XY, Wan L, Huo FQ, Barry DM, Li H, Zhao ZQ et al (2014) B-type natriuretic peptide is neither itch-specific nor functions upstream of the GRP-GRPR signaling pathway. Mol Pain 10:4. doi:10.1186/1744-8069-10-4 PubMedPubMedCentralCrossRef

191.

Sun YG, Zhao ZQ, Meng XL, Yin J, Liu XY, Chen ZF (2009) Cellular basis of itch sensation. Science 325:1531–1534PubMedCrossRef

192.

Sun YG, Chen ZF (2007) A gastrin-releasing peptide receptor mediates the itch sensation in the spinal cord. Nature 448:700–703PubMedCrossRef

193.

Mishra SK, Hoon MA (2013) The cells and circuitry for itch responses in mice. Science 340:968–971PubMedPubMedCentralCrossRef

194.

Akiyama T, Tominaga M, Takamori K, Carstens MI, Carstens E (2014) Role of spinal bombesin-responsive neurons in nonhistaminergic itch. J Neurophysiol 112:2283–2289PubMedPubMedCentralCrossRef

195.

Nattkemper LA, Zhao Z, Nichols AJ, Papoiu ADP, Shively CA, Chen Z et al (2013) Overexpression of the gastrin-releasing peptide in cutaneous nerve fibers and its receptor in the spinal cord in primates with chronic itch. J Invest Dermatol 133:2489–2492PubMedPubMedCentralCrossRef

196.

Kagami S, Sugaya M, Suga H, Morimura S, Kai H, Ohmatsu H et al (2013) Serum gastrin-releasing peptide levels correlate with pruritus in patients with atopic dermatitis. J Invest Dermatol 133:1673–1675PubMedCrossRef

197.

Goswami SC, Thierry-Mieg D, Thierry-Mieg J, Mishra S, Hoon MA, Mannes AJ et al (2014) Itch-associated peptides: RNA-Seq and bioinformatic analysis of natriuretic precursor peptide B and gastrin releasing peptide in dorsal root and trigeminal ganglia, and the spinal cord. Mol Pain 10:44. doi:10.1186/1744-8069-10-44 PubMedPubMedCentralCrossRef

198.

Wessler I, Kirkpatrick CJ (2008) Acetylcholine beyond neurons: the non-neuronal cholinergic system in humans. Br J Pharmacol 154:1558–1571PubMedPubMedCentralCrossRef

199.

Wessler I, Reinheimer T, Kilbinger H, Bittinger F, Kirkpatrick CJ, Saloga J et al (2003) Increased acetylcholine levels in skin biopsies of patients with atopic dermatitis. Life Sci 72:2169–2172PubMedCrossRef

200.

Twycross R, Greaves MW, Handwerker H, Jones EA, Libretto SE, Szepietowski JC et al (2003) Itch: scratching more than the surface. QJM 96:7–26PubMedCrossRef

201.

Benarroch EE, Low PA (1991) The acetylcholine-induced flare response in evaluation of small fiber dysfunction. Ann Neurol 29:590–595PubMedCrossRef

202.

Rukwied R, Lischetzki G, McGlone F, Heyer G, Schmelz M (2000) Mast cell mediators other than histamine induce pruritus in atopic dermatitis patients: a dermal microdialysis study. Br J Dermatol 142:1114–1120PubMedCrossRef

203.

Heyer GR, Hornstein OP (1999) Recent studies of cutaneous nociception in atopic and non-atopic subjects. J Dermatol 26:77–86PubMedCrossRef

204.

Grando SA, Pittelkow MR, Schallreuter KU (2006) Adrenergic and cholinergic control in the biology of epidermis: physiological and clinical significance. J Invest Dermatol 126:1948–1965PubMedCrossRef

205.

Batra S (1990) Influence of chronic oestrogen treatment on the density of muscarinic cholinergic receptors and calcium channels in the rabbit uterus. J Endocrinol 125:185–189PubMedCrossRef

206.

Carrasco-Serrano C, Criado M (2004) Glucocorticoid activation of the neuronal nicotinic acetylcholine receptor alpha7 subunit gene: involvement of transcription factor Egr-1. FEBS Lett 566:247–250PubMedCrossRef

207.

Schlereth T, Birklein F, an Haack K, Schiffmann S, Kilbinger H, Kirkpatrick CJ et al (2006) In vivo release of non-neuronal acetylcholine from the human skin as measured by dermal microdialysis: effect of botulinum toxin. Br J Pharmacol 147:183–187PubMedCrossRef

208.

Chernyavsky AI, Arredondo J, Vetter DE, Grando SA (2007) Central role of alpha9 acetylcholine receptor in coordinating keratinocyte adhesion and motility at the initiation of epithelialization. Exp Cell Res 313:3542–3555PubMedPubMedCentralCrossRef

209.

Kawashima K, Fujii T (2000) Extraneuronal cholinergic system in lymphocytes. Pharmacol Ther 86:29–48PubMedCrossRef

210.

Zimring JC, Kapp LM, Yamada M, Wess J, Kapp JA (2005) Regulation of CD8+ cytolytic T lymphocyte differentiation by a cholinergic pathway. J Neuroimmunol 164:66–75PubMedCrossRef

211.

Skok MV, Grailhe R, Agenes F, Changeux JP (2007) The role of nicotinic receptors in B-lymphocyte development and activation. Life Sci 80:2334–2336PubMedCrossRef

212.

Borovikova LV, Ivanova S, Zhang M, Yang H, Botchkina GI, Watkins LR et al (2000) Vagus nerve stimulation attenuates the systemic inflammatory response to endotoxin. Nature 405:458–462PubMedCrossRef

213.

Pavlov VA, Tracey KJ (2005) The cholinergic anti-inflammatory pathway. Brain Behav Immun 19:493–499PubMedCrossRef

214.

Kawasaki H, Nagao K, Kubo A, Hata T, Shimizu A, Mizuno H et al (2012) Altered stratum corneum barrier and enhanced percutaneous immune responses in filaggrin-null mice. J Allergy Clin Immunol 129:1538–1546.e6PubMedCrossRef

215.

Kupczyk P, Reich A, Szepietowski JC (2009) Cannabinoid system in the skin—a possible target for future therapies in dermatology. Exp Dermatol 18:669–679PubMedCrossRef

216.

Gaffal E, Glodde N, Jakobs M, Bald T, Tuting T (2014) Cannabinoid 1 receptors in keratinocytes attenuate fluorescein isothiocyanate-induced mouse atopic-like dermatitis. Exp Dermatol 23:401–406PubMedCrossRef

217.

Karsak M, Gaffal E, Date R, Wang-Eckhardt L, Rehnelt J, Petrosino S et al (2007) Attenuation of allergic contact dermatitis through the endocannabinoid system. Science 316:1494–1497PubMedCrossRef

218.

Oka S, Wakui J, Gokoh M, Kishimoto S, Sugiura T (2006) Suppression by WIN55212-2, a cannabinoid receptor agonist, of inflammatory reactions in mouse ear: interference with the actions of an endogenous ligand, 2-arachidonoylglycerol. Eur J Pharmacol 538:154–162PubMedCrossRef

219.

Gaffal E, Cron M, Glodde N, Tuting T (2013) Anti-inflammatory activity of topical THC in DNFB-mediated mouse allergic contact dermatitis independent of CB1 and CB2 receptors. Allergy 68:994–1000PubMedCrossRef

220.

Jafferany M (2007) Psychodermatology: a guide to understanding common psychocutaneous disorders. Prim Care Companion J Clin Psychiatry 9:203–213PubMedPubMedCentralCrossRef

221.

Hall JM, Cruser D, Podawiltz A, Mummert DI, Jones H, Mummert ME (2012) Psychological stress and the cutaneous immune response: roles of the HPA axis and the sympathetic nervous system in atopic dermatitis and psoriasis. Dermatol Res Pract 2012:403908PubMedPubMedCentral

222.

Chrostowska-Plak D, Reich A, Szepietowski JC (2013) Relationship between itch and psychological status of patients with atopic dermatitis. J Eur Acad Dermatol Venereol 27:e239–e242PubMedCrossRef

223.

Oh SH, Bae BG, Park CO, Noh JY, Park IH, Wu WH et al (2010) Association of stress with symptoms of atopic dermatitis. Acta Derm Venereol 90:582–588PubMedCrossRef

224.

Morren M, Przybilla B, Bamelis M, Heykants B, Reynaers A, Degreef H (1994) Atopic dermatitis: triggering factors. J Am Acad Dermatol 31:467–473PubMedCrossRef

225.

Cacioppo JT, Berntson GG, Malarkey WB, Kiecolt-Glaser JK, Sheridan JF, Poehlmann KM et al (1998) Autonomic, neuroendocrine, and immune responses to psychological stress: the reactivity hypothesis. Ann N Y Acad Sci 840:664–673PubMedCrossRef

226.

Glaser R, Kiecolt-Glaser JK (2005) Stress-induced immune dysfunction: implications for health. Nat Rev Immunol 5:243–251PubMedCrossRef

227.

Nordlind K, Azmitia EC, Slominski A (2008) The skin as a mirror of the soul: exploring the possible roles of serotonin. Exp Dermatol 17:301–311PubMedCrossRef

228.

Elenkov IJ (2004) Glucocorticoids and the Th1/Th2 balance. Ann N Y Acad Sci 1024:138–146PubMedCrossRef

229.

Theoharides TC, Conti P (2004) Mast cells: the Jekyll and Hyde of tumor growth. Trends Immunol 25:235–241PubMedCrossRef

230.

Mitschenko AV, Lwow AN, Kupfer J, Niemeier V, Gieler U (2008) Atopic dermatitis and stress? How do emotions come into skin? Hautarzt 59:314–318PubMedCrossRef

231.

Pisarchik A, Slominski AT (2001) Alternative splicing of CRH-R1 receptors in human and mouse skin: identification of new variants and their differential expression. FASEB J 15:2754–2756PubMed

232.

Steinhoff M, Vergnolle N, Young SH, Tognetto M, Amadesi S, Ennes HS (2000) Agonists of proteinase-activated receptor 2 induce inflammation by a neurogenic mechanism. Nat Med 6:151–158PubMedCrossRef

233.

Arck P, Paus R (2006) From the brain-skin connection: the neuroendocrine-immune misalliance of stress and itch. Neuroimmunomodulation 13:347–356PubMedCrossRef

234.

Arck PC, Handjiski B, Kuhlmei A, Peters EM, Knackstedt M, Peter A et al (2005) Mast cell deficient and neurokinin-1 receptor knockout mice are protected from stress-induced hair growth inhibition. J Mol Med (Berl) 83:386–396CrossRef

235.

Theoharides TC, Kalogeromitros D (2006) The critical role of mast cells in allergy and inflammation. Ann N Y Acad Sci 1088:78–99PubMedCrossRef

236.

Harvima IT, Nilsson G, Naukkarinen A (2010) Role of mast cells and sensory nerves in skin inflammation. G Ital Dermatol Venereol 145:195–204PubMed

237.

Loden M (1997) Barrier recovery and influence of irritant stimuli in skin treated with a moisturizing cream. Contact Dermatitis 36:256–260PubMedCrossRef

238.

Loden M (2003) Do moisturizers work? J Cosmet Dermatol 2:141–149PubMedCrossRef

239.

Held E, Sveinsdottir S, Agner T (1999) Effect of long-term use of moisturizer on skin hydration, barrier function and susceptibility to irritants. Acta Derm Venereol 79:49–51PubMedCrossRef

240.

Elmariah SB, Lerner EA (2011) Topical therapies for pruritus. Semin Cutan Med Surg 30:118–126PubMedPubMedCentralCrossRef

241.

Vilaplana J, Coll J, Trullas C, Azon A, Pelejero C (1992) Clinical and non-invasive evaluation of 12% ammonium lactate emulsion for the treatment of dry skin in atopic and non-atopic subjects. Acta Derm Venereol 72:28–33PubMed

242.

Msika P, De Belilovsky C, Piccardi N, Chebassier N, Baudouin C, Chadoutaud B (2008) New emollient with topical corticosteroid-sparing effect in treatment of childhood atopic dermatitis: SCORAD and quality of life improvement. Pediatr Dermatol 25:606–612PubMedCrossRef

243.

Grimalt R, Mengeaud V, Cambazard F, Study Investigators’ Group (2007) The steroid-sparing effect of an emollient therapy in infants with atopic dermatitis: a randomized controlled study. Dermatology 214:61–67PubMedCrossRef

244.

Lucky AW, Leach AD, Laskarzewski P, Wenck H (1997) Use of an emollient as a steroid-sparing agent in the treatment of mild to moderate atopic dermatitis in children. Pediatr Dermatol 14:321–324PubMedCrossRef

245.

Szczepanowska J, Reich A, Szepietowski JC (2008) Emollients improve treatment results with topical corticosteroids in childhood atopic dermatitis: a randomized comparative study. Pediatr Allergy Immunol 19:614–618PubMedCrossRef

246.

Wellner K, Wohlrab W (1993) Quantitative evaluation of urea in stratum corneum of human skin. Arch Dermatol Res 285:239–240PubMedCrossRef

247.

Brinkmann I, Muller-Goymann CC (2005) An attempt to clarify the influence of glycerol, propylene glycol, isopropyl myristate and a combination of propylene glycol and isopropyl myristate on human stratum corneum. Pharmazie 60:215–220PubMed

248.

Kurtz ES, Wallo W (2007) Colloidal oatmeal: history, chemistry and clinical properties. J Drugs Dermatol 6:167–170PubMed

249.

Fowler JF, Nebus J, Wallo W, Eichenfield LF (2012) Colloidal oatmeal formulations as adjunct treatments in atopic dermatitis. J Drugs Dermatol 11:804–807PubMed

250.

Alexandrescu DT, Vaillant JG, Dasanu CA (2007) Effect of treatment with a colloidal oatmeal lotion on the acneform eruption induced by epidermal growth factor receptor and multiple tyrosine-kinase inhibitors. Clin Exp Dermatol 32:71–74PubMed

251.

Sur R, Nigam A, Grote D, Liebel F, Southall MD (2008) Avenanthramides, polyphenols from oats, exhibit anti-inflammatory and anti-itch activity. Arch Dermatol Res 300:569–574PubMedCrossRef

252.

Pazyar N, Yaghoobi R, Kazerouni A, Feily A (2012) Oatmeal in dermatology: a brief review. Indian J Dermatol Venereol Leprol 78:142–145PubMedCrossRef

253.

Wertz PW (1992) Epidermal lipids. Semin Dermatol 11:106–113PubMed

254.

Grayson S, Elias PM (1982) Isolation and lipid biochemical characterization of stratum corneum membrane complexes: implications for the cutaneous permeability barrier. J Investig Dermatol 78:128–135PubMedCrossRef

255.

Wertz PW, Downing DT (1983) Ceramides of pig epidermis: structure determination. J Lipid Res 24:759–765PubMed

256.

Enomoto H, Hirata K, Otsuka K, Kawai T, Takahashi T, Hirota T et al (2008) Filaggrin null mutations are associated with atopic dermatitis and elevated levels of IgE in the Japanese population: a family and case-control study. J Hum Genet 53:615–621PubMedCrossRef

257.

Leung DY, Nicklas RA, Li JT, Bernstein IL, Blessing-Moore J, Boguniewicz M et al (2004) Disease management of atopic dermatitis: an updated practice parameter. Joint Task Force on Practice Parameters. Ann Allergy Asthma Immunol 93:S1–S21PubMedCrossRef

258.

Di Nardo A, Wertz P, Giannetti A, Seidenari S (1998) Ceramide and cholesterol composition of the skin of patients with atopic dermatitis. Acta Derm Venereol 78:27–30PubMedCrossRef

259.

Imokawa G, Abe A, Jin K, Higaki Y, Kawashima M, Hidano A (1991) Decreased level of ceramides in stratum corneum of atopic dermatitis: an etiologic factor in atopic dry skin? J Invest Dermatol 96:523–526PubMedCrossRef

260.

Bieber T (2008) Atopic dermatitis. N Engl J Med 358:1483–1494PubMedCrossRef

261.

Cork MJ, Danby SG, Vasilopoulos Y, Hadgraft J, Lane ME, Moustafa M et al (2009) Epidermal barrier dysfunction in atopic dermatitis. J Invest Dermatol 129:1892–1908PubMedCrossRef

262.

Lynde CW, Andriessen A (2014) A cohort study on a ceramide-containing cleanser and moisturizer used for atopic dermatitis. Cutis 93:207–213PubMed

263.

Draelos ZD (2008) Use of topical corticosteroids and topical calcineurin inhibitors for the treatment of atopic dermatitis in thin and sensitive skin areas. Curr Med Res Opin 24:985–994PubMedCrossRef

264.

Rawlings AV, Harding CR (2004) Moisturization and skin barrier function. Dermatol Ther 17(Suppl 1):43–48PubMedCrossRef

265.

Zettersten EM, Ghadially R, Feingold KR, Crumrine D, Elias PM (1997) Optimal ratios of topical stratum corneum lipids improve barrier recovery in chronologically aged skin. J Am Acad Dermatol 37:403–408PubMedCrossRef

266.

Schmid M, Korting HC (1995) The concept of the acid mantle of the skin: its relevance for the choice of skin cleansers. Dermatology 191:276–280PubMedCrossRef

267.

Ali SM, Yosipovitch G (2013) Skin pH: from basic science to basic skin care. Acta Derm Venereol 93:261–267PubMedCrossRef

268.

Akdis CA, Akdis M, Bieber T, Bindslev-Jensen C, Boguniewicz M, Eigenmann P et al (2006) Diagnosis and treatment of atopic dermatitis in children and adults: European Academy of Allergology and Clinical Immunology/American Academy of Allergy, Asthma and Immunology/PRACTALL Consensus Report. Allergy 61:969–987PubMedCrossRef

269.

Mack Correa MC, Nebus J (2012) Management of patients with atopic dermatitis: the role of emollient therapy. Dermatol Res Pract 2012:1CrossRef

270.

Solodkin G, Chaudhari U, Subramanyan K, Johnson AW, Yan X, Gottlieb A (2006) Benefits of mild cleansing: synthetic surfactant based (syndet) bars for patients with atopic dermatitis. Cutis 77:317–324PubMed

271.

Hachem JP, Man MQ, Crumrine D, Uchida Y, Brown BE, Rogiers V et al (2005) Sustained serine proteases activity by prolonged increase in pH leads to degradation of lipid processing enzymes and profound alterations of barrier function and stratum corneum integrity. J Invest Dermatol 125:510–520PubMedCrossRef

272.

Hachem JP, Crumrine D, Fluhr J, Brown BE, Feingold KR, Elias PM (2003) pH directly regulates epidermal permeability barrier homeostasis, and stratum corneum integrity/cohesion. J Invest Dermatol 121:345–353PubMedCrossRef

273.

Nattkemper LA, Lee HG, Valdes-Rodriguez R, Mollanazar NK, Sanders KM, Yosipovitch G (2015) Cholinergic induction of perspiration attenuates non-histaminergic pruritus in the skin of atopic dermatitis subjects and healthy controls. Br J Dermatol. doi:10.1111/bjd.13629 PubMedPubMedCentral

274.

Saeki H, Furue M, Furukawa F, Hide M, Ohtsuki M, Katayama I et al (2009) Guidelines for management of atopic dermatitis. J Dermatol 36:563–577PubMedCrossRef

275.

Ellis C, Luger T, Abeck D, Allen R, Graham-Brown RA, De Prost Y et al (2003) International Consensus Conference on Atopic Dermatitis II (ICCAD II): clinical update and current treatment strategies. Br J Dermatol 148(Suppl 63):3–10PubMedCrossRef

276.

Eichenfield LF, Hanifin JM, Luger TA, Stevens SR, Pride HB (2003) Consensus conference on pediatric atopic dermatitis. J Am Acad Dermatol 49:1088–1095PubMedCrossRef

277.

Tadicherla S, Ross K, Shenefelt PD, Fenske NA (2009) Topical corticosteroids in dermatology. J Drugs Dermatol 8:1093–1105PubMed

278.

Hanifin JM (2004) Atopic dermatitis: broadening the perspective. J Am Acad Dermatol 51:S23–S24PubMedCrossRef

279.

Yarbrough KB, Neuhaus KJ, Simpson EL (2013) The effects of treatment on itch in atopic dermatitis. Dermatol Ther 26:110–119PubMedPubMedCentralCrossRef

280.

Hoare C, Li Wan Po A, Williams H (2000) Systematic review of treatments for atopic eczema. Health Technol Assess 4:1–191PubMedPubMedCentral

281.

Wahlgren CF, Hagermark O, Bergstrom R, Hedin B (1988) Evaluation of a new method of assessing pruritus and antipruritic drugs. Skin Pharmacol 1:3–13PubMedCrossRef

282.

Maloney JM, Morman MR, Stewart DM, Tharp MD, Brown JJ, Rajagopalan R (1998) Clobetasol propionate emollient 0.05% in the treatment of atopic dermatitis. Int J Dermatol 37:142–144PubMedCrossRef

283.

Roth HL, Brown EP (1978) Hydrocortisone valerate. Double-blind comparison with two other topical steroids. Cutis 21:695–698PubMed

284.

Kaplan RJ, Daman L, Rosenberg EW, Feigenbaum S (1978) Topical use of caffeine with hydrocortisone in the treatment of atopic dermatitis. Arch Dermatol 114:60–62PubMedCrossRef

285.

Hanifin JM, Thurston M, Omoto M, Cherill R, Tofte SJ, Graeber M (2001) The eczema area and severity index (EASI): assessment of reliability in atopic dermatitis. EASI Evaluator Group. Exp Dermatol 10:11–18PubMedCrossRef

286.

Luger T, Van Leent EJ, Graeber M, Hedgecock S, Thurston M, Kandra A et al (2001) SDZ ASM 981: an emerging safe and effective treatment for atopic dermatitis. Br J Dermatol 144:788–794PubMedCrossRef

287.

Sher LG, Chang J, Patel IB, Balkrishnan R, Fleischer AB Jr (2012) Relieving the pruritus of atopic dermatitis: a meta-analysis. Acta Derm Venereol 92:455–461PubMedCrossRef

288.

Chang KT, Lin HY, Kuo CH, Hung CH (2015) Tacrolimus suppresses atopic dermatitis-associated cytokines and chemokines in monocytes. J Microbiol Immunol Infect doi:. doi:10.1016/j.jmii.2014.07.006

289.

Kaufmann R, Bieber T, Helgesen AL, Andersen BL, Luger T, Poulin Y et al (2006) Onset of pruritus relief with pimecrolimus cream 1% in adult patients with atopic dermatitis: a randomized trial. Allergy 61:375–381PubMedCrossRef

290.

Bornhovd EC, Burgdorf WH, Wollenberg A (2002) Immunomodulatory macrolactams for topical treatment of inflammatory skin diseases. Curr Opin Investig Drugs 3:708–712PubMed

291.

Stander S, Schurmeyer-Horst F, Luger TA, Weisshaar E (2006) Treatment of pruritic diseases with topical calcineurin inhibitors. Ther Clin Risk Manag 2:213–218PubMedPubMedCentralCrossRef

292.

Senba E, Katanosaka K, Yajima H, Mizumura K (2004) The immunosuppressant FK506 activates capsaicin- and bradykinin-sensitive DRG neurons and cutaneous C-fibers. Neurosci Res 50:257–262PubMedCrossRef

293.

Thaci D, Reitamo S, Gonzalez Ensenat MA, Moss C, Boccaletti V, Cainelli T et al (2008) Proactive disease management with 0.03% tacrolimus ointment for children with atopic dermatitis: results of a randomized, multicentre, comparative study. Br J Dermatol 159:1348–1356PubMedCrossRef

294.

Undre NA, Moloney FJ, Ahmadi S, Stevenson P, Murphy GM (2009) Skin and systemic pharmacokinetics of tacrolimus following topical application of tacrolimus ointment in adults with moderate to severe atopic dermatitis. Br J Dermatol 160:665–669PubMedCrossRef

295.

Lakhanpaul M, Davies T, Allen BR, Schneider D (2006) Low systemic exposure in infants with atopic dermatitis in a 1-year pharmacokinetic study with pimecrolimus cream 1%*. Exp Dermatol 15:138–141PubMedCrossRef

296.

Van Leent EJ, Ebelin ME, Burtin P, Dorobek B, Spuls PI, Bos JD (2002) Low systemic exposure after repeated topical application of Pimecrolimus (Elidel), SD Z ASM 981) in patients with atopic dermatitis. Dermatology 204:63–68PubMedCrossRef

297.

Van Leent EJ, De Vries HJ, Ebelin ME, Burtin P, Scott G, Bos JD (2007) Blood concentrations of pimecrolimus in adult patients with atopic dermatitis following intermittent administration of pimecrolimus cream 1% (Elidel) for up to 1 year. J Dermatolog Treat 18:19–22PubMedCrossRef

298.

Siegfried EC, Jaworski JC, Hebert AA (2013) Topical calcineurin inhibitors and lymphoma risk: evidence update with implications for daily practice. Am J Clin Dermatol 14:163–178PubMedPubMedCentralCrossRef

299.

Remitz A, Harper J, Rustin M, Goldschmidt WF, Palatsi R, van der Valk PG et al (2007) Long-term safety and efficacy of tacrolimus ointment for the treatment of atopic dermatitis in children. Acta Derm Venereol 87:54–61PubMedCrossRef

300.

Schachner LA, Lamerson C, Sheehan MP, Boguniewicz M, Mosser J, Raimer S et al (2005) Tacrolimus ointment 0.03% is safe and effective for the treatment of mild to moderate atopic dermatitis in pediatric patients: results from a randomized, double-blind, vehicle-controlled study. Pediatrics 116:e334–e342PubMedCrossRef

301.

Tan J, Langley R (2004) Safety and efficacy of tacrolimus ointment 0.1% (Protopic) in atopic dermatitis: a Canadian open-label multicenter study. J Cutan Med Surg 8:213–219PubMedCrossRef

302.

McCollum AD, Paik A, Eichenfield LF (2010) The safety and efficacy of tacrolimus ointment in pediatric patients with atopic dermatitis. Pediatr Dermatol 27:425–436PubMedCrossRef

303.

Segal AO, Ellis AK, Kim HL (2013) CSACI position statement: safety of topical calcineurin inhibitors in the management of atopic dermatitis in children and adults. Allergy Asthma Clin Immunol 9(1):24. doi:10.1186/1710-1492-9-24 PubMedPubMedCentralCrossRef

304.

Ohtsuki M, Ohara H, Santos V et al. (2011) Safety profiles of two large cohort studies of tacrolimus ointment for the treatment of atopic dermatitis: a prospective pediatric longitudinal evaluation study (APPLES) and Japanese long-term safety study (J-LSS). Proceedings of the 22nd World Congress of Dermatology Meeting, Seoul, Korea

305.

Kothary N (2011) Update on post-marketing AERS cases of pediatric malignancies reports with topical pimecrolimus and tacrolimus use. Food and Drug Administration Pediatric Advisory Committee. http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/PediatricAdvisoryCommittee/UCM255412.pdf

306.

Jancso N, Jancso-Gabor A, Szolcsanyi J (1967) Direct evidence for neurogenic inflammation and its prevention by denervation and by pretreatment with capsaicin. Br J Pharmacol Chemother 31:138–151PubMedPubMedCentralCrossRef

307.

Tarng DC, Cho YL, Liu HN, Huang TP (1996) Hemodialysis-related pruritus: a double-blind, placebo-controlled, crossover study of capsaicin 0.025% cream. Nephron 72:617–622PubMedCrossRef

308.

Wallengren J, Klinker M (1995) Successful treatment of notalgia paresthetica with topical capsaicin: vehicle-controlled, double-blind, crossover study. J Am Acad Dermatol 32:287–289PubMedCrossRef

309.

Stander S, Luger T, Metze D (2001) Treatment of prurigo nodularis with topical capsaicin. J Am Acad Dermatol 44:471–478PubMedCrossRef

310.

Caterina MJ, Schumacher MA, Tominaga M, Rosen TA, Levine JD, Julius D (1997) The capsaicin receptor: a heat-activated ion channel in the pain pathway. Nature 389:816–824PubMedCrossRef

311.

Basbaum AI, Bautista DM, Scherrer G, Julius D (2009) Cellular and molecular mechanisms of pain. Cell 139:267–284PubMedPubMedCentralCrossRef

312.

Dray A (1992) Neuropharmacological mechanisms of capsaicin and related substances. Biochem Pharmacol 44:611–615PubMedCrossRef

313.

Hong J, Buddenkotte J, Berger TG, Steinhoff M (2011) Management of itch in atopic dermatitis. Semin Cutan Med Surg 30:71–86PubMedPubMedCentralCrossRef

314.

Papoiu AD, Yosipovitch G (2010) Topical capsaicin. The fire of a ‘hot’ medicine is reignited. Expert Opin Pharmacother 11:1359–1371PubMedCrossRef

315.

Yosipovitch G, Maibach HI, Rowbotham MC (1999) Effect of EMLA pre-treatment on capsaicin-induced burning and hyperalgesia. Acta Derm Venereol 79:118–121PubMedCrossRef

316.

Yosipovitch G, Maibach HI (1997) Effect of topical pramoxine on experimentally induced pruritus in humans. J Am Acad Dermatol 37:278–280PubMedCrossRef

317.

Shuttleworth D, Hill S, Marks R, Connelly DM (1988) Relief of experimentally induced pruritus with a novel eutectic mixture of local anaesthetic agents. Br J Dermatol 119:535–540PubMedCrossRef

318.

Sandroni P (2002) Central neuropathic itch: a new treatment option? Neurology 59:778–779PubMedCrossRef

319.

Young TA, Patel TS, Camacho F, Clark A, Freedman BI, Kaur M et al (2009) A pramoxine-based anti-itch lotion is more effective than a control lotion for the treatment of uremic pruritus in adult hemodialysis patients. J Dermatolog Treat 20:76–81PubMedCrossRef

320.

Patel T, Yosipovitch G (2010) Therapy of pruritus. Expert Opin Pharmacother 11:1673–1682PubMedPubMedCentralCrossRef

321.

Freitag G, Hoppner T (1997) Results of a postmarketing drug monitoring survey with a polidocanol-urea preparation for dry, itching skin. Curr Med Res Opin 13:529–537PubMedCrossRef

322.

Oranje AP, Devillers AC, Kunz B, Jones SL, DeRaeve L, Van Gysel D et al (2006) Treatment of patients with atopic dermatitis using wet-wrap dressings with diluted steroids and/or emollients. An expert panel’s opinion and review of the literature. J Eur Acad Dermatol Venereol 20:1277–1286PubMedCrossRef

323.

Devillers AC, de Waard-van der Spek FB, Mulder PG, Oranje AP (2002) Treatment of refractory atopic dermatitis using ‘wet-wrap’ dressings and diluted corticosteroids: results of standardized treatment in both children and adults. Dermatology 204:50–55PubMedCrossRef

324.

Devillers AC, Oranje AP (2006) Efficacy and safety of ‘wet-wrap’ dressings as an intervention treatment in children with severe and/or refractory atopic dermatitis: a critical review of the literature. Br J Dermatol 154:579–585PubMedCrossRef

325.

Wolkerstorfer A, Visser RL, De Waard van der Spek FB, Mulder PG, Oranje AP (2000) Efficacy and safety of wet-wrap dressings in children with severe atopic dermatitis: influence of corticosteroid dilution. Br J Dermatol 143:999–1004PubMedCrossRef

326.

Pei AY, Chan HH, Ho KM (2001) The effectiveness of wet wrap dressings using 0.1% mometasone furoate and 0.005% fluticasone proprionate ointments in the treatment of moderate to severe atopic dermatitis in children. Pediatr Dermatol 18:343–348PubMedCrossRef

327.

Schnopp C, Holtmann C, Stock S, Remling R, Folster-Holst R, Ring J et al (2002) Topical steroids under wet-wrap dressings in atopic dermatitis—a vehicle-controlled trial. Dermatology 204:56–59PubMedCrossRef

328.

Janmohamed SR, Oranje AP, Devillers AC, Rizopoulos D, van Praag MC, Van Gysel D et al (2014) The proactive wet-wrap method with diluted corticosteroids versus emollients in children with atopic dermatitis: a prospective, randomized, double-blind, placebo-controlled trial. J Am Acad Dermatol 70:1076–1082PubMedCrossRef

329.

Ryan C, Shaw RE, Cockerell CJ, Hand S, Ghali FE (2013) Novel sodium hypochlorite cleanser shows clinical response and excellent acceptability in the treatment of atopic dermatitis. Pediatr Dermatol 30:308–315PubMedPubMedCentralCrossRef

330.

Lee M, Van Bever H (2014) The role of antiseptic agents in atopic dermatitis. Asia Pac Allerg 4:230–240CrossRef

331.

Huang JT, Abrams M, Tlougan B, Rademaker A, Paller AS (2009) Treatment of Staphylococcus aureus colonization in atopic dermatitis decreases disease severity. Pediatrics 123:e808–e814PubMedCrossRef

332.

Wong SM, Ng TG, Baba R (2013) Efficacy and safety of sodium hypochlorite (bleach) baths in patients with moderate to severe atopic dermatitis in Malaysia. J Dermatol 40:874–880PubMedCrossRef

333.

Lebwohl MG, Del Rosso JQ, Abramovits W, Berman B, Cohen DE, Guttman E et al (2013) Pathways to managing atopic dermatitis: consensus from the experts. J Clin Aesthet Dermatol 6:S2–S18PubMedPubMedCentral

334.

Draelos Z, Cash K (2013) Evaluation of a gel formulation of hypochlorous acid and sodium hypochlorite to reduce pruritus in mild to moderate atopic dermatitis. 2013 Winter Clinical Dermatology Conference; January 18–23, 2013; Kauai, HI

335.

Hahn GS (1999) Strontium is a potent and selective inhibitor of sensory irritation. Dermatol Surg 25:689–694PubMedCrossRef

336.

Zhai H, Hannon W, Hahn GS, Pelosi A, Harper RA, Maibach HI (2000) Strontium nitrate suppresses chemically-induced sensory irritation in humans. Contact Dermatitis 42:98–100PubMedCrossRef

337.

Zhai H, Hannon W, Hahn GS, Harper RA, Pelosi A, Maibach HI (2000) Strontium nitrate decreased histamine-induced itch magnitude and duration in man. Dermatology 200:244–246PubMedCrossRef

338.

Papoiu AD, Valdes-Rodriguez R, Nattkemper LA, Chan YH, Hahn GS, Yosipovitch G (2013) A novel topical formulation containing strontium chloride significantly reduces the intensity and duration of cowhage-induced itch. Acta Derm Venereol 93:520–526PubMedCrossRef

339.

Johanek LM, Meyer RA, Hartke T, Hobelmann JG, Maine DN, LaMotte RH et al (2007) Psychophysical and physiological evidence for parallel afferent pathways mediating the sensation of itch. J Neurosci 27:7490–7497PubMedCrossRef

340.

Godlewski G, Offertaler L, Wagner JA, Kunos G (2009) Receptors for acylethanolamides—GPR55 and GPR119. Prostaglandins Other Lipid Mediat 89:105–111PubMedPubMedCentralCrossRef

341.

O’Sullivan SE, Kendall DA (2010) Cannabinoid activation of peroxisome proliferator-activated receptors: potential for modulation of inflammatory disease. Immunobiology 215:611–616PubMedCrossRef

342.

Szepietowski JC, Szepietowski T, Reich A (2005) Efficacy and tolerance of the cream containing structured physiological lipids with endocannabinoids in the treatment of uremic pruritus: a preliminary study. Acta Dermatovenerol Croat 13:97–103PubMed

343.

Eberlein B, Eicke C, Reinhardt HW, Ring J (2008) Adjuvant treatment of atopic eczema: assessment of an emollient containing N-palmitoylethanolamine (ATOPA study). J Eur Acad Dermatol Venereol 22:73–82PubMed

344.

Stander S, Reinhardt HW, Luger TA (2006) Topical cannabinoid agonists. An effective new possibility for treating chronic pruritus. Hautarzt 57:801–807PubMedCrossRef

345.

Rivard J, Lim HW (2005) Ultraviolet phototherapy for pruritus. Dermatol Ther 18:344–354PubMedCrossRef

346.

Wallengren J, Sundler F (2004) Phototherapy reduces the number of epidermal and CGRP-positive dermal nerve fibres. Acta Derm Venereol 84:111–115PubMedCrossRef

347.

Jekler J, Larko O (1988) UVB phototherapy of atopic dermatitis. Br J Dermatol 119:697–705PubMedCrossRef

348.

Jekler J, Larko O (1990) Combined UVA-UVB versus UVB phototherapy for atopic dermatitis: a paired-comparison study. J Am Acad Dermatol 22:49–53PubMedCrossRef

349.

Clayton TH, Clark SM, Turner D, Goulden V (2007) The treatment of severe atopic dermatitis in childhood with narrowband ultraviolet B phototherapy. Clin Exp Dermatol 32:28–33PubMed

350.

von Kobyletzki G, Pieck C, Hoffmann K, Freitag M, Altmeyer P (1999) Medium-dose UVA1 cold-light phototherapy in the treatment of severe atopic dermatitis. J Am Acad Dermatol 41:931–937CrossRef

351.

Reynolds NJ, Franklin V, Gray JC, Diffey BL, Farr PM (2001) Narrow-band ultraviolet B and broad-band ultraviolet A phototherapy in adult atopic eczema: a randomised controlled trial. Lancet 357:2012–2016PubMedCrossRef

352.

Der-Petrossian M, Seeber A, Honigsmann H, Tanew A (2000) Half-side comparison study on the efficacy of 8-methoxypsoralen bath-PUVA versus narrow-band ultraviolet B phototherapy in patients with severe chronic atopic dermatitis. Br J Dermatol 142:39–43PubMedCrossRef

353.

Baltas E, Csoma Z, Bodai L, Ignacz F, Dobozy A, Kemeny L (2006) Treatment of atopic dermatitis with the xenon chloride excimer laser. J Eur Acad Dermatol Venereol 20:657–660PubMedCrossRef

354.

Nistico SP, Saraceno R, Capriotti E, Felice CD, Chimenti S (2008) Efficacy of monochromatic excimer light (308 nm) in the treatment of atopic dermatitis in adults and children. Photomed Laser Surg 26:14–18PubMedCrossRef

355.

Schmitt J, Schmitt NM, Kirch W, Meurer M (2009) Outpatient care and medical treatment of children and adults with atopic eczema. J Dtsch Dermatol Ges 7:345–351PubMed

356.

Roekevisch E, Spuls PI, Kuester D, Limpens J, Schmitt J (2014) Efficacy and safety of systemic treatments for moderate-to-severe atopic dermatitis: a systematic review. J Allergy Clin Immunol 133:429–438PubMedCrossRef

357.

Schmitt J, Schmitt N, Meurer M (2007) Cyclosporin in the treatment of patients with atopic eczema—a systematic review and meta-analysis. J Eur Acad Dermatol Venereol 21:606–619PubMed

358.

Harper JI, Ahmed I, Barclay G, Lacour M, Hoeger P, Cork MJ et al (2000) Cyclosporin for severe childhood atopic dermatitis: short course versus continuous therapy. Br J Dermatol 142:52–58PubMedCrossRef

359.

Pacor ML, Di Lorenzo G, Martinelli N, Mansueto P, Rini GB, Corrocher R (2004) Comparing tacrolimus ointment and oral cyclosporine in adult patients affected by atopic dermatitis: a randomized study. Clin Exp Allergy 34:639–645PubMedCrossRef

360.

El-Khalawany MA, Hassan H, Shaaban D, Ghonaim N, Eassa B (2013) Methotrexate versus cyclosporine in the treatment of severe atopic dermatitis in children: a multicenter experience from Egypt. Eur J Pediatr 172:351–356PubMedCrossRef

361.

Neuber K, Schwartz I, Itschert G, Dieck AT (2000) Treatment of atopic eczema with oral mycophenolate mofetil. Br J Dermatol 143:385–391PubMedCrossRef

362.

Haeck IM, Knol MJ, Ten Berge O, van Velsen SG, de Bruin-Weller MS, Bruijnzeel-Koomen CA (2011) Enteric-coated mycophenolate sodium versus cyclosporin A as long-term treatment in adult patients with severe atopic dermatitis: a randomized controlled trial. J Am Acad Dermatol 64:1074–1084PubMedCrossRef

363.

Berth-Jones J, Takwale A, Tan E, Barclay G, Agarwal S, Ahmed I et al (2002) Azathioprine in severe adult atopic dermatitis: a double-blind, placebo-controlled, crossover trial. Br J Dermatol 147:324–330PubMedCrossRef

364.

Meggitt SJ, Gray JC, Reynolds NJ (2006) Azathioprine dosed by thiopurine methyltransferase activity for moderate-to-severe atopic eczema: a double-blind, randomised controlled trial. Lancet 367:839–846PubMedCrossRef

365.

Schram ME, Roekevisch E, Leeflang MM, Bos JD, Schmitt J, Spuls PI (2011) A randomized trial of methotrexate versus azathioprine for severe atopic eczema. J Allergy Clin Immunol 128:353–359PubMedCrossRef

366.

Fuggle NR, Bragoli W, Mahto A, Glover M, Martinez AE, Kinsler VA (2015) The adverse effect profile of oral azathioprine in pediatric atopic dermatitis, and recommendations for monitoring. J Am Acad Dermatol 72:108–114PubMedPubMedCentralCrossRef

367.

Vachiramon V, Tey HL, Thompson AE, Yosipovitch G (2012) Atopic dermatitis in African American children: addressing unmet needs of a common disease. Pediatr Dermatol 29:395PubMedCrossRef

368.

Schmitt J, Schakel K, Folster-Holst R, Bauer A, Oertel R, Augustin M et al (2010) Prednisolone vs. ciclosporin for severe adult eczema. An investigator-initiated double-blind placebo-controlled multicentre trial. Br J Dermatol 162:661–668PubMedCrossRef

369.

Stander S, Luger TA (2010) Itch in atopic dermatitis—pathophysiology and treatment. Acta Dermatovenerol Croat 18:289–296PubMed

370.

Hannuksela M, Kalimo K, Lammintausta K, Mattila T, Turjanmaa K, Varjonen E et al (1993) Dose ranging study: cetirizine in the treatment of atopic dermatitis in adults. Ann Allergy 70:127–133PubMed

371.

Diepgen TL, Early Treatment of the Atopic Child Study Group (2002) Long-term treatment with cetirizine of infants with atopic dermatitis: a multi-country, double-blind, randomized, placebo-controlled trial (the ETAC trial) over 18 months. Pediatr Allergy Immunol 13:278–286PubMedCrossRef

372.

Davis MP, Frandsen JL, Walsh D, Andresen S, Taylor S (2003) Mirtazapine for pruritus. J Pain Symptom Manage 25:288–291PubMedCrossRef

373.

Hundley JL, Yosipovitch G (2004) Mirtazapine for reducing nocturnal itch in patients with chronic pruritus: a pilot study. J Am Acad Dermatol 50:889–891PubMedCrossRef

374.

Demierre MF, Taverna J (2006) Mirtazapine and gabapentin for reducing pruritus in cutaneous T-cell lymphoma. J Am Acad Dermatol 55:543–544PubMedCrossRef

375.

Stimmel GL, Dopheide JA, Stahl SM (1997) Mirtazapine: an antidepressant with noradrenergic and specific serotonergic effects. Pharmacotherapy 17:10–21PubMed

376.

Stander S, Weisshaar E, Luger TA (2008) Neurophysiological and neurochemical basis of modern pruritus treatment. Exp Dermatol 17:161–169PubMedCrossRef

377.

Dawn AG, Yosipovitch G (2006) Butorphanol for treatment of intractable pruritus. J Am Acad Dermatol 54:527–531PubMedCrossRef

378.

Yosipovitch G, Greaves MW, Schmelz M (2003) Itch. Lancet 361:690–694PubMedCrossRef

379.

Pan ZZ (1998) mu-Opposing actions of the kappa-opioid receptor. Trends Pharmacol Sci 19:94–98PubMedCrossRef

380.

Umeuchi H, Togashi Y, Honda T, Nakao K, Okano K, Tanaka T et al (2003) Involvement of central mu-opioid system in the scratching behavior in mice, and the suppression of it by the activation of kappa-opioid system. Eur J Pharmacol 477:29–35PubMedCrossRef

381.

Baumer W, Hoppmann J, Rundfeldt C, Kietzmann M (2007) Highly selective phosphodiesterase 4 inhibitors for the treatment of allergic skin diseases and psoriasis. Inflamm Allergy Drug Targets 6:17–26PubMedCrossRef

382.

Hanifin JM, Chan SC, Cheng JB, Tofte SJ, Henderson WR Jr, Kirby DS et al (1996) Type 4 phosphodiesterase inhibitors have clinical and in vitro anti-inflammatory effects in atopic dermatitis. J Investig Dermatol 107:51–56PubMedCrossRef

383.

Hoppmann J, Baumer W, Galetzka C, Hofgen N, Kietzmann M, Rundfeldt C (2005) The phosphodiesterase 4 inhibitor AWD 12-281 is active in a new guinea-pig model of allergic skin inflammation predictive of human skin penetration and suppresses both Th1 and Th2 cytokines in mice. J Pharm Pharmacol 57:1609–1617PubMedCrossRef

384.

Baumer W, Gorr G, Hoppmann J, Ehinger AM, Rundfeldt C, Kietzmann M (2003) AWD 12-281, a highly selective phosphodiesterase 4 inhibitor, is effective in the prevention and treatment of inflammatory reactions in a model of allergic dermatitis. J Pharm Pharmacol 55:1107–1114PubMedCrossRef

385.

Samrao A, Berry TM, Goreshi R, Simpson EL (2012) A pilot study of an oral phosphodiesterase inhibitor (apremilast) for atopic dermatitis in adults. Arch Dermatol 148:890–897PubMedPubMedCentralCrossRef

386.

Bhattacharya TSJ (2014) Efficacy of systemic treatments for atopic dermatitis in racial and ethnic minorities in the United States. JAMA Dermatol 150:1232–1234PubMedCrossRef

387.

Belgrade MJ, Solomon LM, Lichter EA (1984) Effect of acupuncture on experimentally induced itch. Acta Derm Venereol 64:129–133PubMed

388.

Lundeberg T, Bondesson L, Thomas M (1987) Effect of acupuncture on experimentally induced itch. Br J Dermatol 117:771–777PubMedCrossRef

389.

Pfab F, Hammes M, Backer M, Huss-Marp J, Athanasiadis GI, Tolle TR et al (2005) Preventive effect of acupuncture on histamine-induced itch: a blinded, randomized, placebo-controlled, crossover trial. J Allergy Clin Immunol 116:1386–1388PubMedCrossRef

390.

Kesting MR, Thurmuller P, Holzle F, Wolff KD, Holland-Letz T, Stucker M (2006) Electrical ear acupuncture reduces histamine-induced itch (alloknesis). Acta Derm Venereol 86:399–403PubMedCrossRef

391.

Pfab F, Huss-Marp J, Gatti A, Fuqin J, Athanasiadis GI, Irnich D et al (2010) Influence of acupuncture on type I hypersensitivity itch and the wheal and flare response in adults with atopic eczema—a blinded, randomized, placebo-controlled, crossover trial. Allergy 65:903–910PubMedCrossRef

392.

Pfab F, Kirchner MT, Huss-Marp J, Schuster T, Schalock PC, Fuqin J et al (2012) Acupuncture compared with oral antihistamine for type I hypersensitivity itch and skin response in adults with atopic dermatitis: a patient- and examiner-blinded, randomized, placebo-controlled, crossover trial. Allergy 67:566–573PubMedPubMedCentralCrossRef

393.

Napadow V, Li A, Loggia ML, Kim J, Schalock PC, Lerner E et al (2014) The brain circuitry mediating antipruritic effects of acupuncture. Cereb Cortex 24:873–882PubMedCrossRef

394.

Chida Y, Steptoe A, Hirakawa N, Sudo N, Kubo C (2007) The effects of psychological intervention on atopic dermatitis. A systematic review and meta-analysis. Int Arch Allergy Immunol 144:1–9PubMedCrossRef

395.

Lavda AC, Webb TL, Thompson AR (2012) A meta-analysis of the effectiveness of psychological interventions for adults with skin conditions. Br J Dermatol 167:970–979PubMedCrossRef

396.

Azrin NH, Nunn RG (1973) Habit-reversal: a method of eliminating nervous habits and tics. Behav Res Ther 11:619–628PubMedCrossRef

397.

Rosenbaum MS, Ayllon T (1981) The behavioral treatment of neurodermatitis through habit-reversal. Behav Res Ther 19:313–318PubMedCrossRef

398.

Noren P (1995) Habit reversal: a turning point in the treatment of atopic dermatitis. Clin Exp Dermatol 20:2–5PubMedCrossRef

399.

Melin L, Frederiksen T, Noren P, Swebilius BG (1986) Behavioural treatment of scratching in patients with atopic dermatitis. Br J Dermatol 115:467–474PubMedCrossRef

400.

Noren P, Melin L (1989) The effect of combined topical steroids and habit-reversal treatment in patients with atopic dermatitis. Br J Dermatol 121:359–366PubMedCrossRef

401.

Ehlers A, Stangier U, Gieler U (1995) Treatment of atopic dermatitis: a comparison of psychological and dermatological approaches to relapse prevention. J Consult Clin Psychol 63:624–635PubMedCrossRef

402.

van Os-Medendorp H, Eland-de Kok PC, Ros WJ, Bruijnzeel-Koomen CA, Grypdonck M (2007) The nursing programme ‘Coping with itch’: a promising intervention for patients with chronic pruritic skin diseases. J Clin Nurs 16:1238–1246PubMedCrossRef

403.

Evers AW, Duller P, de Jong EM, Otero ME, Verhaak CM, van der Valk PG et al (2009) Effectiveness of a multidisciplinary itch-coping training programme in adults with atopic dermatitis. Acta Derm Venereol 89:57–63PubMedCrossRef

404.

Balkrishnan R (2005) The importance of medication adherence in improving chronic-disease related outcomes: what we know and what we need to further know. Med Care 43:517–520PubMedCrossRef

405.

Hodari KT, Nanton JR, Carroll CL, Feldman SR, Balkrishnan R (2006) Adherence in dermatology: a review of the last 20 years. J Dermatolog Treat 17:136–142PubMedCrossRef

406.

Elwyn G, Edwards A, Britten N (2003) What information do patients need about medicines? “Doing prescribing”: how doctors can be more effective. BMJ 327:864–867PubMedPubMedCentralCrossRef

407.

Balkrishnan R, Carroll CL, Camacho FT, Feldman SR (2003) Electronic monitoring of medication adherence in skin disease: results of a pilot study. J Am Acad Dermatol 49:651–654PubMedCrossRef

408.

Furue M, Onozuka D, Takeuchi S, Murota H, Sugaya M, Masuda K et al (2015) Poor adherence to oral and topical medication in 3096 dermatological patients as assessed by the Morisky Medication Adherence Scale-8. Br J Dermatol 172:272PubMedCrossRef

409.

Fischer G (1996) Compliance problems in paediatric atopic eczema. Australas J Dermatol 37(Suppl 1):S10–S13PubMedCrossRef

410.

Charman CR, Venn AJ, Williams HC (2004) The patient-oriented eczema measure: development and initial validation of a new tool for measuring atopic eczema severity from the patients’ perspective. Arch Dermatol 140:1513–1519PubMedCrossRef

411.

Cork MJ, Britton J, Butler L, Young S, Murphy R, Keohane SG (2003) Comparison of parent knowledge, therapy utilization and severity of atopic eczema before and after explanation and demonstration of topical therapies by a specialist dermatology nurse. Br J Dermatol 149:582–589PubMedCrossRef

412.

Chisolm SS, Taylor SL, Balkrishnan R, Feldman SR (2008) Written action plans: potential for improving outcomes in children with atopic dermatitis. J Am Acad Dermatol 59:677–683PubMedCrossRef

413.

Ntuen E, Taylor SL, Kinney M, O’Neill JL, Krowchuk DP, Feldman SR (2010) Physicians’ perceptions of an eczema action plan for atopic dermatitis. J Dermatolog Treat 21:28–33PubMedCrossRef

414.

Gonzales AJ, Bowman JW, Fici GJ, Zhang M, Mann DW, Mitton-Fry M (2014) Oclacitinib (APOQUEL((R))) is a novel Janus kinase inhibitor with activity against cytokines involved in allergy. J Vet Pharmacol Ther 37:317–324PubMedPubMedCentralCrossRef

415.

Kumar N, Goldminz AM, Kim N, Gottlieb AB (2013) Phosphodiesterase 4-targeted treatments for autoimmune diseases. BMC Med 11:96. doi:10.1186/1741-7015-11-96 PubMedPubMedCentralCrossRef

416.

Akama T, Baker SJ, Zhang YK, Hernandez V, Zhou H, Sanders V et al (2009) Discovery and structure-activity study of a novel benzoxaborole anti-inflammatory agent (AN2728) for the potential topical treatment of psoriasis and atopic dermatitis. Bioorg Med Chem Lett 19:2129–2132PubMedCrossRef

417.

Nazarian R, Weinberg JM (2009) AN-2728, a PDE4 inhibitor for the potential topical treatment of psoriasis and atopic dermatitis. Curr Opin Investig Drugs 10:1236–1242PubMed

418.

Furue M, Kitahara Y, Akama H, Hojo S, Hayashi N, Nakagawa H (2014) Safety and efficacy of topical E6005, a phosphodiesterase 4 inhibitor, in Japanese adult patients with atopic dermatitis: results of a randomized, vehicle-controlled, multicenter clinical trial. J Dermatol 41:577PubMedCrossRef

Title: Mediators of Chronic Pruritus in Atopic Dermatitis: Getting the Itch Out?
Authors: Nicholas K. Mollanazar
Peter K. Smith
Gil Yosipovitch
Publication date: 01-12-2016
Publisher: Springer US
Published in: Clinical Reviews in Allergy & Immunology / Issue 3/2016
Print ISSN: 1080-0549
Electronic ISSN: 1559-0267
DOI: https://doi.org/10.1007/s12016-015-8488-5

Obesity Clinical Trial Summary

At a glance: The STEP trials

A round-up of the STEP phase 3 clinical trials evaluating semaglutide for weight loss in people with overweight or obesity.

Developed by: Springer Medicine

Highlights from the ACC 2024 Congress

Year in Review: Pediatric cardiology

Pediatric Cardiology Video

Watch Dr. Anne Marie Valente present the last year's highlights in pediatric and congenital heart disease in the official ACC.24 Year in Review session.

Year in Review: Pulmonary vascular disease

Cardiopulmonary Comorbidity Video

The last year's highlights in pulmonary vascular disease are presented by Dr. Jane Leopold in this official video from ACC.24.

Year in Review: Valvular heart disease

Valvular Heart Disease Video

Watch Prof. William Zoghbi present the last year's highlights in valvular heart disease from the official ACC.24 Year in Review session.

Year in Review: Heart failure and cardiomyopathies

Heart Failure Video

Watch this official video from ACC.24. Dr. Biykem Bozkurt discusses last year's major advances in heart failure and cardiomyopathies.

ACC 2024 Congress Coverage

Year in Review: Heart failure and cardiomyopathies

Heart Failure Video

Watch this official video from ACC.24. Dr. Biykem Bozkurt discusses last year's major advances in heart failure and cardiomyopathies.

Watch now

Semaglutide benefits people with type 2 diabetes and obesity-related heart failure

16-04-2024 Type 2 Diabetes News

Incentivised to exercise

11-04-2024 Lifestyle Modifications News

New intervention for STEMI-related cardiogenic shock

10-04-2024 Myocardial Infarction News

» View more highlights on the ACC 2024 congress hub page

Image Credits

STEP AAG HeroTeaserCollection image/© Tarek / Generated with AI / Stock.adobe.com, ACC 2024 Pediatric and Congenital Heart Disease: Year in Review/© 2024 American College of Cardiology, ACC 2024 Pulmonary Vascular Disease: Year in Review/© 2024 American College of Cardiology, ACC 2024 Valvular Heart Disease: Year in Review/© 2024 American College of Cardiology, ACC 2024 HF and Cardiomyopathies: Year in Review/© 2024 American College of Cardiology, Woman out walking/© Seventyfour / stock.adobe.com (symbolic image with model), Woman checking smartwatch /© saltdium / stock.adobe.com (symbolic image with model), Cardiac catheterization/© Damian / stock.adobe.com

At a glance: The STEP trials

Springer Medicine

Abstract

Please log in to get access to this content

Other articles of this Issue 3/2016

Atopy and Specific Cancer Sites: a Review of Epidemiological Studies

The Basis of Structure/Function Claims of Nutraceuticals

Treatment of Eczema: Corticosteroids and Beyond

Cutaneous Manifestations in Dermatomyositis: Key Clinical and Serological Features—a Comprehensive Review

The Genetics and Epigenetics of Atopic Dermatitis—Filaggrin and Other Polymorphisms

Impact of Immunoglobulin Therapy in Pediatric Disease: a Review of Immune Mechanisms

Highlights from the ACC 2024 Congress

ACC 2024 Congress Coverage