Journal of Dermatological Science 73 (2014) 91–100

Contents lists available at ScienceDirect

Journal of Dermatological Science journal homepage: www.jdsjournal.com

Invited review article

Future treatment options for atopic dermatitis – Small molecules and beyond Knut Scha¨kel *, Thomas Do¨bel, Ina Bosselmann Department of Dermatology, University Hospital Heidelberg, Heidelberg, Germany

A R T I C L E I N F O

A B S T R A C T

Article history: Received 20 September 2013 Received in revised form 12 November 2013 Accepted 19 November 2013

Atopic dermatitis (AD) is a common eczematous skin disease with a chronic and relapsing course. Current therapeutic options for moderate to severe AD in children and adults are unsatisfactory. Along with the success of basic research to define pathogenesis-related targets, novel small molecule inhibitors and biologics for the treatment of AD have been developed. These compounds focus on the specific reduction of pruritus, interfere with the pro-allergic Th2deviation of the immune system or inhibit inflammatory pathways in the skin. Based on studies registered at ClinicalTrials.gov we present novel treatment strategies of AD, their molecular mechanisms of action, and discuss the current status of the clinical results. As many of the new compounds target pathogenesis-related traits of the disease, we face a new era in the treatment and understanding of AD. ß 2013 Japanese Society for Investigative Dermatology. Published by Elsevier Ireland Ltd. All rights reserved.

Keywords: Atopic dermatitis Therapy Review Pruritus IgE Th2

Contents 1. 2.

3.

4.

5.

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Targeting inflammatory pathways . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Inhibiting the degradation of cyclic adenosine monophosphate (cAMP) . 2.1. Specific inhibition of NF-kB . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.2. Glucocorticoid receptor agonists . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.3. Cis-urocanic acid. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.4. Nonsteroidal antiinflammatory compound WBI-1001 . . . . . . . . . . . . . . . 2.5. Targeting specific immune targets with biologics . . . . . . . . . . . . . . . . . . . . . . . . 3.1. Anti-IL-1b . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Targeting CD2 with soluble LFA-3 (CD58)-Fc . . . . . . . . . . . . . . . . . . . . . . 3.2. Blocking the IL-4-receptor a-chain . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.3. Blocking thymic stromal lymphopoetin (TSLP) . . . . . . . . . . . . . . . . . . . . . 3.4. 3.5. Targeting IgE . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Targeting pruritus . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Inhibition of chymase-activity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.1. Topical antihistamine and antidepressant . . . . . . . . . . . . . . . . . . . . . . . . . 4.2. m-Opioid receptor (MOR)-antagonist . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.3. Prostanoid DP1 receptor agonist. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.4. Cannabinoid receptor agonist. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.5. Tachykinin receptor antagonist . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.6. Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . . . . . . . .

92 92 92 94 95 95 95 95 95 95 96 96 96 96 96 97 97 97 97 97 97 98 98

* Corresponding author at: Department of Dermatology, University Hospital Heidelberg, Im Neuenheimer Feld 440, 69120 Heidelberg, Germany. Tel.: +49 6221 56 8447. E-mail address: [email protected] (K. Scha¨kel). 0923-1811/$36.00 ß 2013 Japanese Society for Investigative Dermatology. Published by Elsevier Ireland Ltd. All rights reserved. http://dx.doi.org/10.1016/j.jdermsci.2013.11.009

K. Scha¨kel et al. / Journal of Dermatological Science 73 (2014) 91–100

92

1. Introduction Atopic dermatitis (AD) is a chronic inflammatory skin disease characterized by pruritic skin lesions [1], dryness of the skin and Staphylococcus aureus skin infection [2]. Recalcitrant pruritus is the most distressing symptom the patients suffer from. It is usually followed by a scratching response, which aggravates skin inflammation and leads to a sequence of conditions termed the ‘‘itch-scratch cycle’’ [3]. The onset of AD is early in life [4] leading to a prevalence in adults of 2–5% [5]. Due to the chronic and relapsing course of the disease, AD requires long-term and save treatment strategies. Immunologic studies on acute eczematous skin lesions of AD revealed an increased frequency of T cells producing the Th2 and Th22 cytokines Interleukin (IL)-4, IL-5, IL-13 and IL-22. Increased frequencies of IFN-g-producing Th1 cells are characteristic for chronic lichenified lesions [6], while IL-17 producing Th17 cells are found at low levels in acute as well as in chronic lesions [7]. Recent research also highlights the role of an inadequate host response to common cutaneous microbes as well as skin barrier abnormalities that predispose individuals to develop atopic dermatitis [1]. Evidence for a defective skin barrier could be further provided by genetic studies exhibiting linkage between AD and chromosome 1q21, which contains genes of the epidermal differentiation complex (EDC) [8]. Moreover, an association between AD and two loss-of-function mutations in the filaggrin gene (FLG), R501X and 2282del4 were found [9]. Patients with AD require consequent topical treatment with emollients and anti-inflammatory therapies based on topical glucocorticosteroids or calcineurin inhibitors. However, when becoming refractory to topical treatment compensatory systemic treatment options are required. Widely used systemic therapies include glucocorticoids, cyclosporine A, azathioprine and mycophenolate mofetil. Unfortunately, systemic treatment responses

are often short-lived and many patients with AD exhibit a limited clinical response. Moreover, these treatment modalities are associated with significant side effects such as hypothalamuspituitary-adrenal axis suppression, diabetes, osteoporosis, renal or liver toxicity or myelosuppression. For these reasons, there is an unmet need for novel topic and systemic treatment options. A hall mark of AD is the extreme pruritus, which profoundly effects patients’ quality of live through sleeplessness, anxiety, and depression. There is a broad overlap between pain and itch processing in terms of mediators, mechanisms and even therapeutic approaches. Protease-activated receptor 2 (PAR2) and members of the transient receptor potential (TRP) family have been implicated as targets for both analgetic and pruritic mediators. Sensitization of peripheral nerve endings by nerve growth factor (NGF) is known as a pathophysiological mechanism of both chronic itch and pain [10]. Based on this knowledge a good number of ongoing trials are investigating new options for treating pruritus. Our review reports of ongoing studies for treatment of AD with systemic and topical drugs listed on the ClinicalTrials.gov website and discusses the scientific rational for their use. We categorized the therapeutic targets into three main groups: inflammatory pathways, specific immune mechanisms, and pruritus (Fig. 1). All compounds currently under study have been listed according to these categories and are described in the main text (Table 1). 2. Targeting inflammatory pathways 2.1. Inhibiting the degradation of cyclic adenosine monophosphate (cAMP) cAMP is a second messenger that regulates diverse biologic responses including inflammation, apoptosis and lipid

Fig. 1. Categorization and specific modes of action of systemic and topical drugs that are currently under investigation for the treatment of AD.

K. Scha¨kel et al. / Journal of Dermatological Science 73 (2014) 91–100

93

Table 1 List of compounds currently under investigation for the treatment of AD. Specific target/function

Substance

Pharmacodynamics

Study phase

Published resultsa

Lit/NCT-tracking number

Global target: inflammatory pathway Phosphodiesterase/ inhibitor

Apremilast (s)

Binds to the catalytic site of PDE4, blocks cAMP degradation, cAMP levels are increased. This leads to inhibition of the production of TNF-a, IFN-g, IL-2, IL-8, IL-12p70, leukotriene B4 and the chemokines CXCL9, CXCL10, CCL4 [12,16].

Phase 2 Pilot study

Volf et al. [19] Samrao et al. [18]

NCT00931242 NCT01393158

GW842470X (t)

PDE4 inhibitor, specific pharmacodynamics are not posted.

Phase 1

–

NCT00356642

AN2898 (s) AN2728 (s)

Their boron atom binds to the activated water in the bimetal center of the active site of PDE4 [20]. Inhibits NF-kB by mimicing the NFkB binding sequence in the chromosomal DNA. Therefore, production of inflammatory mediators is inhibited [21]. Highly selective glucocorticoid receptor-agonist of the pentanolamine series with nonsteroid structure [23]. Upregulation of UV-inducible genes: COX-2 is dramatically upregulated resulting in enhanced secretion of PGE2 [29,30]. Synthetic compound inhibiting the expression of proinflammatory cytokines (e.g. IL-2, IL-13, IL-17A and TNF-a) and the migration of PBMCs toward LTB4 [data on file at Welichem Biotech Inc, Burnaby, British Columbia, Canada].

Phase 2 Phase 2

– Nazarian et al. [20]

NCT00354510 NCT01301508

Phase 1/2

–

NCT00125333

Phase 2 Phase 2

– –

NCT01228513 NCT01359787

Phase 2

–

NCT01320579

Phase 2a

Bissonnette et al. [38] Bissonnette et al. [39]

NCT00837551

Phase 1

–

NCT01122914

Pilot study

Simon et al. 2008 [46] Moul et al. 2008 [45]

NCT 00376129

NF-kB/inhibitory oligonucleoties

NF-kB decoy (t)

Glucocorticoid receptor/agonist

Mapracorat, BOL-303242-XZK 245186 (t)

Cyclooxigenase-2 (COX-2)/upregulation

cis-UCA (s)

Proinflammatory cytokines and infiltration process of lymphocytes/inhibitor

WBI-1001 (t)

Global target: Specific immune mechanism IL-1b/soluble receptor

Anakinra (s)

CD2/agonist

Alefacept (s)

Inhibits competitively the binding of interleukin-1 to its receptor and thereby inhibits proinflammatory signaling of IL-1b. Blocks the interaction of native LFA-3 with CD2 by binding CD2 [41–43]. It can initiate an antibody-dependent cellular cytotoxicity [44].

Phase 2b

Pilot study

Phase 4

IL-4-Receptor a chain/neutralizing antibody

REGN668 (s)

IL-4-Receptor a chain/mutated ligand

Pitrakinra (s)

TSLP/neutralizing antibody

AMG157 (s)

IgE/neutralizing antibody

Omalizumab (s)

Global target: Pruritus Chymase/inhibitor

Antihistamine and tricyclic antidepressant

SUN 13834 (s)

CRx-197 (t)

Results: see ClinicalTrials. gov – – Radin et al. [48] Groves et al. 2007 [50]

NCT01098734

Alefacept for moderate to severe atopic dermatitis: A pilot study in adults NCT00832585

An antibody targeting the IL-4Ra component and therefore blocks IL-4 as well as IL-13 signaling. An IL-4-derived recombinant protein that binds the IL-4Ra subunit antagonizing both IL-4 and IL-13 binding [49]. A human monoclonal antibody that blocks the interaction of TSLP with its receptor. A recombinant humanized monoclonal anti-IgE antibody binding IgE at the same site as FceRI and FceRII and inhibits mast cell and basophil activation [51].

Phase Phase Phase Phase

Inhibits chymase which is involved in the processing of stem cell factor, a cytokine which is in turn involved in mast cell proliferation [56,63,65]. The combination of these substances acts synergistically in preclinical models of inflammation [based on company’s statement].

Phase 2

–

NCT00717769

Phase 1

–

NCT00721331

1/2 1 1 2a

Phase 1

Phase 2 Phase 4

–

Heil et al. [53] Vigo et al. [51], Belloni et al. [52]

NCT01385657 NCT01259323 NCT01015027 NCT00676884

NCT00757042

NCT01179529 NCT00822783

K. Scha¨kel et al. / Journal of Dermatological Science 73 (2014) 91–100

94 Table 1 (Continued ) Specific target/function

Substance

Pharmacodynamics

Study phase

Published resultsa

Lit/NCT-tracking number

m-Opioid receptor (MOR)/antagonist

SRD174 (t) (Nalmefene)

Phase 2

Herzog et al. [74]

NCT00838708

Prostanoid DP1 receptor/agonist

TS-022 (t)

Phase 2

No results posted

NCT00914186

Cannabinoid receptor 2/agonist

S-777469 (t)

Phase 1b/2a Phase 2

– –

NCT00697710 NCT00703573

Dual tachykinin NK1/NK2/antagonist

DNK333 (t)

Nalmefene, a m-opioid receptorantagonist with activity across a broad spectrum of opiate receptors is the active compound in SRD 174 cream. Opioid antagonists can have anti-pruritic activity in a range of conditions, including AD [66–71]. TS-022 suppresses scratching and improves skin inflammation via a specific prostanoid DP1 receptor [77]. CB2 receptors are the targets of S777469. They are localized on peripheral nerve fibers, T lymphocytes and mast cells [79,80]. Topical application of cannabinoids has analgesic and anti-pruritic effects in acute pain and itch models [81–84]. New dual neurokinin 1/2 receptor antagonist [85]. In previous study in asthma patients it was observed that DNK333 protected against NKAinduced bronchoconstriction [86].

Phase 2

–

NCT01033097

a

Listed in PubMed as of 31/May/2013; –, no results published; s, systemic application; t, topical application.

metabolism. It is produced by adenylate cyclases after stimulation of various G protein-receptors and degraded by phosphodiesterases (PDEs) that hydrolyse cAMP [11]. Blocking of PDE4 reduces TNFa gene expression in macrophages and dendritic cells via altered signaling through protein kinase A (PKA) and nuclear factor ‘kappa-light-chain-enhancer’ of activated B-cells (NF-kB) [12]. Moreover, PDE4 inhibitors enhance expression of the immune suppressive cytokine IL-10 [13]. In T cells proliferation and production of TNF-a, IL-2, IL-4, IL-5 depend on PDE4 activity [14,15] and it was shown to control the activation of neutrophils, eosinophils and the vascular endothelium [12]. Apremilast, a PDE4 inhibitor currently under study inhibits the activity of PDE4 by binding to the catalytic site of this enzyme and thereby blocking cAMP degradation. Studying human peripheral blood mononuclear cells (PBMCs) this compound was shown to inhibit the production of TNF-a, IFN-g, IL-2, IL-8 and IL-12p70 as well as leukotriene B4 and the chemokines CXCL9, CXCL10, CCL4 [12,16]. Several clinical trials studied the anti-inflammatory capacity of apremilast in vivo. In a small phase 2 study 19 patients with psoriasis received 20 mg apremilast orally for 29 days [17]. Responders showed a reduction of epidermal thickness, T cell numbers and of CD11c+ dendritic cells. An improvement of the PASI (Psoriasis Area and Severity Index) scores was demonstrated in 14 of 19 participants. These data suggested that apremilast may be effective as an orally active agent for the treatment of psoriasis and potentially of other inflammatory diseases [17]. Currently, two clinical trials with oral application of apremilast have been completed in patients with recalcitrant atopic or contact dermatitis. Samrao et al. evaluated 2 doses (20 or 30 mg twice daily) of apremilast in 16 patients with atopic dermatitis in an open-label pilot study (NCT01393158) [18]. After 6 months, there was a significant reduction of the Eczema Area and Severity Index (EASI) and the Dermatology Life Quality Index (DLQI). Moreover, gene expression analyses during treatment revealed alterations in immune response pathways, especially those related to cyclic adenosine monophosphate-mediated signaling. Volf et al. performed a proof-of-concept, phase 2, open-label, single institution trial (NCT00931242) to evaluate the efficacy and safety of two daily doses of 20 mg apremilast for twelve weeks in 10 subjects with either atopic dermatitis and/or allergic contact dermatitis [19]. Ten percent of the subjects achieved EASI-75 and another 10% reached EASI-50. Headache, nausea, and soft stool were common side

effects associated with the drug. In general, apremilast was well tolerated with no serious adverse events or withdrawal due to overt side effects. The limitation of this study is its small sample size and the lack of a control group. Beyond oral application of PDE4 inhibitors, the therapeutic action of GW842470X a topical PDE4 inhibitor was assessed both in an open non-placebo controlled phase 1 study in patients with atopic dermatitis (NCT00356642) and in a respective phase 2 study (NCT00354510). Both studies have been completed, the publication of the results is pending. Additional PDE4 inhibitors are AN2898 and AN2728, two boron-containing small molecule inhibitors. In difference to other PDE4 inhibitors, the boron atom of AN2898 and AN2728 directly binds to the activated water in the bimetal center of the active site of the PDE4 enzyme. These compounds are under study in atopic dermatitis [20]. In a phase 2 study the primary endpoint measures were the decrease of the Atopic Dermatitis Severity Index (ADSI) from baseline on day 28 compared to lesions treated with the topical vehicle alone (NCT01301508 and www.anacor.com/ an2898.php). According to a statement of the company the primary endpoint for both compounds was successfully achieved and severe adverse events related to the study drugs were absent. 2.2. Specific inhibition of NF-kB NF-kB can be inhibited by double-stranded deoxyribonucleic acid oligodeoxynucleotides that mimic the NF-kB binding sequence on the chromosomal DNA. Thereby these NF-kB decoy motives efficiently inhibit the production of inflammatory mediators triggered by NF-kB. Initial studies investigated the efficacy of topical NF-kB decoy on experimental AD in mice (NC/Nga mice) [21]. The study reported successful prevention of the manifestation of atopic dermatitis-like skin lesions. Therapeutic efficacy of topical NF-kB decoy for the treatment of atopic dermatitis-like skin lesions was also shown by Dajee et al. in the same mouse model [22]. Here, the efficacy of topical NF-kB decoy was similar to that of betamethason valerate. Moreover, both treatment options decreased the expression of inflammatory cytokines such as IL-1b, TNF-a, macrophage inflammatory protein 2-a precursor, and ICAM-1. Mechanistically, NF-kB decoy acted via inhibition of essential regulators of inflammation and by inducing apoptosis of proinflammatory immune cells. There

K. Scha¨kel et al. / Journal of Dermatological Science 73 (2014) 91–100

was no skin atrophy after treatment and withdrawal of topical application did not cause a rebound of the inflammation. Data from this study also indicated that NF-kB decoy restored the compromised stratum corneum integrity and barrier function of the skin [22]. A subsequent phase 1/2 study was performed to evaluate the safety and tolerability of a twice-daily topical application of NF-kB decoy in adult subjects with mild to moderate atopic dermatitis (NCT00125333). The last update on ClinicalTrials.gov was made in 2008. No additional data have been published. 2.3. Glucocorticoid receptor agonists Mapracorat (also known as BOL-303242-X or ZK 245186) is a selective glucocorticoid receptor-agonists of the pentanolamine series with a non-steroid structure [23]. It is a highly selective glucocorticoid receptor ligand with anti-inflammatory/immunmodulatory activities in a number of cell lines and primary human cells [24]. Therefore, mapracorat is a potential candidate for the topical treatment of atopic dermatitis and other inflammatory diseases. It should be emphasized that it exhibits a better safety profile as the classical glucocorticoids with regard to growth inhibition and induction of skin atrophy after long-term topical application, thymocyte apoptosis, hyperglycemia and hepatic tyrosine aminotransferase activity [23]. Cavet et al. studied the effects of mapracorat at the level of cell signaling and demonstrated inhibition of p38 mitogen-activated protein kinase (MAPK), cJun N-terminal kinase (c-JNK), activator protein 1 (AP-1) and NFkB transcriptional activity [24]. Two clinical phase 2 trials are currently evaluating the safety and efficacy of mapracorat (NCT01228513, NCT01359787) in patients with AD. Both studies compare three different concentrations of topical mapracorat. No study results are published so far. 2.4. Cis-urocanic acid Urocanic acid (UCA) is a major UV-absorbing chromophore in the skin and has been proposed to function as a regulator of UVinduced damage [25]. There are two chemical forms of UCA: trans(T-UCA) and cis-UCA (C-UCA). Interconversion of T-UCA to C-UCA is a UV-induced isomerization [26]. C-UCA but not T-UCA is implicated in the down-regulation of hypersensitivity reactions [27,28]. The presence of C-UCA leads to upregulation of UVinducible genes that are associated with oxidative stress, cell growth arrest, apoptosis, and immunomodulatory mediators. Among them, cyclooxigenase-2 (COX-2), the rate-limiting enzyme in prostanoid biosynthesis, was most dramatically upregulated by C-UCA, resulting in enhanced secretion of prostaglandin E2 (PGE2) [29,30]. PGE2 is considered to be an important immunomodulator as it can initiate the production of IL-4, which then leads to the production of immunosuppressive IL-10 [31]. Injections of C-UCA induce immunosuppression in mice, causing them to become tolerant to cutaneous allergens [32]. Specific effects of C-UCA on immune cells include inhibition of epidermal antigen-presenting cells [33,34], activation of neutrophils [34,35], and prolonged survival of experimental organ transplants [30,36]. Dahl et al. applied different concentrations of C-UCA in a cream base to unexposed skin of 37 human subjects and studied its effects on the induction of a hapten (1-chloro-2,4-dinitrobenzene; DNCB)specific immune response [37]. Application of C-UCA suppressed the induction of cell-mediated immunity to DNCB. However, due to the small sample size these effects were not statistically significant. A phase 2 trial with C-UCA in patients with moderate or severe AD (NCT01320579) was completed in June 2012. The purpose of this study was to evaluate dose response, safety, tolerability, and efficacy of 2.5% and 5% C-UCA in comparison to placebo and Protopic 0.1%. So far, no data have been published.

95

2.5. Nonsteroidal antiinflammatory compound WBI-1001 WBI-1001 is a novel synthetic compound demonstrating nonsteroidal antiinflammatory activities [38]. It is derived from metabolites of bacterial symbionts of entomopathogenic nematodes (insect-specific parasitic nematodes). WBI-1001 inhibits the expression of proinflammatory cytokines such as IL-2, IL-13, IL17A and TNF-a. Moreover, it inhibits the migration of PBMCs toward leukotriene B4 (LTB4) at sub-toxic doses. This indicates that it might block the infiltration process of lymphocytes in vivo, which plays a crucial role in the pathogenesis of various inflammatory diseases (data on file at Welichem Biotech Inc, Burnaby, British Columbia, Canada). In a phase 2a trial with 37 adult patients with AD the safety and efficacy of topical WBI-1001 creams in two different concentrations (0.5% and 1.0%) in comparison to vehicle cream were investigated (NCT00837551) [38]. The WBI-1001 formulation was well tolerated and no serious adverse events occurred. After 4 weeks both the 0.5% and the 1.0% formulations demonstrated significant reduction of EASI (59.3% and 54.9%, respectively, compared with 7.1% for vehicle) and reduction of SCORAD (‘‘SCORing Atopic Dermatitis’’) (56.2% and 50.1% respectively, compared with 18.4% for vehicle). Recently, Bissonette et al. investigated in a phase 2b trial the topical application of WBI-1001 over a 6 week period in patients with mild to severe AD (NCT01098734) [39]. The patients were randomized to receive placebo, 0.5% WBI-1001 or 1.0% WBI-1001 in a cream formulation applied twice daily. After 6 weeks patients who received placebo were re-randomized to 0.5% or 1% WBI-1001 creams while patients already receiving WBI-1001 continued the same treatment for additional 6 weeks. A general improvement in EASI and SCORAD was observed within the WBI-1001 groups. After 6 weeks EASI was reduced by 68.9% and 76.3% for 0.5% and 1.0% WBI-1001, respectively compared to 23.3% for placebo. There was no significant difference in the mean change of EASI from baseline at day 42 and day 84 between the groups treated with WBI-1001 for 12 weeks. Improvement in SCORAD at day 42 was 57.5% and 63.4% for 0.5% and 1.0% WBI-1001, respectively compared to 13.9% for placebo. As with EASI, there was no significant difference in the mean change in SCORAD from baseline at day 42 and day 84 between the groups treated with WBI-1001 for 12 weeks. The drug was well tolerated in this study [39] but this trial did not match the effectiveness of WBI-1001 to an active comparator. Further studies will be needed to confirm the promising results obtained so far. 3. Targeting specific immune targets with biologics 3.1. Anti-IL-1ß Anakinra is an interleukin-1 receptor antagonist, which competitively inhibits binding of interleukin-1 to its receptor and thereby inhibits proinflammatory signaling of IL-1b. This substance is approved for use in the therapy of rheumatoid arthritis. Currently, one study investigates the capacity of anakinra to inhibit inflammation in atopic eczema. A respective pilot study is still recruiting participants (NCT01122914). Special attention will be paid to the safety and efficacy of anakinra in children and teenagers at the age of 10–18 years. The patients receive anakinra as a daily injection over a period of 3 months. This study is still recruiting and there are no results published so far. 3.2. Targeting CD2 with soluble LFA-3 (CD58)-Fc Alefacept is a fusion protein composed of the first extracellular domain of the lymphocyte function associated antigen-3 (LFA-3, CD58) and the human IgG1 Fc-domain [40]. It blocks the interaction of native LFA-3 with CD2 by binding CD2, which is

96

K. Scha¨kel et al. / Journal of Dermatological Science 73 (2014) 91–100

mainly expressed by T cells and NK cells. Optimal cell activation requires interaction of costimulatory molecules with their ligands [41–43]. By inhibiting these interactions alefacept interferes with T lymphocyte and NK cell activation and causes modification of the inflammatory process. Furthermore, alefacept can initiate an antibody-dependent cellular cytotoxicity directed toward T cells when the Fc-portion of the fusion protein binds to Fcg-receptors on cytotoxic effector cells such as NK cells [44]. In a pilot study 9 patients with AD were treated with alefacept. They received an initial intramuscular dose of 30 mg as 2 injections weekly for 8 weeks. In the course of this treatment the dose was reduced to 15 mg at week 9 if patients had developed an EASI 50 Score or higher. The study was terminated prematurely in 5 of 9 patients due to lack of efficacy or worsening of the eczema [45]. In the department of Dermatology in Bern (Switzerland) a second Phase 2 study was performed to evaluate the safety and efficacy of a 12 week-course of alefacept in 10 patients with AD (NCT00376129) [46]. The patients received 15 mg of intramuscular alefacept once a week. All of them showed improvement of clinical symptoms. EASI scores remained low or decreased further during the observation period. At week 12 the mean improvement of EASI was 78% and at week 22 86%. Moreover, pruritus also significantly decreased (2.5  0.17 before therapy, 0.85  0.18 at week 12, and 1.05  0.19 at week 22; P < .001) and all patients could reduce the application of concomitant therapy [46]. These results suggest that alefacept may be effective in the treatment of atopic eczema but further studies are required to confirm these findings. 3.3. Blocking the IL-4-receptor a-chain Inflammatory skin lesions in atopic eczema are characterized by an increase in Th2 cytokines such as IL-4 and IL-13 [6]. REGN668 (SAR231893) is an antibody targeting the IL-4Ra component and therefore blocks IL-4 as well as IL-13 signaling. Two studies (NCT01385657, NCT01259323) were performed to investigate the safety and tolerability of this antibody in patients with moderate to severe AD. In both studies subjects were receiving repeated doses of subcutaneous REGN668. At this time no data of both studies are available. However, there are several other studies investigating the therapeutic efficacy of REGN668 in patients with persistent asthma and elevated levels of eosinophils. Wenzel et al. published a randomized, double-blind, placebo-controlled phase 2a trial with a total of 104 patients suffering from persistent, moderate to severe asthma and a blood eosinophil count of at least 300 cells per microliter or a sputum eosinophil level of at least 3%. The patients received REGN668 for 12 weeks or until a severe asthma exacerbation. Maintenance asthma therapy with long-acting betaagonists and inhaled glucocorticoids was discontinued during the treatment with REGN668. Three REGN668-treated patients had an asthma exacerbation (6%) versus 23 patients with placebotreatment (44%). Moreover, significant improvements were observed for measures of lung function and asthma control and significant reductions were observed for biomarkers associated with Th2-driven inflammation [47]. Another study (NCT01015027) was conducted in healthy volunteers to assess the safety and tolerability of REGN668 [48]. 48 adults received a single intravenous (1, 3, 8 or 12 mg/kg) or subcutaneous (150 or 300 mg) dose of REGN668 or placebo with 12 weeks of follow-up. The safety profile of REGN668/SAR231893 was acceptable and inhibition of the Th2 immune pathway was demonstrated by significant suppression of TARC and IgE compared with placebo. Pitrakinra (also known as Aeroderm1, AER 001, BAY 16-9996) is a second IL-4Ra-blocker under study in AD. It is an IL-4-derived recombinant protein that binds the IL-4Ra subunit antagonizes both IL-4 and IL-13 binding. Previous studies in patients with atopic asthma have shown that pitrakinra reduces the late-phase

response to allergen challenge [49]. A phase 1a randomized, double-blind, placebo-controlled trial (NCT00676884) was performed to investigate the effect of Aeroderm1 on the EASI score in subjects suffering from moderate to severe atopic eczema. The subjects received 30 mg s.c. b.i.d. Aeroderm1 or placebo for 28 days. Treatment with Aeroderm1 lead to a somewhat higher but not statistically significant reduction in AD severity compared to the placebo group (56% versus 34%) [50]. 3.4. Blocking thymic stromal lymphopoetin (TSLP) AMG 157 is a human monoclonal antibody that blocks the interaction of TSLP with its receptor. TSLP is an IL-7-like cytokine expressed by epithelial cells that has been implicated in promoting Th2 cytokine-dependent inflammation in skin and lung. Recently, a phase 1 study was completed, which assessed the safety, tolerability and pharmacokinetics of AMG 157 (NCT00757042). Healthy subjects were randomized in two placebo-controlled groups. Application of AMG 157 or placebo was either intravenously or subcutaneously. The data of this single dose escalation study are not yet published. 3.5. Targeting IgE Omalizumab (Xolair1) is a recombinant humanized monoclonal anti-IgE antibody. It binds IgE at the same binding site as FceRI and FceRII and inhibits mast cell and basophil activation [51]. In an unblinded study performed by Vigo et al., 7 patients with AD were treated with omalizumab [51]. The dose was adjusted to body weight and baseline IgE titers. Eczema symptoms were scored at baseline and after 3 and 7 months of treatment. Six of the patients had at least an IGA score (Investigator Global Assessment) of 3 (moderate disease) or more before starting the study. Clinical improvement was seen within 8 to 12 weeks of treatment. After three months 5 patients had an IGA score of 2 or lower (mild clinical disease) and in the following weeks IGA scores further improved. In second small and unblinded study 11 adult patients suffering from severe generalized atopic eczema were treated with a fixed dose of 150 mg omalizumab regardless of the patients’ IgE titers [52]. Six of the patients revealed a good or satisfying result. The remaining patients showed no clinically relevant changes or had an aggravation of their eczema. A first double-blind, placebocontrolled phase 4 trial explored whether the depletion of IgE from blood and skin might result in a change of immunological parameters and might alter the clinical course of the disease (NCT00822783). This study did not reveal any therapeutic effects. However, omalizumab was effective in reducing free serum IgE, surface IgE and FceRI expression on different PBMCs. The authors also observed a reduced saturation of FceRI with IgE and they could demonstrate a reduced number of IgE+, but not of FceRI+ cells in the skin. These findings indicate that omalizumab as applied in this study proved to be effective in reducing IgE, but did not alleviate skin inflammation [53]. Currently, a phase 2 study with a focus on biomarkers predictive for a positive treatment response has been completed (NCT01179529). The data are not yet available. 4. Targeting pruritus 4.1. Inhibition of chymase-activity Mast cell chymase is stored within granules and is released after cell stimulation. Chymase is a chymotrypsin-like serine protease [54] and there is evidence suggesting that this enzyme plays an important role in the pathogenesis of atopic eczema [55–59]. In a

K. Scha¨kel et al. / Journal of Dermatological Science 73 (2014) 91–100

number of preclinical studies chymase inhibitors such as SUN C8257 or SUN 13350 were investigated in animal models [56,60– 62]. SUN 13834 was also studied in an experimental mouse model of AD (NC/Nga mice) [63]. In this model scratching behavior could be reduced, however, there was no influence on skin swelling and accumulation of inflammatory cells. The mechanisms of action downstream of chymase inhibition are not completely understood. Chymase acts as a chemoattractant for leukocytes [55,64] and stimulates the migration of cells in vitro. Moreover, chymase is involved in the processing of stem cell factor [56,65], a cytokine which is involved in mast cell proliferation. Therefore, it was suggested that the suppression of this processing causes the inhibitory effect of SUN 13834 by inhibiting mast cell proliferation [63]. A randomized, placebo-controlled, double-blind study of SUN 13834 was performed in adult patients with AD (NCT00717769). Patients received SUN 13834 or placebo orally in low doses for 28 days. The results of this study are not yet available. 4.2. Topical antihistamine and antidepressant CRx-197 is a topical cream with antiinflammatory effects containing a combination of loratadine and nortriptyline (www.wikinvest.com/stock/CombinatoRx_(CRXX)/Crx-197). Loratadine is a second-generation antihistamine and nortriptyline is a tricyclic antidepressant. According to the company’s statement these substances have been shown to act synergistically in preclinical models of inflammation. A phase 1 study with healthy volunteers to determine the safety and tolerability of topical CRx197 in comparison to nortriptyline alone, 0.1% mometasone furoate and placebo has been completed (NCT00721331). Results are not yet published. 4.3. m-Opioid receptor (MOR)-antagonist Nalmefene, a m-opioid receptor (MOR)-antagonist with activity across a broad spectrum of opiate receptors is the active compound in SRD 174 cream. Opioid-antagonists have been demonstrated to be effective in opioid-induced pruritus and it has been established in a number of clinical studies that systemically administered opioid-antagonists (largely naloxone and naltrexone) can have anti-pruritic activity in a range of conditions, including AD [66– 71]. The anti-pruritic activity of oral nalmefene itself has already been reported [72,73]. It was hypothesized that topical administration of nalmefene may provide a prolonged improvement of pruritus symptoms. A randomized, double-blind, vehicle controlled, cross-over trial was therefore performed to investigate the safety, efficacy, and tolerability of 7 day treatment with topical nalmefene (NCT00838708) [74]. 62 subjects with moderate to severe AD were enrolled to the study. The study revealed that topically applied SRD147 cream did not demonstrate efficacy in the treatment of pruritus associated with AD. 4.4. Prostanoid DP1 receptor agonist The prostanoid DP1 receptor agonist TS-022 was developed for the treatment of pruritus in patients with AD. In previous studies it was shown, that prostaglandin D2, the major product of arachidonic acid metabolism, suppresses scratching in NC/Nga mice if it is topically applied [75]. Since skin prostaglandin D2 production is induced in mice by mechanical scratching it was suggested, that prostaglandin D2 may have a physiological role in the inhibition of pruritus [76]. A study by Arai et al. [77] demonstrated that topical TS-022 suppresses scratching and improves skin inflammation in NC/Nga mice via a specific

97

prostanoid DP1 receptor. In 2007 Sugimoto et al. could demonstrate that TS-022 exhibited an anti-pruritic activity in NC/Nga mice when used for the treatment of chronic AD like skin lesions [78]. To investigate the efficacy, safety and tolerability of TS-022 in adult patients with AD and pruritus a placebo-controlled study was performed with a 28-day regime of once daily locally applied TS-022 used in three different concentrations (NCT00914186). The study has been completed but the results are not yet published. 4.5. Cannabinoid receptor agonist The cannabinoid receptor 2 (CB2) is the target of the specific agonist S-777469. CB2 receptors are mainly localized on peripheral nerve fibers, T lymphocytes and mast cells [79,80]. Previous studies revealed that topical application of cannabinoids have analgesic and anti-pruritic effects in acute pain and itch models [81–84]. Two clinical trials of S-777469 were conducted and completed. Publications of the results are pending (NCT00697710, NCT00703573). 4.6. Tachykinin receptor antagonist DNK333 is a new dual neurokinin 1/2 (NK1/NK2) receptor antagonist [85]. In one previous study the effects of DNK333 on bronchoconstriction in asthma patients has been studied [86]. It was observed that DNK333 did not affect baseline lung function but did protect against neurokinin A (NKA)-induced bronchoconstriction in asthma patients. To investigate the efficacy of DNK333 in reduction of pruritus in AD a phase 1/2 trial was performed (NCT01033097). The patients received different doses of topical DNK333 for a two-week period. Betamethasone was used as a comparator. The results of this study are not yet published. 5. Conclusion AD is a chronic inflammatory skin disease that in many cases is well controlled by standard treatments according to published guidelines and treatment algorithms derived thereof [87]. For severe cases of AD current protocols for topical treatment fail due to lack of clinical efficacy. Similarly, in these cases broad-spectrum immunosuppressants are often unsuccessful due to insufficient eczema relief and possible side effects. The high number of ongoing treatment studies for AD clearly reflects the unmet medical need for next generation pharmacologic interventions. Many studies are evaluating the efficacy and safety of substances targeting inflammation rather non-specific; other studies aim at interfering with disease-specific traits like Th2 immune responses or pruritus. In psoriasis we have learned that therapeutic approaches targeting single molecules can be surprisingly effective. The tremendous success of TNF-a inhibitors in the treatment of psoriasis was not initially anticipated, however, it greatly fostered research activities in this disease and opened the field for the development and introduction of innovative drugs. Whether targeting just one single molecule may suffice to clear the eczema in AD has to be awaited. Based on our clinical experience and supported by a large body of published evidence, we know that some but not all patients with AD suffer from dry skin, bacterial colonization, IgE-mediated allergic sensitizations to food or pollen and cross-reacting foods. Therefore, AD is frequently seen as a particularly heterogeneous disease, which may be hard to control by targeting just one checkpoint of the disease in all patients.

98

K. Scha¨kel et al. / Journal of Dermatological Science 73 (2014) 91–100

Ongoing therapeutic studies in AD focus on three disease aspects: reducing inflammation non-specifically, targeting the Th2-mediated immune response and blocking pruritus. For a better control of inflammation in AD several topical compounds are under investigation. PDE4 inhibitors block the degradation of cAMP, leading to increased cAMP levels and thereby having broad antiinflammatory effects on different cell types such as DCs and T cells. Cis-UCA may have overlapping effects with PDE4 Inhibitors as it also leads to cAMP upregulation via induction of COX-2 and PGE2. WBI-1001 is another compound studied for topical application. It is reported to inhibit proinflammatory cytokine production, and already proved to be effective in AD. A mechanistically innovative approach is the strategy to use NF-kB decoy sequences applied topically. This treatment proved to be successful in mice with eczema and a phase 1/2 trial in patients was initiated. The best-known treatment targets of the skin are glucocorticoid receptors, for which mapracorat, a new nonsteroidal ligand has been designed and is now tested. A characteristic feature of AD are IgE-mediated sensitizations to aeroallergens and food allergens. Frequently, uptake of these allergens cause flaring of the eczema. Allergen-specific IgE bound via FceRI on epidermal Langerhans cells and inflammatory dermal dendritic cells is perfectly located to capture antigen that is penetrating through the damaged skin and these dendritic cells can then enhance pathogenic Th2 T cells responses. So far, neutralizing IgE with Omalizumab has not demonstrated convincing therapeutic success in the treatment of AD. It may be however, that in a defined subset of patients with AD, blocking of IgE is therapeutically effective. An ongoing study is currently searching for biomarkers that may predict a positive response to omalizumab treatment. The majority of cells infiltrating the inflamed skin of patients with AD are T lymphocytes. In acute eczematous skin lesions Th2 cells producing the cytokines IL-4, IL-5 and IL-13 predominate. Therapeutic blocking of the IL-4 and IL-13 receptor is a long discussed treatment option for allergic diseases and was first tested in allergic asthma. Currently, there are two studies under way that block the IL4/IL-13 receptor with specific monoclonal antibodies or with a mutated ligand. A major discovery in AD research was the finding that keratinocytes of lesional skin in AD but not in e.g. psoriasis, produce large amounts of the IL-7-like cytokine thymic stromal lymphopoietin (TSLP). Blocking this cytokine reduced the programming of Th2 cells by dendritic cells and in addition, blocking of TSLP may reduce the local influx of Th2 cells into the skin. A phase 1 study with an anti-TSLP monoclonal antibody (AMG157) was completed and a single dose study with AMG157 in patients with AD is currently underway. Another cytokine with increased expression in AD is IL-1b. The major sources of IL-1b are dendritic cells and macrophages. Anakinra is a recombinant IL-1 receptor antagonist that is efficiently blocking IL-1b for the treatment of rheumatoid arthritis and it is currently under study in AD. However, a therapeutic role for Anakinra in AD has not yet been described. Pruritus is a clinical hallmark of AD and a massive burden for the patients. The finding that TSLP is a strong pro-allergic immunomodulator that can be induced in keratinocytes by scratching [88] provides important insights how scratching may support proinflammatory immune responses in the skin. Once we have efficient drugs to block pruritus, it will be interesting to see how much improvement of the eczema can be achieved when pruritus is absent. Pruritus can be targeted at different checkpoints. Under study is a long acting topical m-opioid receptor antagonist called nalmefene, which, however, did not prove to be effective in a study published recently [74]. As prostanoids may have a physiological role in the suppression of pruritus, a topically

applied prostanoid DP1 receptor agonist is under study. Also cannabinoids have anti-puritic activity, which led to the development of the CB2 cannabinoid receptor agonist S-777469 for topical application. Furthermore, the effect of a new dual NK1/NK2 tachykinin receptor antagonist that is already tested for asthma patients is currently under study in AD. How much these innovative drug developments will allow us to alleviate symptoms by blocking distinct pathogenic aspects of AD is not yet known. However, the great success of biologics and novel small molecules in controlling a diverse spectrum of chronic inflammatory diseases is on hand. Many of the treatment successes and failures in this field could not be anticipated initially. Therefore, to meet the high medical needs of our patients with severe AD we need a constant search for new targets and novel drug developments. Acknowledgement This work was supported by the Collaborative Research Center (Sonderforschungbereich) 938 (K.S.). References [1] Denby KS, Beck LA. Update on systemic therapies for atopic dermatitis. Curr Opin Allergy Clin Immunol 2012;12:421–6. [2] Bieber T. Atopic dermatitis. N Engl J Med 2008;358:1483–94. [3] Mihara K, Kuratani K, Matsui T, Nakamura M, Yokota K. Vital role of the itchscratch response in development of spontaneous dermatitis in NC/Nga mice. Br J Dermatol 2004;151:335–45. [4] Ong PY. Emerging drugs for atopic dermatitis. Expert Opin Emerg Drugs 2009. [5] Darsow U, Wollenberg A, Simon D, Taieb A, Werfel T, Oranje A, et al. ETFAD/ EADV eczema task force 2009 position paper on diagnosis and treatment of atopic dermatitis. J Eur Acad Dermatol Venereol 2010;24:317–28. [6] Leung DYM, Boguniewicz M, Howell MD, Nomura I, Hamid QA. New insights into atopic dermatitis. J Clin Invest 2004;113:651–7. [7] Gittler JK, Shemer A, Suarez-Farinas M, Fuentes-Duculan J, Gulewicz KJ, Wang CQ, et al. Progressive activation of T(H)2/T(H)22 cytokines and selective epidermal proteins characterizes acute and chronic atopic dermatitis. J Allergy Clin Immunol 2012;130:1344–54. [8] Bowcock AM, Cookson WOCM. The genetics of psoriasis, psoriatic arthritis and atopic dermatitis. Hum Mol Genet 2004;13:R43–55. [9] Palmer CNA, Irvine AD, Terron-Kwiatkowski A, Zhao Y, Liao H, Lee SP, et al. Common loss-of-function variants of the epidermal barrier protein filaggrin are a major predisposing factor for atopic dermatitis. Nat Genet 2006;38:441– 6. [10] Ikoma A, Steinhoff M, Sta¨nder S, Yosipovitch G, Schmelz M. The neurobiology of itch. Nat Rev Neurosci 2006;7:535–47. [11] Conti M, Beavo J. Biochemistry and physiology of cyclic nucleotide phosphodiesterases: essential components in cyclic nucleotide signaling. Annu Rev Biochem 2007;76:481–511. [12] Schett G, Sloan VS, Stevens RM, Schafer P. Apremilast: a novel PDE4 inhibitor in the treatment of autoimmune and inflammatory diseases. Ther Adv Musculoskelet Dis 2010;2:271. [13] Eigler A, Siegmund B, Emmerich U, Baumann KH, Hartmann G, Endres S. Antiinflammatory activities of cAMP-elevating agents: enhancement of IL-10 synthesis and concurrent suppression of TNF production. J Leukoc Biol 1998;63:101–7. [14] Essayan DM, Huang SK, Kagey-Sobotka A, Lichtenstein LM. Differential efficacy of lymphocyte-and monocyte-selective pretreatment with a type 4 phosphodiesterase inhibitor on antigen-driven proliferation and cytokine gene expression. J Allergy Clin Immunol 1997;99:28–37. [15] Essayan DM, Huang SK, Undem BJ, Kagey-Sobotka A, Lichtenstein LM. Modulation of antigen-and mitogen-induced proliferative responses of peripheral blood mononuclear cells by nonselective and isozyme selective cyclic nucleotide phosphodiesterase inhibitors. J Immunol 1994;153:3408. [16] Schafer P, Parton A, Gandhi A, Capone L, Adams M, Wu L, et al. Apremilast, a cAMP phosphodiesterase-4 inhibitor, demonstrates anti-inflammatory activity in vitro and in a model of psoriasis. Br J Pharmacol 2010;159:842–55. [17] Gottlieb A, Strober B, Krueger J, Rohane P, Zeldis J, Hu C, et al. An open-label, single-arm pilot study in patients with severe plaque-type psoriasis treated with an oral anti-inflammatory agent, apremilast. Curr Med Res Opin 2008;24:1529–38. [18] Samrao A, Berry TM, Goreshi R, Simpson EL. A pilot study of an oral phosphodiesterase inhibitor (Apremilast) for atopic dermatitis in adults. Arch Dermatol 2012;148:890–7. [19] Volf E, Au S, Dumont N, Scheinman P, Gottlieb A. A phase 2, open-label, investigator-initiated study to evaluate the safety and efficacy of apremilast in subjects with recalcitrant allergic contact or atopic dermatitis. J Drugs Dermatol 2012;11:341.

K. Scha¨kel et al. / Journal of Dermatological Science 73 (2014) 91–100 [20] Nazarian R, Weinberg JM. AN-2728, a PDE4 inhibitor for the potential topical treatment of psoriasis and atopic dermatitis. Curr Opin Investig Drugs 2009;10:1236. [21] Nakamura H, Aoki M, Tamai K, Oishi M, Ogihara T, Kaneda Y, et al. Prevention and regression of atopic dermatitis by ointment containing NF-kB decoy oligodeoxynucleotides in NC/Nga atopic mouse model. Gene Therapy 2002;9:1221. [22] Dajee M, Muchamuel T, Schryver B, Oo A, Alleman-Sposeto J, De Vry CG, et al. Blockade of experimental atopic dermatitis via topical NF-kB decoy oligonucleotide. J Invest Dermatol 2006;126:1792–803. [23] Scha¨cke H, Zollner T, Do¨cke W, Rehwinkel H, Jaroch S, Skuballa W, et al. Characterization of ZK 245186, a novel, selective glucocorticoid receptor agonist for the topical treatment of inflammatory skin diseases. Brit J Pharmacol 2009;158:1088–103. [24] Cavet ME, Harrington KL, Ward KW, Zhang JZ. Mapracorat, a novel selective glucocorticoid receptor agonist, inhibits hyperosmolar-induced cytokine release and MAPK pathways in human corneal epithelial cells. Mol Vis 2010;16:1791–800. [25] Gibbs NK, Tye J, Norval M. Recent advances in urocanic acid photochemistry, photobiology and photoimmunology. Photochem Photobiol Sci 2008;7:655– 67. [26] Norval M, Simpson T, Bardshiri E, Crosby J. Quantification of uranic acid isomers in human stratum corneum. Photodermatology 1989;6:142–5. [27] Prater M, Blaylock B, Holladay S. Molecular mechanisms of cis-urocanic acid and permethrin-induced alterations in cutaneous immunity. Photodermatol Photoimmunol Photomed 2003;19:287–94. [28] Lauerma A, Aioi A, Maibach H. Topical cis-urocanic acid suppresses both induction and elicitation of contact hypersensitivity in BALB/C mice. Acta Derm Venereol 1995;75:272. [29] Kaneko K, Smetana-Just U, Matsui M, Young AR, John S, Norval M, et al. cisUrocanic acid initiates gene transcription in primary human keratinocytes. J Immunol 2008;181:217. [30] Kaneko K, Walker SL, Lai-Cheong J, Matsui MS, Norval M, Young AR. cisUrocanic acid enhances prostaglandin E2 release and apoptotic cell death via reactive oxygen species in human keratinocytes. J Investig Dermatol 2011;131:1262–71. [31] Shreedhar V, Giese T, Sung VW, Ullrich SE. A cytokine cascade including prostaglandin E2, IL-4, and IL-10 is responsible for UV-induced systemic immune suppression. J Immunol 1998;160:3783. [32] Harriott-Smith TG, Halliday W. Suppression of contact hypersensitivity by short-term ultraviolet irradiation: II. The role of urocanic acid. Clin Exp Immunol 1988;72:174. [33] Hart PH, Grimbaldeston MA, Finlay-Jones JJ. Mast cells in UV-B-induced immunosuppression. J Photochem Photobiol B: Biol 2000;55:81–7. [34] Kivisto¨ K, Punnonen K, Toppari J, Leino L. Urocanic acid suppresses the activation of human neutrophils in vitro. Inflammation 1996;20:451–9. [35] Rinaldi M, Moroni P, Leino L, Laihia J, Paape M, Bannerman DD. Effect of cisurocanic acid on bovine neutrophil generation of reactive oxygen species. J Dairy Sci 2006;89:4188–201. [36] Filipec M, Letko E, Hasˇkova´ Z, Jenı´cˇkova´ D, Holler P, Jancˇa´rek A, et al. The effect of urocanic acid on graft rejection in an experimental model of orthotopic corneal transplantation in rabbits. Graefes Arch Clin Exp Ophthalmol 1998;236:65–8. [37] Dahl MV, McEwen Jr GN, Katz HI. Urocanic acid suppresses induction of immunity in human skin. Photodermatol Photoimmunol Photomed 2010;26:303–10. [38] Bissonnette R, Chen G, Bolduc C, Maari C, Lyle M, Tang L, et al. Efficacy and safety of topical WBI-1001 in the treatment of atopic dermatitis: results from a phase 2A, randomized, placebo-controlled clinical trial. Arch Dermatol 2010;146:446. [39] Bissonnette R, Poulin Y, Zhou Y, Tan J, Hong H, Webster J, et al. Efficacy and safety of topical WBI-1001 in patients with mild to severe atopic dermatitis: results from a 12-week, multicenter, randomized, placebo-controlled doubleblind trial. Brit J Dermatol 2011. [40] Miller GT, Hochman PS, Meier W, Tizard R, Bixler SA, Rosa MD, et al. Specific interaction of lymphocyte function-associated antigen 3 with CD2 can inhibit T cell responses. J Exp Med 1993;178:211–22. [41] Bierer’t BE, Burakoff SJ. T cell receptors: adhesion and signaling. Adv Cancer Res 1991;56:49. [42] Dustin ML, Springer TA. Role of lymphocyte adhesion receptors in transient interactions and cell locomotion. Ann Rev Immunol 1991;9:27–66. [43] Jenkins MK, Taylor PS, Norton SD, Urdahl KB. CD28 delivers a costimulatory signal involved in antigen-specific IL-2 production by human T cells. J Immunol 1991;147:2461. [44] Cooper JC, Morgan G, Harding S, Subramanyam M, Majeau GR, Moulder K, et al. Alefacept selectively promotes NK cell-mediated deletion of CD45R0+ human T cells. Eur J Immunol 2003;33:666–75. [45] Moul DK, Routhouska SB, Robinson MR, Korman NJ. Alefacept for moderate to severe atopic dermatitis: a pilot study in adults. J Am Acad Dermatol 2008;58:984–9. [46] Simon D, Wittwer J, Kostylina G, Buettiker U, Simon H-U, Yawalkar N. Alefacept (lymphocyte function-associated molecule 3/IgG fusion protein) treatment for atopic eczema. J Allergy Clin Immunol 2008;122:423–4. [47] Wenzel S, Ford L, Pearlman D, Spector S, Sher L, Skobieranda F, et al. Dupilumab in persistent asthma with elevated eosinophil levels. N Engl J Med 2013.

99

[48] Radin A, Ren H, Papino-Wood P, Chaudhry U, Hamilton JD. First-in-human study of REGN668/SAR231893 (IL-4Ra mAb): safety, tolerability and biomarker results of a randomized, double-blind, placebo-controlled, single ascending dose study in healthy volunteers. J Allergy Clin Immunol 2013;131:AB158. [49] Wenzel S, Wilbraham D, Fuller R, Getz EB, Longphre M. Effect of an interleukin4 variant on late phase asthmatic response to allergen challenge in asthmatic patients: results of two phase 2a studies. Lancet 2007;370:1422–31. [50] Groves R, Wilbraham D, Fuller R, Longphre M. Inhibition of IL-4 and IL-13 with an IL-4 mutein (Aeroderm) protects against flares in atopic eczema [abstract# 320]. J Invest Dermatol 2007;127:S54. [51] Vigo PG, Girgis KR, Pfuetze BL, Critchlow ME, Fisher J, Hussain I. Efficacy of anti-IgE therapy in patients with atopic dermatitis. J Am Acad Dermatol 2006;55:168. [52] Belloni B, Ziai M, Lim A, Lemercier B, Sbornik M, Weidinger S, et al. Low-dose anti-IgE therapy in patients with atopic eczema with high serum IgE levels. J Allergy Clin Immunol 2007;120:1223–5. [53] Heil PM, Maurer D, Klein B, Hultsch T, Stingl G. Omalizumab therapy in atopic dermatitis: depletion of IgE does not improve the clinical course – a randomized, placebo-controlled and double blind pilot study. J Dtsch Dermatol Ges 2010;8:990–8. [54] Welle M. Development, significance, and heterogeneity of mast cells with particular regard to the mast cell-specific proteases chymase and tryptase. J Leukoc Biol 1997;61:233–45. [55] Tomimori Y, Muto T, Fukami H, Saito K, Horikawa C, Tsuruoka N, et al. Chymase participates in chronic dermatitis by inducing eosinophil infiltration. Lab Invest 2002;82:789–94. [56] Tomimori Y, Muto T, Fukami H, Saito K, Horikawa C, Tsuruoka N, et al. Mast cell chymase regulates dermal mast cell number in mice. Biochem Biophys Res Commun 2002;290:1478–82. [57] Mao XQ, Shirakawa T, Yoshikawa T, Yoshikawa K, Kawai M, Sasaki S, et al. Association between genetic variants of mast-cell chymase and eczema. Lancet 1996;348:581–3. [58] Tanaka K, Sugiura H, Uehara M, Sato H, Hashimoto-Tamaoki T, Furuyama J. Association between mast cell chymase genotype and atopic eczema: comparison between patients with atopic eczema alone and those with atopic eczema and atopic respiratory disease. Clin Exp Allergy 1999;29:800–3. [59] Weidinger S, Rummler L, Klopp N, Wagenpfeil S, Baurecht HJ, Fischer G, et al. Association study of mast cell chymase polymorphisms with atopy. Allergy 2005;60:1256–61. [60] Tomimori Y, Tsuruoka N, Fukami H, Saito K, Horikawa C, Saito M, et al. Role of mast cell chymase in allergen-induced biphasic skin reaction. Biochem Pharmacol 2002;64:1187. [61] Watanabe N, Tomimori Y, Saito K, Miura K, Wada A, Tsudzuki M, et al. Chymase inhibitor improves dermatitis in NC/Nga mice. Int Arch Allergy Immunol 2002;128:229–34. [62] Watanabe N, Tomimori Y, Terakawa M, Ishiwata K, Wada A, Muto T, et al. Oral administration of chymase inhibitor improves dermatitis in NC/Nga mice. J Invest Dermatol 2007;127:971–3. [63] Terakawa M, Fujieda Y, Tomimori Y, Muto T, Tanaka T, Maruoka H, et al. Oral chymase inhibitor SUN13834 ameliorates skin inflammation as well as pruritus in mouse model for atopic dermatitis. Eur J Pharmacol 2008;601:186–91. [64] Tani K, Ogushi F, Kido H, Kawano T, Kunori Y, Kamimura T, et al. Chymase is a potent chemoattractant for human monocytes and neutrophils. J Leukoc Biol 2000;67:585–9. [65] Longley BJ, Tyrrell L, Ma Y, Williams DA, Halaban R, Langley K, et al. Chymase cleavage of stem cell factor yields a bioactive, soluble product. Proc Natl Acad Sci U S A 1997;94:9017. [66] Bergasa NV, Alling DW, Talbot TL, Swain MG, Yurdaydin C, Turner ML, et al. Effects of naloxone infusions in patients with the pruritus of cholestasis: a double-blind, randomized, controlled trial. Ann Intern Med 1995;123:161–7. [67] Metze D, Reimann S, Beissert S, Luger T. Efficacy and safety of naltrexone, an oral opiate receptor antagonist, in the treatment of pruritus in internal and dermatological diseases. J Am Acad Dermatol 1999;41:533–9. ˜ oz AE, Findor J. Efficacy and safety of oral [68] Terg R, Coronel E, Sorda´ J, Mun naltrexone treatment for pruritus of cholestasis, a crossover, double blind, placebo-controlled study. J Hepatol 2002;37:717–22. [69] Pauli-Magnus C, Mikus G, Alscher DM, Kirschner T, Nagel W, Gugeler N, et al. Naltrexone does not relieve uremic pruritus: results of a randomized, doubleblind, placebo-controlled crossover study. J Am Soc Nephrol 2000;11:514–9. [70] Peer G, Kivity S, Agami O, Fireman E, Silverberg D, Blum M, et al. Randomised crossover trial of naltrexone in uraemic pruritus. Lancet 1996;348:1552–4. [71] Kjellberg F, Tramer M. Pharmacological control of opioid-induced pruritus: a quantitative systematic review of randomized trials. Eur J Anaesthesiol 2001;18:346–57. [72] Monroe EW. Efficacy and safety of nalmefene in patients with severe pruritus caused by chronic urticaria and atopic dermatitis. J Am Acad Dermatol 1989;21:135. [73] Bergasa NV, Schmitt JM, Talbot TL, Alling DW, Swain MG, Turner ML, et al. Open-label trial of oral nalmefene therapy for the pruritus of cholestasis. Hepatology 1998;27:679–84. [74] Herzog JL, Solomon JA, Draelos Z, Fleischer Jr A, Stough D, Wolf DI, et al. A randomized, double-blind, vehicle-controlled crossover study to determine the anti-pruritic efficacy, safety and local dermal tolerability of a topical formulation (SRD174 cream) of the long-acting opiod antagonist nalmefene in subjects with atopic dermatitis. J Drugs Dermatol 2011;10:853.

100

K. Scha¨kel et al. / Journal of Dermatological Science 73 (2014) 91–100

[75] Arai I, Takano N, Hashimoto Y, Futaki N, Sugimoto M, Takahashi N, et al. Prostanoid DP1 receptor agonist inhibits the pruritic activity in NC/Nga mice with atopic dermatitis. Eur J Pharmacol 2004;505:229–35. [76] Honma Y, Arai I, Hashimoto Y, Futaki N, Sugimoto M, Tanaka M, et al. Prostaglandin D2 and prostaglandin E2 accelerate the recovery of cutaneous barrier disruption induced by mechanical scratching in mice. Eur J Pharmacol 2005;518:56–62. [77] Arai I, Takaoka A, Hashimoto Y, Honma Y, Koizumi C, Futaki N, et al. Effects of TS-022, a newly developed prostanoid DP1 receptor agonist, on experimental pruritus, cutaneous barrier disruptions and atopic dermatitis in mice. Eur J Pharmacol 2007;556:207–14. [78] Sugimoto M, Arai I, Futaki N, Hashimoto Y, Sakurai T, Honma Y, et al. The antipruritic efficacy of TS-022, a prostanoid DP1 receptor agonist, is dependent on the endogenous prostaglandin D2 level in the skin of NC/Nga mice. Eur J Pharmacol 2007;564:196–203. [79] Galie`gue S, Mary S, Marchand J, Dussossoy D, Carrie`re D, Carayon P, et al. Expression of central and peripheral cannabinoid receptors in human immune tissues and leukocyte subpopulations. Eur J Biochem 1995;232:54–61. [80] Facci L, Dal Toso R, Romanello S, Buriani A, Skaper S, Leon A. Mast cells express a peripheral cannabinoid receptor with differential sensitivity to anandamide and palmitoylethanolamide. Proc Natl Acad Sci U S A 1995;92:3376. [81] Johanek LM, Simone DA. Activation of peripheral cannabinoid receptors attenuates cutaneous hyperalgesia produced by a heat injury. Pain 2004;109:432–42. [82] Diaz-Laviada I, Ruiz-Llorente L. Signal transduction activated by cannabinoid receptors. Mini Rev Med Chem 2005;5:619–30. [83] Dvorak M, Watkinson A, McGlone F, Rukwied R. Histamine induced responses are attenuated by a cannabinoid receptor agonist in human skin. Inflamm Res 2003;52:238–45. [84] Rukwied R, Watkinson A, McGlone F, Dvorak M. Cannabinoid agonists attenuate capsaicin-induced responses in human skin. Pain 2003;102:283–8.

[85] Gerspacher M, La Vecchia L, Mah R, von Sprecher A, Anderson GP, Subramanian N, et al. Dual neurokinin NK1/NK2 antagonists: N-[(R,R)-(E)-1-arylmethyl-3(2-oxo-azepan-3-yl) carbamoyl] allyl-N-methyl-3,5-bis (trifluoromethyl) benzamides and 3-[N0 -3,5-bis (trifluoromethyl) benzoyl-N-arylmethyl-N0 methylhydrazino]-N-[(R)-2-oxo-azepan-3-yl] propionamides. Bioorg Med Chem Lett 2001;11:3081–4. [86] Joos G, Vincken W, Louis R, Schelfhout V, Wang J, Shaw M, et al. Dual tachykinin NK1/NK2 antagonist DNK333 inhibits neurokinin A-induced bronchoconstriction in asthma patients. Eur Res J 2004;23:76–81. [87] Schmitt J, Meurer M, Schwanebeck U, Gra¨hlert X, Scha¨kel K. Treatment following an evidence-based algorithm versus individualised symptom-oriented treatment for atopic eczema. Dermatology 2008;217:299–308. [88] Jariwala S, Abrams E, Benson A, Fodeman J, Zheng T. The role of thymic stromal lymphopoietin in the immunopathogenesis of atopic dermatitis. Clin Exp Allergy 2011.

Dr. Knut Scha¨kel studied medicine at the Medical School in Hannover and Buffalo, USA, and received his MD degree in 1993. Following his clinical training in dermatology at the University of Go¨ttingen, Dr. Scha¨kel studied Immunology at Institute of Immunology at the University of Dresden. Under the supervision of Professor Peter Rieber he identified and characterized the proinflammatory population of slan(6 sulfo LacNAc) dendritic cells in human blood and skin. In the year 2000 Dr. Scha¨kel joined the department of Dermatology in Dresden and in 2009 he accepted the professorship for Immunodermatology in Heidelberg. His research focuses on the immune function of cutaneous dendritic cells in psoriasis, atopic dermatitis, lupus and melanoma.