Full Terms & Conditions of access and use can be found at http://www.tandfonline.com/action/journalInformation?journalCode=iett20 Download by: [Vito Di Lernia] Date: 29 November 2015, At: 08:13 Expert Opinion on Therapeutic Targets ISSN: 1472-8222 (Print) 1744-7631 (Online) Journal homepage: http://www.tandfonline.com/loi/iett20 Therapeutic strategies in extrinsic atopic dermatitis: focus on inhibition of IL-4 as a new pharmacological approach Vito Di Lernia MD To cite this article: Vito Di Lernia MD (2015) Therapeutic strategies in extrinsic atopic dermatitis: focus on inhibition of IL-4 as a new pharmacological approach, Expert Opinion on Therapeutic Targets, 19:1, 87-96 To link to this article: http://dx.doi.org/10.1517/14728222.2014.965682 Published online: 04 Oct 2014. Submit your article to this journal Article views: 239 View related articles View Crossmark data Citing articles: 1 View citing articles
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Full Terms & Conditions of access and use can be found athttp://www.tandfonline.com/action/journalInformation?journalCode=iett20
Download by: [Vito Di Lernia] Date: 29 November 2015, At: 08:13
Therapeutic strategies in extrinsic atopicdermatitis: focus on inhibition of IL-4 as a newpharmacological approach
Vito Di Lernia MD
To cite this article: Vito Di Lernia MD (2015) Therapeutic strategies in extrinsic atopicdermatitis: focus on inhibition of IL-4 as a new pharmacological approach, Expert Opinion onTherapeutic Targets, 19:1, 87-96
To link to this article: http://dx.doi.org/10.1517/14728222.2014.965682
Therapeutic strategies in extrinsicatopic dermatitis: focus oninhibition of IL-4 as a newpharmacological approachVito Di LerniaArcispedale Santa Maria Nuova-IRCCS, Dermatology Unit, Reggio Emilia, Italy
Introduction: Recent data about atopic dermatitis (AD) pathogenesis
postulate that T cells and their related cytokines and chemokines are primarily
responsible for the inflammatory responses.
Areas covered: AD, the primary complex disease associated with filaggrin
deficiency, is characterized by cutaneous inflammation driven by type 2
helper T (TH2) cells. TH2-related molecules, such as IL-4, IL-13, dominate the
immune infiltrate. Experimental evidences suggest that these cytokines may
be considered attractive therapeutic targets in AD, particularly in extrinsic
AD with IgE overproduction. Recently, a fully human monoclonal antibody
directed against the IL-4 receptor a subunit blocking IL-4 and IL-13 signaling
has been evaluated in Phase I and Phase II clinical trials in patients with mod-
erate-to-severe AD with significant improvement in disease severity. Phase III
trials are ongoing.
Expert opinion: Treatment of AD represents a therapeutic challenge. TH2
cytokine-targeted therapies represent promising treatment options that
could improve the therapeutic armamentarium for AD. These therapies are
likely to become future therapeutic options in AD, particularly in the extrinsic
Atopic dermatitis (AD) is a chronic, pruritic, inflammatory skin disease whosepathogenesis still remains to be fully elucidated. It is considered a primarily T-celldriven disorder characterized by a type 2 helper T (TH2) environment and epider-mal barrier dysfunction. Current models associate AD with progressive activation ofTH2 and type 22 helper T (TH22) cytokines, with the association of a type 1 helperT (TH1) component in patients with chronic AD and a possible contribution oftype 17 helper T (TH17) cells [1].
The prevalence of AD is high. Reports range from 10 to 20% prevalence inchildren and 1 to 3% in adults [2-4]. New diagnoses are estimated at almost 11%per year [4]. Prevalence of the disease has been found to have increased greatly insome parts of the world [5].
For the past decades, research has been focused on pathogenesis of AD with stud-ies showing a complex etiology, due to the activation of multiple immunologic andinflammatory pathways including TH1/TH2 cell dysregulation, IgE overproduction,mast cell hyperactivity and dendritic cell signaling. Subsequently, proofs emergedshowing structural abnormalities in the epidermis [6] and resulting inflammation [7].Thus, a leaky epithelial barrier as well as chronic immune activation have been con-sidered the central players of the pathophysiology of this disease [6]. In particular, a
primary defect in the skin barrier followed by epiphenomenalimmunologic sequelae is considered the core of the so-called‘outside-in’ hypothesis [7]. The opposing hypothesis is the‘inside-out’ or immune-driven which advocates that AD is aprimarily immunologically driven disease caused by increasedexpression of cytokines produced by distinct T-cell subsetswith a secondary barrier defect [7-10]. However, the twopathogenic models could not be mutually exclusive and inde-pendent. As a matter of fact, a primary inherited barrierabnormality in AD could stimulate downstream paracrinemechanisms that could further compromise permeability bar-rier function, finalizing a possible ‘outside--inside--outside’pathogenic vicious circle [7].AD usually presents during early infancy and childhood. It
can disappear with age, go into remission and recur aftermany years or persist into adulthood [11]. AD may less fre-quently start around puberty or even in adulthood. In thiscase, patients continue to suffer throughout their lives [12].Various reports set the prevalence of adult onset AD atbetween 13 and 47% [13].At least two forms of AD have been delineated, the
‘extrinsic’ form associated with IgE-mediated sensitizationinvolving 70 -- 80% of the patients and the ‘intrinsic’ form,without IgE-mediated sensitization affecting 20 -- 30% ofthe patients [14]. Extrinsic AD has a pivotal role in the emer-gence of IgE-related disorders, in particular allergic rhinitisand asthma, in the so-called ‘atopic march’ [15,16]. Additionalatopic comorbidities consist of allergic eye disease, atopickeratoconjunctivitis and immediate-type food allergy [17].Beyond IgE-mediated diseases, other associated disease mayinclude skin infections, sleep disruption and mental healthdisorders [18,19].
The individual, family and public health burden of AD issignificant. The signs and symptoms of the disease negativelyaffect quality of life for patients and their families. In addi-tion, the comorbidities can amplify noticeably the negativeimpact of the disease [20]. Adults with severe AD are usuallygreatly affected by the disease. Indeed, even when the clinicalpresentation is mild, the psychosocial and economic burdenof the disease can be profound [21]. Nevertheless, moderatelylittle has been published on adult AD compared to the bodyof literature devoted to childhood.
Management of AD must consider the individual symp-tomatic variability of the disease. Basic therapy is focused ontopical glucocorticosteroids and calcineurin inhibitors [22].Adjuvant therapy includes UV irradiation, preferably withUVA1 wavelength or UVB 311 nm [22], which show variableefficacy in controlling the disease. Systemic corticosteroids arefrequently utilized for severe and acute exacerbations witheffectiveness, but long-term side effects advise against theiruse in a chronic disease such as AD. Mainstays of the manage-ment of severe or difficult-to-control patients require broadT-cell-targeting therapeutics. Depending on geographicareas, several immunosuppressive drugs, as cyclosporine A,methotrexate, azathioprine and mycophenolate mofetil areadministered to improve the clinical symptoms of severeAD [23-26]. However, with the exception of cyclosporine A,none of these drugs has a registered indication for AD(Table 1). Recently, different biologic drugs, such as mepoli-zumab, omalizumab, rituximab and tocilizumab, have beentried out for the treatment of AD [27-32].
The chronic and severe nature of AD would require moreeffective and better-tolerated therapeutic options. With theidentification of various cytokines abnormally expressed inthe skin affected by AD, a crucial challenge is to identifymolecules that are ‘driver’ cytokines. Emerging evidencenow suggests that IL-4 is central in the pathogenesis ofAD [33]. This paper reviews the rationale for targeting IL-4and then describes the preliminary results of clinical trialswith anti-IL-4 inhibitors.
2. Genetics
The association of mutations in filaggrin gene and AD is con-sidered one of the strongest between any gene and a complexdisease [34]. Overall, patients with AD show a prevalence offilaggrin (FLG) mutations of between 20 and 50% [35].Hershey et al. showed that a R576 allele of IL-4 receptor a,which is common among patients with allergic inflammatorydisorders, was strongly associated with atopy [36]. However,the frequency of these substitutions is very variable amongracial and ethnic groups. Polymorphisms have been found ingenes encoding IL-4, IL-13, signal transducer and activatorof transcription 6 (STAT-6), and the high-affinity IgEreceptor [37]. Genome-wide linkage studies identified multiplesusceptibility loci on 3q and 17q [38]. Candidate region linkagestudies discovered other susceptibility loci on 5q23-33,
Article highlights.
. Atopic dermatitis (AD) is a chronic, inflammatory skindisorder. Adults with severe AD are usually greatlyaffected by the disease with a profound psychosocialand economic burden of the disease.
. Adult patients with AD may be included in dermatologicareas with a high unmet medical need.
. AD is characterized by a type 2 helper T (TH2)environment. A TH1 component and a possiblecontribution of TH17 cells characterize chronic AD.
. TH2 cytokines can modulate and alter barrierfunction, through modulation of the expressionof filaggrin.
. IL-4 and IL-13 are key cytokines that are required forthe initiation and maintenance of theTH2 immune response.
. Clinical studies with a monoclonal antibody that targetsIL-4 and IL-13 provide concrete evidence for a key roleof TH2 activation in the pathogenesis of AD.
. The blockade of IL-4 and IL-13 signaling may be anattractive therapeutic target for AD.
This box summarizes key points contained in the article.
11q13 and 13q12-14. Finally, although at least 28 candidategenes have to date been verified in association studies, only cor-relation with genes of IL-4, IL-13, IL-4 receptor a, mast cellchymase and serine protease inhibitor, kazal-type 5 have beenreplicated in more than two different studies [38]. Interestingly,low quantities of IFN-g and high amounts of IL-4-producingCD4+ cord blood T cells were considered to be associatedwith the risk to develop AD during the first 2 years of life [39].
3. Role of IL-4 in AD from a historicalperspective
As IL-4 was considered able to enhance IgE production andIgE-Fc receptor expression by B cells, Furue et al. hypothesizedits key role in the regulation of the immune response in ADalready in 1989 [40]. High levels of the IL-4 gene expressionwere demonstrated in peripheral blood mononuclear cellsobtained from highly atopic patients [41]. In 1991, Reinholdet al. showed that high levels of IL-4 could promote a largeexpansion of skin-infiltrating lymphocytes from AD in vitro[42]. IL-4 was proved to control the selective endothelium-driven transmigration of eosinophils from allergic individuals.IL-4 showed chemotactic properties only for eosinophils fromthe peripheral blood of patients with AD and not for eosino-phils from normal individuals [43,44]. IL-4 production andIL-4 receptor expression was enhanced in AD and modulatedby IFN-g [45]. A predominant TH2 cytokine milieu in the ini-tiating stages of acute AD lesions was explained because acutelesions are associated with a T cells expressing mRNA forIL-4 and IL-13 compared with chronic lesions [46,47]. Chroniclichenified AD skin lesions show fewer IL-4 mRNA-andIL-13 mRNA expressing cells but significantly greater num-bers of IL-5, GM-CSF, IL-12 and IFN-g mRNA-expressingcells, a TH1 component and a possible contribution of TH17cells. These cytokines substantiate the growth of eosinophilsand macrophages and promote the mixed TH1/TH2 pattern,which is more characteristic of chronic lesions of AD.
3.1 Eosinophil chemoattractionIL-4 is a potent inducer of CC chemokine eotaxin expressionin dermal fibroblasts which in turn may account for
eosinophilic infiltration of involved skin areas in AD [48].IL-4, at both the mRNA and protein levels, promotes expres-sion of the eotaxin-3/CCL26, a strong chemoattractant foreosinophils and member of the CC chemokine subfamily [49],the chemokine receptor CCR7, a marker linked to migratoryevents in adaptive immune function, and the chemokineligand 23 [50,51].
3.2 Other IL-4 regulated factorsIL-4 strongly enhances the generation of CD1a(+) Langerhanscells (LC)/dendritic cells. In addition to LC, a distinct popula-tion of inflammatory dendritic epidermal cells (IDEC) isexclusively present in inflammatory skin lesions, includingAD. They are epidermally located; express CD1a, CD11band class II molecules; and do not contain Birbeck granules.IDEC of skin lesions of AD display the highest expression ofthe high-affinity receptor for IgE (FcepsilonRI) ever detectedon human antigen-presenting cells. [52,53].
IL-4 also upregulates the expression of the skin-homingstructures E-cadherin and cutaneous lymphocyte antigen.IL-4 is able to induce also IL-31, a tissue-signaling cytokinecorrelated with the induction of pruritus in the AD skinlesions [54-56].
3.3 Filaggrin and skin barrier disruptionFLG is an epidermal protein thought to be important forcutaneous barrier integrity. FLG mutations may play a rolein the development of each of the key features of AD througha functional barrier defect and enhanced cutaneous allergeningress [57] leading to a TH2-dominant infiltrate [58]. FLGdeficiency may contribute to defective extracellular lamellaethrough a number of different mechanisms. Tight junctionsare decreased in FLG-deficient individuals who show also areduced density of corneodesmosin, the major protein com-ponent of corneodesmosomes [57]. In addition, the increaseof skin-surface pH that is detected in FLG-deficient individu-als may enhance the activities of multiple serine proteaseswhich all show neutral-to-alkaline pH optimal. Serumproteases in turn may induce the maturation and release ofprimary cytokine IL-1a and IL-1b from their precursor
Table 1. Current systemic therapeutic approaches for AD and relative limitation.
Drug Registration for AD Limitations
Cyclosporine A Yes Long-term use limited by nephrotoxicityMethotrexate No Gastrointestinal disturbances, contraception indicated also in
malesAzathioprine No Monitoring for bone marrow suppression, hepatotoxicity,
increase risk of malignancyMycophenolate mofetil No Gastrointestinal disturbances, risk of infectionsCorticosteroids - Short courses (limited to flares)PUVA therapy - Long term use limited by risk of non melanoma skin cancer risk.
molecules and drive kallikrein 5-mediated TH2 inflammation,even in the absence of allergen priming [57,59].However, AD dermatitis develops in only ~ 42% of all
FLG heterozygotes suggesting the interplay of genetic modi-fiers and environmental factors [60]. TH2 cytokines can mod-ulate barrier function, through modulation of the expressionof FLG, other structural proteins and peptides important formicrobial barrier function [61,62]. In particular, TH2 cytokinesIL-4 and IL-13 attenuate the expression of genes that regulateepidermal cellular structures and the barrier function [63]. Inaddition, IL-4 and IL-13 may alter epidermal barrier func-tions through STAT6 decreasing expressions of FLG, loricrinand involucrin in keratinocytes [64]. IL-4 suppresses thesynthesis of ceramides, the cutaneous permeability barrierfunctions, the recovery of cutaneous permeability barrier dys-function [65] and the cohesion of stratum corneum by reduc-ing epidermal differentiation [66]. Indeed, it was observedthat IL-4 decreased the amount of corneodesmosomes anddown-regulated the expression of desmoglein 1. It enhancesexpression of kallikrein 7 which in turn degrades corneodes-mosome proteins such as desmoglein 1, desmocollin 1 andcorneodesmosin [67]. These multifaceted interactions may beconsidered a link between outside and inside hypothesesshowing the way for a ‘outside--inside--outside’ pathogenicloop [68].
3.4 Antimicrobial peptides expressionKeratinocytes produce and secrete several antimicrobial pepti-des which function as endogenous antibiotics and as signalingmolecules within the cutaneous innate immune system.Defensins are constitutively expressed or induced after exoge-nous stimuli, contact with bacteria or tissue injury [69]. Theyplay a part in the host defense by disrupting the cytoplasmicmembrane of microorganisms. In this way, the innate immunesystem quickly activates an unspecific, standardized first-linedefense against different pathogens. Human b-defensins(HBDs) are one major class of antimicrobial peptides that areprimarily expressed in the epithelial cells [69,70]. They are alsoable to recruit dendritic and T cells to inflammatory sites. Inthis way, they mobilize and amplify adaptive immune hostdefenses linking the innate and adaptive immune responses[71,72]. Defects in this system cause barrier dysfunction whichresults in increased allergen penetration through the epidermisand predispose to secondary skin infections [73,74]. AD hasbeen associated with decreased or impaired production ofHBDs [74,75]. In addition, overexpression of TH2 cytokinessuch as IL-4 and IL-13, but also IL-10, downregulate endoge-nous antimicrobial peptide expression, as HBDs and cathelici-din LL-37, in AD keratinocytes [74-76]. Further mechanismspotentially causing mechanical and chemical epidermal barrierdysfunction in AD involve the enhancement of protease activ-ity. IL-4 and IL-13 are able to enhance KLK7 expression andfunction in keratinocytes [77]. KLK7 is a chymotrypsin-likeserine protease which may degrade human cathelicidin antimi-crobial peptide LL-37 [77].
3.5 Staphylococcus aureusPatients with AD have a distinctive predisposition to coloni-zation or infection by a number of microbial organisms,especially Staphylococcus aureus and herpes simplex virus [78].Bacterial colonization is directly correlated with the severityof eczema and highest on lesional skin, but colony countsare high on clinically normal skin of AD patients aswell [79,80]. S. aureus toxins induce expansion of IL-4- andIL-5-producing TH2 clones, leading to increased IgE synthesisand eosinophil activation. An elevation in the pH of the stra-tum corneum, which is commonly observed in FLG-deficientpersons, may lead to enhanced S. aureus adhesion and multi-plication [81]. Staphylococcal-specific T cell are primarily ofthe TH17 subset. AD patients show an ineffective IL-17-dependent upregulation of HBD-2 due to a partial inhibitioninduced by the type 2 microenvironment [80,81]. Also, HBD-3has potent killing activity against S. aureus, but increasedlevels of TH2 cytokines IL-4 and IL-13 inhibit keratinocytemobilization of HBD-3 [82]. Thus, barrier disruption itselffavors bacterial colonization and secondary infections; onthe other hand, TH2 cytokines inhibit mobilization of antimi-crobial peptides (Figure 1). Barrier disruption and TH2 micro-environment act as interdependent cofactors in defectiveS. aureus killing in patients with AD [83].
4. IL-4 in intrinsic versus extrinsic AD
A subgroup of patients affected with ‘intrinsic’ AD (20% ofcases) are known to have normal total and specific IgE levels,and negative skin prick tests and Radio-Allergo-Sorbent Teststowards common environmental allergens. The incidence ofFLG gene mutations was discovered to be significantly lowerin the intrinsic or ‘nonatopic’ AD [84]. The existence of such‘nonatopic’ or intrinsic form of AD raised the questionwhether this form may be characterized by distinct immuno-logic features and cytokine pattern with respect to the classicTH2-related cytokine pattern [85,86].
A higher immune activation has been found in patientswith intrinsic compared with extrinsic AD, involving otherT-cell subsets, such as the TH17 and TH22 cells. IL-22mRNA expression is significantly increased in lesional versusnonlesional skin in the setting of both AD variants but is sig-nificantly higher in lesional intrinsic compared with extrinsicAD [87]. Both intrinsic and extrinsic AD lesions show markedTH2 activation with high IL-4/IL-13 expression, with IL-13higher levels in extrinsic AD [88].
5. Treatments affecting IL-4 expression
A significant decrease of soluble IL-4 receptor (sIL-4R) in theserum of patients with AD has been observed after successfulUVA1 phototherapy [89]. Also, cyclosporine and dexametha-sone significantly downregulate the activity of IL-4 in adose-dependent manner [90]. Phosphodiesterase inhibitors
suppress IL-4 and IL-5 secretion by human T-helper type 2cells [91,92]. Treatment with recombinant IFN-g was assessedin patients with AD with the aim to decrease serum IgE andIL-4 levels, to shift the cytokine balance, and thereby lead toclinical improvement. After treatment with rIFN-g , serumlevels of IL-4 and IL-6 decline without affecting IgE produc-tion [93,94] and patients often showed marked improvement.However, toxicity and the short half-life of IFN-g in serumwere leading causes of reduced enthusiasm to manage it forthe treatment of AD. A pioneering experience was conductedwith a highly efficient mouse dominant negative IL-4/IL-13antagonist blocking both IL-4 and IL-13 signal transductionsin an AD model. The simultaneous suppression of both sig-nals successfully controlled TH2-type chronic dermatitis [95].
6. IL-4 as a therapeutic target
A fully human monoclonal antibody directed against theIL-4 receptor a subunit and administered via subcutaneousinjection has recently been developed. As IL-4 and IL-13signaling occurs through two different IL-4 receptors (type Iand II), which both contain a common IL-4R a subunit,this antibody inhibits both IL-4 and IL-13 signaling. It hasbeen shown to be efficacious in patients with persistent, mod-erate-to-severe asthma and elevated eosinophil levels [96]. Noclear pattern of change in blood eosinophil levels wasobserved, but reduced levels of TH2-associated inflammatorybiomarkers, in particular fractional exhaled nitric oxide level,
serum IgE, eotaxin-3 and thymus and activation-regulatedchemokine (TARC) were assessed after treatment. Interest-ingly, serum TARC levels reflect disease activity of AD aswell [97,98]. Pruritus correlates with the ratio of serum TARCwhich is actually considered the most sensitive disease markerof AD [98]. Recently, IL-4 receptor a antagonist was evaluatedin a series of four randomized, double-blind, placebo-controlled trials in adults with moderate-to-severe AD [99].The treatment was given as monotherapy in two 4-week trialsand in one 12-week trial and in combination with topicalglucocorticoids in another 4-week study. End points includedthe Eczema Area and Severity Index score, the investigator’sglobal assessment score, pruritus, safety assessments andserum biomarker levels. A significant improvement in skinlesions together with a rapid and substantial reduction inpruritus was observed in patients treated with the IL-4 recep-tor a antagonist. The treatment was associated with a decreasein serum biomarker levels. Particularly, there was adose-dependent reduction of K16, a marker of keratinocyteproliferation and innate immunity. A significant associatedreduction in the level of TARC was confirmed [96,99]. Aboutsafety, there were more mild-to-moderate adverse events inthe patients treated with the active treatment (i.e., nasophar-yngitis and headache), but there were more serious adverseevents in the placebo group, mostly due to skin infections.Therapeutics designed for targeting IL-4 are limited so farto asthma and LP; however, speculative hypothesis may beput forward for other diseases (Table 2).
IL-4IL-31induction
PruritusReduced AMP
mobilization
Eosinophilchemoattraction
Increased IgEproduction
Enhanced DCgeneration
Epidermalbarrier
alteration
DefectiveS.Aureus killing
Enhancedallergen
penetration
Figure 1. Main activities of IL-4 in atopic dermatitis.AMP: Antimicrobial peptides; DC: Dendritic cells.
Therapeutic strategies in extrinsic atopic dermatitis
The identification of driver cytokines is a priority in the devel-opment of new therapeutic concepts against AD. TH2 immu-nity seems to be the end stream of a heterogeneous group ofconditions with the clinical phenotype of AD. In acute lesionsof AD, the TH2 cells produce IL-4, IL-13 and IL-31, whichmay potentiate barrier dysfunction and contribute to pruritus.In chronic lesions, a distinct T-cell infiltrate with TH1,TH17 and TH22 is present. However, many other cells areinvolved in the pathogenesis of AD, including TH9 cells, LCand IDEC, although the precise contribution of some ofthem remains to be fully understood. Preliminary data suggestthat blockade of IL-4 and IL-13 signaling may be an attractivetherapeutic target for AD.
8. Expert opinion: future place ofanti-IL-4-based strategies in the treatmentof AD
Adult patients with AD may be included in dermatologicareas with a high unmet medical need. Systemic agents forthe treatment of moderate-to-severe AD have not been devel-oped in the last two decades. Treatment options for refractoryAD consist of phototherapy and broad-spectrum immuno-suppressant, sometimes in an off-label basis. Some of thesedrugs, such as cyclosporine, cannot often be administeredfor a long time because of organ toxicity. However, ADresearch is entering a new era. Development in definingimmunogenetics and pathomechanisms of AD takes with itthe demand to understand better the clinical spectrum ofdisease and integrate phenotype with genetics. The biologicrevolution in therapy of inflammatory diseases is going toinvolve AD, bringing with it an urgent need for rationaldrug design based on known biological targets. A concertedeffort between academia, industry and patients will take for-ward the understanding of, and therapy for, AD.
AD and some types of asthma are characterized by theinduction of an immune response that is driven byTH2 cells. Besides intrinsic mechanisms, the nature of classicalallergens might drive the immune system into TH2 direction.IL-4 and IL-13 are key cytokines that are required for theinitiation and maintenance of this TH2 immune response.Consequently, such cytokines may be considered new andappealing therapeutic targets in AD. Phase I and II studieswith a monoclonal antibody that targets a subunit of theIL-4 and IL-13 receptors provide additional proofs for a keyrole of TH2 activation in the pathogenesis of AD. Theoreti-cally, IL-4 blocking could induce more significant improve-ment in extrinsic AD with IgE overproduction. However, byblocking IL-4 receptor a, signaling of both IL-4 and IL-13cytokines is modulated. As IL-13 appears to be a key cytokinein the pathogenesis of both extrinsic and intrinsic forms ofAD, the double signaling inhibition could be beneficial inintrinsic AD as well. Whereas it is arduous to predict theeffect of IL-4 and IL-13 inhibition on chronic, lichenifiedskin lesions of AD, which show fewer IL-4 mRNA, IL-13mRNA expressing cells and a distinct T-cell infiltrate withTH1, TH17 and TH22 dominance. Results of ongoingPhase III studies will be crucial in determining the clinicalutility of the targeting of IL-4 and IL-13 as well as the long-term effectiveness and tolerability of the treatment. Theycould help to identify disease phenotypes that can predicttreatment response. The advantages and weaknesses of block-ing IL-4 and IL-13 as compared with molecular targetshaving broader impact on the immune system, as cyclosporineand methotrexate should be proved. Neutralization of IL-4and IL-13 should theoretically improve skin barrier integrityand the expression of endogenous antimicrobial peptidespreventing dermatitis flares. Thus, ancillary analysis shouldassess patients for microbial colonization before and aftertreatment.
If on-going clinical trials will confirm the efficacy andsafety results of preliminary studies, an IL-4 receptor a inhib-itor is likely to become the first biologic therapy for refractoryadult AD.
Declaration of interest
The author has no relevant affiliations or financial involve-ment with any organization or entity with a financial interestin or financial conflict with the subject matter or materialsdiscussed in the manuscript. This includes employment,consultancies, honoraria, stock ownership or options, experttestimony, grants or patents received or pending, or royalties.
Table 2. Potential therapeutic applications for
IL-4 inhibitors.
Disease Evidence
Asthma Phase II trial [96]Adult atopic dermatitis Phase II trial [99]Systemic sclerosis Hypothesis [100]
