REVIEW

Treatment of Atopic Dermatitis with Biologic Drugs

Gabriella Fabbrocini . Maddalena Napolitano . Matteo Megna .

Nicola Balato . Cataldo Patruno

Received: July 19, 2018 / Published online: September 4, 2018� The Author(s) 2018

ABSTRACT

Atopic dermatitis (AD) is a chronic, pruritic,inflammatory skin disease which predominatelyaffects children and usually clears up duringinfancy or childhood. However, AD may persistwith a chronic relapsing course until adulthoodor develop at a later age. AD treatment can oftenbe complicated. Treating moderate-to-severeAD can be challenging: only a few therapeuticoptions are available, with cyclosporine beingthe only approved and labeled systemic drug. Inthe last few years, advances in the knowledge ofAD pathogenesis have been made that canprovide the basis for developing new topicaland systemic drugs. Among them, biologicdrugs targeting specific cytokines involved inthe development of the disease will probablyrevolutionize AD therapy. Currently, dupilu-mab, a monoclonal antibody that binds to the

shared alpha chain subunit of the receptors forIL-4 and IL-13, is the only biologic drug licensedfor the treatment of AD in adults. However,other biologic drugs that selectively target somekey cytokines in AD pathogenesis (IL-13, IL-31,and IL-22) are also being studied. In this review,we discuss all of the biologic drugs that havebeen studied for AD treatment.

Keywords: Atopic dermatitis; Biologic drug;Biologics; Therapy; Treatment

INTRODUCTION

Atopic dermatitis (AD) is the most commoninflammatory skin disease of childhood, affect-ing about 20% of children [1]. AD usuallyresolves before adolescence. However, it some-times persists in adulthood (persistent AD), andin some cases the disease starts in adulthood(adult-onset AD) [2]. It is reported that theprevalence of childhood AD is steadily increas-ing, especially in industrialized countries [3]. Inthe same way, it is likely that the frequency ofthe adult form has also been increasing inrecent years, as even reported for elderlypatients [4]. Current prevalence data regardingadult AD are very variable, with values rangingfrom 0.3 to 14.3%, even though most authorsagree that AD affects 1–3% of adults [5]. AD hasa chronic relapsing course and significantly

Enhanced Digital Features To view enhanced digitalfeatures for this article go to https://doi.org/10.6084/m9.figshare.6990209.

G. Fabbrocini � M. Megna � N. Balato �C. Patruno (&)Department of Dermatology, University of NaplesFederico II, Naples, Italye-mail: cataldopatruno@libero.it

M. NapolitanoDepartment of Medicine and Health Science‘‘Vincenzo Tiberio’’, University of Molise,Campobasso, Italy

Dermatol Ther (Heidelb) (2018) 8:527–538

https://doi.org/10.1007/s13555-018-0258-x

affects the quality of life of patients, especiallyadults with severe and long-lasting AD [6]. Thediagnosis of adult AD is usually clinical, sincetraditional diagnostic criteria used for childrenare not always applicable to adults [5]. Studiesare now underway that aim to better define theclinical characteristics of the disease [7, 8]. Inmild cases, topical treatment includes corticos-teroids and calcineurin inhibitors in addition toemollient agents, which are the cornerstone oftreatment in all cases of AD [1]. Adjunctivesystemic treatment is needed in moderate-to-severe cases [9]. Phototherapy, cyclosporine A(CsA), methotrexate, and azathioprine are themain immunosuppressors used in AD treat-ment, while corticosteroids are used only foracute exacerbations [1]. Currently, cyclosporineis the only labeled medicament available for thetreatment of AD. Due to the chronicity of thecondition, long-term immunosuppressivetreatment is often required. Subsequently, con-tinuous follow-up is needed, as all of theabovementioned drugs may have importantside effects [9]. Moreover, these therapies showdifferent efficacies [9]. In recent years, severalstudies have elucidated the pathogenesis of thedisease, especially as regards the roles of somecytokines [10]. This has led to the introductionof new drugs targeting individual cells or amediator of the inflammatory response [1, 9].Among these new drugs, biologic agents areplaying a leading role. Currently, the mono-clonal antibody dupilumab is the only biologicdrug licensed for the treatment of AD in adults[1, 7]. Dupilumab blocks interleukin (IL)-4 andIL-13, two cytokines that play a key role in thedevelopment of type 2 helper (Th2) lympho-cyte-mediated skin inflammation in AD [11].Other biologic medicaments—drugs that selec-tively inhibit some cytokines (namely IL-13, IL-31, and IL-22) that play prominent roles in thepathogenesis of DA—are also under investiga-tion [1].

This review summarizes currently availablebiologic therapies for adult AD based on ananalysis of the literature in this field, andhighlights possible future scenarios for this kindof treatment.

METHODS

For the current review, relevant literature pub-lished in English was searched for. The studieswe selected concerned systemic biologic ther-apy of adult atopic dermatitis. We selectedcontrolled phase II and III trials as well asreviews, guidelines, and consensus. Researchwas carried out by searching the followingdatabases through to June 30, 2018: PubMed,Embase, The Cochrane Library, Google Scholar,EBSCO, and clinicaltrials.gov. The followingkeywords were used: ‘‘atopic dermatitis,’’ ‘‘atopiceczema,’’ ‘‘adult atopic dermatitis,’’ ‘‘adult atopiceczema,’’ ‘‘systemic treatment,’’ ‘‘systemic ther-apy,’’ ‘‘biologics,’’ ‘‘monoclonal antibody,’’ ‘‘IL-4monoclonal antibody,’’ ‘‘IL-13 monoclonalantibody,’’ ‘‘IL-31 monoclonal antibody,’’ and‘‘IL-22 monoclonal antibody.’’ This article isbased on previously conducted studies and doesnot involve any new study of human or animalsubjects performed by any of the authors.

BIOLOGIC DRUGS

The development of biological therapies hasprogressed rapidly in the last few years. Biologicdrugs are a class of pharmacological agents thatare engineered to target specific mediators ofinflammation. Recently, multiple clinical trialshave demonstrated the efficacy of targetedtherapy involving the blocking of cytokines ormediators that play a pivotal role in thepathogenesis of AD. Dupilumab is currently theonly biologic drug that has been approved byboth the US Food and Drug Administration(FDA) and the European Medicines Agency(EMA) for the treatment of adult patients withinadequately controlled moderate-to-severe AD[12]. Biological drugs appear to be promisingtreatments for adult AD patients because theyoffer more convenient dose regimens and allowless frequent laboratory monitoring than othersystemic therapies, as well as having fewer sideeffects [1]. Future studies are needed to fulfillunmet needs and achieve better standards ofcare for AD patients, to clarify the roles of otherbiologic drugs under investigation for AD

528 Dermatol Ther (Heidelb) (2018) 8:527–538

therapy, and to completely revolutionize adultAD treatment.

IL-4 and/or IL-13 Inhibitors

Dupilumab is a fully human monoclonal anti-body that binds to the shared alpha chain sub-unit of the receptors for IL-4 and IL-13 [13]. Thisresults in downregulation of receptor signalingdownstream of the JAK/STAT pathway, whichregulates the expression of many genesinvolved in the pathogenesis of AD [14]. InMarch 2017, dupilumab received its firstnational approval, from the USA, for its use inthe treatment of adult patients with moderate-to-severe AD whose disease is not adequatelycontrolled with topical therapies, or when thosetherapies are not advisable. In September 2017,it was also approved in Europe by EMA as asystemic first-line treatment for adults sufferingfrom AD [9]. Dupilumab is supplied in a single-dose pre-filled syringe and is administered bysubcutaneous injection into the thigh, abdo-men, or upper arm. The recommended dosage isa loading dose of 600 mg (two 300-mg injec-tions at different sites) followed by 300 mgevery other week, with rotation of the injectionsite. Dupilumab can be used with or withoutconcomitant topical corticosteroids (TCS) [15].It has also showed efficacy in patients withpersistent asthma and elevated eosinophils,where it improved lung function, reducedexacerbations, and decreased Th2 biomarkers[16]. Randomized, double-blind, placebo-con-trolled trials involving adults who had moder-ate-to-severe AD were performed to check theapplicability of dupilumab in the treatment ofadults with moderate-to-severe AD. The firsttwo clinical trials, SOLO 1 (NCT02277743) andSOLO 2 (NCT02277769), investigated the safetyand efficacy of the dupilumab dosage regimencompared with placebo [17]. Patients were ran-domly assigned in a 1:1:1 ratio to receive weekly(qw) subcutaneous injections of dupilumab(300 mg) or placebo or the same dose of dupi-lumab every other week (q2w) alternating withplacebo for 16 weeks. Significantly, more of thepatients receiving dupilumab showed animprovement of at least 75% in the Eczema Area

and Severity Index (EASI) score compared to theplacebo group. The percentages of the patientswho reached EASI-50 and EASI-90 as well as theimprovement in the Scoring Atopic Dermatitis(SCORAD) and the decrease in the affected bodysurface area were all significantly higher in thedupilumab groups than in the placebo group(Table 1). A further phase III trial, LIBERTY ADCHRONOS, aimed to analyze the long-termmanagement of moderate-to-severe AD withdupilumab and concomitant topical corticos-teroids [18] (Table 1). At week 52, more of thepatients who received dupilumab plus topicalcorticosteroids achieved the co-primary end-points of IGA 0/1 and EASI-75 compared to theother two groups (Table 1). The efficacy ofdupilumab has been demonstrated in adultpatients with a history of inadequate responseto/intolerance of CsA [19]. In the LIBERTY ADCAFE trial, 390 patients with an inadequateresponse to/intolerance of CsA or for whom CsAtreatment was medically inadvisable werescreened [19]. The proportion of the patientsachieving EASI-75 at week 16 was significantlyhigher in the dupilumab qw ? TCS and q2w ?

TCS groups compared to placebo ? TCS. In allof the clinical studies performed in this field todate, dupilumab has shown a favorable safetyprofile with no dose-limiting toxicity and fewadverse effects. The most common adverseevents (AEs) associated with dupilumab areinjection-site reactions, which mainly consist oftransient erythema or edema. Conjunctivitisseems the only specific side effect, and this canbe treated successfully with fluorometholone0.1% eye drops or tacrolimus 0.03% eye oint-ment [20]. The reason why dupilumab causesconjunctivitis is not fully understood, and iscurrently being evaluated in ophthalmologicalsubtrials. It was hypothesized that blockage ofIL-4 and IL-13 would increase the activities ofspecific ligands involved in atopic keratocon-junctivitis, such as the OX40 ligand [21]. Gen-erally, the severity of dupilumab-inducedconjunctivitis in the majority ([ 90%) ofpatients is only mild or moderate, and itresolves easily. Actually, there is only one caseof bilateral conjunctivitis with consequentcicatricial ectropion associated with dupilumabtherapy for AD in the literature [22].

Dermatol Ther (Heidelb) (2018) 8:527–538 529

Table1

The

mainfeatures

ofclinicaltrialsregardingbiologicdrugsformoderate-to-severeatopicderm

atitis

Drug[ref.]

Trial

phaseand

no.of

patients

enrolled

Dosageanddu

ration

Results

Dupilumab

[17]

III

N=671

(1)Aninitialdose

of600mgdupilumab

(two300mg

injections)on

day1,

followed

by300mgonce

every

2weeks

(q2w

);(2)an

initialdose

of600mg

dupilumab

onday1followed

by300mgonce

weekly

(qw);or

(3)matchingplacebo

Duration:

16weeks

The

percentage

ofpatientswho

hadascoreof

0or

1(clear

or

almostclear)

intheInvestigator

GlobalAssessm

ent(IGA)at

16weeks

was

38%

inthegroupthat

received

dupilumab

every

otherweek,37%in

thedupilumab

weeklygroup,and10%in

the

placebogroup(P

\0.0001)

Areductionof

75%or

morein

EASI

scorewasmorecommon

for

the300-mgdupilumab

group(q2w

andqw

)withrespectto

placebo(51.3%

and52.5%

vs14.7,P

\0.0001)

MeanSC

ORAD

percentageswere57.7

±2.7in

thedupilumab

w2q

arm

and29.0

±3.21

forplacebo(P

\0.001)

Changefrom

baselin

epruritus

NRSscoreat

week16:-

51.0,

-48.9,and

-26.1

intheq2w,q

w,and

placebogroups,

respectively

Dupilumab

[17]

III

N=701

(1)Aninitialdose

of600mgdupilumab

(two300mg

injections)on

day1,

followed

by300mgonce

every

2weeks

(q2w

);(2)an

initialdose

of600mg

dupilumab

onday1,followed

by300mgonce

weekly

(qw);or

(3)matchingplacebo

Duration:

16weeks

The

percentage

ofpatientsthat

hadascoreof

0or

1(clear

or

almostclear)

intheInvestigator

GlobalAssessm

ent(IGA)at

16weeks

was

36.1%

inthegroupthat

received

dupilumab

every

otherweek,36.4%

inthedupilumab

weeklygroup,and8.5%

in

theplacebogroup(P

\0.0001)

Areductionof

75%or

morein

EASI

scorewasmorecommon

for

the300-mgdupilumab

group(q2w

andqw

)withrespectto

placebo(44.2%

and48.1%

vs11.9,P

\0.0001)

MeanSC

ORAD

percentageswere51.1

±2.02

inthedupilumab

w2q

arm

and19.7

±2.52

forplacebo(p\

0.001)

Changefrom

baselin

epruritus

NRSscoreat

week16:-

44.3,

-48.3,and

-15.4

intheq2w,q

w,and

placebogroups,

respectively

530 Dermatol Ther (Heidelb) (2018) 8:527–538

Table1

continued

Drug[ref.]

Trial

phaseand

no.of

patients

enrolled

Dosageanddu

ration

Results

Dupilumab

[18]

III

N=740

Patientswererand

omlyassigned

(3:1:3)to

dupilumab

300mgweekly,dupilumab

300mgevery2weeks,o

r

placeboweekly;allpatientsused

concom

itanttopical

corticosteroids(TCS)

Duration:

52weeks

The

percentage

ofpatientsthat

hadascoreof

0or

1in

the

Investigator

GlobalAssessm

ent(IGA)was

36.0%

inthegroup

that

received

dupilumab

w2q

?TCS,

40.0%

indupilumab

wq?

TCS,

and13%

intheplacebogroup(P

\0.0001)

Areductionof

75%or

morein

EASI

scorewasmorecommon

for

the300-mgdupilumab

?TCSgroup(q2w

andqw

)withrespect

toplacebo(65%

and64%

vs22,P

\0.0001)

Dupilumab

[19]

III

N=390

Patientswithinadequateresponseto/intolerance

ofCsA,

orforwhom

CsA

treatm

entwasmedicallyinadvisable,

wererand

omized

1:1:1to

subcutaneous

dupilumab

300mgweekly(qw)or

every2weeks

(q2w

)or

placebo;

allpatientsused

concom

itanttopical

corticosteroids(TCS)

Duration:

16weeks

Proportion

ofpatientsachievingEASI-75at

week16

was

significantlyhigher

inthedupilumab

qw?

TCSand

q2w?

TCSgroups

comparedto

placebo?

TCS(59.1%

and

62.6%

vs29.6%,respectively;P\

0.001)

Proportionsof

patientswho

achieved

anim

provem

ent(reduction)

ofC

4pointsfrom

baselin

eto

week16

intheq2w,q

w,and

placebogroups

were,respectively,4

5.7,

40.4,and

14.3%

(P\

0.001)

Proportionsof

patientswithIG

Aof

0or

1andareductionfrom

baselin

eof

C2pointsat

week16

intheq2w,q

w,and

placebo

groups

were,respectively,4

0.2,

39.1,and

15%

(P\

0.001).

MeanDLQIchangesfrom

baselin

eatweek16

intheq2w,qw,and

placebogroups

were,respectively,-

9.5,

-8.8,

and-

4.5

(P\

0.001)

Fezakinu

mab

[31]

II N=60

600mgivat

baselin

e,followed

by300mgevery2weeks

orplacebo

Duration:

10weeks

andfollowup

until20

weeks

MeanSC

ORAD

reductions

were13.8

±2.7in

thefezakinu

mab

arm

and8.0±

3.1forplacebo(P

=0.134)

Bodysurfacearea

reductions:12.4%

±2.4vs

6.2%

±2.7in

fezakizumab

andplacebo,

respectively(P

=0.009)

Investigator

GlobalAssessm

entdecline:0.7±

0.2vs

0.3±

0.1

(P=0.034)

Dermatol Ther (Heidelb) (2018) 8:527–538 531

Table1

continued

Drug[ref.]

Trial

phaseand

no.of

patients

enrolled

Dosageanddu

ration

Results

Lebrikizumab

[29]

II N=209

125mgsingledose,2

50mgsingledose,1

25mgevery

4weeks

orplacebo

Duration:

12weeks

EASI-50was

reachedin

82.4%

ofpatientswithlebrikizum

ab

125mgevery4weeks

and62.3%

intheplacebogroup

(P=0.026)

Patientsreceivingasingledose

oflebrikizum

abshow

edno

statistically

significant

improvem

entin

EASI-50comparedwith

placebo

Nem

olizum

ab

[35]

II N=264

0.1,

0.5,

or2.0mg/kg

(subcutaneous)or

placeboevery

4weeks

oran

exploratorydose

of2.0mg/kg

every

8weeks

Duration:

12weeks

Changesin

thepruritus

visual-analoguescalewere-

43.7%in

the

0.1mggroup,

-59.8%

inthe0.5mggroup,

and-

63.1%

in

the2.0mggroupversus

-20.9%

intheplacebogroup

(P\

0.01)

EASI

reductions:-

23.0,-

42.3,and

-40.9%,respectively,in

thenemolizum

abgroups

versus

-26.6%

intheplacebogroup

Changes

inbody-surface

area

affected

byatopicderm

atitiswere

-7.5,-

20.0,and

-19.4%withnemolizum

abversus

-15.7%

withplacebo

Nem

olizum

ab

[36]

II N=191

0.1,

0.5,

or2.0mg/kg

scevery4or

8weeks

Duration:

52weeks

Changefrom

baselin

ein

pruritus

visualanalog

scalescoreat

week

64:-

73.0,-

89.6,-

74.7,and

-79.1in

the0.1,0.5,and2.0-

mg/kg

q4wand2.0-mg/kg

q8wgroups,respectively

EASI

reductions:-

68.5,-

75.8,-

78.9,and

-69.3in

the0.1-,

0.5-,and

2.0-mg/kg

q4wand2.0-mg/kg

q8wgroups,respectively

532 Dermatol Ther (Heidelb) (2018) 8:527–538

Table1

continued

Drug[ref.]

Trial

phaseand

no.of

patients

enrolled

Dosageanddu

ration

Results

Tralokinu

mab

[25]

II N=204

45,1

50,o

r300mgof

subcutaneous

tralokinum

abor

placeboevery2weeks

Duration:

12weeks

300mgof

tralokinum

absignificantlyim

proved

thechange

from

baselin

eEASI

scoreversus

placebo(adjustedmeandifference,

-4.94;95%

CI-

8.76

to-

1.13;P=0.01)

Agreaterpercentage

ofthesubjectstreatedwith300mgachieved

anInvestigator

GlobalAssessm

entresponse

withrespectto

placebo(26.7%

vs11.8%,P

=0.06)

Areductionof

50%or

morein

EASI

scorewasmorecommon

for

the300-mgtralokinum

abgroupwithrespectto

placebo(73.4%

vs51.9%,P

=0.03)

The

percentage

ofparticipantswithareductionof

75%or

morein

EASI

scorewas

higher

inthe300mgtralokinum

abgroup

(42.5%

)than

intheplacebogroup(15.5%

,P=0.003)

Dermatol Ther (Heidelb) (2018) 8:527–538 533

As with all therapeutic proteins, dupilumabhas the potential for immunogenicity. Anti-drug antibodies were developed by approxi-mately 7% of patients with AD who receiveddupilumab 300 mg every 2 weeks for 16 weeksin SOLO 1 and 2 [23]. Approximately 30% ofpatients with anti-drug antibodies (2% overall)had neutralizing antibodies. Similarly, approxi-mately 7% of the patients who received dupi-lumab 300 mg once every 2 weeks (plus TCS) for52 weeks in CHRONOS developed antibodies todupilumab, with approximately 14% of thosepatients (1% overall) having neutralizingantibodies.

Several ongoing studies involving both chil-dren and adolescents will show if these sub-groups of the AD population experience equallypositive effects, expanding the treatment indi-cation for dupilumab even further [24].

Tralokinumab is a human monoclonal anti-body (mAb) that specifically neutralizes IL-13[25]. IL-13 is a pleiotropic Th2 cytokine that hasbeen implicated in the pathogenesis of AD, as itimpairs skin barrier function by downregulatingfilaggrin [26, 27]. IL-13 is increased in bothlesional and nonlesional skin of AD subjects,and correlates with disease severity [28]. A ran-domized, placebo-controlled, double-blind,clinical phase II study involving 204 adultpatients with moderate-to-severe AD was per-formed [25]. At week 12, a dose of 300 mg oftralokinumab every 2 weeks resulted in a sig-nificant improvement in AD compared withplacebo (Table 1). Indeed, the drug significantlyimproved the EASI change from baseline versusplacebo (P = 0.01; Table 1). In particular, agreater percentage of the 300 mg tralokinumab-treated participants achieved EASI-50 versusplacebo at week 12 (73.4% vs 51.9%, P = 0.03)as well as EASI-75 (42.5% vs 15.5%, P = 0.003),although concomitant TCS use may constitute aconfounding factor that could explain the highplacebo efficacy. Interestingly, patients withhigher concentrations of biomarkers ofincreased IL-13 levels showed a better responseto tralokinumab. The most frequent AEs in allgroups were upper respiratory tract infections,nasopharyngitis, and headache [25]. All of thesedata indicated that tralokinumab treatment wasassociated with early improvements in AD

symptoms and an acceptable safety and tolera-bility profile.

Lebrikizumab is a humanized monoclonalantibody that specifically targets IL-13 [29]. Aphase II randomized, double-blind, prospective,placebo-controlled, multicenter study has beenperformed in adult subjects with moderate-to-severe AD [30]. In total, 209 patients were ran-domized (1:1:1:1) to lebrikizumab 125 mg sin-gle dose, lebrikizumab 250 mg single dose,lebrikizumab 125 mg every 4 weeks for12 weeks, or placebo every 4 weeks for 12 weeks.At week 12, EASI-50 was more commonlyachieved in patients receiving lebrikizumab125 mg every 4 weeks than in placebo patientsevery 4 weeks (82.4% vs 62.3%, P = 0.026). Thehigh placebo performance may due to thebackground of daily TCS application (Table 1).Lebrikizumab was well tolerated; adverse eventswere similar between groups (66.7% all lebrik-izumab vs 66.0% placebo) and were mostly mildor moderate; no AE dose–response relationshipswere found for the drug. In that study, theefficacy of lebrikizumab 125 mg every 4 weeksled to a significant improvement in patientswith moderate-to-severe AD.

IL-22 Inhibitor

IL-22 was found to be increased in both acuteand chronic AD lesions, correlating with ADseverity [28]. It is produced primarily by Th22cells and is able to impair epithelial barrierfunction through its effect on keratinocytes[31].

Fezakinumab is a fully human monoclonalantibody directed against IL-22. A recent ran-domized, double-blind, placebo-controlled trialwith intravenous fezakinumab monotherapyevery 2 weeks for 10 weeks and follow-upassessments until 20 weeks has been completed[32]. Sixty-seven adult AD patients were asses-sed for eligibility, and 60 patients were ran-domized 2:1 to fezakinumab (n = 40) or placebo(n = 20). Results showed that the SCORADimprovement was significantly greater withfezakinumab versus placebo in patients withsevere AD at 12 weeks (36.4% vs 22.3%,P\ 0.05) and 20 weeks (46.2% vs 22.6%,

534 Dermatol Ther (Heidelb) (2018) 8:527–538

P\ 0.01), while patients with moderate ADseemed to be less responsive to treatment(Table 1) [31]. AEs occurred with similar fre-quencies in the fezakinumab and placebogroups [32]. Taken together, these data showedthat fezakinumab was well tolerated, with sus-tained clinical improvements after the last drugdosing.

IL-31 Receptor Inhibitor

It is already known that the skin expression ofIL-31 and IL-31R is increased in patients withAD [33]. Moreover, AD subjects also showhigher serum levels of IL-31 as well as IL-31-producing lymphocytes [34]. In addition, bothserum and skin IL-31 levels have been shown tocorrelate with AD severity [33, 34], indicatingan important role for IL-31 in AD pathogenesisapart from itch pathophysiology [35].

Nemolizumab is a monoclonal antibodydirected against IL-31 receptor A [33]. A phaseII, randomized, double-blind, placebo-con-trolled, 12-week trial involving 264 adultpatients with moderate-to-severe AD has beenrecently completed [36]. Patients received sub-cutaneous nemolizumab (at doses of 0.1, 0.5, or2.0 mg/kg of body weight) or placebo every4 weeks. Significant reductions in pruritus wereseen from baseline to week 12 in all armsreceiving nemolizumab every 4 weeks; theresult was statistically significant with respect toplacebo in all drug groups (Table 1). EASI scorechanges were significantly higher for 0.5 and2 mg nemolizumab with respect to placebo(Table 1). AD exacerbation, nasopharyngitis,upper respiratory tract infection, peripheraledema, and increased creatine kinase levelswere the most common AEs registered. In par-ticular, exacerbation of AD and peripheraledema were more common in the nemolizumabgroups than in the placebo group.

More recently, the long-term efficacy andsafety of nemolizumab injected subcutaneouslyevery 4 weeks (q4w) or 8 weeks (q8w) wereevaluated in a phase II, 52-week, double-blindextension trial [37]. Patients (n = 191) contin-ued the previous nemolizumab dose (0.1, 0.5, or2.0 mg/kg q4w or 2.0 mg/kg q8w) [36]. An

improvement from baseline in the pruritusvisual analog scale score was maintained/in-creased from weeks 12 to 64, with the greatestimprovement seen for the 0.5-mg/kg q4w group(Table 1). The EASI improvement was alsomaintained/increased to week 64, with thehighest results observed with a dosage of2.0 mg/kg q4w (Table 1), showing that nemoli-zumab for up to 64 weeks was efficacious andwell tolerated overall in patients with moderate-to-severe AD inadequately controlled by topicaltherapy. The most common AEs in patientstreated over the long term with nemolizumab(C 5% of patients were randomized to nemoli-zumab throughout the study period) werenasopharyngitis (27%), exacerbation of AD(25%), increased blood creatine phosphokinase(11%), upper respiratory tract infection (9%),headache (8%), peripheral edema (6%), andimpetigo (6%).

CONCLUSION

The frequency of AD is increasing all over theworld, especially in industrialized countries andurbanized areas. The frequency of this disease inadults also seems to be increasing, although it isprobably underdiagnosed. Due to its chronicityand subjective symptoms, the disease greatlyimpacts on the quality of life of the patients.Currently, only few systemic immunosuppres-sive drugs are available for moderate-to-severeforms, and CsA is the only licensed drug for thetreatment. Moreover, the important side effectsof immune suppressors limit their use. There-fore, having more secure and effective medici-nes would be desirable. Over the last few years,increased knowledge about AD pathogenesishas made it possible to develop new therapeuticagents capable of blocking individual mediatorsof inflammation. Some monoclonal antibodiesagainst specific cytokines (IL-4, IL-13, IL-22, IL-31) have been developed. Data obtained fromthe trials regarding efficacy and safety areencouraging for most of the agents. Dupilumab(anti-IL-4/IL-13) is the only biologic agentapproved for AD in some countries. In conclu-sion, biologic therapies will probably markedlychange the natural history of AD. Indeed, they

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will hopefully be able to increase the disease-free periods and decrease the number of exac-erbations, thus improving the quality of life ofAD patients.

ACKNOWLEDGEMENTS

Funding. No funding or sponsorship wasreceived for this study or the publication of thisarticle.

Authorship. All named authors meet theInternational Committee of Medical JournalEditors (ICMJE) criteria for authorship for thismanuscript, take responsibility for the integrityof the work as a whole, and have given finalapproval for the version to be published.

Disclosures. Cataldo Patruno is an investi-gator for AbbVie and Almirall, an advisoryboard member and speaker for Sanofi Genzyme,and a speaker for Novartis. Gabriella Fabbrocini,Maddalena Napolitano, Matteo Megna, andNicola Balato have nothing to disclose.

Compliance with Ethics Guidelines. Thisarticle is based on previously conducted studiesand does not involve any new study of humanor animal subjects performed by any of theauthors.

Open Access. This article is distributedunder the terms of the Creative CommonsAttribution-NonCommercial 4.0 InternationalLicense (http://creativecommons.org/licenses/by-nc/4.0/), which permits any noncommer-cial use, distribution, and reproduction in anymedium, provided you give appropriate creditto the original author(s) and the source, providea link to the Creative Commons license, andindicate if changes were made.

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