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REVIEW

The Efficacy of Biologic Therapy for the Managementof Palmoplantar Psoriasis and PalmoplantarPustulosis: A Systematic Review

Isabelle M. Sanchez . Eric Sorenson . Ethan Levin . Wilson Liao

Received: September 22, 2017 / Published online: November 15, 2017� The Author(s) 2017. This article is an open access publication

ABSTRACT

Introduction: Palmoplantar psoriasis (PP) andpalmoplantar pustulosis (PPP) are diseasesaffecting the hands and/or feet that can causemarked physical discomfort and functionaldisability. The tumor necrosis factor-alphaantagonists adalimumab, etanercept, andinfliximab, the interleukin (IL)-17A inhibitorsixekizumab and secukinumab, and the IL-23 orIL-12/IL-23 inhibitors guselkumab and ustek-inumab have been well studied for the treat-ment of moderate to severe plaque psoriasis.

Less is known about the efficacy and safety ofthese agents for the treatment of PP (hyperker-atotic and pustular forms) and PPP. The aim ofthis review was to investigate the efficacy ofbiologic therapy for the treatment of hyperker-atotic PP, pustular PP, and PPP.Methods: A systematic search of the medicalelectronic databases (Medline, Embase, andCochrane Library) was conducted to identifystudies or case reports which both used biologictherapy for the treatment of hyperkeratotic PP,pustular PP, and PPP and reported treatmentoutcomes.Results: The systematic search identified 579published articles, of which 44 were included inthe analysis. Seven of the articles involved ran-domized placebo-controlled trials, two wereopen label trials, and the remaining were cohortstudies, case series, or case reports. In the ran-domized controlled trials on the treatment ofhyperkeratotic PP, adalimumab, guselkumab,infliximab, ixekizumab, and secukinumab eachdemonstrated superiority to placebo at 16, 16,14, 12, and 12 or 16 weeks, respectively(p\0.05). For the treatment of pustular PP,ustekinumab 45 mg was not superior to placeboat 12 and 16 weeks, respectively (p[0.05),although an open label study demonstrated thatfour of five patients on a therapeutic regimen ofustekinumab 90 mg achieved clinical clearanceat 16 weeks. For the treatment of PPP, etanerceptand ustekinumab 45 mg were not superior toplacebo at 12 and 16 weeks, respectively

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Isabelle M. Sanchez and Eric Sorenson contributedequally.

Electronic supplementary material The onlineversion of this article (doi:10.1007/s13555-017-0207-0)contains supplementary material, which is available toauthorized users.

I. M. Sanchez (&) � E. Levin � W. LiaoDepartment of Dermatology, University ofCalifornia San Francisco, San Francisco, USAe-mail: [email protected]

I. M. SanchezUniversity of Illinois at Chicago College ofMedicine, Chicago, USA

E. SorensonDivision of Dermatology, University of CaliforniaLos Angeles, Los Angeles, USA

Dermatol Ther (Heidelb) (2017) 7:425–446

DOI 10.1007/s13555-017-0207-0

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(p[0.05). A combined analysis of studies forhyperkeratotic PP demonstrated that 94.7%,90.0%, 82.5%, 89.1%, and 86.7% of patientsexperienced an improvement of at least 50%upon treatment with adalimumab, guselkumab,ixekizumab, secukinumab, and ustekinumab,respectively. In a combined analysis of casereports examining PPP, infliximab showed thegreatest efficacy at 100.0% clinical improvementof patients from case reports, followed by ustek-inumab at 58.8% clinical improvement. Fewserious adverse events were reported, but severalwere reported in patients treated with infliximabor secukinumab.Conclusion: Biologic therapy is effective andwell-tolerated for the treatment of hyperkera-totic PP, but less data are available on the treat-ment of pustular PP or PPP. Adalimumab,guselkumab, ixekizumab, secukinumab, andustekinumab all showed[80% efficacy for thetreatment of hyperkeratotic PP, while infliximaband ustekinumab showed moderate efficacy forthe treatment of pustular PP, and infliximab wasthe most efficacious treatment for PPP.

Keywords: Adalimumab; Biologic therapy;Etanercept; Infliximab; Ixekizumab;Palmoplantar psoriasis; Palmoplantarpustulosis; Pustular psoriasis; Secukinumab;Ustekinumab

INTRODUCTION

Palmoplantar psoriasis (PP) is a chronic, debili-tating disease of the palms and/or soles thataffects 11–39% of psoriasis patients [1–3]. Themorphology of PP can range from thick,hyperkeratotic plaques with fissuring to pustu-lar lesions of the palms and/or soles, and PP isoften classified into subtypes based on thismorphologic distinction [4, 5]. HyperkeratoticPP refers to sharply defined erythematous scalyplaques with overlying hyperkeratosis andwithout the presence of sterile pustules, pre-dominantly at the palms and/or soles [6]. Pus-tular PP is a variant that includes macroscopicsterile pustules and erythema with intermixedyellow–brown macules localized to the palmsand/or soles [6]. PP causes greater physical

discomfort and functional disability than pso-riasis limited to other body areas, and it is oftenrecalcitrant to treatment [2].

Palmoplantar pustulosis (PPP) is a bilateral,symmetric dermatosis that also affects thehands and/or feet and is clinically distin-guished from PP based on the absence ofpsoriasis at other body sites and a predilectionfor histologic involvement of the acrosy-ringium (the terminal duct of eccrine sweatglands) [6, 7]. Pustular PP and hyperkeratoticPP mostly occur concomitantly with psoriasisat other body areas, while PPP consists ofpustular lesions typically limited to the palmsand/or soles that appear on a clear, non-ery-thematous background [6–8]. However, whe-ther PPP can be considered a clinical spectrumof plaque psoriasis or whether it is an inde-pendent disease is open to much debate.Consequently, in the literature, pustular PPand PPP are often not well distinguished.Some studies have identified the involvementof the acrosyringium as being more specific toPPP [7, 9]. Demographically, PPP is character-ized by a female predominance and strongassociation with smoking, whereas no suchassociations exist for pustular PP [6, 7]. Inter-estingly, in individuals with PPP, nicotine isthought to be secreted into eccrine glands topromote inflammation and alter the localresponse to infection [7]. Recent geneticstudies have challenged the relationship ofPPP with plaque psoriasis, although boththese conditions can respond to similar treat-ments and have a similar impact on quality oflife.

Topical therapy and phototherapy are first--line modalities for the management of PP andPPP. However, the majority of patients eventu-ally require treatment with systemic medica-tions [3]. Traditionally, agents such as oralretinoids, methotrexate, and cyclosporin havebeen utilized, but these medications carry risksof adverse effects that may limit their use inclinical practice.

Biologic agents have been well studied forthe treatment of moderate to severe chronicplaque psoriasis, but less is known about theefficacy of these medications for the treatmentof PP and PPP. We have therefore performed a

426 Dermatol Ther (Heidelb) (2017) 7:425–446

systematic review of the use of biologic agentsfor the treatment of hyperkeratotic PP, pustularPP, and PPP with the aim to provide clinicianswith helpful information when consideringmanagement options for these disablingconditions.

METHODS

The biomedical and healthcare journal data-bases of Ovid National Library of Medicine’sMedical Literature Analysis and Retrieval Sys-tem (MEDLINE), Embase, and the CochraneLibrary were searched to identify publishedarticles that assessed the efficacy and safety ofbiologic agents for the treatment of hyperkera-totic PP, pustular PP, and PPP. The detailedsearch strategy is presented in Electronic Sup-plementary Material Fig. 2. Abstracts werescreened, and articles that appeared to meet theinclusion criteria were assessed further. Refer-ence lists of relevant articles were scrutinized toidentify additional reports.

Eligibility Criteria

Publications were included if subjects werediagnosed with PP or PPP based on the assess-ment by the authors of each publication and ifsubjects received treatment with one of thecurrently approved biologics for psoriasis,namely, adalimumab, brodalumab, etanercept,guselkumab, infliximab, ixekizumab, secuk-inumab, or ustekinumab. Publications wererequired to report the efficacy and/or safetyoutcomes of the biologic treatment. Publica-tions describing the treatment of cases of PPPinduced by exposure to biologic medicationswere excluded due to the likely distinct patho-physiology of drug-induced PPP.

Study Selection and Data Extraction

Three reviewers (E.S., I.S., E.L.) independentlyconducted publication selection (Fig. 1). Anydiscrepancies were resolved by an additionalreviewer (W.L.). Studies were categorized basedon the morphology of palmoplantar lesions.

Study characteristics (author, year of publica-tion, design, number of patients, intervention,duration of treatment, outcome, and key safetyindicators) and subject characteristics (age, sex,comorbidities, morphological variant, severityat baseline, involvement of sites other than thepalms and soles, and prior treatments) wereextracted using a standardized data abstractionform designed for this review. Efficacy out-comes were recorded in Table 1, defined as a50% reduction in the PPP Area and SeverityIndex (PPASI-50) if available, otherwise a 75%reduction in PPASI (PPASI-75) or an Investiga-tor Global Assessment (IGA) score of 0/1(cleared/minimal disease) was used. If twobiologics were studied in one study, both weredescribed in Tables 1, 2, 3 and 4 under thecategory of the primary biologic that wasstudied, but the efficacy data of both biologicswere used to calculate the summary of clinicalimprovement outcomes in Table 5. Due to theheterogeneity of outcome measures, outcomeswere reported as described by the authors ofeach publication.

Compliance with Ethics Guidelines

This article is based on previously conductedstudies and does not involve any new studies ofhuman or animal subjects performed by any ofthe authors.

RESULTS

The initial search yielded 731 articles. Afterexcluding duplicates, we screened 579 reportsby title and abstract, of which identified 76articles for full-text review. Following the full--text review, we ultimately included 44 publica-tions reporting the use of a biologic medicationin the treatment of PP and PPP in the analysis,seven and two of which were randomized con-trolled trials (RCTs) and open-label trials,respectively (Table 1) [10–22]. The remainingpublications were case reports or case series[20–53].

A total of 722 cases of hyperkeratotic PP, 63cases of pustular PP, and 58 cases of PPP wereincluded in the analysis. Almost all patients in

Dermatol Ther (Heidelb) (2017) 7:425–446 427

the included studies were adults. The specificsof age, gender, comorbidities, and previoustherapies are shown in Tables 1, 2, 3 and 4. Theprevious use of systemic therapy was not con-sistently reported in all patients. Many patientsreceived prior systemic therapy and some hadreceived prior biologic therapy. Several subjectshad responded to phototherapy, and nearly allhad not responded to topical therapy.

Efficacy

The results of each publication are summarizedin Tables 1, 2, 3 and 4. The characteristicsdescribing each study are reported in Tables S1,S2, S3, and S4. The proportion of patientsdemonstrating clinical improvement is reportedin Table 5.

Hyperkeratotic PP

In the RCT performed by Leonardi et al. [14], agreater number of patients with hyperkeratoticPP treated with adalimumab achieved a clinical

score of clear or almost clear at 16 weeks com-pared to patients treated with placebo (30.6%vs. 4.3%; p = 0.01). Response was maintained at28 weeks by 80% of these subjects. Of thepatients in the RCT or case reports who weretreated with adalimumab, 94.7% demonstratedan overall clinical improvement. In anotherRCT by Bissonnette et al. [13], a greater pro-portion of patients with hyperkeratotic PPtreated with infliximab achieved at least a 50%reduction in clinical severity at 14 weeks com-pared to patients treated with placebo (66.7%vs. 8.3%; p = 0.01). These authors also reportedthat infliximab was superior to placebo in thereduction of mean area of involvement (50decrease vs. 15% increase; p = 0.01). Overall,75% of all patients studied using infliximabdemonstrated clinical improvement. In theirclinical trial, Blauvelt et al. [15] observed a sig-nificant clinical clearance among those patientstreated with guselkumab when compared tothose receiving placebo at 16 weeks (85.1%reaching an IGA score of 0 or 1; p\0.001).Clinical improvement was observed in 90% ofall patients studied receiving treatment with

Fig. 1 Process of study selection


Table1

Hyperkeratoticpalmoplantar

psoriasis,efficacyandsafety

ofbiologicagents

Reference,typeof

stud

yNum

ber

ofsubjects

Treatment

Treatment

duration

Outcome

Safety/com

ments

Adalim

umab

Leonardi2011

[14],D

ouble-blind

rand

omized

placebo-controlled

trial

722:1adalim

umab

80mgSC

at

week0and40

mgSC

q

2weeks

thereafter

vs.p

lacebo

16weeks

30.6%

(15)

adalim

umab-treated

subjectsachieved

hfPG

Aof

0or

1at

week16

vs.4

.3%

(1)

placebo-treatedsubject

(p=

0.01)

NoAEsreported

Alefacept

Myers2005

[21],case

report

2Alefacept

(15mgIM

once

weekly)

12weeks

(1)completeresolution

at

5weeks;

(2)im

provem

entat

10weeks,

reducedscaling,redn

ess,

inflammation,

plaque

thickness

NoAEsreported;2=

some

recurrence

whenalefacept

stopped,

requiring

restarting

treatm

entfor10

additionalweeks

Etanercept

Meyer

2011

[25],

case

report

1Alitretinoin

30mgPO

daily

?etanercept

50mgSC

weekly

13months

Markedreductionwithin4weeks,

completeresolution

in8weeks

NoAEsreported

Guselkumab

Blauvelt2017

[15],

VOYAGE1RCT

100 (subset

of837

psoriasis

patients)

Guselkumab

(2:1:2

rand

omization,

100mgat

week0,

4,then

q8weeks)or

placeboto

guselkum

ab

(placebo

weeks

0,4,

12then

guselkum

abweeks

16,20then

q8weeks),or

adalim

umab

80mgweek0,

then

40mg

week1,then

40mgq2weeks)

16a , 24,or48

weeks

a

Atweek16,guselkumab

73.3%

reachedIG

A0/1vs.

adalim

umab

55.8%,vs.placebo

14%;week24,guselkumab

IGA

0/178.9%

vs.adalim

umab

56.8%;week48,guselkumab

IGA

0/175.6%

vs.adalim

umab

62.1%

Overallcohort:

Nasopharyngitis,U

RI,

cellulitis(2

inadalim

umab

group),basalcellcarcinom

a

(1in

guselkum

abgroup),

2myocardialinfarctions


Table1

continued

Reference,typeof

stud

yNum

ber

ofsubjects

Treatment

Treatment

duration

Outcome

Safety/com

ments

Infliximab

Bissonn

ette

2011

[13],d

ouble-blind

rand

omized

placebo-controlled

trial

241:1infliximab

5mg/kg

IVat

week0,2,6,14,22vs.placebo

atweeks

0,2,

6,then

infliximab

atweeks

14,1

6,20

14aor

22weeks

Atweek14,3

3.3%

achieved

m-PPP

ASI-75and66.7%

achieved

m-PPP

ASI-50vs.8.3%

foreither

(p=

0.317and

p=

0.009);50.3%

reductionin

meansurfacearea

vs.1

4.9%

increase

withplacebo

3SA

Es:1hepatitis,1

cellulitis,1

sternu

m

fracture

Brunasso2012

[33],caseseries

5Infliximab

5mg/kg

atweeks

0,

2,6,

andevery8weeks

thereafter

30weeks

Atweek14,m

eanm-PPP

ASI

improved

27.69%

;at

week30,

meanm-PPP

ASI

improved

41.2%

NoAEsreported;compared

changesin

m-PPP

ASI

with

PASI:PA

SIim

proved

86.8%and89.11%

atweeks

14and30,respectively

Ixekizum

ab

Menter2017

[17],

UNCOVERRCT

206

Ixekizum

ab(1:1:1

rand

omization,

160mgat

week0,

80mgevery2or

4weeks);etanercept

(2:2:2:1

rand

omization,

160mg

ixekizum

abat

week0,

then

80mgevery2or

4weeks,

50mgetanercept

twice

weekly)

12a ,48,o

r

60weeks

Atweek12,P

PASI

improvem

ent

of80%

withixekizum

abvs.

placebo(28.1%

)or

vs.

etanercept

(53%

)(p\

0.05

for

allcomparisons)Greater

PPASI-50im

provem

entwith

ixekizum

ab(80%

)vs.p

lacebo

(32.9%

)or

vs.etanercept

(67.8%

).Greater

PPASI-75

improvem

entwithixekizum

ab

(70%

)vs.placebo

(18.8%

)or

vs.

etanercept

(44.1%

),(p\

0.05

forallcomparisons)

NoAEsreported


Table1

continued

Reference,typeof

stud

yNum

ber

ofsubjects

Treatment

Treatment

duration

Outcome

Safety/com

ments

Secukinu

mab

Gottlieb

2017

[16],

GEST

URERCT

137

Secukinu

mab

(1:1:1

rand

omization,

300mg,

150mgor

placebo)

16weeks

PPIG

A0(clear)or

1(m

inim

al):

33.3%

with300mgregimen,

22.1%

with150mgregimen,

1.5%

onplacebo(p\

0.001and

p=

0.002,

respectivelyvs.

placebo).D

LQI0/1higher

w

secukinu

mab

300mg(26.6%

)

and150mg(16.9%

)vs.p

lacebo

(1.5%),p\

0.0001

and

p\0.005

SAEs:150mg5.9%

,300

mg

2.9%

,placebo

2.9%

;AEs

(40):Headache(17),

naropharyngitis(11),

URI(10),C

andida

(3)

Paul

2014

[18],R

CT

103(46

patients

inearly

regimen)

Secukinu

mab

(1:2:2:1

rand

omization,

150mgSC

of

either

single(week0),

monthly(weeks

0,4,

8),early

(weeks

0,1,

2,4)

orplacebo)

12weeks

IGA

response

of0(clear)or

1

(minim

al)?

improvem

ent

ofC2points;Earlyregimen

response:54.0%

NoAEsreported

Ustekinum

ab

Heinecke2013

[41],

case

series

2(subset

of22

psoriasis

patients)

Ustekinum

ab45

mgor

90mg

SCat

weeks

0,4,

andevery

12weeks

thereafter?

acitretinPO

Not

described

Bothpatientsdemonstrate

‘‘excellent

control’’withonly

mild

scaling

NoAEsrelatedto

PPsubjects

reported

Nun

o-Gonzalez2012

[42],casereport

1Ustekinum

ab45

mgSC

at

weeks

0,4,andevery12

weeks

thereafter

12months

Com

pleteresolution

at16

weeks,

maintainedclearat

12months

NoAEsreported


guselkumab. In three phase 3 trials conductedby Menter et al. [17], a greater proportion of thepatients treated with ixekizumab showed clini-cal improvement compared to those treatedwith etanercept or those receiving placebo(PPASI-50: 80 vs. 67.8 vs. 32.9, respectively;p\0.05). Overall, 82.5% of the patients studiedwho were using ixekizumab demonstratedclinical improvement. Significant clinicalclearance was achieved in a RCT that comparedsecukinumab at a dose of 300 or 150 mg toplacebo [palmoplantar psoriasis IGA (PPIGA)score of 0 or 1: 33.3% (300 mg dose), 22.1% (150mg dose), vs. 1.5%; p\0.001 and p = 0.002,respectively] [16]. The proportion of patients inall studies demonstrating clinical improvementafter completing treatment with secukinumabwas 89.1%. In an uncontrolled open label studyof ustekinumab, 20% patients with hyperkera-totic PP achieved clinical clearance after16 weeks of therapy [10]. Clinical clearance wasachieved by 50% of patients receiving a 90 mgdosage regimen, while no patients receiving a45 mg regimen achieved clearance.

A number of case series and case reportsdescribe effective treatment of hyperkeratoticPP with etanercept, alefacept, infliximab, andustekinumab (Tables 1, 4) [21, 25, 26, 33, 34,41–43, 52].

Pustular PP

In a small RCT by Bissonnette et al. [11],ustekinumab 45 mg was not superior to placeboin achieving at least a 50% reduction in clinicalseverity among patients with pustular PP after16 weeks of therapy (p = 1.00). In an open labelstudy by Au et al. [10], half of the patients withpustular PP treated with ustekinumab achievedclinical clearance after 16 weeks of therapy. Agreater proportion of patients receiving a 90 mgregimen of ustekinumab achieved clearancecompared to those receiving a 45 mg regimen(80% vs. 20%). In another open label study,54.5% of patients with pustular or hyperkera-totic PP who were treated with adalimumabreached clinical clearance after 12 weeks oftherapy [19].

Table1

continued

Reference,typeof

stud

yNum

ber

ofsubjects

Treatment

Treatment

duration

Outcome

Safety/com

ments

BulaiLivideanu

2010

[43],caseseries

2Ustekinum

ab45

mgand90

mg

SCrespectivelyat

weeks

0,4,

andevery12

weeks

thereafter

(1)7months

(2)4months

(1)Dramaticim

provem

entat

7months,localized

PPASI

improved

by85%;(2)Palms

clearedat1month,goodclinical

improvem

entandlocalized

PPASI

improved

65%

at

4months

NoAEsreported

AEAdverse

event,BSA

body

surfacearea,DLQIDermatologyLife

QualityIndex,Ffemale,hfPG

APh

ysicianGlobalAssessm

entof

thehand

andfoot,HTN

hypertension,IG

AInvestigator

GlobalAssessm

ent,IM

intram

uscular,IV

intravenous,M

male,m-PPP

ASI

modified

Palmoplantar

PustulosisAreaandSeverity

Index,PA

SIPsoriasisAreaandSeverityIndex,PG

APh

ysicianGlobalA

ssessm

ent,PO

orally,P

Ppalmoplantar

psoriasis,PP

IGApalmoplantar

psoriasisInvestigator

GlobalAssessm

ent,

PPPpalmoplantar

pustulosis,P

sApsoriaticarthritis,PU

VApsoralen

?ultravioletA,q

every,RCTrand

omized

controlledtrial,SA

Eserious

adverseevent,SC

subcutaneous,U

RIupperrespiratoryinfectionUVAultravioletA,U

VBultravioletB

aPrim

aryendpoint

ofstudy


Table2

Pustular

palmoplantar

psoriasis,efficacyandsafety

ofbiologicagents

Reference,type

ofstud

yNum

ber

ofsubjects

Treatment

Treatment

duration

Outcome

Safety/com

ments

Adalim

umab

Ghate

2009

[24],

case

report

1Adalim

umab

40mgSC

q

2weeks

6months

Atweek16,B

SAdecreasedfrom

4to

1%,

resolution

ofPsA

symptom

s;8months

afterd/c,no

jointsymptom

sor

PP

NoSA

Esreported;m

ild,diffuse

scalpalopecia(leading

tod/c

at6months)

Etanercept

Ahm

ad2007

[27],caseseries

1(subset

of49

psoriasis

patients)

Etanercept25

mgor

50mg

SCBIW

Totalmean

58.2weeks

Failed

Unclear

Floristan2011

[28],casereport

1Etanercept0.4mg/kg

SC

BIW

for8months

increasedto

0.6mg/kg

SCBIW

12months

Slow

butprogressiveim

provem

entoverfirst

month;at

12months‘‘striking

improvem

ent’’of

plantarlesions

NoAEsreported

Kitam

ura2009

[30],case

report

1Etanercept50

mgSC

BIW

?efalizum

b80

mg

weekly

C11

months

PsoriasisandPsA

‘‘verywell-controlled’’

(but

pustular

PPnotresponsive

to

etanercept

alone)

1SA

E:reactivation

TB

Infliximab

Kam

ili2011

[35],caseseries

6(subset

of120

psoriasis

patients)

Infliximab

5mg/kg

IVat

weeks

0,2,

and6and

every8weeks

thereafter

Atleast1year

2patientswith‘‘com

pleteresponses’’

Unclear

Wozel2008

[37],case

report

1Infliximab

5mg/kg

IVat

week0,

2,and6and

every8weeks

thereafter

8months

‘‘Markedim

provem

ent’’4days

afterstaring

infliximab,w

ith‘‘severe’’

relapseat

8months

NoSA

Esreported

Ahm

ad2006

[39],caseseries

1(seriesof

12 psoriasis

patients)

Infliximab

5mg/kg

IVat

week0,

2,6andevery

8weeks

thereafter

Not

described

Excellent

improvem

entafterthirdinfusion

NoSA

Esreported;discontinued

dueto

elevated

liver

function

tests


In addition, case series and case reportsdescribe effective treatment of pustular PP withadalimumab, etanercept, infliximab, andustekinumab[24, 26, 28, 30, 34, 35, 37, 39, 45, 51, 52, 54]. Incontrast, other case reports show ineffectivetreatment with adalimumab or mixed responsesto ustekinumab (Tables 2, 4) [27, 54].

Palmoplantar Pustulosis

In a RCT of patients with PPP conducted byBissonnette et al. [12], treatment with etaner-cept was not found to be superior to placebo atthe primary endpoint of 12 weeks of therapy(p = 0.426). Interestingly, smoking may haveplayed a role in treatment efficacy, as theauthors noted that three of three nonsmokersachieved clinical improvement with etanercepttherapy while only three of seven active smok-ers demonstrated improvement. In a small RCTby Bissonnette et al. [11], ustekinumab 45 mgwas not found to be superior to placebo at16 weeks of therapy (p = 1.00).

Case reports and case series describe effectivetreatment of PPP with etanercept, infliximab,and ustekinumab [20, 29, 31, 32, 46–50, 53, 54].Multiple reports of treatment with infliximabdescribe a period of initial improvement witheventual recurrence (Tables 3, 4) [36, 38, 40].

Safety

Serious adverse events (SAEs) were infrequentlyreported. The majority of cases occurred inpatients treated with infliximab, and the SAEsincluded cellulitis, hepatitis, an urticarial infu-sion reaction, a serum sickness-like infusionreaction, and autoimmune hepatitis[13, 34, 36, 38]. One subject with a history of apositive tuberculin skin test developed reacti-vation tuberculosis while undergoing treatmentwith etanercept for pustular PP [30]. In theGESTURE RCT that used secukinumab as treat-ment for hyperkeratotic PP, 5.9% of patientsdeveloped SAEs while on a 150 mg therapeuticregimen and 2.9% of patients developed SAEswhile on a 300 mg therapeutic regimen, com-pared to 2.9% that developed SAEs while usingT

able2

continued

Reference,type

ofstud

yNum

ber

ofsubjects

Treatment

Treatment

duration

Outcome

Safety/com

ments

Ustekinum

ab

Morales-M

unera

2013

[45],case

series

5Ustekinum

ab45

mgSC

at

weeks

0,4,

andevery

12weeks

thereafter

Mean

15.2months,

range

11–2

3months

Allpatientswithpositive

response

2-3weeks

afterfirstdose,allwith

completeresolution

atweek20

maintainedto

date

withno

flares

NoAEsreported

Buder

2016

[51],

case

series

9Ustekinum

ab(45mg

if\

100kg

body

weight,

90mgif[

100kg

body

weightat

weeks

0,4,

12,

24)

24weeks

After

24weeks,4

4.4%

reachedPP

ASI-75,

22.2%

reachedPP

ASI-100,P

PASI

improvem

entwas

71.6%;goal:im

prove

PPASI

by75%after12

weeks

orim

prove

DLQIby

5points

NoAEsreported;recurrence

in

1patientrequired

stopping

treatm

entandswitchingto

golim

umab

with

improvem

ent

BIW

Twiceweekly,d/cdiscontinu

edDM

diabetes

mellitus,T

Btuberculosis,P

PDpurifiedproteinderivative,H

CVhepatitisC


Table3

Palmoplantar

pustulosis,efficacy

andsafety

ofbiologicagents

Reference,type

ofstud

yNum

berof

subjects

Treatment

Treatment

duration

Outcome

Safety/com

ments

Adalim

umab

Olazagasti2017

[22],

retrospective

cohortstudy

8Adalim

umab,etanercept,

infliximab

1996–2

013

Partialresponseto

adalim

umab

(2;n

o

response

toadalim

umab

(2);no

response

toetanercept

(3);partial

response

toinfliximab

(1)

NoAEsreported

He2012

[23],

case

report

1Adalim

umab

40mgSC

q

2weeks

?methotrexate

15mgweekly

1month

Responseof

PPnotdescribed

NoSA

Esreported;

acneifo

rmeruption,

alopeciaareata,and

urticariaafterthird

injectionleadingto

d/c

Etanercept

Bissonn

ette

2008

[12],D

ouble-

blindrand

om-

ized

placebo-

controlledtrial

152:1etanercept

50mgSC

BIW

week0-24

vs.p

lacebo

weeks

0–12

then

etanercept

50mg

SCBIW

weeks

12–2

4

6vs.3

months

Significant

decrease

inmedian

PPPA

SIat

week24

inetanercept

group;

nosignificant

difference

betweengroups

at12

weeks

(primaryendpoint)(p

=0.426)

NoSA

Esreported;

Decreased

PPPA

SIin

3/3

nonsmokers(increased

PPPA

SIin

4/7sm

okers)

inetanercept

groupat

12weeks

Lopez-Estebaranz

2010

[29],case

report

1Etanercept50

mgSC

BIW

for12

weeks,then

weeklyfor12

weeks

6months

Atweek12,com

pleteresolutio

n;

maintainedclearancefor6months

afterdiscontin

uatio

nof

etanercept

NoAEsreported

Kasche2007

[31],

case

report

1Etanercept25

mgSC

BIW

7months

‘‘Suddenanddram

aticim

provem

ent’’

at2weeks;restarteddueto

flare

afterd/cwith‘‘dramaticandrapid

improvem

ent’’after1week

NoSA

Esreported

Weinberg2003

[32],C

ase

report

1Etanercept25

mg

SCBIW

19weeks

At19

weeks,‘‘almosttotalclearing’’of

hand

swith‘‘m

ildto

moderate

scaling’’

offeet,resolutionof

PsA

symptom

s

NoAEsreported


Table3

continued

Reference,type

ofstud

yNum

berof

subjects

Treatment

Treatment

duration

Outcome

Safety/com

ments

Abourazzak2014

[49],casereport

1Etanercept25

mg

twiceweekly

12months

Resolved;

‘‘goodim

provem

entwithin

thefirstmonth’’

NoAEsreported

Infliximab

Burgemeister

2012

[20],case

series

2(subsetof

3PP

P)

Infliximab

(5mg/kg

q8weeks)

Not

reported

completeresolution

NoAEsreported

Aljuhani

2015

[50],caseseries

2(subsetof

20PP

P)

(1)Infliximab;

(2)adalim

umab,etanercept

(1)3years;

(2)9months

(1)completelyresolved;

(2)no

response

toadalim

umab,then

switched

toetanercept

withno

response

NoAEsreported

Yaw

alkar2009

[36],C

ase

report

1Infliximab

5mg/kg

IVatweesk

0,2,

6;then

atweek14

adalim

umab

40mgSC

q2weeks

then

40mg

SCweekly

6weeks

infliximab,

then

C3months

adalim

umab

‘‘Markedim

provem

ent’’at

2weeks

withrecurrence

atweek14;slo

wer

butsatisfactory

clinicalresponse

withadalim

umab

1SA

E:infusion

related

reaction

with

polyarthalgia,myalgiaand

feverat

week6leadingto

discontinu

ation

Fairhurst2008

[38],C

asereport

1Infliximab

5mg/kg

IV

atweesk

0,2,

6

6weeks

‘‘Dramaticim

provem

ent’’afterfirst2

infusions,‘‘deterioration’’afterthird

infusion

1SA

E:autoim

mun

e

hepatitis

Barland

2003

[40],C

ase

report

1Infliximab

5mg/kg

IV

monthly

months0–

4,infliximab

10mg/kg

IVmonthly

months5-6,

then

infliximab

10mg/kg

IVmonthly

?methotrexate7.5mgPO

weekly

Not

reported

Initial‘‘dramaticresponse’’followed

byrelapse;addition

ofmethotrexate

ledto

‘‘virtuallyabsent’’lesions

within2weeks

with‘‘lasting

remission’’

NoAEsreported


Table3

continued

Reference,type

ofstud

yNum

berof

subjects

Treatment

Treatment

duration

Outcome

Safety/com

ments

Ustekinum

ab

Torre

2017

[53],

case

report

1Adalim

umab

(40mgSC

every

otherweek9

4months

then

40mgweekly9

6

months)?

mycophenolate

?Ustekinum

ab(90mgon

dayafter10

monthsat

days

1,28,thenq3months)

14months

95%

clearanceafter14

months

NoAEsreported

Pinto-Alm

eida

2013

[46],C

ase

report

1Ustekinum

ab45

mgSC

atweeks

0,4,

andevery

12weeks

thereafter

12months

Clin

icalim

provem

entnotedat

3weeks

andclearanceachieved

at

16weeks;sustainedresponse

at

12months

NoAEsreported

deUnamun

o-

Bustos2011

[47],C

asereport

1Ustekinum

ab45

mgSC

q

12weeks

8months

After

2doses‘‘almostcomplete

clearance’’;rem

ainedclearof

lesions

at8months

NoAEsreported

Gerdes2010

[48],

case

series

4Ustekinum

ab45

mgor

90mg

(ifC

100kg)SC

q12

weeks

2monthsto

unclear

Failure

in2subjects(1

and2);slo

w

improvem

entin

1subject(palms

clearbutsolesstill

affected

at

3months);decreasedpustules

and

involved

area

ofboth

solesat

3monthsin

1subject

NoAEsreported


Table4

HyperkeratoticPP

,pustularPP

,and

/orPP

P,efficacyandsafety

ofbiologicagents

Reference,

type

ofstud

yNum

berof

subjects

Treatment

Treatment

duration

Outcome

Safety/com

ments

Adalim

umab

Richetta

2012

[19],

open

label

study

11(hyperkeratoticor

pustular

PP;variant

notreported)

Adalim

umab

(40mgq2

weeks)

12weeks

PGA

improvem

ent54.5%,m

ean

PGA:1.09,P

GA

036.1%;

DLQIim

provem

ent:72.3%,m

ean

DLQI:7.45,C

50%

DLQI

improvem

ent45.5%

NoAEsreported

Anakinra

Tauber2014

[52],case

report

(1)pustular

PP,

(2)hyperkeratoticPP

Anakinra(100

mgSC

)(1)3months;

(2)1month

(1)Partialresponseto

PPASI

20.7

andDLQI13

at2weeks

but

relapsed

at3months,stopped

dueto

lack

ofefficacy/

recurrence

(2)Partialresponseto

PPASI

13.5

at1mo,

stoppeddueto

fever

without

cause

(1)relapseof

pustular

lesions;

(2)AEof

fever

Etanercept

Spuls2003

[26],C

ase

series

1(etanercept)and1

(infl

ixim

ab)(subsetof

26patientswithPP

;

hyperkeratoticor

pustular

variantnot

reported)

(1)Etanercept;

(2)infliximab

Not

described

(1)Com

pleteresolution

(2)Com

pleteresolution

NoAEsreported

Infliximab

DiLernia

2010

[34],

Caseseries

3(hyperkeratoticPP

),

1(PPP

)

Infliximab

5mg/kg

IVat

weesk

0,2,

6andevery

8weeks

thereafter

10–1

6months

At16

weeks,(1)

PPPA

S-100;

(2)

and(3)PP

PASI-75;

(4)

PPPA

SI-50

1SA

E:infusion-related

urticarial

reaction

inpatient2atweek46

leadingto

discontinu

ation


Table4

continued

Reference,

type

ofstud

yNum

berof

subjects

Treatment

Treatment

duration

Outcome

Safety/com

ments

Ustekinum

ab

Bissonn

ette

2013

[11],

Double-

blind

rand

omized

placebo-

controlled

trial

10(pustularPP

),

5(PPP

)

1:1ustekinu

mab

45mgSC

atweeks

0,4,

and16

vs.

placeboat

weeks

0and4,

then

ustekinu

mab

45mg

SCat

weeks

16and20

28weeks

(primary

endpoint

at

week16)

Atweek16,10%

ofsubjectswith

pustularPP

achieved

PPPA

SI-50

vs.20%

inplacebogroup

(p=

1.00);20%ofsubjectswith

PPPachieved

PPPA

SI-50vs.

37.5%inplacebogroup

(p=

1.00)

NoSA

Esreported;1legcellulitis

(possiblyrelated)

and1

pneumonia(unrelated)

Au2013

[10],

Open-label

prospective

trial

10(hyperkeratoticPP

),

10(pustularPP

)

Ustekinum

ab45

mgfor

body

weight\

100kg,

90mgforbody

weightC

100kg

SCat

weeks

0,4,

16

16weeks

Atweek16,3

5%(7/20)

achieved

clinicalclearance,60%

(12)

Palm-SolePG

Aim

proved

C2

points

NorelatedSA

Esreported;67%

receiving90

mgachieved

clinicalclearancevs.9%of

those

on45

mg

Bertelsen

2014

[54],

Caseseries

6(pustularPP

),

5(PPP

)

Ustekinum

ab45

mgSC

at

weeks

0,4,

andevery

12weeks

thereafter

Upto

44months

PustularPP

:1Com

pleteresolutio

n

(1),partialresponse

(3),no

response

(1),progression(1);

PPP:

Partialresponse

(3),no

response

(1),progression(1)

Flu-likesymptom

s,headache,

fatigue(1);no

difference

reported

inresponse

between

patientswithpalmoplantar

pustular

psoriasisand

palmoplantar

pustulosis

AEAdverse

event,BSA

body

surfacearea,DLQIDermatologyLife

QualityIndex,Ffemale,hfPG

APh

ysicianGlobalAssessm

entof

thehand

andfoot,HTN

hypertension

,IG

AInvestigator

GlobalAssessm

ent,IM

intram

uscular,IV

intravenous,M

male,m-PPP

ASI

modified

Palmoplantar

PustulosisAreaandSeverity

Index,PA

SIPsoriasisAreaandSeverity

Index,PG

APh

ysicianGlobalA

ssessm

ent,PO

orally,P

Ppalmoplantar

psoriasis,PP

IGApalmoplantar

psoriasisInvestigator

GlobalAssessm

ent,

PPPpalmoplantar

pustulosis,P

sApsoriaticarthritis,PU

VApsoralen

?ultravioletA,q

every,RCTrand

omized

controlledtrial,SA

Eserious

adverseevent,SC

subcutaneous,U

RIupperrespiratoryinfectionUVAultravioletA,U

VBultravioletB

aPrim

aryendpoint

ofstudy


Table 5 Clinical improvement of palmoplantar psoriasis or palmoplantar pustulosis following treatment with biologicagent

Medication Variant treated Totalnumber ofcases

Cases in which patientsdemonstratedimprovementa

Serious adverse events

Adalimumab Hyperkeratotic PP [14, 15] 150 142 (94.7%) No SAEs reported

Pustular PP [24] 1 1 (100.0%) No SAEs reported

PPP [22, 23, 50, 53] 7 2 (28.6%) No SAEs reported

Totalb 169 152 (89.9%)

Alefacept Hyperkeratotic PP [21] 2 2 (100.0%) No SAEs reported

Pustular PP 0 0

PPP 0 0

Total 2 2 (100.0%)

Anakinra Hyperkeratotic PP [52] 1 1 (100.0%) No SAEs reported

Pustular PP [52] 1 1 (100.0%) No SAEs reported

PPP 0 0

Total 2 2 (100.0%)

Etanercept Hyperkeratotic PP [17, 25] 60 41 (68.3%) No SAEs reported

Pustular PP [27, 28, 30] 3 2 (66.7%) Reactivation of latent TB

PPP [12, 22, 29, 31, 32, 49] 23 13 (56.5%) No SAEs reported

Totalb 87 57 (65.5%)

Guselkumab Hyperkeratotic PP [15] 100 90 (90.0%) No SAEs reported

Pustular PP 0 0

PPP 0 0

Total 100 90 (90.0%)

Infliximab Hyperkeratotic PP

[13, 33, 34]

32 24 (75.0%) Cellulitis, hepatitis,

infusion-related urticarial

reaction

Pustular PP [35, 37, 39] 8 4 (50.0%)

PPP

[20, 22, 34, 36, 38, 40, 50]

8 8 (100.0%) Serum sickness-like infusion

reaction, autoimmune

hepatitis

Totalb 49 37 (75.5%)


placebo. However, the authors of this study didnot report the statistical significance of theSAEs. None of these SAEs were cardiac-related,and there were no opportunistic infections orfatalities [16].

Special Populations

Three patients with chronic hepatitis C virus(HCV) were treated with biologic medicationsfor PP without hepatologic complications[30, 34, 45]. One patient with chronic HCVdisplayed an infusion-related urticarial reactionduring infliximab treatment, leading to dis-continuation of the medication [34]. Onepatient with comorbid untreated latent

tuberculosis developed reactivation tuberculosisafter 4 years of therapy with etancercept [34].One pediatric patient was treated with etaner-cept with no reported SAEs [28].

DISCUSSION

The advent of biologic medications has greatlyenhanced the treatment of moderate to severeplaque psoriasis. Current evidence suggests thatbiologic agents may also be effective therapeuticoptions for the treatment of hyperkeratotic PP,with less evidence supporting their use in pus-tular PP and PPP.

For hyperkeratotic PP, results from RCTs(level 1 evidence) suggest that adalimumab,

Table 5 continued

Medication Variant treated Totalnumber ofcases

Cases in which patientsdemonstratedimprovementa

Serious adverse events

Ixekizumab Hyperkeratotic PP [17] 206 170 (82.5%) No SAEs reported

Pustular PP 0 0

PPP 0 0

Total 206 170 (82.5%)

Secukinumab Hyperkeratotic PP [16, 18] 183 63 (89.1%) 150 mg 5.9% SAE, 300 mg

2.9% SAE, placebo 2.9%

SAEc

Pustular PP 0 0

PPP 0 0

Total 183 63 (89.1%)

Ustekinumab Hyperkeratotic PP

[10, 41–43]

15 13 (86.7%) No SAEs reported

Pustular PP

[10, 11, 45, 51, 54]

40 22 (55.0%) No SAEs reported

PPP [11, 46–48, 53, 54] 17 10 (58.8%) No SAEs reported

Total 72 45 (62.5%)

SAE serious adverse eventa Using most conservative estimate [PPASI-50 if available; otherwise, if reported, a PPASI-75 or an IGA score of 0/1(cleared/minimal disease)]b Includes data from Richetta et al. [19], and Spuls et al. [26] in which specific morphology is not describedc No SAEs were fatal, no cardiac events, and no opportunistic infections


guselkumab, ixekizumab, infliximab, andsecukinumab are effective treatment options.While ustekinumab has not been evaluated in aRCT of patients with hyperkeratotic PP, in anopen label study (level 3 evidence), one-half ofpatients receiving a 90 mg regimen achievedclinical clearance.

For pustular PP, ustekinumab 45 mg did notappear to be more effective than placebo (level 1evidence) in patients participating in a smallRCT. However, the majority of patients (80%)with pustular PP receiving a 90 mg regimen ofustekinumab in an open label study did achieveclinical clearance [10]. With the exception ofustekinumab, limited information on pustularPP treatment can be found in the literature. Wefound only eight pustular PP patients treatedwith infliximab, three patients with etanercept,and one patient each treated with adalimumaband anakinra. We found no reports of pustularPP treatment with alefacept, guselkumab, ixek-izumab, or secukinumab. Of note, in all of thepustular PP case reports, patients were treatedwith the standard dose of biologic for plaquepsoriasis. The lack of response in many of thesecases suggests the possibility that pustular PPmay require higher doses of biologics thanhyperkeratotic PP or body plaque psoriasis inorder to achieve efficacy.

For the treatment of PPP, the results of twosmall RCTs suggest that treatment with etaner-cept and ustekinumab 45 mg may not be moreeffective than placebo (level 1 evidence). How-ever, the study of ustekinumab included onlyfive patients in the active treatment arm, andno patient received a 90 mg regimen of thisbiologic [11, 54]. Overall, infliximab appearedto have the greatest efficacy for PPP comparedto other biologics, followed by ustekinumab. Itis important to note that the quality of theseconclusions is limited since most of the datawere from case reports or case series.

Although case series and case reports offerless rigorous evidence for the efficacy of biologicagents in PP and PPP, they do illustrate a fewnotable trends. For example, ustekinumab hasbeen shown to be effective in multiple cases ofPP and PPP refractory to tumor necrosis fac-tor-alpha (TNF-a) inhibitor therapy[10, 43, 45, 47, 48]. Additionally, infliximab

appears to have a higher risk of SAEs comparedto other biologics, and it may also demonstrateloss of efficacy over the course of treatment[13, 34, 36–38, 40]. In one RCT, patients treatedwith secukinumab 150 mg showed a greaterpercentage of SAEs than those receiving placebo(5.9% vs 2.9%, respectively), but there was nodose effect, with the secukinumab 300 mggroup having a SAE rate of 2.9%, which wasidentical to that of the group receiving placebo[16]. These data indicate that secukinumab maynot be truly associated with SAEs, since there isnot an observable dose–response relationship ortrend.

Importantly, while there have been reportsof new-onset PPP or exacerbation of existingPPP during TNF-a inhibitor therapy [55–58],only one clearly reported case of exacerbation ofPPP, in response to infliximab, was identified inour review of patients with baseline PP and PPP[37]. In one RCT, four patients (40.0%) with PPPtreated with etanercept experienced increases indisease severity over the first 12 weeks of treat-ment, but it is not clear whether these weredrug-induced exacerbations or simply reflectiveof a nonresponse to treatment and disease pro-gression [12].

Notably, two recent studies based on sub-analysis of Phase II data for secukinumabdemonstrated high rates of response amongpatients with hyperkeratotic PP, with up to 71%of patients achieving clinically significantimprovement [59, 60]. Further studies of novelbiologic agents developed for the treatment ofmoderate to severe plaque psoriasis may yieldnew therapeutic options for PP and PPP.

The difference in response to biologicsobserved between PP and PPP may be explainedby some notable differences in their geneticprofiles. The psoriasis susceptibility gene locus(PSORS1) that is strongly linked to psoriasis isnot found in patients with PPP. Additionally,both a missense mutation in the interleukin(IL)-36 receptor antagonist (IL36RN) and cas-pase recruitment domain family member 14(CARD14) have been identified in patients withPPP, which could influence patient response totreatment with biologics [9, 61]. However, bothPP and PPP involve IL-17 as a mediator ofinflammation, in addition to interferon-gamma


and TNF-a. The shared histologic features of thediseases, consisting of spongiform pustules andinflammatory infiltrates, may account for someof the overlap in treatment response and clini-cal appearance [7, 9]. There is a need for futurestudies to explore these genetic differencesfurther.

Several limitations to our analysis make itdifficult to assess the efficacy of biologic med-ications in PP and PPP. First, patients with PPand PPP are often excluded from clinical trialsdue to recruitment requirements that patientsbe diagnosed with stable plaque psoriasis withno pustular component and demonstrateinvolvement of at least 10% of the body sur-face area. Second, some of the RCTs usingbiologics for these skin diseases, especially forpustular PP, although completed, are not pub-lished yet and therefore could not be includedin our review. Third, reporting bias in casereports and case series makes it difficult todetermine the true rates of response to biologicagents. Fourth, differences in the use of metricsto quantify the severity of PP and PPP imposechallenges when comparing rates of responseacross studies. In addition, only one small RCTwas available for pustular PP and another forPPP, with the majority of RCTs specific tohyperkeratotic PP.

Currently, a number of different scales areused to assess the severity of PP and PPP, and inmany case reports and case series no metrics areused at all. Future studies should attempt tostandardize the heterogeneity of clinical metricsto allow for a more rigorous comparison of theefficacy of biologic medications in PP and PPP.In some RCTs, only mean changes in clinicalscores are reported without information onpatient-specific responses. In the most basicschema, the number of patients who achieveclearance and the number who demonstrateobjective improvement should be reported.Further, studies should consistently report thepresence or absence of psoriasis at other bodyareas and stratify results based on thisinformation.

Nonetheless, patient reported outcomes andfunctional metrics, such as the survey devel-oped by Farley et al., may be more importantthan visual metrics in evaluating response to

treatment in PP and PPP [5]. Complete clear-ance may not be necessary if patients achievesufficient improvement to perform activities ofdaily living and occupational tasks without painor discomfort [2].

CONCLUSION

Overall, biologics are effective and well-toler-ated for the treatment of hyperkeratotic PP, asdemonstrated by the [ 80% efficacy for adali-mumab, guselkumab, ixekizumab, secuk-inumab, and ustekinumab. The strong supportfor effective hyperkeratotic PP treatment isderived from multiple large RCTs, and thusproviders may consider tailoring their treat-ment to include biologics earlier when a patientpresents with this recalcitrant chronic disease.Infliximab and ustekinumab showed moderateefficacy for pustular PP, but the data were lim-ited to small trials or case reports. Less data areavailable for the treatment of PPP; however, todate infliximab is the most efficacious treat-ment. Future studies are needed to further assessthe efficacy of biologic medications in thetreatment of PP and PPP. In addition, futureresearch should be performed to compare theefficacy and safety of biologics with traditionalsystemic therapy and phototherapy for thesedebilitating and therapeutically challengingconditions.

ACKNOWLEDGEMENTS

No funding or sponsorship was received for thisstudy or publication of this article. All namedauthors meet the International Committee ofMedical Journal Editors (ICMJE) criteria forauthorship for this manuscript, take responsi-bility for the integrity of the work as a whole,and have given final approval for the version tobe published.

Disclosures. I. Sanchez, E. Sorenson, and E.Levin have nothing to disclose. W. Liao hasreceived research funding from AbbVie, Jans-sen, Novartis, and Pfizer.


Compliance with Ethics Guidelines. Thisarticle is based on previously conducted studiesand does not involve any new studies 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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