REVIEW

Systemic Treatment of Psoriasis with JAK Inhibitors:A Review

Amanda Kvist-Hansen . Peter Riis Hansen . Lone Skov

Received: November 7, 2019 / Published online: December 31, 2019� The Author(s) 2019

ABSTRACT

Psoriasis is a prevalent chronic inflammatorydisease. The inflammatory response is driven byT cells and mediated by multiple cytokines suchas tumor necrosis factor and the interleukins IL-17 and IL-23. Moderate-to-severe psoriasis istreated systemically, using either biologics orconventional treatments with small-moleculedrugs. The newer biologics are very effectiveand well tolerated, but not all patients respond

to treatment with biologics, so there is a needfor new treatment options for psoriasis. Januskinase (JAK) inhibitors are a new drug class thatmay be of use in this respect. These inhibitorsare already on the market for rheumatoidarthritis, psoriatic arthritis, and ulcerative coli-tis. They block the intracellular signal pathwaymediated by JAK and signal transducer andactivator of transcription (STAT) proteins,thereby inhibiting gene transcription of proin-flammatory cytokines. JAK inhibitors are cur-rently being tested as potential treatments forpsoriasis. They have shown clinical efficacy asmeasured by the Psoriasis Area and SeverityIndex 75 response in both phase 2 and 3 trials,and appear to be well tolerated overall. Thisreview provides an overview of the mechanismsunderlying the actions of JAK inhibitors inpsoriasis, together with the results of clinicaltrials testing their efficacies when used to treatthe disease.

Keywords: Efficacy; JAK inhibitors; JAK-STATsignaling pathway; Psoriasis; Tofacitinib;Treatment; TYK2 inhibitors

Enhanced Digital Features To view enhanced digitalfeatures for this article go to https://doi.org/10.6084/m9.figshare.11316773.

A. Kvist-Hansen (&)Department of Dermatology and Allergy, Herlev andGentofte Hospital, University of Copenhagen,Copenhagen, Denmarke-mail: amanda.kvist-hansen@regionh.dk

P. R. HansenDepartment of Cardiology, Herlev and GentofteHospital, University of Copenhagen, Copenhagen,Denmark

L. SkovDepartment of Dermatology and Allergy, Herlev andGentofte Hospital, University of Copenhagen,Copenhagen, Denmark

Dermatol Ther (Heidelb) (2020) 10:29–42

https://doi.org/10.1007/s13555-019-00347-w

Key Summary Points

Psoriasis is a prevalent chronicinflammatory disease. The inflammatoryresponse is driven by T cells and mediatedby multiple cytokines such as tumornecrosis factor (TNF) and the interleukinsIL-17 and IL-23.

Janus kinase (JAK) inhibitors are apotential new systemic treatment optionfor psoriasis.

JAK inhibitors block the production ofproinflammatory cytokines in psoriasis byinhibiting the JAK–signal transducer andactivator of transcription (STAT) signalingpathway downstream of the receptor.

Different JAK inhibitors have been and arecurrently being tested in phase 2 and 3clinical trials as treatments for moderate-to-severe psoriasis.

The results of these trials havedemonstrated the clinical efficacy of JAKinhibitors in psoriasis as measured byPASI75, and have shown that they have asafety profile comparable to biologicsalready on the market. However, theseresults are based on short-term use, andmore studies are needed to determine thelong-term efficacy and safety of JAKinhibitors in psoriasis.

INTRODUCTION

Psoriasis is a systemic chronic inflammatorydisease characterized by scaly erythematouslesions of the skin. The skin of psoriatic lesionstypically shows epidermal hyperplasia andparakeratosis together with an accumulation ofinflammatory cells in the dermis. The inflam-matory response is driven by T cells, especially Thelper (Th)17 cells, and is mediated by multiplecytokines, especially tumor necrosis factor(TNF), interleukin (IL)-17 and IL-23 [1, 2].

Psoriasis can be classified into mild, moderate,or severe disease according to the Psoriasis Areaand Severity Index (PASI). Mild disease canoften be controlled by topical treatment,whereas moderate-to-severe disease additionallyrequires systemic treatment or phototherapy[2]. Systemic treatments can be divided intotreatments utilizing small-molecule drugs andmonoclonal antibodies (biologics). Treatmentwith biologics is very effective in psoriasis and iswell tolerated overall. New biologics are muchmore effective than conventional treatmentswith small-molecule drugs [1, 3], but they dohave limitations. Some patients with psoriasisdo not respond to the treatment, while otherpatients experience a loss of drug responseduring treatment. Overall, drug survival of olderbiologics is 70–80% after 1 year of treatment[4, 5]. The side effects of biologics are relativelylimited, but these drugs must be administeredby subcutaneous injection, and they areexpensive. Therefore, new treatment options forpsoriasis are needed. One possibility is a newclass of small-molecule drugs called Januskinase (JAK) inhibitors, which are currentlybeing tested in clinical trials.

JAKS AND THEIR SIGNALINGPATHWAY

The JAKs are four intracellular protein tyrosinekinases: JAK1, JAK2, JAK3, and tyrosine kinase 2(TYK2) [6]. JAK1, JAK2, and TYK2 are expressedin a variety of cell types, while JAK3 is mainlyexpressed in hematopoietic cells [7]. JAK inhi-bitors are small-molecule drugs that inhibitJAKs and thereby hinder the function of theJAK–signal transducer and activator of tran-scription (STAT) signal pathway. In contrast tobiologics that target either the extracellularcytokine receptor or the cytokine outside thecell, JAK inhibitors target JAKs inside the cellthat contribute to signal transduction.

The term ‘‘cytokine’’ covers many struc-turally unrelated proteins. They can be groupedbased on the receptor superfamily they bind to.Different receptor superfamilies use differentkinds of signal transduction pathways. Manyproinflammatory cytokines—for example IL-23,

30 Dermatol Ther (Heidelb) (2020) 10:29–42

which is part of the inflammatory response inpsoriasis—bind to type I and II cytokine recep-tors, which leads to the activation of intracel-lular signaling mediated by JAKs [6]. When acytokine binds to a receptor on the cell surface,intracellular JAKs are recruited and bind in pairsto the intracellular part of the receptor. Thedimerization of JAKs, in most cases with for-mation of heterodimers, causes autophospho-rylation and modifies the receptors so that STATproteins can bind and become activated. Acti-vated STAT proteins then dimerize andtranslocate to the cell nucleus to regulate genetranscription [8]. In psoriasis, inhibition of JAKsresults in inhibition of the signal pathway andgene transcription, leading to further produc-tion of inflammatory cytokines, thereby reduc-ing psoriatic inflammation (Fig. 1).

The functions of each JAK and of JAKs ingeneral are not yet fully understood. JAK1 isassociated with interferon (IFN) and IL-6 and IL-10 receptors and with receptors containing thecommon c chain or the gp130 subunit. JAK2 isassociated with the IL-3 receptor and hormone-like receptors, e.g., those for erythropoietin,growth hormone, and prolactin; these receptorsare dependent on a homodimer of JAK2 forintracellular signal transduction. Dimers ofJAK2 and TYK2 are associated with INF, IL-12,and IL-23 receptors. JAK3 is limited tohematopoietic cells and binds in conjunctionwith JAK1 exclusively to receptors containing cchains, which include IL-2, IL-4, IL-7, IL-9, IL-15, and IL-21 receptors. JAK dysfunction isassociated with polycythemia vera, essentialthrombocytopenia, myelofibrosis, and severecombined immunodeficiency and

Fig. 1 Overview of the interleukin (IL)-23 signal pathwayand the mechanism of tyrosine kinase (TYK) 2 inhibition.The IL-23 signal pathway is implicated in the pathogenesisof psoriasis and is an example of a signal pathway that ismediated by Janus kinases (JAKS) and signal transducerand activator of transcription (STAT) proteins. There arefour JAKs: JAK1, JAK2, JAK3, and TYK2. When IL-23binds to the IL-23 receptor (R), it attracts a heterodimer ofJAK2 and TYK2 that binds to the intracellular domain ofthe receptor. JAK2 and TYK2 then autophosphorylate

(P), which activates the receptor and attracts STATproteins. The STAT proteins bind and are phosphorylatedbefore dimerizing and translocating to the cell nucleus,where they regulate gene transcription and thus furthercytokine production. TYK2 inhibitors inhibit TYK2function, which in turn suppresses intracellular signaltransduction downstream of the receptor and thus furthercytokine production through IL-23 during the psoriaticinflammation process

Dermatol Ther (Heidelb) (2020) 10:29–42 31

hyperimmunoglobulin E syndrome. Further-more, dysregulation of JAK signaling is seen invarious autoimmune diseases [8, 9].

JAK INHIBITORS IN PSORIASIS

The IL-23/Th17 axis is key part of the patho-genesis of psoriasis. IL-23 drives the differenti-ation of Th17 cells. These cells produce IL-17and IL-22, which induce keratinocyte prolifer-ation and other features typical of psoriasis [2].Several biologics used for psoriasis, such asustekinumab, secukinumab, ixekizumab,guselkumab, risankizumab, tildrakizumab, andbrodalumab, target this axis. The IL-23 receptorrelies on a heterodimer of JAK2 and TYK2 forsignal transduction, thus highlighting the roleof JAKs in the pathogenesis of psoriasis and thetherapeutical potential of JAK inhibitors [10].Furthermore, TYK2-deficient mice display sig-nificantly reduced ear swelling and less epider-mal hyperplasia when injected with IL-23compared to wild-type mice. Skin infiltration ofvarious immune cells and production of theproinflammatory cytokines IL-17 and IL-22were also impaired in the absence of TYK2 [11].These results, together with the known clinicalsuccess of biologics targeting the IL23/IL17 axis,shows the great potential for JAK inhibitors andperhaps particularly for TYK2 inhibitors in thetreatment of psoriasis.

The JAK inhibitors currently tested in clinicaltrials target different members of the JAK fam-ily, with some being more selective than others.First-generation JAK inhibitors typically targettwo or three different JAKs and thus have abroader effect but also present more side effectscompared to the newer generation (e.g., selec-tive TYK2 inhibitors), which specifically targetone JAK [6]. To date, three JAK inhibitors havebeen approved and are on the market for thetreatment of various human diseases: ruxoli-tinib for myelofibrosis and polycythemia vera,tofacitinib for rheumatoid arthritis (RA), psori-atic arthritis, and ulcerative colitis, and barici-tinib for RA [6].

The aim of the present review is to providean overview of the mechanism underlying theeffects of JAK inhibitors on psoriasis as well as

the results of clinical trials testing their efficacyin treating this disease.

METHODS

Our search included literature published inEnglish on clinical trials of JAK inhibitors inadults with chronic plaque psoriasis. We sear-ched the Medline database via PubMed until 1August 2019 using the following combinationsof MeSH search terms: ‘‘psoriasis’’ AND ‘‘januskinases;’’ ‘‘psoriasis’’ AND ‘‘TYK2 kinase;’’ and‘‘psoriasis’’ AND ‘‘tofacitinib.’’ Further trials weresearched for manually in the reference lists ofrelevant papers. We additionally searched clin-icaltrials.gov for unpublished trials. We onlyincluded clinical phase 2 or 3 trials examiningthe efficacy and safety of systemic JAK and TYK2inhibitors compared to placebo, another activetreatment, or no treatment in adult patientswith chronic plaque psoriasis. This article isbased on previously conducted studies and doesnot contain any studies with human partici-pants or animals performed by any of theauthors.

RESULTS

Tofacitinib and Psoriasis

Tofacitinib is the most studied JAK inhibitor fortreatment of chronic plaque psoriasis. Tofaci-tinib primarily targets JAK3, JAK2, and JAK1. Itis a first-generation JAK inhibitor that is on themarket as a treatment for RA, psoriatic arthritis,and ulcerative colitis [7, 9]. We identified fiveclinical trials testing tofacitinib in psoriasis,including one phase 2 trial and four phase 3trials (Table 1). All studies were performed inpatients with moderate-to-severe plaque psori-asis, classified as PASI[12 (phase 3 studies) orPASI[13 (phase 2 study). In the phase 2 study,tofacitinib had efficacies of 25.0% (2 mg twicedaily), 40.8% (5 mg twice daily), and 66.7%(15 mg twice daily) compared to 2% for theplacebo in terms of PASI75 response at week 12of treatment [12]. Across the phase 3 studies,tofacitinib had efficacies of 39.5–54.3% (5 mg

32 Dermatol Ther (Heidelb) (2020) 10:29–42

Table1

Outlin

eof

tofacitinibstudies

Stud

y/research

IDResearchph

aseandstatus

Description

Primaryendpo

int

Key

results

Papp

etal.(2012)

NCT00678210

[12]

2b Com

plete

197patientswererand

omized

to2mg,5mg,15

mg,or

placebotwicedaily

for12

weeks

PASI75

PASI75

response

ratesat

week12

were

significantlyhigher

foralltofacitinibgroups

vs.p

lacebo

PASI75:25.0%

(2mg),4

0.8%

(5mg),6

6.7%

(15mg),2

%(placebo)

Papp

etal.(2015)

NCT01276639

NCT01309737

[13]

3 Com

plete

901and960(intwoparallelstudies)wererand

omized

to5mg,10

mg,or

placebotwicedaily

for16

weeks

PASI75

PGA(0

or1)

Forboth

studies,PG

A(0

or1)

andPA

SI75

response

ratesat

week16

weresignificantly

higher

foreach

dose

comparedto

placebo

PGA(0

or1)

Study1:

41.9%

(5mg),5

9.2%

(10mg),9

.0%

(placebo)

Study2:

46.0%(5

mg),59.1%

(10mg),10.9%

(placebo)

PASI75

Study1:

39.9%

(5mg),5

9.2%

(10mg),6

.2%

(placebo)

Study2:

46.0%(5

mg),59.6%

(10mg),11.4%

(placebo)

Bachelezet

al.(2015)

NCT01241591

[15]

3 Com

plete

1106

patientsrand

omized

to5mg,10

mg,or

placebotwice

daily

oretanercept

50mgsubcutaneouslytwiceaweek

for12

weeks

PASI75

PGA(0

or1)

PASI75

andPG

A(0

or1)

response

ratesat

week12

weresignificantlyhigher

for

tofacitinibandetanercept

comparedto

placebo

Tofacitinib

10mgtwicedaily

was

noninferior

toetanercept

andsuperior

toplacebo

PASI75:

39.5%

(5mg),6

3.6%

(10mg),5

8.8%

(etanercept),5

.6%

(placebo)

PGA(0

or1)

47.1%

(5mg),6

8.2%

(10mg),6

6.3%

(etanercept),1

5.0%

(placebo)

Dermatol Ther (Heidelb) (2020) 10:29–42 33

Table1

continued

Stud

y/research

IDResearchph

aseandstatus

Description

Primaryendpo

int

Key

results

Bissonn

ette

etal.(2015)

NCT01186744

[14]

3 Com

plete

Withdrawalandretreatm

entstudy

Initialp

hase

included

666patientsrand

omized

to5mgor

10mgtwicedaily

for24

weeks

Inthewithdrawalphase,291patientscontinuedandwere

rand

omized

toeither

continuedactive

treatm

ent(5

mg

or10

mg)

orplacebotwicedaily

forup

to16

weeks

264patientscontinuedto

theretreatm

entphaseandwere

retreatedwiththesamedose

of5mgor

10mgtwice

daily

asthey

hadreceived

intheinitialphase.The

study

endedat

week54

Treatmentwithdrawal

PASI75

PGA(0

or1)

Retreatment

PASI75

PGA(0

or1)

Initialphase:

PASI75

response

atweek24

43.8%

(5mg)

and67.6%

(10mg)

PGA(0

or1)

response

41.6%

(5mg)

and62.8%

(10mg)

33.5%

(5mg)

and55.2%

(10mg)

ofpatients

achieved

aPA

SI75

andaPG

Aresponse,

respectively,and

continuedto

thewithdrawal

phase

Withdrawalphase:

Agreaterproportion

ofthepatientscontinuing

treatm

entmaintainedaPA

SI75

response

than

thosewho

switched

toplaceboafter

16weeks.A

tweek16;92.3%

(5mg)

and

93.0%

(10mg)

didnotrelapse,as

compared

to32.8%

(placebo,5

mgin

theinitialphase)

and42.9%

(placebo,1

0mgin

theinitial

phase)

Retreatmentphase:

Ofpatientstreatedwithplaceboin

the

withdrawalphase,48.0/52.0%

(5mg

retreatm

ent)and72.5/64.2%

(10mg

retreatm

ent)regained

ormaintaineda

PASI75/PGAresponse

after16

weeks

of

retreatm

ent

Ofpatientsthat

relapsed

onplaceboin

the

withdrawalphase,36.8%

(5mg)

and61.0%

(10mg)

achieved

aPA

SI75

response

after

16weeks

ofretreatm

ent,while44.8%(5

mg)

and57.1%

(10mg)

ofthosewho

lostaPG

Aresponse

achieved

aPG

Aresponse

upon

retreatm

ent

34 Dermatol Ther (Heidelb) (2020) 10:29–42

twice daily) and 59.2–81.1% (10 mg twice daily)compared to 5.6–12.5% for the placebo in termsof PAS75 response at weeks 16–24 [13–16]. Thehighest PASI75 responses at both dosages wereobserved in an Asian population [16]. Thesestudies also showed the clinical efficacy oftofacitinib for secondary end points such as theDermatology Life Quality Index (DLQI), NailPsoriasis Severity Index (NAPSI), and PASI90compared to placebo. None of the tofacitinibstudies included PASI100 responses. In onestudy, treatment with tofacitinib was noninfe-rior to treatment with etanercept [15]. Whiletofacitinib was well tolerated overall, the fol-lowing were observed in most studies: increasedcirculating total cholesterol, low-densitylipoprotein (LDL) cholesterol, high-densitylipoprotein (HDL) cholesterol, and creatininephosphokinase levels and decreased bloodhemoglobin and lymphocyte counts.

TYK2 Inhibitors and Psoriasis

TYK2 inhibitors were developed to obtain moreselective inhibitors than first-generation JAKinhibitors. The TYK2 inhibitor BMS-986165 hasbeen tested in one phase 2 trial, where thePASI75 response was 75% compared to 7% inthe placebo group after 12 weeks of treatmentwith the highest dosage tested (12 mg daily).Secondary end points included PASI90 andPASI100 responses. The PASI90 response was43% after 12 weeks (daily dose of 12 mg) com-pared to placebo. The PASI100 response was25% after 12 weeks (daily dose of 12 mg) com-pared to placebo. The treatment did not lead tosignificant changes in blood cell counts orserum levels of liver enzymes, lipids, creatinine,and immunoglobulins [17]. However, therewere three serious adverse events in the BMS-986165 groups, as well as one case of malignantmelanoma that occurred 3 months after thestart of treatment. According to clinicaltrials.-gov, three phase 3 trials testing BMS-986165 arein progress. Another TYK2 inhibitor(PF06826647) is also currently being tested in aphase 2 study (Table 2). However, TYK2 inhibi-tors are yet to enter the market.

Table1

continued

Stud

y/research

IDResearchph

aseandstatus

Description

Primaryendpo

int

Key

results

Zhang

etal.(2017)

NCT01815424

[16]

3 Com

plete

266Asian

patientswererand

omized

to5mg,10

mg,or

placebotwicedaily

for16

weeks.T

heactive

treatm

ent

groups

werethen

followed

upfor36

weeks

PASI75

PGA(0

or1)

PASI75

andPG

A(0

or1)

response

ratesat

week16

weresignificantlyhigher

for

tofacitinibgroups

comparedto

placebo

PASI75:

54.3%(5

mg),81.1%

(10mg),12.5%

(placebo)

PGA(0–1

):

52.3%(5

mg),75.6%

(10mg),19.3%

(placebo)

BothPA

SI75

andPG

Aresponseswere

generally

sustainedduring

the36

weeks

offollow-up

Dermatol Ther (Heidelb) (2020) 10:29–42 35

Other JAK Inhibitors and Psoriasis

Four other JAK inhibitors have been tested astreatments for psoriasis: peficitinib (ASP015K), apan-JAK inhibitor; solcitinib (GSK 2586184), aJAK1 inhibitor; baricitinib, an inhibitor of JAK1and JAK2; and itacitinib adipate, a JAK1 inhi-bitor (Table 3) [18–21]. The efficacies of theseJAK inhibitors were either similar or inferior tothat of tofacitinib. No serious adverse eventswere reported for peficitinib, baricitinib, anditacitinib, but changes in laboratory parameterssimilar to those reported for tofacitinib were

observed in most studies [19–21]. For solcitinib,five serious adverse events were reported, two ofwhich were considered to be related to the studytreatment, including one case of ureteral cal-culus and one case of severe thrombocytopenia.No changes in other laboratory parameters werereported [18]. All of these studies were phase 2studies, and no further studies of these JAKinhibitors in relation to the treatment of psori-asis are planned to our knowledge.

Table 2 Outline of TYK2 inhibitor studies

Study/drug/research ID

Researchphase andstatus

Description Key results

Papp et al.

(2018) BMS-

986165

NCT02931838

[17]

2

Complete

267 patients randomized to 3 mg every

other day, 3 mg daily, 3 mg twice daily,

6 mg twice daily, 12 mg daily, or placebo

for 12 weeks

All groups receiving the study drug (except

the 3 mg every other day group) had a

significantly greater PASI75 response at

week 12 compared to placebo

PASI75: 9% (3 mg every other day), 39%

(3 mg daily) 69% (3 mg twice daily), 67%

(6 mg twice daily), 75% (12 mg daily), 7%

(placebo)

BMS-986165

NCT04036435

[41]

3

Not

recruiting

yet

Safety and efficacy study –

BMS-986165

NCT03924427

[42]

3

Recruiting

Safety and efficacy evaluation in Japanese

patients

–

BMS-986165

NCT03611751

NCT03624127

[43, 44]

3

Recruiting

Two parallel studies of efficacy compared to

apremilast and placebo

–

PF06826647

NCT03895372

[45]

2

Recruiting

Safety and efficacy study –

36 Dermatol Ther (Heidelb) (2020) 10:29–42

Table 3 Outline of other JAK inhibitor studies

Study/drug/research ID

Researchphaseandstatus

Description Primaryend point

Key results

Papp et al.

(2015)

ASP015K

NCT01096862

[20]

2a

Complete

124 patients were randomized to

10 mg twice daily, 25 mg twice

daily, 60 mg twice daily, 100 mg

twice daily, 50 mg once daily, or

placebo for 6 weeks

Mean PASI

reduction

from

baseline

All treatment groups showed

significant improvements in PASI

compared to placebo

Dose-dependent effect observed

Mean change in PASI from baseline:

- 6.4 (10 mg twice daily), - 6.5

(25 mg twice daily), - 8.3 (60 mg

twice daily), - 11.9 (100 mg twice

daily), - 6.6 (50 mg once daily), -

4.2 (placebo)

Ludbrook et al.

(2016)

GSK2586184

NCT01782664

[18]

2a

Complete

60 patients were randomized to

100 mg, 200 mg, 400 mg, or

placebo twice daily for 12 weeks

PASI75 PASI 75 response rate at week 12 for

the 400 mg group was significantly

different from that of the placebo

group. Dose-dependent

improvements in PASI75

described: 13% (100 mg), 25%

(200 mg), 57% (400 mg), 0%

(placebo)

Papp et al.

(2016)

Baricitinib

NCT01490632

[21]

2b

Complete

238 North American patients were

randomized to 2 mg, 4 mg, 8 mg,

10 mg once daily, or placebo for

12 weeks

PASI75 PASI75 response at week 12 was only

significantly different for the 8 mg

group (43%) and the 10 mg group

(54%) compared to placebo (17%)

Bissonnette

et al. (2016)

INCB039110

NCT01634087

[19]

2

Complete

50 patients were randomized to

100 mg daily, 200 mg daily, 200 mg

twice daily, 600 mg daily, or

placebo for 28 days

Mean PGA

reduction

from

baseline

A significant improvement in mean

percent reduction in PGA from

baseline was observed for the

200 mg twice daily and 600 mg

daily groups compared to placebo

Mean PGA reduction from baseline:

22.2% (100 mg daily), 29.4%

(200 mg daily), 35.2% (200 mg

twice daily), 42.4% (600 mg daily),

12.5% (placebo)

Dermatol Ther (Heidelb) (2020) 10:29–42 37

DISCUSSION

The number of studies on JAK inhibitors forpsoriasis remains limited. Many of the drugstested have only been examined in phase 2 tri-als and it is doubtful that they will be testedfurther. Only tofacitinib has been tested tophase 3, and several phase 3 trials are currentlyin progress for the TYK2 inhibitor BMS-986165.The selective TYK2 inhibitor BMS-986165 hasshown the highest efficacy towards psoriasis ofany JAK inhibitor to date, with a PASI75response of 75% after 12 weeks of treatment in aphase 2 trial [17]. Tofacitinib is the most studiedJAK inhibitor for the treatment of psoriasis,with four reported phase 3 trials showing con-siderable efficacy in terms of the PASI75response, especially at a high dose of 10 mgtwice daily [13–16]. Other JAK inhibitors havealso been tested for psoriasis; these have yieldedPASI75 responses that are less than or similar tothat achieved with tofacitinib. However, noneof these have been tested beyond phase 2[18–21].

There is fierce competition in the pharma-ceutical industry due to the number of biologi-cal drugs on the market that are all veryeffective at treating psoriasis and have relativelyfew side effects. The standard efficacy target fornew biological treatments for psoriasis isPASI90, as seen in up to 60–70% of patients[3, 22]. For the highest dose of BMS-986165tested, PASI90 was 43% [16]. Accordingly, cur-rent data do not indicate that new JAK inhibi-tors, including TYK2 inhibitors, will outperformthe newest biologics. However, the efficaciesobserved for JAK inhibitors are better than thoseobserved for some current systemic treatmentssuch as apremilast, and some of the older bio-logics such as etanercept [3]. Provided that theydo not present increased adverse reaction rates,JAK inhibitors could be incorporated into thepsoriasis treatment algorithm because they areoral treatments and are less expensive thancontemporary biologics.

Knowledge of the safety of JAK inhibitors ispredominantly based on studies of tofacitinib,especially when administered for RA. Tofaci-tinib has been associated with changes in

laboratory parameters in patients with RA andpsoriasis, and increases in HDL and LDLcholesterol levels have been observed in bothpatient groups [23, 24]. Patients with psoriasisare known to have an increased risk of cardio-vascular disease—especially patients with mod-erate-to-severe disease [25, 26]. In a studyinvestigating the effects of tofacitinib on lipidlevels in such patients, increases from baselinelevels of LDL cholesterol, HDL cholesterol, andtriglycerides were observed at week 4 comparedto placebo, but these levels were relativelystable from weeks 4 to 16. The total cholesterolto HDL cholesterol ratio did not change and theinvestigators therefore concluded that theobserved changes in lipid levels were not sug-gestive of an increased cardiovascular risk [23].Also, an investigation of circulating levels ofproteins associated with inflammation and car-diovascular risk in patients with moderate-to-severe psoriasis treated with tofacitinib for12 weeks showed that this drug reduced severalinflammatory cardiovascular risk markers.However, it only did so in treatment responders[26]. The conclusion was that short-term sys-temic treatment of psoriasis with tofacitinib cancause reductions in circulating levels ofinflammatory proteins and other proteins asso-ciated with cardiovascular risk [27]. Notably,increased serum creatinine levels are associatedwith tofacitinib, but these levels usually returnto baseline upon drug discontinuation, andchronic renal dysfunction is not reported to bean adverse effect of tofacitinib [6, 28].

These studies indicate that treatment withtofacitinib probably does not increase cardio-vascular risk in patients with psoriasis, but theresults are based on short-term use, so furtherstudies are needed to explore the effects of long-term use in particular.

An increased risk of infection should alwaysbe considered when a treatment targeting theimmune system is used. Minor decreases inblood lymphocyte counts and hemoglobin havebeen observed in patients with psoriasis treatedwith tofacitinib. These decreases were not pro-gressive and were often transient or reversible[29]. Tofacitinib has been associated with anincreased risk of herpes zoster virus infectioncompared to placebo. Risk factors included

38 Dermatol Ther (Heidelb) (2020) 10:29–42

Asian race, increasing age, higher drug dose,and prior exposure to biologics [30]. Also, aninvestigation of the effects of tofacitinib on theviral loads of Cytomegalovirus and Epstein–Barrvirus pointed to no clinically significant effectsof this JAK inhibitor [31]. The risk of infectionduring treatment with tofacitinib seems to besimilar to that during treatment with biologics[6, 9], and the overall benefit/risk profile of thedrug when used for psoriasis appears to becomparable to those of other systemic treat-ments [32].

Both the US Food and Drug Administrationand the European Medicines Agency recentlyissued black-box warnings of increased risks ofpulmonary embolism and overall mortality inpatients with RA receiving tofacitinib 10 mgtwice daily. These warnings were given due tothe results of an interim analysis of an ongoingopen-label clinical trial evaluating the safety oftofacitinib 5 mg twice or 10 mg twice dailycompared with a TNF inhibitor in patients withRA (NCT A3921133) [33, 34]. An independentstudy also indicated a numerically higher, albeitstatistically insignificant, risk of venous throm-boembolism in RA patients receiving tofacitinibcompared to those receiving TNF inhibitors[35].

We do not yet know the complete safetyprofiles and side effects of TYK2 inhibitors whenthey are used for psoriasis, but judging from theresults of the only published phase 2 study ofBMS-986165, where no changes in laboratoryparameters were observed, this agent may havea better risk profile than tofacitinib [17]. It willbe exciting to see the results of the phase 3studies of this agent that are currently in pro-gress, and these data will provide a much betterbasis for comparison with currently marketedbiologics.

Tofacitinib is approved for psoriatic arthritisby both the US Food and Drug Administrationand the European Medicines Agency. It is indi-cated for patients that have an inadequateresponse to conventional treatment with dis-ease-modifying antirheumatic drugs (DMARDs),and it is further recommended for use in com-bination with a DMARD such as methotrexate,sulfasalazine, and leflunomide [36]. In clinicaltrials, the efficacy of tofacitinib has been

measured in terms of the American College ofRheumatology 20 (ACR20) response and thechange from baseline in the Health AssessmentQuestionnaire—Disability Index (HAQ-DI)score. In one study testing tofacitinib inpatients with active psoriatic arthritis that hadresponded inadequately to DMARDs, theACR20 was 50% (5 mg twice daily) and 61%(10 mg twice daily) compared to 33% for pla-cebo after 3 months. The mean change in theHAQ-DI score was - 0.35 (5 mg twice daily) and- 0.40 (10 mg twice daily) compared with -

0.18 for placebo [37]. Another study testedtofacitinib in patients with active psoriaticarthritis that had responded inadequately toTNF inhibitors. The ACR20 response after3 months was 50% (5 mg twice daily) and 47%(10 mg twice daily) compared with 24% forplacebo; the corresponding mean changes inthe HAQ-DI score from baseline were - 0.39and - 0.35, compared with - 0.14 for placebo[38].

Although not covered in this review, oneparticularly exciting area of research is the useof JAK inhibitors as a local treatment for psori-asis, since new topical treatments for mild pso-riasis are urgently needed. Topical formulationsof tofacitinib and ruxolitinib have been testedin a few phase 2 trials for psoriasis. Topicaltofacitinib showed significant efficacy at8 weeks of treatment compared to placebo, butthe effect was transient and was not apparent at12 weeks, when the study ended [39]. Ruxoli-tinib showed clinical efficacy towards psoriasisafter 4 weeks of treatment, and was shown tomodulate proinflammatory cytokines in psori-atic lesions [40]. Importantly, no local or sys-temic adverse effects were observed with topicaltreatment, and more studies on this interestingfield of research are awaited.

CONCLUSIONS

JAK inhibitors are an exciting new group ofdrugs for the treatment of psoriasis. Tofacitinibis the best-studied JAK inhibitor for psoriasis todate; it has demonstrated considerable clinicalefficacy and is well tolerated overall when usedfor a short period. Selective TYK2 inhibitors

Dermatol Ther (Heidelb) (2020) 10:29–42 39

have shown even better clinical efficacy inpsoriasis, and seem to have an improved safetyprofile, but only the results from one phase 2trial of a selective TYK2 inhibitor have beenpublished. It is therefore clear that more studiesare needed to determine the long-term effectsand safety of JAK inhibitors.

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 thisarticle, take responsibility for the integrity ofthe work as a whole, and have given theirapproval for this version to be published.

Disclosures. Amanda Kvist-Hansen hasnothing to disclose. Peter Riis Hansen is sup-ported by a Borregaard Clinical Scientist fel-lowship from the Novo Nordisk Foundation andresearch grants from the LEO Foundation. LoneSkov has received speaker honoraria from Abb-Vie, Eli Lilly & Co, Novartis, and LEO Pharma,and has attended advisory boards for AbbVie,Janssen-Cilag, Novartis, Eli Lilly & Co, UCB,Almirall, LEO Pharma, and Sanofi. She hasserved as an investigator for Pfizer, AbbVie, EliLilly, Novartis, Amgen, Regeneron, Almirall,and LEO Pharma, and received research andeducational grants from Pfizer, AbbVie, Novar-tis, Sanofi, Janssen-Cilag, and LEO Pharma.

Compliance with Ethics Guidelines. Thisarticle is based on previously conducted studiesand does not contain any studies with humanparticipants or animals performed by any of theauthors.

Data Availability. Data sharing is notapplicable to this article as no datasets weregenerated or analyzed during the current study.

Open Access. This article is licensed under aCreative Commons Attribution-NonCommer-cial 4.0 International License, which permitsany non-commercial use, sharing, adaptation,distribution and reproduction in any mediumor format, as long as you give appropriate creditto the original author(s) and the source, providea link to the Creative Commons licence, andindicate if changes were made. The images orother third party material in this article areincluded in the article’s Creative Commonslicence, unless indicated otherwise in a creditline to the material. If material is not includedin the article’s Creative Commons licence andyour intended use is not permitted by statutoryregulation or exceeds the permitted use, youwill need to obtain permission directly from thecopyright holder. To view a copy of this licence,visit http://creativecommons.org/licenses/by-nc/4.0/.

REFERENCES

1. Nestle FO, Kaplan DH, Barker J. Psoriasis. N Engl JMed. 2009;361:496–509.

2. Boehncke W-H, Schon MP. Psoriasis. Lancet.2015;386:983–94.

3. Sawyer LM, Malottki K, Sabry-Grant C, et al.Assessing the relative efficacy of interleukin-17 andinterleukin-23 targeted treatments for moderate-to-severe plaque psoriasis: a systematic review andnetwork meta-analysis of PASI response. PLoS One.2019;14:e0220868.

4. Egeberg A, Ottosen MB, Gniadecki R, et al. Safety,efficacy and drug survival of biologics and biosim-ilars for moderate-to-severe plaque psoriasis. Br JDermatol. 2018;178:509–19.

5. Warren RB, Smith CH, Yiu ZZN, et al. Differentialdrug survival of biologic therapies for the treatmentof psoriasis: a prospective observational cohortstudy from the British Association of Dermatolo-gists Biologic Interventions Register (BADBIR). J In-vest Dermatol. 2015;135:2632–40.

6. Schwartz DM, Kanno Y, Villarino A, Ward M,Gadina M, O’Shea JJ. JAK inhibition as a therapeuticstrategy for immune and inflammatory diseases.Nat Rev Drug Discov. 2017;17:78.

40 Dermatol Ther (Heidelb) (2020) 10:29–42

7. He X, Chen X, Zhang H, Xie T, Ye XY. SelectiveTyk2 inhibitors as potential therapeutic agents: apatent review (2015–2018). Expert Opin Ther Pat.2019;20:137–49.

8. Hsu L, Armstrong AW. JAK inhibitors: treatmentefficacy and safety profile in patients with psoriasis.J Immunol Res. 2014;2014:283617.

9. Szilveszter KP, Nemeth T, Mocsai A. Tyrosine kina-ses in autoimmune and inflammatory skin diseases.Front Immunol. 2019;10:1862.

10. Singh S, Pradhan D, Puri P, et al. Genomic alter-ations driving psoriasis pathogenesis. Gene.2019;683:61–71.

11. Ishizaki M, Muromoto R, Akimoto T, et al. Tyk2 is atherapeutic target for psoriasis-like skin inflamma-tion. Int Immunol. 2014;26:257–67.

12. Papp KA, Menter A, Strober B, et al. Efficacy andsafety of tofacitinib, an oral Janus kinase inhibitor,in the treatment of psoriasis: a phase 2b random-ized placebo-controlled dose-ranging study. Br JDermatol. 2012;167:668–77.

13. Papp KA, Menter MA, Abe M, et al. Tofacitinib, anoral Janus kinase inhibitor, for the treatment ofchronic plaque psoriasis: results from two ran-domized, placebo-controlled, phase III trials. Br JDermatol. 2015;173:949–61.

14. Bissonnette R, Iversen L, Sofen H, et al. Tofacitinibwithdrawal and retreatment in moderate-to-severechronic plaque psoriasis: a randomized controlledtrial. Br J Dermatol. 2015;172:1395–406.

15. Bachelez H, van de Kerkhof PCM, Strohal R, et al.Tofacitinib versus etanercept or placebo in moder-ate-to-severe chronic plaque psoriasis: a phase 3randomised non-inferiority trial. Lancet (London,England). 2015;386:552–61.

16. Zhang J, Tsai T-F, Lee M-G, et al. The efficacy andsafety of tofacitinib in Asian patients with moderateto severe chronic plaque psoriasis: a phase 3, ran-domized, double-blind, placebo-controlled study.J Dermatol Sci. 2017;88:36–45.

17. Papp K, Gordon K, Thaci D, et al. Phase 2 trial ofselective tyrosine kinase 2 inhibition in psoriasis.N Engl J Med. 2018;379:1313–21.

18. Ludbrook VJ, Hicks KJ, Hanrott KE, et al. Investi-gation of selective JAK1 inhibitor GSK2586184 forthe treatment of psoriasis in a randomized placebo-controlled phase IIa study. Br J Dermatol. 2016;174:985–95.

19. Bissonnette R, Luchi M, Fidelus-Gort R, et al. Arandomized, double-blind, placebo-controlled,

dose-escalation study of the safety and efficacy ofINCB039110, an oral Janus kinase 1 inhibitor, inpatients with stable, chronic plaque psoriasis.J Dermatolog Treat. 2016;27:332–8.

20. Papp K, Pariser D, Catlin M, et al. A phase 2a ran-domized, double-blind, placebo-controlled,sequential dose-escalation study to evaluate theefficacy and safety of ASP015K, a novel Janus kinaseinhibitor, in patients with moderate-to-severe pso-riasis. Br J Dermatol. 2015;173:767–76.

21. Papp KA, Menter MA, Raman M, et al. A random-ized phase 2b trial of baricitinib, an oral Januskinase (JAK) 1/JAK2 inhibitor, in patients withmoderate-to-severe psoriasis. Br J Dermatol.2016;174:1266–76.

22. Puig L. PASI90 response: the new standard in ther-apeutic efficacy for psoriasis. J Eur Acad DermatolVenereol. 2015;10:645–8.

23. Wolk R, Armstrong EJ, Hansen PR, et al. Effect oftofacitinib on lipid levels and lipid-related param-eters in patients with moderate to severe psoriasis.J Clin Lipidol. 2017;11:1243–56.

24. Charles-Schoeman C, Wicker P, Gonzalez-Gay MA,et al. Cardiovascular safety findings in patients withrheumatoid arthritis treated with tofacitinib, anoral Janus kinase inhibitor. Semin Arthritis Rheum.2016;46:261–71.

25. Ahlehoff O, Gislason GH, Charlot M, et al. Psoriasisis associated with clinically significant cardiovas-cular risk: a Danish nationwide cohort study. J In-tern Med. 2011;270:147–57.

26. Samarasekera EJ, Neilson JM, Warren RB, ParnhamJ, Smith CH. Incidence of cardiovascular disease inindividuals with psoriasis: a systematic review andmeta-analysis. J Invest Dermatol. 2013;133:2340–6.

27. Kim J, Tomalin L, Lee J, et al. Reduction ofinflammatory and cardiovascular proteins in theblood of patients with psoriasis: differentialresponses between tofacitinib and etanercept after 4weeks of treatment. J Invest Dermatol. 2018;138:273–81.

28. Kremer JM, Kivitz AJ, Simon-Campos JA, et al.Evaluation of the effect of tofacitinib on measuredglomerular filtration rate in patients with activerheumatoid arthritis: results from a randomisedcontrolled trial. Arthritis Res Ther. 2015;17:95.

29. Strober B, Buonanno M, Clark JD, et al. Effect oftofacitinib, a Janus kinase inhibitor, on haemato-logical parameters during 12 weeks of psoriasistreatment. Br J Dermatol. 2013;169:992–9.

Dermatol Ther (Heidelb) (2020) 10:29–42 41

30. Winthrop KL, Lebwohl M, Cohen AD, et al. Herpeszoster in psoriasis patients treated with tofacitinib.J Am Acad Dermatol. 2017;77:302–9.

31. Valenzuela F, Papp KA, Pariser D, et al. Effects oftofacitinib on lymphocyte sub-populations, CMVand EBV viral load in patients with plaque psoriasis.BMC Dermatol. 2015;20:15.

32. Strober BE, Gottlieb AB, van de Kerkhof PCM, et al.Benefit–risk profile of tofacitinib in patients withmoderate-to-severe chronic plaque psoriasis: pooledanalysis across six clinical trials. Br J Dermatol.2019;180:67–75.

33. US Food and Drug Administration. Safety trial findsrisk of blood clots in the lungs and death withhigher dose of tofacitinib (Xeljanz, Xeljanz XR) inrheumatoid arthritis patients; FDA to investi-gate [Internet]. Silver Spring: US FDA; 2019. Avail-able at: https://www.fda.gov/drugs/drug-safety-and-availability/safety-trial-finds-risk-blood-clots-lungs-and-death-higher-dose-tofacitinib-xeljanz-xeljanz-xr. Accessed November 2019.

34. European Medicines Agency. Restrictions in use ofXeljanz while EMA reviews risk of blood clots inlungs. London: EMA; 2019. Available at: https://www.ema.europa.eu/en/news/restrictions-use-xeljanz-while-ema-reviews-risk-blood-clots-lungs. AccessedNovember 2019.

35. Desai RJ, Pawar A, Weinblatt ME, Kim SC. Com-parative risk of venous thromboembolism inrheumatoid arthritis patients receiving tofacitinibversus those receiving tumor necrosis factor inhi-bitors: an observational cohort study. ArthritisRheumatol. 2019;71:892–900.

36. Ly K, Beck KM, Smith MP, Orbai A-M, Liao W.Tofacitinib in the management of active psoriaticarthritis: patient selection and perspectives. Psoria-sis (Auckland, NZ). 2019;9:97–107.

37. Mease P, Hall S, FitzGerald O, et al. Tofacitinib oradalimumab versus placebo for psoriatic arthritis.N Engl J Med. 2017;377:1537–50.

38. Gladman D, Rigby W, Azevedo VF, et al. Tofacitinibfor psoriatic arthritis in patients with an inadequateresponse to TNF inhibitors. N Engl J Med. 2017;377:1525–36.

39. Papp KA, Bissonnette R, Gooderham M, et al.Treatment of plaque psoriasis with an ointmentformulation of the Janus kinase inhibitor, tofaci-tinib: a phase 2b randomized clinical trial. BMCDermatol. 2016;16:15.

40. Punwani N, Burn T, Scherle P, et al. Downmodula-tion of key inflammatory cell markers with a topicalJanus kinase 1/2 inhibitor. Br J Dermatol. 2015;173:989–97.

41. US National Library of Medicine. ClinicalTrials.govdatabase [Internet]. Bethesda: US National Libraryof Medicine; 2019. Available at: https://clinicaltrials.gov/ct2/results?cond=&term=NCT04036435&cntry=&state=&city=&dist=. Accessed August 2019.

42. US National Library of Medicine. ClinicalTrials.govdatabase [Internet]. Bethesda: US National Libraryof Medicine; 2019. Available at: https://clinicaltrials.gov/ct2/results?cond=&term=NCT03924427&cntry=&state=&city=&dist=. Accessed August 2019.

43. US National Library of Medicine. ClinicalTrials.govdatabase [Internet]. Bethesda: US National Libraryof Medicine; 2019. Available at: https://clinicaltrials.gov/ct2/results?cond=&term=NCT03611751&cntry=&state=&city=&dist=. Accessed August 2019.

44. US National Library of Medicine. ClinicalTrials.govdatabase [Internet]. Bethesda: US National Libraryof Medicine; 2019. Available at: https://clinicaltrials.gov/ct2/results?cond=&term=NCT03624127&cntry=&state=&city=&dist=. Accessed August 2019.

45. US National Library of Medicine. ClinicalTrials.govdatabase [Internet]. Bethesda: US National Libraryof Medicine; 2019. Available at: https://clinicaltrials.gov/ct2/results?cond=&term=NCT03895372&cntry=&state=&city=&dist=. Accessed August 2019.

42 Dermatol Ther (Heidelb) (2020) 10:29–42