-
From the Depa
University Med
Funding sources:
Dr Ramot has rec
Drs Shreberk-Has
study.
Accepted for pub
Reprints not avai
Janus kinase inhibitors in dermatology:A systematic review
Rony Shreberk-Hassidim, MD, Yuval Ramot, MD, MSc, and Abraham
Zlotogorski, MDJerusalem, Israel
Background: Janus kinase (JAK) inhibitors are emerging as a
promising new treatment modality for manyinflammatory
conditions.
Objective: Our aim was to systematically review the available
data on the use of JAK inhibitors incutaneous diseases.
Methods: This is a systematic review of PubMed and
ClinicalTrials.gov.
Results: One hundred thirty-four articles matched our search
terms, of which 78 were original articles and12 reports on adverse
events. Eighteen clinical trials were found. JAK inhibitors have
been extensivelystudied for psoriasis, showing beneficial results
that were comparable to the effects achieved by
etanercept.Favorable results were also observed for alopecia
areata. Promising preliminary results were reported forvitiligo,
dermatitis, graft versus host disease, cutaneous T cell lymphoma,
and lupus erythematosus. Themost common adverse events reported
were infections, mostly nasopharyngitis and upper respiratory
tractinfections.
Limitations: It was not possible to perform a meta-analysis of
the results.
Conclusions: This systematic review shows that while JAK
inhibitors hold promise for many skindisorders, there are still
gaps regarding the correct dosing and safety profile of these
medications fordermatologic indications. Additional trials are
necessary to address these gaps. ( J Am Acad
Dermatol2017;76:745-53.)
Key words: alopecia areata; atopic dermatitis; baricitinib;
dermatology; graft versus host disease; JAKinhibitors; psoriasis;
ruxolitinib; tofacitinib; vitiligo.
Recent years have brought great progress inour understanding of
the pathogenesis ofinflammatory and immunologic diseases,
thereby uncovering novel therapeutic targets. Oneof these newly
identified targets is the Janus kinase(JAK)/signal transducer and
activator of transcription(STAT) pathway, which is pivotal for the
downstreamsignaling of inflammatory cytokines and of
differentgrowth factors. JAKs belong to the group of thecytoplasmic
tyrosine kinases. They are activated afterstimulation of several
cellular receptors by theirspecific growth factors, growth
hormones, chemo-kines, and cytokines. After activation, they
rtment of Dermatology, Hadassah - Hebrew
ical Center, Jerusalem.
None.
eived speaker’s honorarium from Pfizer.
sidim and Ramot contributed equally to this
lication December 6, 2016.
lable from the authors.
phosphorylate STAT transcription factors, resultingin the
transportation of STAT factors to the nucleus,affecting expression
of specific genes. There are 4known types of JAKs: JAK1, JAK2,
JAK3, and TYK2,expressed mainly in hematopoietic cells.1,2
The realization that JAKs contribute substantiallyto the
immunologic processes in inflammatorydiseases (eg, rheumatoid
arthritis [RA],3 ankylosingspondylitis,4 and inflammatory bowel
disease5) ledto the development of JAK inhibitors as
therapeuticimmunosuppressive agents. At present, 2 JAK in-hibitors
have been approved by regulatory agencies,and additional compounds
are being developed and
Correspondence to: Abraham Zlotogorski, MD, Department of
Dermatology, Hadassah-Hebrew University Medical Center,
Jerusalem 9112001, Israel. E-mail: [email protected].
Published online February 4, 2017.
0190-9622/$36.00
� 2016 by the American Academy of Dermatology,
Inc.http://dx.doi.org/10.1016/j.jaad.2016.12.004
745
Delta:1_given nameDelta:1_surnameDelta:1_given
namehttp://ClinicalTrials.govhttp://crossmark.crossref.org/dialog/?doi=10.1016/j.jaad.2016.12.004&domain=pdfmailto:[email protected]://dx.doi.org/10.1016/j.jaad.2016.12.004
-
J AM ACAD DERMATOLAPRIL 2017
746 Shreberk-Hassidim, Ramot, and Zlotogorski
tested. In 2011, ruxolitinib, a JAK1/2 inhibitor, wasapproved by
the US Food and Drug Administration(FDA) for myelofibrosis,6 and
was later approved inother countries for the same indication.
Tofacitinib,which is mainly directed against JAK1/3,7 wasrecently
approved in several countries for thetreatment of RA.8
CAPSULE SUMMARY
d There is increasing evidence that Januskinase inhibitors may
effectively treat avariety of inflammatory skin diseases.
d This systematic review includes asummary of studies exploring
their usein psoriasis, alopecia areata, and a varietyof other skin
conditions.
d Janus kinase inhibitors have thepotential to significantly
impactdermatologic therapy, although moredata regarding their
safety and efficacyare needed.
The interest of the derma-tology field in JAK inhibitorshas been
piqued mainlybecause of the large clinicaltrials that were
performedwith tofacitinib and are beingperformed with other
JAKinhibitors for psoriasis.Alopecia areata (AA) isanother
condition thatshowed promising resultsfrom treatment with JAK
in-hibitors. Other immunologicdiseases with cutaneousmanifestations
that are beingstudied include vitiligo,atopic dermatitis (AD),
graftversus host disease (GVHD)
and lupus erythematosus (LE; Table I). Because ofthe constantly
accumulating literature on JAK in-hibitors in dermatology, there is
a need for a currentand comprehensive summary on their use in
patientswith cutaneous conditions. Therefore, we performeda
systematic review on the use of JAK inhibitors incutaneous
diseases, describing their regimen, effi-cacy, and adverse events
(AEs).
METHODSA systematic review of studies describing the use
of JAK inhibitors in dermatologic disorders wasperformed. We
performed an electronic literaturesearch of PubMed database on JAK
inhibitors anddermatology twicedin January 2016 and inNovember
2016. The references of each relevantarticle were also reviewed. In
addition, clinical trialswere searched using ClinicalTrials.gov in
October2016. The methodology of the systematic search isdescribed
in Fig 1.
RESULTSOur first search in January 2016 yielded 278
PubMed database results. The same search per-formed 10 months
later (November 2016) found439 results, a 58% increase. Three
hundred fivesearch results were excluded because of duplica-tions
(articles that appeared twice using differenttypes of search words)
or because they did not focuson JAK inhibitors and dermatology. One
hundred
thirty-four articles matched our search terms, andconsisted of
44 reviews, 78 original articles (53clinical studies and 25 in
vitro and in vivo preclinicalstudies), and 12 reports on AEs (Fig
1; SupplementalTable I; available at http://www.jaad.org). All
studieswere in English, except 1 review article that waspublished
in French. In addition, at least 18 clinical
trials are still ongoing or notyet published (SupplementalTable
II; available at http://www.jaad.org). Psoriasis andpsoriatic
arthritis (PsA) werethe most common diseasesevaluated among the
originalclinical studies (43%) andclinical trials (39%).Dermatitis
was the mostprevalent condition evalu-ated in preclinical
studies(Supplemental Table I).
PsoriasisThirty-four studies on the
effect of JAK inhibitors inpsoriasis and PsA were
found, consisting of 4 preclinical studies, 23 originalclinical
studies, and 7 clinical trials (Table II; avail-able at
http://www.jaad.org). In 79% of the studies,tofacitinib was the
drug that was assessed.
Tofacitinib has a regulatory effect on the synovialinflammatory
process in PsA samples.9 In addition,when examined in an in vitro
model of psoriasis, itreduced expression of JAK1 and 3.10
SAR-20347, aJAK1 and TYK2 inhibitor, and R-348, a JAK3
inhibitor,were tested on psoriatic murine models, resulting
inlesional improvement accompanied by decreasedlevels of
proinflammatory cytokines.11,12 The dosageof oral tofacitinib for
plaque-type psoriasis wasevaluated in a phase 1 study, using a
range of doses(5-50 mg twice daily or 60 mg once daily). All
dosesexcept for the 5 mg twice daily dose resulted inimprovement in
psoriatic lesions when compared toplacebo.13 Two large phase 3
studies demonstrated a75% reduction in Psoriasis Area and Severity
Indexscores (PASI75) and physician’s global assessment(PGA) scores
for both the 5 and 10 mg doses giventwice daily for 16 weeks in
comparison to placebo.14
The PASI75 rates were better for the 10 mg twicedaily dose than
for the 5 mg twice daily dose(approximately 40% and 60%,
respectively).Pruritus improved rapidly with both doses of
tofaci-tinib, as soon as 1 day after starting the drug.15
Withdrawal after 24 weeks of tofacitinib resulted in[70%
reduction in the proportion of patients withPASI75, which were
regained in most of the patients
http://ClinicalTrials.govhttp://www.jaad.orghttp://www.jaad.orghttp://www.jaad.orghttp://www.jaad.org
-
Abbreviations used:
AA: alopecia areataAD: atopic dermatitisAE: adverse eventCANDLE:
chronic atypical neutrophilic derma-
tosis with lipodystrophy and elevatedtemperature
CTCL: cutaneous T cell lymphomaFDA: Food and Drug
AdministrationGVHD: graft versus host diseaseJAK: Janus kinaseLE:
lupus erythematosusPASI: Psoriasis Area and Severity IndexPGA:
physician’s global assessmentPsA: psoriatic arthritisRA: rheumatoid
arthritisRCT: randomized controlled trialSTAT: signal transducer
and activator of
transcription
J AM ACAD DERMATOLVOLUME 76, NUMBER 4
Shreberk-Hassidim, Ramot, and Zlotogorski 747
following retreatment.16 In 1 of the phase 3 studies,tofacitinib
was compared to etanercept, given at adose of 50 mg twice weekly.
The PASI75 responserates were 39.5% (n = 330) and 63.6% (n = 332)
forthe 5 and 10 mg tofacitinib treatment groups,respectively, and
58.8% (n = 336) for the etanercepttreatment group, with similar
rates for ‘‘clear’’ or‘‘almost clear’’ PGA score.17 Only 1
randomizedcontrol trial (RCT) included PsA patients, with
goodclinical response to tofacitinib 5 or 10 mg twicedaily.18
Topical tofacitinib has also been tested in patientswith
psoriasis, with conflicting results. Whencompared to its vehicle,
tofacitinib 2% ointmentdemonstrated higher response rates.19
However, inan intrasubject RCT, no difference between tofaciti-nib
solutions at 0.02%, 0.2%, and 2% concentrationsand
contralateral-applied vehicles was observed.20
Later, it was shown that the 2% ointment led to asignificant
improvement in comparison with vehicleafter 8 weeks of treatment,
while this effect was notsignificant after 12 weeks.21
In a few studies, the use of the JAK 1/2 inhibitorsruxolitinib
and baricitinib was evaluated in psoriaticpatients. Baricitinib 2
to 10 mg once daily showedgreater mean change in PASI score than
placebo,except for the 2-mg dose.21 Topical ruxolitinib (1.5%cream
twice daily or 1% cream once daily) wassignificantly better in
achieving [50% reduction inlesion score when compared with the
0.5%, calcipo-triene, betamethasone, and vehicle creams.22
Another study reported on decreased lesionalinflammation using
similar topical concentrations.23
Tofacitinib is the most studied JAK inhibitor inmoderate to
severe plaque type psoriasis. Ten milli-grams twice daily results
in the greatest clinicalresponse rates, which is comparable to
etanercept.
However, additional randomized controlled com-parisons between
JAK inhibitors and existing thera-pies for psoriasis are
needed.
Alopecia areataSeventeen studies assessing the use of JAK
in-
hibitors in AA have been found: 1 preclinical study,14 original
clinical studies, and 2 clinical trials (TableIII; available at
http://www.jaad.org). Ten studies(58%) used tofacitinib and
ruxolitinib was used in 5studies (29%). Using a murine model, both
topicaltofacitinib and ruxolitinib led to significant hairregrowth,
attributed to anagen initiation. In additionto their
anti-inflammatory effects, it was furthershown that those JAK
inhibitors promote the activa-tion of hair follicles stem cells.24
These results mayexplain the rationale and positive effects of
JAKinhibitor treatment in patients with AA. Hair growthwas also
observed in mouse models for AA treatedtopically or systemically
with ruxolitinib, baricitinib,or tofacitinib.25,26
Sixty-six patients with AA participated in an open-label phase 2
study evaluating the effect of tofacitinibat a dosage of 5 mg twice
daily. Improvement of$50% in the severity of AAwas demonstrated in
32%of patients. Relapse occurred after a median of8.5 weeks after
drug cessation.27 An additional studyinvolving 90 AA patients
treated with tofacitinib 5 mgtwice daily reported [50% improvement
in 42% ofthe patients.28 In both studies, changes were
moresignificant in multifocal AA versus alopecia totalis
oruniversalis. Thirteen adolescents were treated withtofacitinib 5
mg twice daily, of which 9 showedsignificant hair regrowth.29
Ruxolitinib (20 mg twice daily) was given as partof an
open-label study to 12 patients. A significanthair regrowth (an
average of 92%) was observed in 9patients after 3 to 6 months.30
There was 1 report ontopical treatment with ruxolitinib that
resulted incomplete regrowth of eyebrows but only 10% re-growth of
scalp hair.31 The use of baricitinib wasreported in 1 patient with
concomitant chronicatypical neutrophilic dermatosis with
lipodystrophyand elevated temperature (CANDLE) syndrome,exhibiting
full scalp hair regrowth after 9 months.26
Up to now, there are only a few case reports and 4open-label
studies on the efficacy of JAK inhibitors insevere and recalcitrant
AA. These results seempromising, especially for tofacitinib.
Nevertheless,the high relapse rates upon cessation of
treatmentimply that a maintenance treatment will be neededfor most
of the patients. The efficacy and safety of theJAK inhibitors for
AA should be tested in RCTs,especially because of the nature of the
disease,which includes spontaneous remissions.32,33
http://www.jaad.org
-
Table I. Characteristics of Janus kinase inhibitors that are
most commonly studied for the treatment ofdermatologic diseases
Agent/trade name Targeted JAK Manufacturer FDA-approved
indication Tested dermatologic diseases*
Tofacitinib/Xeljanz JAK1/3 Pfizer Rheumatoid arthritis Psoriasis
(topical and oral), psoriatic arthritis,alopecia areata, atopic
dermatitis (onlytopical), and systemic lupuserythematosus
Ruxolitinib/Jakafi JAK1/2 Incyte/Novartis Myelofibrosis
andpolycythemia vera
Psoriasis (only topical), alopecia areata(topical and oral),
vitiligo (only topical),and GVHD
Baricitinib JAK1/2 Incyte/Eli Lilly d Psoriasis, atopic
dermatitis, GVHD, systemiclupus erythematosus, CANDLE, JDM,
andSAVI
CANDLE, Chronic atypical neutrophilic dermatosis with
lipodystrophy and elevated temperature; FDA, US Food and Drug
Administration;
GVHD, graft versus host disease; JDM, juvenile dermatomyositis;
SAVI, stimulator of interferon geneseassociated vasculopathy with
onset
during infancy.
*Refers to oral treatment, unless mentioned otherwise.
Fig 1. Search methodology and results of the literature review
on Janus kinase inhibitors indermatologic diseases.
J AM ACAD DERMATOLAPRIL 2017
748 Shreberk-Hassidim, Ramot, and Zlotogorski
Other dermatologic diseasesJAK inhibitors are being tested for
several other
inflammatory or immunologic chronic skin disorders(Table IV;
available at http://www.jaad.org). Theimpact of JAK inhibitors on
dermatitis and chroniccutaneous inflammation was evaluated in 7
preclin-ical studies, exhibiting anti-inflammatory effects
andcutaneous improvement.34-39
Two case reports describe the use of JAK in-hibitors in
vitiligo, including 5 mg daily tofacitinib40
and 20 mg twice daily ruxolitinib,41 resulting inrepigmentation
after several weeks. Followingtreatment cessation, however,
regression wasobserved.
Atopic dermatitis is the only dermatologic diseaseother than
psoriasis with a published RCT with JAKinhibitors.42 This was a
phase 2 study comparingtopical tofacitinib 2% with vehicle, showing
a moresignificant reduction in the area and severity ofeczema in
the tofacitinib group.
http://www.jaad.org
-
Table V. Summary of dermatologic andnondermatologic adverse
events and related dataof Janus kinase inhibitors
Cutaneous Noncutaneous
InfectiousHerpes zoster* Nasopharyngitis*Reactivation of
herpessimplexy66
Upper respiratory tractinfection*
Disseminated molluscumcontagiosumy65
Pulmonarycryptococcosisy58
OtherEruptive squamous cellcarcinomasy69
Gastrointestinal complaints*
DRESS syndromey51 Distal symmetricpolyneuropathyy62
Drug eruptiony67 Laboratory abnormalitiesDose-dependent
decreasein hemoglobin levels,RBCs, and neutrophilcounts61
Dose-dependent increase inCPK, HDL, LDL, and totalcholesterol
levels64
CPK, Creatine kinase; DRESS, drug reaction with eosinophilia
and
systemic symptoms; HDL, high-density lipoprotein; LDL, low-
density lipoprotein; RBC, red blood cell.
*In multiple randomized control trials, as described in Table
II.yIn only 1 case report.
J AM ACAD DERMATOLVOLUME 76, NUMBER 4
Shreberk-Hassidim, Ramot, and Zlotogorski 749
A positive effect on the acute GVHD process andsurvival was
observed in 5 studies using JAK in-hibitors in murine models of
GVHD, with preserva-tion of the graft versus tumor effect.43-47
Ruxolitinibtreatment was reported in 106
steroid-recalcitrantpatients with acute or chronic GVHD (in 4
differentstudies), at doses of 5 to 10 mg once or twice
daily.Improved survival and relapse rates were shown in[80% of the
patients.48-51
Treatment of chronic mucocutaneous candidiasis,dermatomyositis,
stimulator of interferon geneseas-sociated vasculopathy with onset
in infancy and LEwith JAK inhibitors was found to be beneficial
inseveral case reports. Interim analysis of a RCT on theuse of the
selective JAK1 inhibitor GSK2586184 insystemic LE patients showed
ineffectiveness, whichled to the cessation of the study.52 The use
of JAKinhibitors in cutaneous T cell lymphoma and S�ezarysyndrome
was examined only experimentally in6 preclinical studies using
different agents.53-58
Inhibition of STAT3 or STAT5 in malignant cells wasdemonstrated,
thereby decreasing their growth.
Adverse eventsTwelve studies concentrated on adverse events
with the use of JAK inhibitors (and not their efficacy).
These studies included 1 systematic review, 4 RCTs,and 7 case
reports. We divided the side effects of JAKinhibitors into
cutaneous and noncutaneous groups(Table V).
Noncutaneous. Data for noncutaneous side ef-fects are based on
AEs reported in the RCTs shown inTable II. In 1 patient treated
with tofacitinib forpsoriasis, a pulmonary cryptococcosis was
re-ported.59 No cases of reactivation of tuberculosiswere found in
a systematic review of 5 RCTs withtofacitinib.60 In addition,
changes in cytomegalo-virus or EpsteineBarr virus viral load did
not haveany clinical significance with tofacitinib treatment.61
As part of a RCTon tofacitinib in psoriasis patients,
itsinfluence on hematologic values was evaluated.Hemoglobin levels,
red blood cells, and neutrophiland eosinophil counts were reduced
in a dose-dependent manner, and were reversible after thetreatment
was stopped.62 Distal symmetric polyneur-opathy was reported in 1
patient with psoriasis whowas treated with tofacitinib.63 Pregnancy
outcomes,which were analyzed in patients with RA or psoriasiswho
were treated with tofacitinib, were similar tothose in the general
population and patients treatedwith biologic therapies.64
Cardiovascular risk factorsand outcomes were evaluated for patients
withpsoriasis who were treated with tofacitinib andcompared to
placebo. While laboratory levels oflipids were elevated, no change
was observed in theratio between total cholesterol/high-density
lipopro-tein cholesterol, in addition to unaffected values ofblood
pressure. In addition, the risk of major adversecardiovascular
events in the treatment group was notelevated.65
Cutaneous. Dermatologic infections, includingdisseminated
molluscum contagiosum66 and reacti-vation of herpes simplex
virus,67 were reported inpatients treated with ruxolitinib. One
case of drugeruption was attributed to ruxolitinib,68 while
severedrug eruptions were described in 2 patients withsystemic LE
who were treated with GSK2586184.52,69
No cases of malignancies were reported, except for 1case of
eruptive squamous cell carcinomas in apatient with myelofibrosis
treated with ruxolitinib.70
DISCUSSIONJAK inhibitors are emerging as an exciting new
treatment modality in the field of dermatology. Thisis reflected
by the constant increase in the data on theuse of these medications
in dermatology. Here, wesystematically reviewed the available
literature onthe potential uses of this family of inhibitors
indermatology. A metaanalysis could not be per-formed because of
the paucity of RCTs and the lackof proper standardization of the
other studies.
-
J AM ACAD DERMATOLAPRIL 2017
750 Shreberk-Hassidim, Ramot, and Zlotogorski
This review shows that promising results, whichwere assessed by
RCTs, have been reported inpatients with psoriasis and PsA. AA is
another con-dition for which there are encouraging results,although
more clinical trials are needed to ascertainthese promising
effects. For the other indications forwhich JAK inhibitors were
tested, the improvementof cutaneous responsewas rapid (of several
weeks insome diseases), especially in the chronic
systemicinflammatory diseases, such as GVHD and dermato-myositis.
The agents and dosages that were reportedare similar to those
approved by the FDA formyelofibrosis (ruxolitinib) and RA
(tofacitinib),probably because of a lack of data on other
dosages.The promising results achieved in preliminarystudies
performed on patients with cutaneous Tcell lymphoma and S�ezary
syndrome (describedpreviously) prompt the exploration of these
medi-cation in future clinical trials.
Side effects that are associated with JAK inhibitorsare an
additional hurdle that must be taken intoaccount. This is
especially true when considering theuse of higher doses of these
medications, which arenot approved for other indications, and
therefore thesafety data are still limited. Because of these
safetyconcerns, the FDA rejected last year a supplementalnew drug
application by Pfizer (New York, NY) forthe use of tofacitinib in
psoriasis. Long-term safetydata with tofacitinib, together with
additional clinicaltrials with these compounds, will increase
theamount of information on possible adverse effects,and can help
the dermatologist decide whether ornot to start these
medications.
Taken together, studies to date on JAK inhibitorsshow that they
hold promise as a new treatmentmodality for a variety of skin
disorders. Concernsabout their safety, together with their high
cost, maylimit their use. Based on the promising results so farand
the large number of ongoing clinical trials,however, it is likely
that JAK inhibitors will becomean important part of the
dermatologist’s treatmentarmamentarium in the future.
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Table II. Summary of original clinical studies on the use of
Janus kinase inhibitors in psoriasis and psoriatic arthritis
Reference/
year
Type of study/
comparison
No. of
patients Agent Dosage/duration Type of psoriasis
Assessment
scores used Description of efficacy AEs
Boyet al13/2009
Phase 1 RCT/placebo
59 Tofacitinib 5, 10, 20, 30, 50 mgtwice daily and60 mg
oncedaily/14 days
Plaque LSM ofpercentagechange in PLSSscore
Dose-dependentimprovement for alldosages (from �47%to
�71.8%),excluding 5 mg twicedaily (�27.5%) andplacebo (�11.5%)
Mild AEs includedheadache andnausea. Serious AEsincluded mild
atrialfibrillation, mostprobably not relatedto treatment
Punwaniet al22
/2012
Phase 2 RCT/vehicle,calcipotrieneandbetamethasone
57 Ruxolitinib(topical)
0.5%, 1% oncedaily and 1.5%twice daily/28 days
Limited plaque Percentagechange inlesion score;scored on ascale
of 0-4 forerythema,scaling, andthickness
Major decrease inlesion score wasobserved using the1.5% cream
twicedaily (54%) or 1%cream once daily(53%) in comparisonwith
0.5%,calcipotriene,betamethasone, andvehicle (32%)
No serious AEs
Pappet al71/2012
Phase 2b RCT*/placebo
197 Tofacitinib 2, 5, 15 mg twicedaily/12 weeks
Moderate tosevereplaque
PASI75 For all doses, thePASI75 responserates were higher:2 mg
(25%), 5 mg(40.8%) and 15 mg(66.7%) incomparison withplacebo
(2%)
Infections andinfestations - lower intherapy groupcompared to
theplacebo group.Increase in meanserum HDL, LDL andtotal
cholesterol, anddecrease in hemo-globin and neutro-phils, which
weredose-dependent
Portset al19/2013
Phase 2a RCT/vehicle
71 Tofacitinib(topical)
2% tofacitinibointment 1,vehicle 1, 2%tofacitinibointment 2twice
daily/4 weeks
Mild tomoderateplaque
LSM ofpercentagechange inTPSS
Significant reduction inTPSS for ointment 1(-54.4%) vs vehicle
1(-41.5%), while forointment 2 thisreduction was notobserved
No serious AEs
Menter Phase 2b RCT*/placebo
197 Tofacitinib 2, 5, 15 mg twicedaily/12 weeks
Moderate to LSM ofpercentage
TPSS in responsive andnonresponsive areas
d
Continued
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Table II. Cont’d
Reference/
year
Type of study/
comparison
No. of
patients Agent Dosage/duration Type of psoriasis
Assessment
scores used Description of efficacy AEs
et al72/2014
severeplaque
change inTPSS in 4 bodyregions
improved with alldoses compared toplacebo
Mamoloet al73/2014
Phase 2b RCT*/placebo
197 Tofacitinib 2, 5 or 15 mg twicedaily/12 weeks
Moderate tosevereplaque
Patient-reportedoutcomes asDLQI, ISS, SF-36, PDA, PtGA,and PSSM
item
For all doses, animprovement inpatient-reportedoutcomes
wasobserved, incomparison toplacebo
d
Punwaniet al23/2015
Open-labelsequential-cohort
25 Ruxolitinib(topical)
1.5% cream twicedaily to 2-7%BSA; 1.5% creamtwice daily to 8-13%
BSA; 1.5%cream oncedaily to 14-20%BSA; 1.0% creamtwice daily
to14-20% BSA;and 1.5% creamtwice daily to14-20% BSA/4 weeks
Plaque Percentagechange inlesion score (asin Punwaniet al22)
All cream concentrationgiven 1-2 times
dailywerepharmacologicallyactive and showedclinical improvementwith
decreasedlesionalinflammatorymarkers
No serious AEs. Plasmaconcentration ofruxolitinib wasmeasured
low
Bushmakinet al74/2015
Phase 2b RCT*/placebo
197 Tofacitinib 2, 5 or 15 mg twicedaily/12 weeks
Moderate tosevereplaque
PGA and ISS The effect of tofacitinibon pruritus was 70.2-80.5%,
and it wasindependent ofimprovements inerythema,induration,
andscaling
d
Mamoloet al75/2015
Phase 2b RCT*/placebo
197 Tofacitinib 2, 5 or 15 mg twicedaily/12 weeks
Moderate tosevereplaque
ISS In comparison toplacebo, tofacitinibimproves pruritus.This
effect, showing[30% improvementin pruritus, washighest
amongpatients receiving15 mg twice daily
d
Continued
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Table II. Cont’d
Reference/
year
Type of study/
comparison
No. of
patients Agent Dosage/duration Type of psoriasis
Assessment
scores used Description of efficacy AEs
Pappet al14/2015
Two phase 3RCTsy/placebo
1861 Tofacitinib 5, 10 mg twicedaily/16 weeks
Moderate tosevereplaque
Clear/almostclear PGA andPASI75
The improvement inthe PGA responsewas significant inboth RCTs,
of 41.9-46% in 5 mg and59.2-59.1% in 10 mgdosage. In both RCTs,the
PASI75 rateswere greater thanthe placebo group asfollows: 5 mg
(39.9-46%) and 10 mg(59.2-59.6%)
There was no differencein AEs betweentreatment vs placebogroups.
There were12 patients with her-pes zoster in thetreatment
groupwithout similar re-ports in the placebogroup. Nasopharyng-itis
was the mostcommon AE in allpatients
Bissonnetteet al16/2015
Phase 3 RCTz/placebo
666 Tofacitinib 5, 10 mg twicedaily/24 weeks/ randomizedfor
tofacitinib orplacebo at thesame dosages/until relapse or40 weeks
/initial dose/16 weeks
Moderate tosevereplaque
Clear/almostclear PGA andPASI75
After 24 weeks, 33.5-55.2% of patients ineach treatmentgroup
that achievedclinical responsewere randomized forwithdrawal.
ThePASI75 rate was56.2% and 62.3% for5 and 10 mg
doses,respectively, incomparison with23.3% and 26.1%
ofmatching-doseplacebo duringwithdrawal. After16 weeks
ofretreatment, 48%and 72% regainedPASI75 responsewith tofacitinib 5
and10 mg doses. Amongpatients whocontinued tofacitinib,the median
PASIscores weremaintained for56 weeks
Most common AEswere infections andinfestations as
naso-pharyngitis, with nodifference betweenthe groups. Othercommon
AEs weregastrointestinal com-plaints. Elevation inLDL levels
followinginitial treatment,which return tobaseline
followingwithdrawal
Continued
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Table II. Cont’d
Reference/
year
Type of study/
comparison
No. of
patients Agent Dosage/duration Type of psoriasis
Assessment
scores used Description of efficacy AEs
Bachelezet al17/2015
Phase 3 RCTx/etanerceptand placebo
1106 Tofacitinib 5, 10 mg twicedaily/12 weeks
Moderate tosevereplaque
Clear/almostclear PGA andPASI75
PASI75 responses were39.5% (5 mg), 63.6%(10 mg) fortofacitinib
treatmentand 58.8% foretanercepttreatment, and only5.6% for
placebo.Similar percentageswere shown for thePGA score
There was no differencein AEs betweentreatment vs placebogroups.
There were 5patients with herpeszoster in treatmentgroup (3
withtofacitinib and 2 withetanercept) andnone in the
placebo.Dose-dependentelevations in HDL,LDL, and CPK wereobserved
in thetofacitinib group,with a decrease inhemoglobin levels
Portset al20/2015
Phase 2intrasubjectRCT/vehicleappliedon contralateralplaques
81 Tofacitinib(topical)
2%, 0.2%, 0.02%solution/4 weeks
Plaque Meanpercentagechange inTPSS
Treatment and vehicleplaques exhibitedsimilar results
No serious AEs
Pappet al76/2016
Phase 2b RCT/placebo
271 Baricitinib 2, 4, 8, 10 mg oncedaily/12 weeks/
doseadjustmentaccording toPASI score/12 weeks
Moderate tosevereplaque
PASI All dosages ofbaricitinib, except2 mg, demonstratedhigher
mean changein PASI scorecompared toplacebo. During theadditional 12
weekstreatment for PASI75responders[80%preserved theirresponse
Most common AEswere infections andinfestations
asnasopharyngitis, withno differencebetween the groups.Laboratory
changesincluded mildelevations in HDL,LDL, creatinine levels,mild
decrease inneutrophils, andhemoglobin anddose-dependentincrease in
CPK
Pappet al77/2016
Two phase 3 RCTsy
long-termextension
1861 Tofacitinib 5, 10 mg twicedaily/16 weeks/ 10 mg twice
Moderate tosevereplaque
Clear/almostclear PGA andPASI75
PASI75 was achieved in55.6%, and 68.8% ofpatients treated
with
Nasopharyngitis wasthe most commonAE. Serious
Continued
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Table II. Cont’d
Reference/
year
Type of study/
comparison
No. of
patients Agent Dosage/duration Type of psoriasis
Assessment
scores used Description of efficacy AEs
daily/3 months/ 5, 10 mgtwice daily/28 weeks
5 or 10 mg tofacitinibfor 28 weeks,respectively. PASI75and PGA
scores weremaintained for12 months in[75%of responders and inabout
60% for24 months
infections, herpeszoster, and NMSCshowed dose-dependent
manner
Asahinaet al18/2016
Phase 3 RCT 95 Tofacitinib 5, 10 mg twicedaily/16 weeks/ 10 mg
twicedaily/4 weeks/ 5, 10 mgtwice daily/52 weeks
Moderate tosevereplaque andPsA
Clear/almostclear PGA,PASI75, andACR20
PASI75 was achieved asfollows: 62.8% (5 mg)and 72.7% (10
mg)after 16 weeks oftreatment. Similarresults were shownfor PGA,
and allpatients with PsAachieved ACR20. At52 weeks, theseresponse
rates weremaintained
Serious AEs in 4.3%,including severeherpes zoster andvertigo
Kruegeret al78/2016
Phase 2 RCT/placebo
12 Tofacitinib 10 mg twice daily/12 weeks
Moderate tosevereplaque
Histopathologicresponse,PASI, andTPSS
Histologic changes intreated plaquesincluded inhibitionof the
JAK-STATpathways withreducedcytokines, lowernumbers of DC andT
cells, anddecreasedIL-23/Th17 activity.The clinicalimprovement
inPASI and TPSS scoreswas correlated withchanges in
psoriasis-related genes
No seriousAEs in thetreatmentgroup
Menteret al79/2016
Two phase 3RCTsy/placebo
1843 Tofacitinib 5, 10 mg twicedaily/16 weeks
Moderate tosevereplaque
Clear/almostclear PGA and
Efficacy of tofacitinibwas shown in allsubgroups, with
d
Continued
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Table II. Cont’d
Reference/
year
Type of study/
comparison
No. of
patients Agent Dosage/duration Type of psoriasis
Assessment
scores used Description of efficacy AEs
PASI75 insubgroups
higher improvementusing the 10-mgdosage. Increasedweight and
priorbiologic treatmentwere associated withlower response rates
Valenzuelaet al80/2016
Phase 3 RCTx/etanerceptand placebo
1101 Tofacitinib 5, 10 mg twicedaily/12 weeks
Moderate tosevereplaque
Patient-reportedoutcomes,includingDLQI, ISS, andPtGA
Improvement of DLQIscore showed similarrates betweentofacitinib
10 mg andetanercept of 47.3%and 43.6%,respectively. Itch
wassignificantly reducedby tofacitinibcompared withetanercept
andplacebo
d
Tanet al81/2016
Two phase 3RCTsy/placebo
1329 Tofacitinib 5, 10 mg twicedaily/16 weeks
Moderate tosevereplaque
PASI Improvement of 50% inPASI at week 8 oftreatment maypredict
reachingPASI75 at week 16
d
Griffithset al82/2016
Phase 3 RCTz/placebo
666 Tofacitinib 5, 10 mg twicedaily/24 weeks/ randomizedfor
tofacitinib orplacebo at thesame dosages/until relapse or40 weeks
/initial dose/16 weeks
Moderate tosevereplaque
Patient-reportedoutcomesincludingDLQI, ISS,SF-36, andPtGA
All patient-reportedoutcomes weresignificantlyimproved during
theinitial treatment.They worsenedduring withdrawal,but
recoveredfollowingretreatment. Whentofacitinib was
givencontinuously, theimprovement wasmaintained for56 weeks
d
Feldmanet al15/2016
Two phase 3RCTsy/placebo
1861 Tofacitinib 5, 10 mg twicedaily/16 weeks/
Moderate tosevereplaque
Patient-reportedoutcomesincluding
All patient-reportedoutcomes weresignificantly
d
Continued
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Table II. Cont’d
Reference/
year
Type of study/
comparison
No. of
patients Agent Dosage/duration Type of psoriasis
Assessment
scores used Description of efficacy AEs
rerandomizationof placebogroup fortofacitinibtreatment/28 weeks
ifthere was noresponse or52 weeks
DLQI, ISS,PtGA, and JPA
improved in patientsreceiving tofacitinibin comparison
withplacebo. The greatereffect was observedfor the 10-mgdosage.
Theresponse wasmaintained for52 weeks
Pappet al21/2016
Phase 2b RCT/vehicle
435 Tofacitinib(topical)
2% and 1%ointments onceor twice daily/12 weeks
Mild tomoderateplaque
PGA, PASI75, ISS,and DLQI
After 8 weeks, responserate of ‘‘clear’’ or‘‘almost clear’’
PGAwas 18.6 % and 8.1 %
for 2 % tofacitinib andvehicle given oncedaily and
22.5 % and 11.3 % for 2% tofacitinib andvehicle given
twicedaily. This differencewas significant, whileafter 12 weeks
nosignificantlydifference wasobserved betweentofacitinib
ointmentsand vehicles
AE rate was highest inpatients treatedwith vehicle oncedaily.
The mostcommon AE wasnasopharyngitis.
There were not soserious AE in the 2%tofacitinib group.
Application site AEwere mainly psoriasisand pruritus
ACR20, American College of Rheumatology Criteria; AE, adverse
event; BSA, body surface area; CPK, creatine phosphokinase; DLQI,
Dermatology Life Quality Index; HDL, high-density lipoprotein;
ISS,
Itch Severity Score; JPA, joint pain assessment; LDL,
low-density lipoprotein; LSM, least squares mean; NMSC, nonmelanoma
skin cancer; PASI, Psoriasis Area Severity Index; PDA,
pain/discomfort
assessment; PGA, physician’s global assessment; PtGA, patient
global assessment; PLSS, psoriatic lesion severity sum; PsA,
psoriatic arthritis; PSSM, patient satisfaction with study
medication; RCT,
randomized controlled trial; SF-36, Short Form-36 questionnaire;
TPSS, Target Plaque Severity Score.
*Studies based on the same clinical trial, which was initially
described by Papp et al.71
yStudies based on the same clinical trial, which was initially
described by Papp et al.14zStudies based on the same clinical
trial, which was initially described by Bissonnette et
al.16xStudies based on the same clinical trial, which was initially
described by Bachelez et al.17
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Table III. Summary of original clinical studies on the use of
Janus kinase inhibitors in patients with alopecia areata
Reference/year No. of patients Sex/age (y) Agent Dosage/duration
Type of AA Description of efficacy AEs
Craiglow andKing83/2014
1 M/25 Tofacitinib 5 mg twice daily/2 months /10 mg with5 mg
once daily/8 months
AU (therapy wasgiven forpsoriasis)
Partial hair regrowth on the scalpand face was observed after2
months of therapy. Fullregrowth at all body regionswas observed
after 8 months oftherapy
No AEs or laboratoryabnormalities
Xing etal25/2014*
3 d Ruxolitinib 20 mg twice daily/5 months
Moderate tosevere AA
All patients showed nearlycomplete hair regrowth after3-5 months
of treatment
d
Craiglowet al31/2015
1 F/late teens Ruxolitinib(topical)
0.6% cream twicedaily/12 weeks
AU There was complete regrowth ofeyebrows hair and 10% of
scalphair after 12 weeks of treatment
No AEs or laboratoryabnormalities,except slightgradual WBC
countdecrease
Pieriet al84/2015
1 F/24 Ruxolitinib 15 mg twice daily/71 months
AU (therapy wasgiven for ET)
Nearly complete hair regrowthafter 10 months of treatment,with
maintenance of theresponse for the followingmonths
No AEs or laboratoryabnormalities
Dhayalanand King85/2015
3 M/20sF/40sM/20s
Tofacitinib 5 mg twice daily or10 mg with5 mg once daily/5-6
months
AU withdystrophic nailchanges
Hair regrowth was observed in 2patients (66%). In all
patients,there was improvement of nailchanges after 5-6 months
oftreatment
No AEs or laboratoryabnormalities
Jabbariet al26/2015y
1 F/17 Baricitinib 7 mg once daily/6 months /7 mg with 4 mgonce
daily/12 months
Long-standingpatchyAA (therapy wasgiven forCANDLE)
Regrowth was exhibited after3 months in all patches, exceptone
occipital patch. In thispatch, there was graduallyregrowth in the
following9 months. The response wasmaintained during the
therapyperiod
d
Guptaet al86/2016
2 M/42M/unknown
Tofacitinib 5 mg twice daily/8 months
AU In both patients, the maximal hairregrowth was
observedfollowing 8 months oftreatment. In 1 patient, therapywas
continued for 2 years
Viral infection andcomplaints offatigue in 1 patientled to a
temporarydiscontinuation oftherapy for1 month
Continued
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Table III. Cont’d
Reference/year No. of patients Sex/age (y) Agent Dosage/duration
Type of AA Description of efficacy AEs
Jabbariet al87/2016
1 F/40 Tofacitinib 5 mg twice daily/4 months
Moderate tosevere patchyAA
Regrowth of 94% was shown after3 months. Cessation oftreatment
resulted in relapse ofhair loss. Serum and lesionalinflammatory
markers weredecreased after 4 weeks oftreatment
No AEs or laboratoryabnormalities
Anzengruberet al88/2016
1 M/51 Tofacitinib 5 mg twice daily/4 months
AU Growth of short terminalpigmented hair was noticed onthe
scalp after 3 months. Hairloss relapsed after anothermonth. This
patient was treatedat the same time withmethotrexate at 15 mg
perweek
d
Mrowietzet al89/2016
1 F/20 Tofacitinib 15 mg once daily/6 weeks /10 mg oncedaily/9
months
AU, psoriasis, andPsA
Significant scalp hair regrowth wasobserved after 4 weeks
withresolution of dactylitis. Psoriaticskin lesions were not
affected.There was no effect oftofacitinib on psoriasis lesions
Herpes zoster
Mackay-Wigganet al30/2016
12 d Ruxolitinib 20 mg twice daily/3-6 months
Moderate tosevere AA
Seventy-five percentage ofpatients showed average hairregrowth
of 92% at the end oftreatment
No serious AEs
Crispinet al27/2016
66 d Tofacitinib 5 mg twice daily/3 months
AA with[50%scalp hair loss,AT, and AU
Improvement of 50% or greater inSALT score was observed in 32%of
patients. Changes in SALTscore were more significant inmultifocal
AA and ophiasis AAvs AT or AU. Relapse occurredafter a median of
8.5 weeksfollowing drug cessation
Most common AEswere infections,mainly upperrespiratory
tractinfections
Liuet al28/2016
90 d Tofacitinib 5 mg twice daily/4-18 months
AA with[40%scalp hair loss,AT, and AU
Improvement of $50% in SALTscore was observed in 42% ofpatients.
Improvement rateswere higher in patients with AAvs AT and AU
No serious AEs. Mostcommon AEs wereupper respiratorytract
infections,affecting 29% ofpatients
Continued
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Table III. Cont’d
Reference/year No. of patients Sex/age (y) Agent Dosage/duration
Type of AA Description of efficacy AEs
Craiglow et al29/2016 13 d Tofacitinib 5 mg twice daily/2-16
months
AA, AT, and AU inadolescents
Nine patients responded totherapy with 100% change inSALT
score
No serious AEs. MildAEs includedheadaches,
upperrespiratoryinfections, and mildincreases in livertransaminase
levels
AA, Alopecia areata; AE, adverse event; AT, alopecia totalis;
AU, alopecia universalis; CANDLE, chronic atypical neutrophilic
dermatosis with lipodystrophy and elevated temperature; ET,
essential
thrombocytosis; SALT, Severity of Alopecia Tool; WBC, white
blood cell.
*This study included AA murine model experiments as well,
demonstrating hair growth in all topically or systemically
ruxolitinib and tofacitinib-treated mice.yThis study included AA
murine model experiments as well, demonstrating hair growth in all
topically or systemically baricitinib-treated mice, in comparison
with vehicle.
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Table IV. Summary of original clinical studies on the use of
Janus kinase inhibitors in other dermatologic diseases (not
including psoriasis or alopecia areata)
Reference/year No. of patients Sex/age (y) Agent Dosage/duration
Description of efficacy AEs
VitiligoCraiglow andKing40/2015
1 F/50 Tofacitinib 5 mg every other day/3 weeks / 5 mgonce
daily/5 months
Nearly complete repigmentation of theforehead and hands, with
only 5% of totalBSA remaining depigmented
No AEs or laboratoryabnormalities
Harris et al41/2016
1 M/35 Ruxolitinib 20 mg twice daily/20 weeks
A patient with AA and vitiligo. Majorimprovement in AA and
vitiligo wasobserved after 12 weeks of treatment.However, 12 weeks
after cessation oftreatment there was regression of
therepigmentation
d
Atopic dermatitisLevy et al90/2015
6 F/24F/55F/42F/55M/32M/18
Tofacitinib 5 mg twice daily (5patients) and 5 mgonce daily
(1patient)/29 weeks
For all patients, there was a decrease in theBSA of rash and
decreased pruritus. After29 weeks, the SCORAD index
decreasedgradually to12.2%
No AEs or laboratoryabnormalities
Bissonnetteet al42/2016
69 d Tofacitinib -topical
2% tofacitinib orvehicle ointmenttwice daily/4 weeks
The reduction in EASI was 81% in thetofacitinib group in
comparison to 30% inthe vehicle group. After 2 days oftreatment,
improvement in pruritus wasshown
The most commonAEs were mildinfections,
mainlynasopharyngitis.Local AEs weremore common inthe vehicle
groupand includedmainly contactdermatitis
Graft versus host diseaseSpoerl et al50/2014*
6 4 acute,2 chronic
Ruxolitinib 5 mg twice daily/3 days / 10 mgtwice daily
Skin involvement in acute or chronic GVHDwas improved in all
patients, exhibitingresponse after 1-1.5 weeks
No AEs or laboratoryabnormalities
Continued
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Table IV. Cont’d
Reference/year No. of patients Sex/age (y) Agent Dosage/duration
Description of efficacy AEs
Zeiser et al51/2015
95 54 acute,41 chronic
Ruxolitinib 5-10 mg twice daily The response rate was 81.5%
within amedian time of 1.5 weeks for acute GVHDand 85.5% for
chronic GVHD within3 weeks. In addition, decreased relapserates and
longer survival were observed
AEs included CMVreactivation, mildand severecytopenias,
andrelapse of theunderlyingmalignancy, all ofwhich were higherin
acute GVHDpatients
Mori et al49/2016
4 1 acute,3 chronic
Ruxolitinib 5-10 mg once daily In 2 patients with chronic
disease, a maintenance dose of 5 mg oncedaily was effective and
prevented GVHD for long periodsdup to14 months. One patient with
acute disease was treated with 10mgonce daily but developed severe
cytopenia which required gradualtapering of ruxolitinib. A patient
with chronic disease hadgastrointestinal bleeding shortly after 10
mg once daily treatmentinitiation which required therapy
discontinuation, with resultantrebound of GVHD
Maffini et al48/2016
1 Acute Ruxolitinib 5 mg twice daily/123 days
51-year-old man with acute GVHD refractorycorticosteroids
started treatment withruxolitinib on day 33 following
HSCT.Impro