Janus kinase inhibitors in dermatology: A systematic...

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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

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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.



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.



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.



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

JAM

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erk-Hassid

im,Ramot,andZlotogorski

Table II. Cont’d

Reference/

year

Type of study/

comparison

No. of


Assessment


et al72/2014

severeplaque

change inTPSS in 4 bodyregions

improved with alldoses compared toplacebo

Mamoloet al73/2014


197 Tofacitinib 2, 5 or 15 mg twicedaily/12 weeks


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




PGA and ISS The effect of tofacitinibon pruritus was 70.2-80.5%, and it wasindependent ofimprovements inerythema,induration, andscaling

d

Mamoloet al75/2015




ISS In comparison toplacebo, tofacitinibimproves pruritus.This effect, showing[30% improvementin pruritus, washighest amongpatients receiving15 mg twice daily

d

Continued

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753.e2

Table II. Cont’d

Reference/

year

Type of study/

comparison

No. of


Assessment


Pappet al14/2015

Two phase 3RCTsy/placebo

1861 Tofacitinib 5, 10 mg twicedaily/16 weeks


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



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


Assessment


Bachelezet al17/2015

Phase 3 RCTx/etanerceptand placebo




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


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


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



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


Assessment


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


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




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


Assessment


PASI75 insubgroups

higher improvementusing the 10-mgdosage. Increasedweight and priorbiologic treatmentwere associated withlower response rates

Valenzuelaet al80/2016

Phase 3 RCTx/etanerceptand placebo



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




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


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


1861 Tofacitinib 5, 10 mg twicedaily/16 weeks/


Patient-reportedoutcomesincluding

All patient-reportedoutcomes weresignificantly

d

Continued

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Table II. Cont’d

Reference/

year

Type of study/

comparison

No. of


Assessment


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


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


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


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


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


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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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


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%


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


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

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