Partial repigmentation of vitiligo with tofacitinib, without exposure to ultraviolet radiation,

AnBrasDermatol.2020;95(4):473---476

Anais

Brasileiros

de

Dermatologia

CASE

REPORT

Partial

repigmentation

of

vitiligo

with

tofacitinib,

without

exposure

to

ultraviolet

radiation

夽,夽夽

Melpone

Komnitski

_,

_Angelo

_Komnitski

_,

_Amilton

_Komnitski

_Junior

_,

Caio

César

Silva

de

Castro

a_{SchoolofMedicine,PontifíciaUniversidadeCatólicadoParaná,Curitiba,PR,Brazil} b_{SchoolofMedicine,UniversidadedoValedoItajaí,Itajaí,SC,Brazil}

c_{PrivateRheumatologyClinic,Curitiba,PR,Brazil}

d_{DepartmentofDermatology,FaculdadedeMedicina,PontifíciaUniversidadeCatólicadoParaná,Curitiba,PR,Brazil}

Received12March2019;accepted18August2019

Availableonline5May2020

KEYWORDS

Januskinases; Phototherapy; Vitiligo

Abstract Vitiligoisadiseasethatcausesmaculesandachromicand/orhypochromicpatches,

whichcanaffectfromsmallareastotheentiretegument.Treatmentoptionsarefewandare

generallyineffective.Recently,somecasereportshaveappearedwhichshowpositiveresults

withtheuseofJanuskinaseinhibitorsassociatedwithphototherapy.Thisreportdetailsthe

caseofapatientwithrheumatoidarthritisassociatedwithvitiligointreatmentfortwoyears,

whoseconditionpartiallyimprovedinitiallyaftereightmonthsoforaltofacitinibatadoseof

5mgtwiceaday,withoutexposuretoultravioletradiationandwithcontinuousimprovement

duringthesetwoyearsoftreatment.

©2020SociedadeBrasileira deDermatologia.PublishedbyElsevierEspa˜na,S.L.U.Thisisan

openaccessarticleundertheCCBYlicense(http://creativecommons.org/licenses/by/4.0/).

夽 _{Howto citethisarticle: KomnitskiM,KomnitskiA, Komnitski}

JuniorA,CastroCCS.Partialrepigmentationofvitiligowith tofaci-tinib,withoutexposuretoultravioletradiation.AnBrasDermatol. 2020;95:473---6.

夽夽_{StudyconductedatthePrivateRheumatologyClinic,Curitiba,}

PR,Brazil.

∗_{Correspondingauthor.}

E-mail:melki12@globo.com(M.Komnitski).

Introduction

Vitiligo is a chronic autoimmune disease which affects around0.5% of the population.1 _{It presents withmacules}

and achromic and/or hypochromic patcheson any region of the body. It is a condition that has triggering factors, suchasburnsandemotional stress, inadditiontogenetic predisposition. Treatment is performed with topical and systemic corticosteroids, calcineurin inhibitors, and pho-totherapywithnarrowbandultraviolet(UV)Bradiationand phototherapywithUVAassociatedwithpsoralen.However,

https://doi.org/10.1016/j.abd.2019.08.032

0365-0596/©2020SociedadeBrasileiradeDermatologia.PublishedbyElsevierEspa˜na,S.L.U.ThisisanopenaccessarticleundertheCC BYlicense(http://creativecommons.org/licenses/by/4.0/).

474 KomnitskiMetal.

Figure1 Patient’shandsunderWood’slamp.(A)Priortotreatment,variouswhitemaculesonbothhands.(B)Aftertwoyearsof

treatment,repigmentationimprovementisnotedonbothhands.

Figure2 (AandB)Priortotreatment,whitemaculesallovertheface.(C)Aftertwoyearsoftreatment,completerepigmentation

oftheforeheadandperilabialmaculesisobserved,aswellasanimprovementoftherestoftheface.

these treatments have limited efficacy.2 _{Several articles}

haveshownthatblockingtheJanuskinase/signal transduc-ersandactivatorsoftranscription(JAK-STAT)pathwaywith tofacitinibmayproducerepigmentation,providedfrequent exposurestothesunorphototherapy.3

Case

report

A 40-year-old female patient with comorbid rheumatoid arthritisandvitiligo. Herbrotherandmotherhavea posi-tivehistoryforvitiligo.Thevitiligoconditionstartedin2012, withhypochromicandachromicmaculesintheleftinguinal region.

In the same year, she sought medical attention. Pho-totherapy with narrow band ultraviolet B radiation and systemiccorticosteroidmini-pulsewasperformed. Atthat time,shereportedpartialimprovementforafewmonths,

but other lesions began to appear on her face, neck, elbows, hands, and feet, diagnosed as common vitiligo. She stoppedphototherapy treatment in 2013because she sawlittleimprovement,andhadnodermatological mainte-nancetreatment.In2014,jointpainsinherhandsstarted andshereceivedadiagnosisofrheumatoidarthritis.Some previoustreatmentswerereinstated,suchas hydroxychloro-quine, deflazacort,and loxoprofen,but theydidnot lead toremissionofthearthritis.In2017,anewtreatmentwas introduced totreat therheumatologic conditionwithonly tofacitinib5mg,twiceaday,whichobtainedasatisfactory result.Coincidentally,aftereightmonthsofmedicationuse, thepatientnotedimprovementofthemaculesandpatches, with formation of several islets of repigmentation in the hands and face, without being exposed to any source of ultravioletradiation,sincethepatientusesintense photo-protection with sunscreens, rarely exposes herself to the sun, and did not take any trips to the beach during this

Partialrepigmentationofvitiligowithtofacitinib,withoutexposuretoultravioletradiation 475

Figure3 (A)Priortotreatment,variouswhitemacules.(B)Aftertwoyearsoftreatment,repigmentationimprovementisnoted.

Figure4 (A)Priortotreatment,numerouswhitemacules.(B)Aftertwoyearsoftreatment,repigmentationisnearlycomplete.

timeoftreatmentsoasnottoexacerbatethevitiligo.After two years,complete repigmentationof the forehead and perilabialmaculescanbenoted,aswellaspartial repigmen-tationintheposterior regionof theneckandupperchest whilethepatientisstillbeingtreatedwithtofacitinib.

Discussion

Thepathophysiologyofvitiligohasstillnotbeenfully elu-cidated, but it is believed that theIFN-␥ and theCD8+ _T

cells playakeyroleinthe destructionof melanocytes.2---4

Evidence shows that the CD8+ _{T lymphocytes produce}

IFN-␥, which will express CXCL9 and CXCL10 chemokines by keratinocytes, resulting in the recruitment of more CD8+ _{T lymphocytes, and resulting in the destruction of}

melanocytesbyIFN-␥andperforin/granzyme.2

In2013, tofacitinibwasapprovedbythe National Sani-tary SurveillanceAgencyfor the treatment ofrheumatoid arthritisasitactsasaninhibitoroftheJAKkinasefamilyof enzymes,mainlyJAK1andJAK3.3,5_{Assuch,itinterruptsthe}

productionofIFN-␣andIFN-␥,andsomeinterleukinssuchas

IL-2andIL-6,decreasingtheinflammatoryresponse.5,6

How-ever,itwasalsoseenthatitwasanalternativeforpatients withvitiligo.

In2015,Craiglowetal.7_{reportedthefirstpossible}

mech-anismof action of tofacitinib on vitiligo, which proposed thatsincethe signaltransduction ofIFN-␥ occursthrough JAK1/2,theuse ofaninhibitorofJAK1/3 could,infact, blockIFN-␥signalling,whichwouldreduceCXCL10 expres-sion,interruptingthevitiligoactivity.Kimetal.,4_inamore

recentcasereport,showedthatinordertohavesatisfactory results,sunexposureor phototherapywould benecessary simultaneouslywithdrugtreatment.

Inaretrospectivestudyoftenvitiligopatientson tofaci-tinib,Liuetal.2_{alsodefendedtheideathattreatmentwith}

theJAKinhibitorwouldrequireexposuretolight.Whatwas proposed is that for repigmentationto occur, two events needtohappen:(1)immunosuppressionofinflammationof theskin,whichisobtainedwiththeuseoftofacitiniband(2) stimulationofmelanocytes,either byexposuretosunlight orthroughnarrowbandUVB.

In the case presented, the patient only used 5mg of tofacitinibtwiceaday,withimprovementinhands(Fig.1),

476 KomnitskiMetal. face(Fig.2),chest(Fig.3),andmainlyinthecervicalregion

(Fig.4)wherethereisnosunexposure.Theseresultsarein contrasttothelatestcasereports,showingthattofacitinib can indeed be effective as monotherapy. It is notewor-thythat,unlikethereportsandstudiesonthesubject,in which theaverage treatment timewas5.38 months,2,4,7,8

thepresentpatientusedthemedicationlong-term, show-ingthat longer treatmentswill probablybe necessary for spontaneousrepigmentationtooccuraftertheautoimmune attack ceases, without the patient being exposed to UV radiationtoaidintherapy.However,studiesoflarger pop-ulationsusing tofacitinibwho areexposed (or not)to UV radiationarenecessary,inordertodemonstratetheactual efficacyofthismedication.

Financial

support

Nonedeclared.

Authors’

contributions

MelponeKomnitski:Draftingandeditingofthemanuscript; criticalreviewoftheliterature.

AngeloKomnitski:Draftingandeditingofthemanuscript; criticalreviewoftheliterature.

Amilton Komnitski Junior: Conception and planning of study,drafting and editing of the manuscript; collection, analysis,andinterpretation ofdata;criticalreviewofthe literature.

CaioCésarSilvadeCastro:Approvalofthefinalversion ofthemanuscript;conceptionandplanningofstudy, draft-ingandeditingofthemanuscript;collection,analysis,and interpretationofdata;participationindesignofthestudy;

participationin thepropaedeuticand/or therapeutic con-ductofthestudiedcases;criticalreviewoftheliterature; criticalreviewofthemanuscript.

Conflicts

of

interest

Nonedeclared.

References

1.Cesar Silva de Castro C, Miot HA. Prevalence of vitiligo in Brazil --- a population survey. Pigment Cell Melanoma Res. 2018;31:448---50.

2.LiuLY, Strassner JP, Refat MA, HarrisJE, King BA. Repigmen-tation in vitiligo using the Janus kinase inhibitor tofacitinib mayrequireconcomitantlightexposure.JAmAcadDermatol. 2017;77:675---82.

3.CinatsA,HeckE,RobertsonL.Januskinaseinhibitors:areview oftheiremergingapplicationsindermatology.SkinTherapyLett. 2018;23:5---9.

4.KimSR,HeatonH,LiuLY,KingBA.Rapidrepigmentationofvitiligo usingtofacitinibpluslow-dose,narrowbandUV-Bphototherapy. JAMADermatol.2018;154:370---1.

5.CiechanowiczP,RakowskaA,SikoraM,RudnickaL.JAK-inhibitors indermatology:currentevidenceandfutureapplications.J Der-matolTreat.2019;30:648---58.

6.DamskyW,KingBA.JAKinhibitorsindermatology:thepromise ofanewdrugclass.JAmAcadDermatol.2017;76:736---44. 7.Craiglow BG, King BA. Tofacitinib citrate for the treatment

of vitiligo: a pathogenesis-directed therapy. JAMA Dermatol. 2015;151:1110---2.

8.JoshipuraD,PlotnikovaN,GoldminzA,DeverapalliS,Turkowski Y,GottliebA,etal.Importanceoflightinthetreatmentofvitiligo withJAK-inhibitors.JDermatolTreat.2018;29:98---9.