CASE SERIES

Brazilian Experience of the Treatment of AlopeciaUniversalis with the Novel Antirheumatic TherapyTofacitinib: A Case Series

Morton Scheinberg . Regina Adalva de Lucena Couto Océa . Boris Afonso Cruz .

Sineida Berbert Ferreira

Received: June 1, 2017 / Published online: July 28, 2017� The Author(s) 2017. This article is an open access publication

ABSTRACT

Introduction: Alopecia universalis is anautoimmune disorder for which there is noknown effective therapy. Tofacitinib—a novelantirheumatic therapy for rheumatoid arthri-tis—has been shown in some reports to inducesustained hair growth in patients with alopeciauniversalis.Case Series: Here, we review the experiences offour different rheumatologists across the coun-try regarding four Brazilian patients withalopecia universalis who were treated withtofacitinib . Two of these four patients hadidiopathic alopecia and the other two hadrheumatoid arthritis; in each case, the alopecia

universalis was apparently induced byetanercept.Conclusion: Tofacitinib should be consideredfor the treatment of severe alopecia areata, butthe optimal dose and duration of therapyshould be defined in randomized controlledtrials.

Keywords: Alopecia; Biologic therapy;Rheumatoid arthritis; Tofacitinib; Universalis

INTRODUCTION

Alopecia universalis (AU) is a variant of alopeciaareata (AA) that can affect both children andadults and is associated with the complete lossof all body hair [1]. It is well known that theetiology of AU is related to a complex interac-tion between genetic and immune abnormali-ties that target the hair follicle. T cells have beenshown to be important effector cells in theappearance of AU, as they express cytokines—particularly interferon gamma—that target thehair follicle [2]. While several therapies for AUhave been tested, they have all shown onlypartial or no clinical efficacy [3]—there arecurrently no effective therapies for AU. In thepast 3 years, a few reports have been publishedsuggesting that some AU patients appear torespond to Janus kinase inhibitors (JAKi),implying that JAKi should be evaluated as apromising novel therapy [4, 5]. JAKi

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M. Scheinberg (&)Hospital Israelita Albert Einstein, São Paulo, Brazile-mail: morton@osite.com.br

M. ScheinbergAACD Hospital, São Paulo, Brazil

R. A. de Lucena Couto OcéaRheumatology Section Universidade Federal,Sergipe, Brazil

B. A. CruzBiocor Hospital Belo Horizonte, Minas Gerais, Brazil

S. B. FerreiraDermatoSineida Clinic Maringa, Paraná, Brazil

Rheumatol Ther (2017) 4:503–508

DOI 10.1007/s40744-017-0069-z

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downregulate interferon expression. Given thatthe expression of interferon is known to beincreased in AU, this could explain the reportedresponse of AU to JAKi [6]. In this paper, wereport the short-term follow-up of four cases ofAU in Brazil that remitted after the administra-tion of tofacitinib. The individual aspects ofeach case are discussed and compared to thelimited literature available on this topic at thepresent time.

CASE SERIES

Patient 1: Male, 38 years of age, who haddeveloped AU 10 years earlier. The patient wasinitially treated with oral, topical, andintralesional corticosteroids followed byminoxidil, methotrexate, and cyclosporine,all with no response. He also presented withdystrophic fingernails. On examination, heshowed a total absence of eyebrows, eyelashes,beard, hair on the trunk, scalp, genitals, arms,and legs. He was started on 5 mg of tofacitinibtwice a day—an off-label indication with priorpatient consent. After 2 months he developedinitial hair growth on the scalp, and there wasprogressive hair growth after 9 months oftherapy (Fig. 1). Currently, the hair is stillgrowing despite a reduction in the dose to5 mg a day [5].

Patient 2: Female, 20 years of age, who haddeveloped AU at age ten and had tried severaltreatments, including oral and intralesionalsteroids, methotrexate, and cyclosporine, all

with no detectable response. After 6 weeks oftherapy with tofacitinib 5 mg twice a day, it waspossible to observe partial growth of scalp,eyebrow, and axillary hair (Fig. 2).

Patient 3: Male, 45 years of age, who haddeveloped rheumatoid arthritis 7 years earlier.The patient was treated initially with lefluno-mide, then prednisone 5 mg for 2 years, whichwas followed by etanercept, leading to clinicalremission of the disease. Two years ago thepatient presented with diffuse pruritus, erythe-matous skin, and initial hair loss on the eye-brows. Leflunomide was initially discontinuedand a conventional antiallergic medication wasadministered but the skin disease persisted.Etanercept was discontinued and abatacept wasintroduced, but the joint disease remainedactive and the clinical picture for the skinevolved to alopecia universalis. Tofacitinib wasstarted at 5 mg twice a day, and hair growthappeared on the scalp, eyebrows, and skin after7 months (Fig. 3).

Patient 4: Female, 60 years of age, who haddeveloped seropositive rheumatoid arthritis2 years earlier. The patient was in remission dueto treatment with etanercept and methotrexatewhen progressive hair loss developed. All med-ications were withdrawn; subsequent treatmentwith oral prednisone and intralesional triamci-nolone injections had no effect. She progressedto universal alopecia and her arthritis becameactive again. Tofacitinib was introduced, and6 months after that the patient’s arthritis hadimproved and the alopecia had fully resolved(Fig. 4).

Fig. 1 Patient 1: before and 9 months after the introduction of tofacitinib 10 mg daily

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Fig. 2 Patient 2: before and 10 months after the introduction of tofacitinib 10 mg daily

Fig. 3 Patient 3: hair growth after 7 months of tofacitinib 10 mg daily

Fig. 4 Patient 4: hair growth 1 and 4 months after the introduction of tofacitinib 10 mg daily

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This case series complied with the ethicalstandards of the AACD Hospital. All proceduresfollowed the ethical standards for humanexperimentation, and informed consent wasobtained from all patients.

DISCUSSION

Tofacitinib citrate is a small molecule thatselectively inhibits Janus kinase 1 and 3 and wasapproved for the treatment of moderate to sev-ere rheumatoid arthritis [7]. Since it affectsvarious T cell effector functions, it is also beingevaluated for the treatment of other autoim-mune inflammatory conditions of the skin,such as psoriasis and atopic dermatitis. Alopeciaareata and universalis are considered to beautoimmune in their pathogenesis due to theattack of T cells on hair follicles, which leads totransient or permanent nonscarring hair loss[8]. Recently, new molecular pathways that areinvolved in AA were discovered, includingautophagy/apoptosis, transforming growth fac-tor/Tregs, and Janus kinase signaling [6]. In thispaper, we have presented four Brazilian patientswho developed progressive hair growth upontreatment with tofacitinib at the recommendeddose approved for the treatment of rheumatoidarthritis. All four cases had a clinical diagnosisand no biopsy was performed in any of thepatients. There are very few reports on this topic

in the literature. The first was from the YaleDermatology Group, who reported that tofaci-tinib appeared to ‘‘kill two birds with onestone:’’ alopecia was reversed in a patient withpsoriasis [9]. That was followed by the largestreport yet from the same group—Liu andcoworkers reported on 90 patients who hadalopecia areata or variants of it. These results aresummarized in Table 1.

In the report by the Yale group, almost 60%of the patients showed a [50% change in thealopecia score (SALT severity of alopecia scoretool), which was sustained for variable periodsof time.

The duration of the response varied from 4 to18 months. The lack of a control group makesthe conclusions of the study somewhat limited,but the results do appear to confirm those givenin other isolated reports from a few groups thatare available in the literature [10]. In one of thereported cases, initial signs of hair regrowthwere observed in the same timeframe as repor-ted by Azengruber and coauthors, but the effi-cacy of the drug quickly waned again, leading toa relapse of the disease [11]. In a recentlyreleased report, the authors conducted a reviewand suggested that hair growth followingtofacitinib treatment may be partial and tran-sient for some patients [12]. In our cases, theefficacy of tofacitinib persisted; indeed, reduc-ing the dose by half in one of those cases didnot affect the positive response (see Fig. 1).

Table 1 Clinical response of patients with alopecia to tofacitinib

Magnitude of clinical responseSALT score

Percentage of patients (%) Number of patients

Complete response ([90%) 20 13

Intermediate response (51–90%) 38.4 25

Moderate response (6–50%) 18.5 12

No response (\5%) 23.1 15

Therapy Percentage of patients (%) Number of patients

Standard monotherapy. Tofacitinib 5 mg BID 43.1 25

Adjuvant therapy 56.9 37

Tofacitinib[5 mg BID 29.2 19

Tofacitinib 5 mg BID ? prednisone 13.8 9

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Thus, even though tofacitinib is a promisingnew treatment option, we need to learn moreabout its potential, including the appropriateduration of treatment, the maintenance dose,the possibility of relapse if the drug is discon-tinued, and the loss of response during treat-ment, as described in one of the reports in theliterature. None of our patients developedadverse events, but it is important to monitorfor such effects (including infections andhyperlipidemia) during long-term therapy.

Patient 3 in this report developed alopeciaareata during anti-TNF treatment. A few suchcases have been reported previously [13, 14]. Itis worth noting that the induction of otherautoimmune diseases by prolonged anti-TNFtreatment has been extensively reported in themedical literature [13, 14].

The possible application of JAKi to otherautoimmune disorders such as psoriasis andinflammatory bowel disease is currently beingresearched [15]. Nail dystrophy is a heteroge-neous skin condition, but in some subtypes itsdevelopment has autoimmune origins. Werecently reported that tofacitinib appears to bebeneficial in patients with this nail disorder,which can also be associated with other rheu-matic disorders such as psoriatic arthritis and isobserved in approximately 50% of AU patients[16].

The long-term safety of tofacitinib inpatients with rheumatic disease will be closelymonitored in years to come, as will its long--term safety in patients with AU. Tofacitinib issimilar to biologics in that long-term use canlead to opportunistic infections, in particularthose associated with persistent viral infections.In such cases vaccination can help patients whorequire the long-term use of tofacitinib [17].

CONCLUSIONS

In conclusion, targeting the intracellular JAKsignaling pathway appears to be a promisingtherapeutic strategy for AA patients, and thefuture should bring new information along withthe advent of second-generation selective JAKinhibitors which are currently being investi-gated. It is expected that prospective

randomized controlled trials will be performedto determine the real efficacy of tofacitinib inpatients with AA only or AA in association withother rheumatic diseases.

ACKNOWLEDGEMENTS

No sponsorship or funding was received for thisstudy, and the article processing charges werefunded by the authors. All of the named authorsmeet the International Committee of MedicalJournal Editors (ICMJE) criteria for authorshipfor this manuscript, take responsibility for theintegrity of the work as a whole, and gave theirfinal approval for the version to be published.

Disclosures. Morton Scheinberg, ReginaOcéa, Boris Cruz, and Sineida Ferreira havenothing to disclose.

Compliance with Ethics Guidelines. Allprocedures followed the ethical standards forhuman experimentation, and informed consentwas obtained from all patients.

Open Access. This article is distributedunder the terms of the Creative CommonsAttribution-NonCommercial 4.0 InternationalLicense (http://creativecommons.org/licenses/by-nc/4.0/), which permits any noncommer-cial use, distribution, and reproduction in anymedium, provided you give appropriate creditto the original author(s) and the source, providea link to the Creative Commons license, andindicate if changes were made.

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Brazilian Experience of the Treatment of Alopecia Universalis with the Novel Antirheumatic Therapy Tofacitinib: A Case SeriesAbstractIntroductionCase SeriesConclusion

IntroductionCase SeriesDiscussionConclusionsAcknowledgementsReferences