Research

Case Report/Case Series

Treatment of Scarring Alopecia in Discoid Variant of Chronic

Cutaneous Lupus Erythematosus With Tacrolimus Lotion, 0.3%
Emily C. Milam, BA; Sarika Ramachandran, MD; Andrew G. Franks Jr, MD

IMPORTANCE Discoid lupus erythematosus (DLE) is a chronic variant of cutaneous lupus

erythematosus, an autoimmune inflammatory disorder of the skin. Lesions are often localized
to the scalp and can result in permanent scarring, disfiguration, and irreversible alopecia.
Although DLE usually responds to topical or intralesional corticosteroids and/or oral
antimalarials, some DLE is resistant to these treatments or adverse effects limit their
effectiveness.

OBSERVATIONS Three patients with treatment-refractory, biopsy-proved DLE were

prescribed a novel, off-label preparation of tacrolimus lotion, 0.3%, in an alcohol base as an
adjunct to oral antimalarial therapy. All 3 patients demonstrated improvement in lesion
severity and hair regrowth with the use of this regimen after 3 months and continued
improvement thereafter. We report a retrospective analysis of these 3 cases.
Author Affiliations: Ronald O.
Perelman Department of
CONCLUSIONS AND RELEVANCE This report is, to our knowledge, the first mention of
Dermatology, New York University
tacrolimus being used in a lotion formulation to treat DLE lesions, resulting in hair regrowth. School of Medicine, New York,
Topical tacrolimus lotion, 0.3%, in an alcohol base may be a potential therapeutic option for New York.
patients with DLE that is refractory to first-line therapies and who risk late-stage disease with Corresponding Author: Andrew G.
permanent scarring alopecia. Franks Jr, MD, Ronald O. Perelman
Department of Dermatology,
New York University School of
JAMA Dermatol. doi:10.1001/jamadermatol.2015.1349 Medicine, 240 E 38th St, 12th Floor,
Published online June 3, 2015. New York, NY 10016
(andrew.franks@nyumc.org).

D
iscoid lupus erythematosus (DLE) is a chronic variant of
cutaneous lupus erythematosus characterized by well-
defined erythematous plaques with scale, often pre-
dominantly featured on the face, ears, anterior neck, and scalp.
More than half of patients with DLE first present with scalp in-
volvement. Discoid lupus erythematosus is one of the most com-
mon causes of inflammatory cicatricial, or scarring, alopecia.
Complications can include ulceration or permanent cosmetic dis-
figurement, with in situ squamous cell carcinoma occasionally
seen in long-standing lesions. At later stages, the lesions may ap-
pear as smooth atrophic scars with central hypopigmentation and
loss of follicular ostia, occasionally resembling lichen planopi-
laris or Brocq psuedopelade.
Although DLE is often managed successfully by topical or
intralesional corticosteroids and/or oral antimalarials, some
cases are refractory to these first-line therapies. Alternative
therapies, such as methotrexate sodium, oral corticoste-
roids, thalidomide, and dapsone, may also be ineffective and/or
limited by their risks and adverse effects. Among the topical
therapies, corticosteroids and calcineurin inhibitors are most
commonly used.
Topical and intralesional corticosteroids, however, have
well-known adverse effects, including atrophy, telangiec-
tasia, and rosacealike dermatitis. Although not approved by
the US Food and Drug Administration for treatment of cuta-
neous lupus erythematosus, calcineurin inhibitors are often
used to treat cutaneous lupus erythematosus variants.1-10 Com-
mercially available preparations include pimecrolimus cream,
1%, and tacrolimus ointment, 0.03% or 0.1%. No lotions are
commercially available for topical use.
In our clinic, we used a novel off-label preparation of
higher-potency tacrolimus, 0.3%, in an alcohol base as an ad-
junct therapy in 3 patients with recalcitrant alopecia second-
ary to biopsy-proved DLE. We herein retrospectively review
their treatment responses.
Report of Cases
We retrospectively reviewed the medical records of 3 pa-
tients with recalcitrant alopecia secondary to biopsy-proved
DLE (Table 1) who demonstrated treatment success after being
prescribed an off-label preparation of tacrolimus lotion, 0.3%.
The patients had previously attempted prolonged trials of an-
timalarials and topical and intralesional corticosteroids. All 3
patients had a negative finding for antinuclear antibodies by
indirect fluorescent antibody analysis.
The patients were prescribed thirty-six 5.0-mg tacrolimus
capsules. We instructed the patients to add the contents of the
capsules to 60 mL of 70% isopropyl alcohol and vigorously shake

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 Research Case Report/Case Series Treatment of Alopecia in Chronic Cutaneous Lupus Erythematosus

Table 1. Patient Characteristics and Lesion Activity Before and After Treatment With Topical Tacrolimus Lotion, 0.3%

Patient No.
Characteristic 1 2 3
Sex/age, decade/race F/50s/white F/30s/black F/50s/white
Time since DLE diagnosis >10 y 6 mo >10 y
Prior therapy Chloroquine phosphate (>2 y), topical Hydroxychloroquine sulfate (>5 mo), Hydroxychloroquine and chloroquine
corticosteroids, and intralesional intralesional corticosteroids (>3 y), quinacrine hydrochloride (>5 mo),
corticosteroids and topical corticosteroids
Adjunct antimalarial Chloroquine phosphate, 250 mg 3 times Hydroxychloroquine sulfate, 200 mg, Quinacrine hydrochloride, 50 mg 2 times
per week, tapered to 2 times per week twice daily per week
Scalp lesion location Crown and midscalp Frontal scalp margin and temples Frontal scalp margin

Abbreviation: DLE, discoid lupus erythematosus.

the mixture until the powder was completely in suspension. The

Figure. Treatment of Active Chronic Discoid Lupus Erythematosus of the
patients applied the lotion twice daily and were counseled to Scalp in Patient 1
shake the lotion thoroughly before each use. The lotion was used
as an adjunct therapy to oral antimalarials. A Before treatment

Results
At the 3-month follow-up, all patients demonstrated improve-
ment in disease activity consistent with the Cutaneous Lu-
pus Erythematosus Disease Area and Severity Index criteria,
including a reduction in erythema, scale, pruritus, and sur-
face area of the lesions.1 All patients also exhibited increased
terminal hair regrowth within the center and the periphery of
the lesions. They reported decreased pruritus and increased
treatment satisfaction. No adverse events were noted. Pa-
tients 1 and 3 continued to use the lotion for 1 to 2 years, with
continued hair regrowth and reduction of lesion surface area
and pruritus. Representative photographs of patient 1 before B After 2 mo of treatment with topical tacrolimus lotion, 0.3%
and after use of the tacrolimus lotion are provided (Figure).

Discussion
Discoid lupus erythematosus is a common cause of scarring
alopecia among patients with scalp involvement. The inflam-
matory cell infiltrate is especially prominent around the hair
follicle at the level of the sebaceous glands and bulge, the lo-
cation of the hair’s regenerative stem cells. In advanced DLE,
many, if not all, of the hair follicles and sebaceous glands are
destroyed, leaving residual fibrosis and atrophy. Early diag-
nosis and treatment are necessary because scarring can lead
to irreversible alopecia and disfiguration.
Topical tacrolimus was one of the first nonsteroidal drugs A, Before application of topical tacrolimus lotion, 0.3%, the scalp demonstrates
approved for use in atopic dermatitis by the US Food and Drug alopecia and signs of disease activity, including erythema and scale. B, After 2
months of tacrolimus therapy as an adjunct to chloroquine phosphate, the scalp
Administration. Given its low adverse effect profile, the lower-
shows a reduction in erythema and scale and increased hair regrowth.
potency formulations are considered safe in children as young
as 2 years. Topical tacrolimus has many off-label uses, par-
ticularly for autoimmune and inflammatory conditions such phosphatase, by binding to an intracytoplasmic protein termed
as psoriasis, vitiligo, chronic actinic dermatitis, lichen pla- FK506 binding protein. Downstream, calcineurin inhibition by
nus, and pyoderma gangrenosum, among others. the tacrolimus–FK506 binding protein complex blocks the de-
As an immunomodulator, tacrolimus primarily targets in- phosphorylation of the nuclear factor of activated T cells, ul-
tracellular signaling pathways implicated in T cell–receptor ac- timately preventing entry of the factor into the nucleus. As a
tivation. Tacrolimus inhibits calcineurin, a serine-threonine transcription factor, the nuclear factor of activated T cells would

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 Treatment of Alopecia in Chronic Cutaneous Lupus Erythematosus Case Report/Case Series Research

Table 2. Results of Literature Review on Topical Tacrolimus Use in Discoid Lupus Erythematosus
Patients,
Source Study Design No. Drug Compound and Duration Outcome
Tacrolimus Ointment
Avgerinou et al,5 2012 Retrospective 10a Tacrolimus ointment and Statistically significant improvement in
hydroxychloroquine or tacrolimus erythema, desquamation, and edema
ointment monotherapy for 60 d,
dose unknown
Han et al,6 2010 Case series 2 Tacrolimus ointment, 0.1%, twice daily Good improvement in both patients,
for 8 wk quantified as 75% and 57% reduction in total
clinical severity score (an assessment of
erythema, scale/thickness, and
scarring/atrophy)
Tzung et al,9 2007 Randomized 4 Tacrolimus ointment, 0.1%, vs clobetasol No significant difference in collective lesion
double-blind propionate, 0.05%, twice daily on improvement with tacrolimus vs clobetasol
opposite sides of face for 4 wk, with
microdermabrasion
Sugano et al,7 2006 Case series 4 Tacrolimus ointment, 0.1%, twice daily Improvement in 4 of 4 patients
for 4-8 wk
Heffernan et al,8 2005 Open-label pilot 5 Tacrolimus ointment, 0.1%, twice daily Three of 5 patients completed the study,
for 12 wk with 1 case each of mild, moderate, and
marked improvement
de la Rosa Carillo and Case report 1 Tacrolimus ointment, 0.1%, monotherapy Improvement in erythema, infiltration, and
Christensen,3 2004 twice daily for 8 wk hyperkeratosis; hair regrowth in center and
periphery of the lesion
Lampropoulos et al,4 2004 Open-label pilot 6 Tacrolimus ointment, 0.1%, twice daily “Certain” improvement in 2 of 5 patients;
for >6 wk “minor” improvement in 1 patient; the sixth
patient discontinued treatment owing to
adverse effects (burning and peeling)
Yoshimasu et al,10 2002 Case series 4 Tacrolimus ointment, 0.1%, once daily Improvement in 1 of 4 patients
Topical Tacrolimus Compounded With Clobetasol Ointment
Madan et al,2 2010 Retrospective 14 Ointment compound of tacrolimus, “Excellent” response in 5, “good” response
0.3%, and clobetasol propionate, 0.005% in 4, and “slight” response in 1 of 10 patients
(TCPO), in 11 patients vs tacrolimus who completed TCPO therapy; “good”
ointment, 0.1% (TO), monotherapy twice response in 1 and “slight” improvement in
daily in 3 patients 2 of 3 patients who completed TO therapy
Walker et al,1 2002 Case series 2 Tacrolimus ointment, 0.3%, in clobetasol Improvement in both cases, with almost
propionate ointment, 0.05%, twice daily complete resolution of inflammation in patient
for 6-8 wk 1; both patients continued using antimalarials
and patient 1 continued to receive oral
corticosteroids throughout the treatment
period, with ability to decrease dose after
tacrolimus use
a
This study involved use of topical tacrolimus in 18 patients with cutaneous hydroxychloroquine sulfate. Specific statistical results of patients with DLE
lupus erythematosus, 10 of whom had the DLE variant. An additional 20 receiving tacrolimus monotherapy compared with combined treatment were
patients received topical pimecrolimus monotherapy or in combination with not reported.

otherwise bind to the promoter region of various proinflam-
matory cytokine and chemokine genes to induce their syn-
thesis, including those genes responsible for interleukin 2 (IL-2)
(a T-cell growth and differentiation factor), tumor necrosis fac-
tor, interferon-γ, IL-4, and IL-10.
Targeting the calcineurin signaling pathways ultimately lim-
its lymphocyte proliferation, which is a predominant feature of
the scarring alopecia in DLE. In general, cutaneous lupus ery-
thematosus lesions demonstrate a state of proinflammation, with
increased expression of cytokines such as IL-2, interferon-γ, and
tumor necrosis factor noted in biopsy samples.11 In contrast to
corticosteroids—which nonselectively affect epidermal and der-
mal cells—topical tacrolimus spares keratinocytes, fibroblasts,
and endothelial cells, precluding the more robust adverse effects
seen with corticosteroids.12
Topical tacrolimus ointment has demonstrated mixed suc-
cess in treating DLE lesions of the face and scalp as outlined
in Table 2. Most of the clinical studies and case series3-10 use
ointment preparations of the commercially available, lower-
potency tacrolimus, such as 0.1% or 0.03%. Two exceptions are
the studies by Walker et al1 and Madan et al,2 in which a higher-
potency tacrolimus ointment, 0.3%, was compounded with clo-
betasol propionate with a good clinical response. However, the
inclusion of a corticosteroid obscures the precise role of ta-
crolimus and potentially begets a similar adverse effect pro-
file to that of corticosteroids used alone.
Some authors13 have incorporated tacrolimus into other
lotionlike vehicles, such as glycerine. To our knowledge, no
studies have used higher-potency topical tacrolimus in lo-
tion form with isopropyl alcohol. Moreover, the only study that
notes hair regrowth is that by de la Rosa Carillo and
Christensen,3 in which 1 patient had regrowth of terminal hair
in the outer regions of her lesions with application of tacroli-
mus ointment, 0.1%, as monotherapy. The successful re-
growth of hair among our 3 patients may be owing to en-
hanced delivery of tacrolimus to the site of inflammation and
a subsequent reduction in disease activity mitigated by calci-
neurin inhibition. Thus, tacrolimus may prevent the lesions
from entering a final scarred stage, thereby allowing an op-
portunity for the hair to regrow.

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 Research Case Report/Case Series Treatment of Alopecia in Chronic Cutaneous Lupus Erythematosus

Commercially available tacrolimus ointments are mini-
mally absorbed, with a bioavailability of less than 0.5%. The
distinctly significant hyperkeratosis of DLE likely leads to even
lower penetration of compounds. Our preparation of tacroli-
mus in an alcohol base may enhance percutaneous drug ab-
sorption and delivery to the dermis, in which the lymphoid in-
filtrates responsible for DLE lesions reside. The contents of oral
tacrolimus capsules are lipophilic, and the scalp’s abundant
hair follicles provide a lipid-laden path for drug absorption in
addition to being the target of interest. Moreover, 70% isopro-
pyl alcohol is favored as a solvent because it is safe, readily dis-
solves lipophilic compounds, and enhances permeation of the
stratum corneum barrier (particularly in areas of decreased skin
integrity, such as DLE lesions), and its evaporation after ap-
plication provides a cooling relief. Secondary advantages of the
tacrolimus lotion are that it leaves little to no residue on the
scalp and does not require occlusion, both of which increase
patient burden and dissatisfaction with treatment. Similar
products, including oral suspensions of tacrolimus, have been
shown to be stable for approximately 60 days at room tem-
perature. The adverse effects of topical tacrolimus not expe-
rienced by our patients but reported elsewhere include peel-
ing and burning.4 Although the degree of systemic absorption
was not assessed in our 3 patients, we have tested the same
topical tacrolimus preparation, 0.3%, for the diagnosis of li-
chen planopilaris in another patient (A.G.F., unpublished data,
March 2015). Her serum tacrolimus level was undetectable af-
ter using the lotion on a large region of her scalp for many
months. The same was true for another patient using a tacro-
limus mouthwash for oral lichen planus despite mucosal ex-
posure (S.R., unpublished data, 2014). Moreover, a veterinary
study14 using tacrolimus lotion, 0.3%, for canine atopic der-
matitis demonstrated mean blood concentrations below toxic
levels among the 8 dogs receiving large doses for 4 weeks.
Of note, the US Food and Drug Administration has placed
a black box warning on calcineurin inhibitors owing to the theo-
retical risk for hematologic cancers after long-term use, with
observations of increased incidence in murine models.15 The
available evidence in humans is not supportive at this time.
As a chronic hypertrophic and scarring disease, DLE lesions
demonstrate an increased risk for neoplastic transformation.
Thus, a reduction of disease activity is essential to avoid irre-
versible damage and these long-term complications.
Conclusions
Although further studies are required, our limited observa-
tions support the use of topical tacrolimus lotion, 0.3%, in an
alcohol base in treatment-resistant cases of DLE-associated alo-
pecia. The results support a new potential therapeutic option
for this disease.

ARTICLE INFORMATION REFERENCES discoid lupus erythematosus. Arch Dermatol. 2005;

Accepted for Publication: April 8, 2015. 1. Walker SL, Kirby B, Chalmers RJ. The effect of 141(9):1170-1171.

Published Online: June 3, 2015.
doi:10.1001/jamadermatol.2015.1349.
Author Contributions: Drs Ramachandran and
Franks had full access to all of the data in the study
and take responsibility for the integrity of the data
and the accuracy of the data analysis.
Study concept and design: Ramachandran, Franks.
Acquisition, analysis, or interpretation of data: All
authors.
Drafting of the manuscript: All authors.
Critical revision of the manuscript for important
intellectual content: All authors.
Statistical analysis: Ramachandran, Franks.
Administrative, technical, or material support: All
authors.
Study supervision: Ramachandran, Franks.
Conflict of Interest Disclosures: None reported.
Funding/Support: The Carl J. Herzog Foundation
awards a fellowship stipend that supports the
annual salary of junior faculty (Dr Ramachandran).
Role of the Funder/Sponsor: The funding source
had no role in the design and conduct of the study;
collection, management, analysis, and
interpretation of the data; preparation, review, or
approval of the manuscript; and decision to submit
the manuscript for publication.
Previous Presentations: A portion of this study
was presented at the 2014 annual meeting of the
Society for Investigative Dermatology; May 8, 2014;
Albuquerque, New Mexico; and the 2014 annual
meeting of the Rheumatologic Dermatology
Society; November 14, 2014; Boston,
Massachusetts.
topical tacrolimus on severe recalcitrant chronic
discoid lupus erythematosus. Br J Dermatol. 2002;
147(2):405-406.
2. Madan V, August PJ, Chalmers RJ. Efficacy of
topical tacrolimus 0.3% in clobetasol propionate
0.05% ointment in therapy-resistant cutaneous
lupus erythematosus: a cohort study. Clin Exp
Dermatol. 2010;35(1):27-30.
3. de la Rosa Carrillo D, Christensen OB. Treatment
of chronic discoid lupus erythematosus with topical
tacrolimus. Acta Derm Venereol. 2004;84(3):
233-234.
4. Lampropoulos CE, Sangle S, Harrison P,
Hughes GR, D’Cruz DP. Topical tacrolimus therapy
of resistant cutaneous lesions in lupus
erythematosus: a possible alternative.
Rheumatology (Oxford). 2004;43(11):1383-1385.
5. Avgerinou G, Papafragkaki DK, Nasiopoulou A,
Arapaki A, Katsambas A, Stavropoulos PG.
Effectiveness of topical calcineurin inhibitors as
monotherapy or in combination with
hydroxychloroquine in cutaneous lupus
erythematosus. J Eur Acad Dermatol Venereol.
2012;26(6):762-767.
6. Han YW, Kim HO, Park SH, Park YM. Four cases
of facial discoid lupus erythematosus successfully
treated with topical pimecrolimus or tacrolimus.
Ann Dermatol. 2010;22(3):307-311.
7. Sugano M, Shintani Y, Kobayashi K, Sakakibara N,
Isomura I, Morita A. Successful treatment with
topical tacrolimus in four cases of discoid lupus
erythematosus. J Dermatol. 2006;33(12):887-891.
8. Heffernan MP, Nelson MM, Smith DI, Chung JH.
0.1% Tacrolimus ointment in the treatment of
9. Tzung TY, Liu YS, Chang HW. Tacrolimus vs
clobetasol propionate in the treatment of facial
cutaneous lupus erythematosus: a randomized,
double-blind, bilateral comparison study. Br J
Dermatol. 2007;156(1):191-192.
10. Yoshimasu T, Ohtani T, Sakamoto T, Oshima A,
Furukawa F. Topical FK506 (tacrolimus) therapy for
facial erythematous lesions of cutaneous lupus
erythematosus and dermatomyositis. Eur J Dermatol.
2002;12(1):50-52.
11. Kirchhof MG, Dutz JP. The immunopathology of
cutaneous lupus erythematosus. Rheum Dis Clin
North Am. 2014;40(3):455-474, viii.
12. Sticherling M. Update on the use of topical
calcineurin inhibitors in cutaneous lupus
erythematosus. Biologics. 2011;5:21-31.
13. Sugiura H, Uehara M, Hoshino N, Yamaji A.
An open study of a lotion formulation to improve
tolerance of tacrolimus in facial atopic dermatitis. Br
J Dermatol. 2001;145(5):795-798.
14. Marsella R, Nicklin CF. Investigation on the use
of 0.3% tacrolimus lotion for canine atopic
dermatitis: a pilot study. Vet Dermatol. 2002;13(4):
203-210.
15. Berger TG, Duvic M, Van Voorhees AS,
VanBeek MJ, Frieden IJ; American Academy of
Dermatology Association Task Force. The use of
topical calcineurin inhibitors in dermatology: safety
concerns: report of the American Academy of
Dermatology Association Task Force. J Am Acad
Dermatol. 2006;54(5):818-823.

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