Received: 15 May 2019 Revised: 18 June 2019 Accepted: 27 June 2019

DOI: 10.1111/dth.13013

THERAPEUTIC HOTLINE: SHORT PAPER

Topical methotrexate 1% gel for treatment of vitiligo: A case

report and review of the literature

Ayman Abdelmaksoud1 | Dharmendra Dineshchandra Dave2 | Torello Lotti3 |

Michelangelo Vestita4,5

1
Mansoura Dermatology, Venerology and
Leprology Hospital, Mansoura, Egypt Abstract
2
Dave Skin & Laser Clinic, Patan, Gujarat, India Vitiligo is quite a common hypopigmentary disorder, which may affect both children
3
University of Rome "G.Marconi", Rome, Italy and adults with important psychological effects due to the well-known leopard skin-
4
Unit of Plastic and Reconstructive Surgery,
like appearance. Even if asymptomatic and not life threatening, vitiligo has to be
Department of Emergency and Organ
Transplantation, University of Bari, Bari, Italy increasingly studied and treated. Hitherto, the efficacy of topical methotrexate in
5
Department of Dermatology, Brigham and treatment of vitiligo has not been reported. We herein reporting our preliminary
Women's Hospital, Harvard Medical School,
Boston, Massachusetts
observation on the promising efficacy of topical methotrexate in one patient with
stable vitiligo. The patient applied topical methotrexate 1% gel twice daily for
Correspondence
Ayman Abdelmaksoud, 5-Amien Alsamanoudy
12 weeks. Significant improvement of the lesion with no local or systemic side
Street, from AbdelsalamAaref Street, effects were noted during the course of therapy. We propose that this well-tolerated
Mansoura, Egypt.
Email: behcet.behcet@yahoo.com
drug can be used for vitiligo therapy; however, further investigations should be per-
formed to ascertain the exact topically effective dose.

KEYWORDS
methotrexate, topical, vitiligo

1 | I N T RO D UC T I O N Vitiligo lesion showed mild response to conventional therapies over the

Vitiligo is a nonlethal, immune-mediated, and generally progressive skin
disease, with unclear etiopathogenesis. A wide variety of treatment
modalities exist for its management. However, late clinical presentation,
nontreatment, undertreatment, and treatment dissatisfaction represent
past 1.5 year, including topical steroids, PUVA, and systemic corticoste-
roids. The patient was reluctant to any systemic immunosuppressive
therapies such as systemic steroids. We discussed the possible effect of
other steroid-sparing immunosuppressive therapy in a topical formula.
After full explanation, taking a personal consent of the patient, and

key clinical challenges (Valle et al., 2018). The goal of treating vitiligo is agreement on regular follow up, we decided to try topical methotrexate

to make it less noticeable either by restoring lost pigment or by elimi-
nating remaining pigment. The reports on the role of MTX in vitiligo are
scarce. Herein, we report for the first time, a case of adult patient with
stable, treatment resistant vitiligo, showed excellent response to topical
methotrexate 1% gel.
2 | REPORT
An otherwise healthy, 23-year-old female patient, presented with a
2-year history of asymptomatic vitiligo lesion on left side of her waist.
The patient had no personal or family history of autoimmune diseases.
1% in gel formula (TREXJOY 1% 20 g gel; Methotrexate 1%W/W).
The patient underwent laboratory tests, such as complete blood
cell count, serum ALT, serum AST, blood nitrogen, serum creatinine,
urinalysis, viral hepatitis serology (HCV, HBV), ESR, CRP, serum IgE,
thyroid function test, and QuantiFerron-TB gold test revealed no out-
liers. Chest-x ray was normal. Negative pregnancy test.
The patient was instructed to apply topical methotrexate 1% gel,
twice daily (for 12 weeks or until significant regimentation detected)
together with folic acid, 5 mg/day. An initial regimentation of the
depigmented patch was noted 4 weeks later. T the 10th week, further
regimentation progressed with significant improvement (Figure 1a,b).
No local or systemic side effects were noted during and at the end of

Dermatologic Therapy. 2019;e13013. wileyonlinelibrary.com/journal/dth © 2019 Wiley Periodicals, Inc. 1 of 4

https://doi.org/10.1111/dth.13013
2 of 4
the therapeutic course. The result encouraged us to continue the same
regimen. The patient is still under follow up till writing this report.
3 | DISCUSSION
Vitiligo is an acquired skin disorder that poses major challenges in
terms of dermatological care. The primary goal of treatment is always
regimentation; secondary objectives include disease stabilization to
stop the loss of functional melanocytes, as well as ensuring adequate
psychosocial care and a better quality of life. The treatment decision
should be made on a case-by-case basis. Several months are expected
for any response to treatment to occur and that proactive treatment
may be necessary in the long run (Bleuel & Eberlein, 2018).
MTX as an antimetabolite and antifolate drug is a time-tested
effective treatment extensively used in various autoimmune disorders
like psoriasis, psoriatic arthritis, alopecia areata, lupus erythematosus,
and rheumatoid arthritis in low to moderate doses with good efficacy,
safety, and tolerability on a long-term basis (Sung et al., 2000).
In 1998, Sandra et al. reported a 54-year-old female patient with a
10-year history of rheumatoid arthritis presented with a 6 month his-
tory of rapidly progressing vitiligo lesions over trunk and limbs. After a
failed course of chloroquine for 3 years, and for a presumed risk of
keratopathy, the drug was discontinued. Then, the patient put on a sin-
gle dose of 7.5 mg MXT per week. At 3 months follow up after starting
MXT her arthritis had improved and it was noticed that she had stopped
developing new depigmented lesions. The rapid spread of depigmenta-
tion had ceased and there was considerable repigmentation of the
existing vitiligo lesions (Sandra, Pai, & Shenoi, 1998). Alghamdi and
Khurrum tried MXT in a dose of 25 mg/week over a 6-month course
for six patients with generalized vitiligo. However, no clinical improve-
ment was noted (Alghamdi & Khurrum, 2013). Recently, Garza-Mayers
and Kroshinsky reported a successful trial of MXT, in an up-titrating
dose of 12.5–25 mg/week, in the treatment of vitiligo. The authors
demonstrated three patients, one of which had rapidly progressive gen-
eralized vitiligo. Improvement was noted as early as 6 weeks (for rapidly
progressive generalized vitiligo) to 14 months after failure of topical cal-
cineurin inhibitors and phototherapy with no reported serious side
effects. Intriguingly, one of the patients had been treated for psoriatic
arthritis and other for rheumatoid arthritis concurrently with vitiligo,
with symptomatic relieve of arthritis in both (Abdelmaksoud, 2017;
ABDELMAKSOUD ET AL.
F I G U R E 1 A 23-year-old female with
stable vitiligo lesion on the left side of the
waist. (a) At time of presentation.
(b) 10 weeks post-initiation of topical
methotrexate 1% gel, with significant
repigmentation
Garza-Mayers & Kroshinsky, 2017). In a study by Singh et al., the
authors noted a similar reduction in the vitiligo disease activity score in
vitiligo patients received 10 mg methotrexate weekly compared to
those patients received corticosteroid OMP; dexamethasone 2.5 mg,
taken on two consecutive days in a week. Interestingly, during the
course of treatment for 24 weeks, overall six patients developed new
vitiliginous lesions in methotrexate side compared to 7/25 patients in
OMP side (Singh, Kumaran, Bains, & Parsad, 2015). MXT is, hence, com-
parable to OMP corticosteroid in controlling disease progression. Sum-
marizing data on the previous reports of oral MXT in vitiligo are
presented in (Table 1).
An increase in the production of proinflammatory cytokines such
as IL-6 and IL-2 in vitiligo patients may play an important role in
melanocytic cytotoxicity, as observed by Singh, Singh, and Pandey
(2012). MTX treatment resulted in the decrease of the number of
TNF-α-producing T cells, whereas the number of T cells producing
IL-10 after polyclonal activation increased, in another study (Rudwaleit
et al., 2000). Further, MTX possibly suppresses TNF-α-induced nuclear
factor-κB activation through the release of adenosine, with subse-
quent anti-inflammatory, immunomodulatory and antiproliferative
effects (Majumdar & Aggarwal, 2001). Moreover, modulations of IL-6
synthesis and reactive oxygen species production may also contribute
to the therapeutic effects of MTX (Sung et al., 2000).
Unlike oral MXT, topical preparations of the drug, that was adapted
for the treatment of localized lesions, showed nonsignificant related
hepatotoxic and hematologic adverse effects (Sutton, Swinehart, Cato, &
Kaplan, 2001; Syed, Hadi, Qureshi, & Ali, 2001; Weinstein, McCullough, &
Olsen, 1989).
Topical MXT has been tried with varied efficacy for treatment of
psoriasis vulgaris and palmoplantar pustulosis. Also, reports on myco-
sis fungoides (premycotic stage), lymphomatoid papulosis recently
added to the list (Wohlrab, Neubert, Michael, & Naumann, 2015).
Practically, and based on the theoretical systemic absorption of
the locally applied MXT with varied concentrations and different vehi-
cles, the same follow-up examinations should be conducted as rec-
ommended for systemic MTX use. Prophylactic folic acid substitution
is not recommended. However, no robust safety data available regard-
ing the topical application of MTX (Wohlrab et al., 2015).
To the best of our knowledge, this is the first report of successful
trial of topical MXT 1% gel in treatment of stable vitiligo lesion. We
ABDELMAKSOUD ET AL. 3 of 4

propose that this well-tolerated drug can be used for vitiligo therapy

of disease activity
1: Stop progression
2: Repigmentation
and may be considered as a lone or adjunct line to the current arma-

of the existing
vitiligo lesions

regimentation

regimentation
in 19 patients
mentarium. However, further investigations should be performed to

Stabilization
No change

Significant
ascertain the precise mechanism of action, and exact topically effective
Response

Excellent
dose. We think the clinical response in our patient to topical MXT 1%
gel may be partly due to dose and vehicle-dependent systemic absorp-
tion, resulting in “immune-editing” at the application site. Despite not

11–16 months
clinically or laboratory observed in our patient, we could raise a query;
of therapy
3 months

6 months

6 months

3 months
Duration

whether associated arthropathy/arthritis be a clinical predictor of

response of the vitiligo lesion to MXT. MXT in either formula; oral and
topical, may be a valuable therapeutic option for stable vitiligo.

Topical 1% gel, twice/day

Oral, 12.5–25 mg/week
Oral, 7.5 mg/week

Oral, 25 mg/week

Oral, 10 mg/week

CONFLIC T OF INT ER E ST
of methotrexate
Route and dose

The authors declare no potential conflict of interest.

OR CID
and lichen planus (7 patients)

Ayman Abdelmaksoud https://orcid.org/0000-0003-4848-959X

Michelangelo Vestita https://orcid.org/0000-0002-2203-0353
rheumatoid arthritis
Psoriatic arthritis and
Hypothyroidism, DM
Rheumatoid arthritis
Summary of reported cases/studies of methotrexate-alone or in combination-treatment trials for vitiligo

RE FE RE NCE S
Associations

Abdelmaksoud, A. (2017). Methotrexate for treatment of vitiligo. Dermato-

logic Therapy, 30. https.//doi.org/10.1111/dth.12532
None

None

Alghamdi, K., & Khurrum, H. (2013). Methotrexate for the treatment of

generalized vitiligo. Saudi Pharmaceutical Journal, 21, 423–424.
14 Females and

Bleuel, R., & Eberlein, B. (2018). Therapeutic management of vitiligo. Jour-

and 1 males

nal der Deutschen Dermatologischen Gesellschaft, 16, 1309–1313.

4 Males and
2 females

11 males
Sex of the

2 Females

Garza-Mayers, A. C., & Kroshinsky, D. (2017). Low-dose methotrexate for

patients
Female

Female

vitiligo. Journal of Drugs in Dermatology, 16, 705–706.

Majumdar, S., & Aggarwal, B. B. (2001). Methotrexate suppresses NF-
kappaB activation through inhibition of IkappaBalpha phosphorylation
patients (years)

and degradation. Journal of Immunology, 167, 2911–2920.

33, 26 and 46

Rudwaleit, M., Yin, Z., Siegert, S., Grolms, M., Radbruch, A., Braun, J., &
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Sieper, J. (2000). Response to methotrexate in early rheumatoid arthritis

14–46

14–62

is associated with a decrease of T cell derived tumour necrosis factor

54

23

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Sandra, A., Pai, S., & Shenoi, S. D. (1998). Unstable vitiligo responding to meth-
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otrexate. Indian Journal of Dermatology, Venereology and Leprology, 64, 309.

Singh, H., Kumaran, M. S., Bains, A., & Parsad, D. (2015). A randomized com-
25

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1

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Singh, S., Singh, U., & Pandey, S. S. (2012). Serum concentration of IL-6, IL-2,
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TNF-alpha, and IFNgamma in vitiligo patients. Indian Journal of Dermatol-

Letter to the editor

open label study

ogy, 57, 12–14.

Sung, J. Y., Hong, J. H., Kang, H. S., Choi, I., Lim, S. D., Lee, J. K., &
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Hur, G. M. (2000). Methotrexate suppresses the interleukin-6 induced

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(MAZ) gel applied topically once daily in patients with psoriasis

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5: Our report

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2: Alghamdi
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