Project on treatment discontinuation.Melasma is found to be

Project
Summary/Proposal

Topic:
Tranexamic Acid in Melasma Treatment

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Student
Name:  Salman Ahmad

MSc
Dermatology in Clinical Practice

University
of South Wales

Date
of Submission: 2 March 2018

 

Background
and Introduction:

 A
common pigmentary condition, melasma, is best defined as localized, chronic –
acquired hyper melanosis of the skin characterized by light to dark brown
macules and patches symmetrically involving the sun-exposed areas of the face,
neck and occasionally the forearms. It is commonly observed in reproductive age
group women, rarely in postmenopausal females and males (10% of cases).
Causative factors implicated in the melasma pathogenesis include genetic
susceptibility, ultraviolet (UV) light exposure, pregnancy, sex hormones,
thyroid disease, cosmetics and medication include oral contraceptive pills, phototoxic
drugs e.g., antiseizure.(Grimes PE,1995)(Park et al,2017)

There
are three clinical patterns of melasma, malar (most
common), centro facial and mandibular. On the basis of visible light,
wood’s light and lesional histology, melasma has been classified as epidermal,
which has increased melanin predominantly in basal and suprabasal layers of the
epidermis with pigment accentuation on Wood’s lamp. The dermal type has
perivascular melanin-laden macrophages in the superficial and deep dermis and
does not accentuate with Wood’s lamp. The mixed variety has elements of both
and appears as deep brown colors with Wood’s lamp accentuation of only the
epidermal component.(Sanchez NP et al,1981)

Melasma
is well known for treatment resistance and relapses on treatment
discontinuation.Melasma is found to be refractory to treatment, with a tendency
to recur after treatment. There is not a single satisfactory treatment
modality to date.(Del Rosario E., et al, 2018) 

In
melasma treatment, the introduction of tranexamic acid ( oral, topical or
intralesional) is relatively a novel concept. The skin?whitening effects of
Tranexamic acid were incidentally found when it was used in the treatment of
aneurysmal subarachnoid hemorrhage. Nijor from Japan,1979 first reported
Tranexamic Acid to be effective in melasma treatment.

 

Objective:

 This
dissertation proposal seeks to offer therapeutic benefits of the use of
Tranexamic acid (TXA) as an innovative agent, either as an oral, topical or
intralesional method for melasma treatment.

 

Importance
of this Proposal: Tranexamic acid being originally a hemostatic agent. Its use
in treating and gaining clinical benefits in Melasma treatment is not highly
documented and there is scope for establishing and validating Tranexamic acid
with accurate, medically focused perspectives.

 

Hypothesis:

HI:
Alternative hypothesis: There have been medically documented and validated
evidence that smaller doses use of Tranexamic acid (250 mg BD) has a beneficial
role in Melasma Treatment(Poojary & Minni, 2015). 

 HO:
Null Hypothesis: There is no medical evidence to even remotely suggest that
smaller doses use of Tranexamic acid (250 mg BD) has a beneficial role in
Melasma Treatment.

 

Methodology:

 This
Proposal uses the qualitative method of research, to achieve the quantum of
literature, findings, and studies to ascertain research question, as the first
step.  The literature used is secondary sources such as trial proceedings
of peers and data from published papers on the effect of TXA treatment on
Melasma. All of the referenced publications will be no older than 10 years and
will not have a low rating. In the next step, the author will infer from the
research and use the new-found knowledge to address the use of TXA. 

 Methods:
The first phase of the research will investigate literature on the chosen topic
to establish the effects of administering Tranexamic acid on Melasma
treatment. 

 At
the outset, it is important to understand Melasma as a disorder and explore the
reasons for its occurrence. Melasma is a pigmentation disorder and is common
among women of Hispanic and Asian groups. The etiology of melasma has yet to be
established, and the course of treatment continues to be a challenge.

Treatment
modalities include use of hypo pigmenting agents such as hydroquinone,
tretinoin, topical corticosteroids, superficial peeling (lactic acid, glycolic
acid, trichloroacetic acid and kojic acid), LASERS (including Q-switched ruby
laser, Q-switched Alexandrite laser, erbium: yttrium-aluminum-garnet (Er: YAG)
laser, Fraxel laser, and intense pulsed light.(Gupta AK et al,2006)

Despite
the availability of these therapies, melasma is often recalcitrant to
treatment, melasma poses a great challenge as its treatment can be often
unsatisfactory with high recurrence rates.(Prignano F et al,2007)

Additionally,
the success rates of all these procedures are considered paradoxical darkening
and low, apart from their recognizable side-effects.

 
Journal paper by Budamakuntla L., et al., titled “A Randomized,
Open-label, Comparative Study of Tranexamic Acid Microinjections’ and
Tranexamic Acid with Microneedling in Patients with Melasma”,

Cho,
Choi, Cho, and Lee titled “Role of oral tranexamic acid in melasma
patients treated with IPL and low fluence QS ND: Yag laser.

Karn
et al, 2012 concluded addition of oral Tranexamic acid to routine treatment
measures provide a rapid and better lightning in patients with melasma. Low
dose oral Tranexamic acid is thus recommended for melasma treatment.

Aamir
S.et al, 2014 concluded a rapid and sustained improvement can be provided
with the introduction of tranexamic acid in melasma treatment which none of the
existing treatment modalities for melasma has provided till date.

Na
Ji, et al., titled” Effect of tranexamic acid on melasma- a clinical trial
with Histological evaluation”

Ebrahim
Naeini study called “Topical tranexamic acid as a promising treatment for
melasma”.

 Anju
George (2015) review article in Journal Pigment International, established that
Tranexamic acid is an effective depigmenting agent as it is a synthetic
derivative of lysine amino acid and useful in arresting the conversion of
plasminogen into plasmin (inhibiting plasminogen activator). The result is a
lower production of arachidonic acid and thereby lowering prostaglandin levels.
Thus, Tranexamic acid becomes responsible for lowered melanocyte tyrosinase
activity and therefore, useful in treating melasma or UV-induced hyperpigmentation.

AWM Tan et al, 2016 concluded low-dose oral Tranexamic acid
can serve as a safe and useful adjunct in the treatment of refractory melasma.
How Tranexamic acid works in lightening melasma is unknown, but it
is possibly by modulating keratinocyte-melanocyte interactions and by
reducing vascularity in melasma lesions and through its effects on mast cells.

 

Padhi T et al,2015 concluded oral tranexamic acid can be
used as an adjunct with fluocinolone based triple combination cream for the
faster and sustained improvement in melasma treatment.

 

Del
Rosario E, Florez- Pollack S, Zapata Jr. L, Hernandez K, Tovar-Garza A,
Rodrigues M, Hynan LS, Pandya AG’s (2017), “Randomized,
placebo-controlled, double-blind study of oral tranexamic acid in the treatment
of moderate to severe melasma” treated 250mg of TA/placebo capsules (2
times a day, for three months) to 44 patients. 39 completed the study and the
primary outcomes were the Modified Melasma Area and the Severity Index (mMASI)
score showing 49% lower mMASI in TA group and 18% in the control
group. Severe melasma showed higher rates of improvement over moderate melasma.
Further, after treatment stopped for three months, there was 26% reduction
in mMASI in the TA Group, over the baseline results. Additionally, they
witnessed 19% reduction in the placebo arm and reported no adverse events in
both the groups. Hence, this study established that oral TXA was effective and
superior to placebo in patients who had moderate to severe melasma, and thus
ideal alternative to standard therapies. The limitations of this group
were:  the study was conducted at a single center where patient demography
was predominantly Hispanic women.

 Other
studies which tested the efficacy of oral Tranexamic acid vs Triple combination
for melasma treatment ( Neerja Puri, 2015) and concluded that recurring melasma
is satisfactorily treated with oral TXA in comparison to the combination of
other modalities. 

Expected
Outcomes

The
therapeutic benefits of the use of Tranexamic acid (TXA), as an innovative
agent, either as an oral, topical or intralesional method for the treatment of
melasma

Gnat
Chart

January-
February: Proposal writing create a list of potential studies to review.

February-March:
Initial review of primary resources with best results on use of TXA for melasma

March–
April: Establish outline by cross-references and secondary data from journal
articles, studies

June
– July: Propose the best way to arrive at proposal objective 

July
– August: Submit Thesis

 

Recommendation:

From
the research studies listed above and literature review, it can be said that
Tranexamic acid as a liposomal topical formulation, Intralesional/Intradermal
Injection of Tranexamic acid and Low-dose oral Tranexamic acid can be a safe
and effective alternative for treating refractory melasma.

 

Conclusion:

Across
the nearly 30 journal articles, books, review articles on the therapeutic
effects of Tranexamic acid in melasma, the conclusion that can be drawn is as
follows: Topical, Intralesional, and low dose oral Tranexamic Acid are highly
useful in treating refractory melasma.

 

Limitations
of study: The research includes the study of two different demographics –
Hispanic and Asians. Therefore, the results of the studies vary in terms of
moderate or high rates of success, is subjective to the population where the
study was conducted.

 

References:

 

·         Grimes
PE (1995) Melasma. Etiologic and therapeutic considerations.Arch Dermatol 131:
1453-1457.

 

·         Sanchez
NP, Pathak MA, Sato S et al. Melasma: A clinical, light microscopic,
ultrastructural, and immunofluorescence study. J Am Acad Dermatol 1981;4:698-
710.

 

 

·         Park,
K.C., and Kim, I.S., 2017. Pathogenesis of Melasma. In Melasma and Vitiligo in
Brown Skin (pp. 21-31). Springer India.

 

·         Gupta
AK, Gover MD, Nouri K, Taylor S. Treatment of melasma: A review of clinical
trials. J Am Acad Dermatol 2006; 55:1048-65.

 

·         Prignano
F, Ortonne J, Buggiani G, Lotti T. Therapeutical approaches in melasma.
Dermatol Clin 2007; 25:337– 342.

 

·         Del
Rosario, E., Florez-Pollack, S., Zapata, L., Hernandez, K., Tovar-Garza, A.,
Rodrigues, M., Hynan, L.S. and Pandya, A.G., 2018. Randomized,
placebo-controlled, double-blind study of oral tranexamic acid in the treatment
of moderate-to-severe melasma. Journal of the American Academy of Dermatology,
78(2), pp.363-369.

 

·         Nijor
T. Treatment of melasma with tranexamic acid. Clin Res 1979;13:3129?31.

 

·         Aamir,
S. and Naseem, R., 2014. The oral tranexamic acid in the treatment of melasma
in Pakistani population: a pilot study. Journal of Pakistan Association of
Dermatology, 24(3), pp.198-203.

 

·         Wu S,
Shi H, Wu H et al. Treatment of melasma with oral administration of tranexamic
acid. Aesthetic Plast Surg. 2012;36:964-70

 

 

·         Atefi,
N., Dalvand, B., Ghassemi, M., Mehran, G. and Heydarian, A., 2017. Therapeutic
Effects of Topical Tranexamic Acid in Comparison with Hydroquinone in Treatment
of Women with Melasma. Dermatology and therapy, 7(3), pp.417-424.

 

·         Ayer,
J., Watson, R., Beck, P., Duncan-Parry, E., Ahmed, A. and Griffiths, C.E.M.,
2014. British Cosmetic Dermatology Group Orals. safety, 13, pp.861-2.

 

·         Banihashemi,
M., Zabolinejad, N., Jaafari, M.R., Salehi, M. and Jabari, A., 2015. Comparison
of therapeutic effects of liposomal Tranexamic Acid and conventional
Hydroquinone on melasma. Journal of cosmetic dermatology, 14(3), pp.174-177.

 

·         Budamakuntla,
L., Loganathan, E., Suresh, D.H., Shanmugam, S., Suryanarayan, S., Dongare, A.,
Venkataramiah, L.D. and Prabhu, N., 2013. A randomized, open-label, comparative
study of tranexamic acid microinjections and tranexamic acid with micro
needling in patients with melasma. Journal of cutaneous and aesthetic surgery,
6(3), p.139.

 

·          Karn
D, KC S, Amatya A, Razouria EA, Timalsina M. Oral Tranexamic Acid for the
Treatment of Melasma. Kathmandu Univ Med J 2012;10(4):40-43.

 

·         Li Y,
Sun Q, He Z et al. Treatment of melasma with oral administration of compound
tranexamic acid: a preliminary clinical trial. J. Eur. Acad. Dermatol.
Venereol. 2014; 28: 393–4.

 

·         Kanechorn
Na Ayuthaya P, Niumphradit N, Manosroi A et al.Topical 5% tranexamic acid for
the treatment of melasma in Asians: a double-blind randomized controlled
clinical trial. J Cosmet Laser Ther. 2012; 14: 150–4.

 

·         Dashore,
S. and Mishra, K., 2017. Tranexamic acid in melasma: Why and how?. Indian
Journal of Drugs in Dermatology, 3(2), p.61.

 

·         George,
A., 2016. Tranexamic acid: An emerging depigmenting agent. Pigment
International, 3(2), p.66.

 

·         Guevara,
I.L. and Pandya, A.G., 2003. Safety and efficacy of 4% hydroquinone combined
with 10% glycolic acid, antioxidants, and sunscreen in the treatment of
melasma. International journal of dermatology, 42(12), pp.966-972.

 

·         Hurley,
M.E., Guevara, I.L., Gonzales, R.M. and Pandya, A.G., 2002. Efficacy of
glycolic acid peels in the treatment of melasma. Archives of Dermatology,
138(12), pp.1578-1582.

 

·         Lee,
D.H., Oh, I.Y., Koo, K.T., Suk, J.M., Jung, S.W., Park, J.O., Kim, B.J. and
Choi, Y.M., 2014. Reduction in facial hyperpigmentation after treatment with a
combination of topical niacinamide and tranexamic acid: a randomized, double?blind, vehicle?controlled
trial. Skin Research and Technology, 20(2), pp.208-212.

 

·         Lee,
J.H., Park, J.G., Lim, S.H., Kim, J.Y., Ahn, K.Y., KIM, M.Y. and Park, Y.M.,
2006. Localized intradermal microinjection of tranexamic acid for treatment of
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·         Kim,
H.J., Moon, S.H., Cho, S.H., Lee, J.D. and Kim, H.S., 2017. Efficacy and Safety
of Tranexamic Acid in Melasma: A Meta-analysis and Systematic Review. Acta
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·         Kwon,
S.H., Hwang, Y.J., Lee, S.K. and Park, K.C., 2016. Heterogeneous pathology of
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·         Machekposhti,
S.A., Soltani, M., Najafizadeh, P., Ebrahimi, S.A. and Chen, P., 2017.
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·         Manosroi,
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·         Padhi,
T., & Pradhan, S. (2015). Oral tranexamic acid with fluocinolone based
triple combination cream versus fluocinolone-based triple combination cream
alone in melasma: An open-labeled randomized comparative trial. Indian
Journal of Dermatology, 60, 520–525.

 

 

·         Na,
J.I., Choi, S.Y., Yang, S.H., Choi, H.R., Kang, H.Y. and Park, K.C., 2013.
Effect of tranexamic acid on melasma: a clinical trial with histological
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·         Nanda,
S., Grover, C. and Reddy, B.S., 2004. Efficacy of hydroquinone (2%) versus
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with melasma. Dermatologic surgery, 30(3), pp.385-389.

 

·         Poojary,
S. and Minni, K., 2015. Tranexamic acid in melasma: A review. Pigmentary
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·         Tulika Rai. Role of
Tranexamic Acid in Management of Melasma.
Cosmetol J 2017, 1(1): 000102

 

 

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M. and Pandya, A.G., 2015. Melasma: clinical diagnosis and management options.
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·         Sharma,
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·         Tan,
A.W.M., Sen, P., Chua, S.H. and Goh, B.K., 2016. Oral tranexamic acid lightens
refractory melasma. Australasian Journal of Dermatology, 58(3).

 

·         Veggalam,
V. and Perumalla, N., 2017. Intralesional tranexamic acid: Safe and effective
way of treatment for melasma. Indian Journal of Drugs in Dermatology, 3(2),
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·         Yoo,
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·         Taraz
M, Niknam S, and Ehsani AH.Tranexamic acid in the treatment of melasma: A
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·         Lee,
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