Project of cases). Causative factors implicated in the melisma

Project Summary/ProposalTopic: Tranexamic Acid in Melasma TreatmentStudent Name:  Salman AhmadMSc Dermatology in Clinical PracticeUniversity of South WalesDate 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 melisma pathogenesis include genetic susceptibility, ultraviolet (UV) light exposure, pregnancy, sex hormones, contraceptive pills, thyroid disease, cosmetics, phototoxic drugs (e.g., antiseizure medications).(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 OutcomesThe 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 melasmaGnat ChartJanuary- 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 melasmaMarch– April: Establish outline by cross-references and secondary data from journal articles, studiesJune – 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 is 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 melasma in Asian patients: a preliminary clinical trial. Dermatologic surgery, 32(5), pp.626-631. ·         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 Dermatol-venereologica. ·         Kwon, S.H., Hwang, Y.J., Lee, S.K. and Park, K.C., 2016. Heterogeneous pathology of melasma and its clinical implications. International journal of molecular sciences, 17(6), p.824. ·         Machekposhti, S.A., Soltani, M., Najafizadeh, P., Ebrahimi, S.A. and Chen, P., 2017. Biocompatible polymer microneedle for topical/dermal delivery of tranexamic acid. Journal of Controlled Release, 261, pp.87-92. ·         Manosroi, A., Podjanasoonthon, K., and Manosroi, J., 2002. Development of novel topical tranexamic acid liposome formulations. International Journal of Pharmaceutics, 235(1), pp.61-70. ·         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 evaluation. Journal of the European Academy of Dermatology and Venereology, 27(8), pp.1035-1039. ·         Nanda, S., Grover, C. and Reddy, B.S., 2004. Efficacy of hydroquinone (2%) versus tretinoin (0.025%) as adjunct topical agents for chemical peeling in patients with melasma. Dermatologic surgery, 30(3), pp.385-389. ·         Poojary, S. and Minni, K., 2015. Tranexamic acid in melasma: A review. Pigmentary Disorders, 2(228), pp.2376-0427. ·         Tulika Rai. Role of Tranexamic Acid in Management of Melasma. Cosmetol J 2017, 1(1): 000102  ·         Rodrigues, M. and Pandya, A.G., 2015. Melasma: clinical diagnosis and management options. Australasian Journal of Dermatology, 56(3), pp.151-163. ·         Sharma, R., Mahajan, V.K., Mehta, K.S., Chauhan, P.S., Rawat, R., and Shiny, T.N., 2017. Therapeutic efficacy and safety of oral tranexamic acid and that of tranexamic acid local infiltration with microinjections in patients with melasma: a comparative study. Clinical and experimental dermatology, 42(7), pp.728-734. ·         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), p.81. ·         Viyoch, J., Tengamnuay, I., Phetdee, K., Tuntijarukorn, P. and Waranuch, N., 2010. Effects of trans-4-(aminomethyl) cyclohexane carboxylic acid/potassium azeloyl diglycinate/niacinamide topical emulsion in Thai adults with melasma: a single-center, randomized, double-blind, controlled study. Current Therapeutic Research, 71(6), pp.345-359. ·         Yoo, J., Ahn, H., Kim, M.S., Jue, M.S. and Choi, K.H., 2017. Efficacy of Topical Tranexamic Acid in Treatment of Melasma. Korean Journal of Dermatology, 55(5), pp.283-289. ·         Taraz M, Niknam S, and Ehsani AH.Tranexamic acid in the treatment of melasma: A comprehensive review of clinical studies. Dermatologic Therapy. 2017;00:e12465. doi:10.1111/dth.12465. ·         Lee, H. C., Thng, T. G., & Goh, C. L. (2016). The oral tranexamic acid in the treatment of melasma: A retrospective analysis. Journal of The American Academy of Dermatology, 75, 385–392.