European Journal of Cardiovascular Medicine

Chloasma (now known as Melasma) is derived from a Greek word which means “to become green”.1 Melasma is also known as the “mask of pregnancy” when associated with pregnancy it ends as soon as pregnancy ends.2 Melasma (Chloasma) is more commonly found in females with darker skin complexions.3. Sanchez N.P. et al4 classified Melasma into three patterns; 1. Centro facial i.e., 63% cheek, forehead, upper lip, nose, chin. 2. Malar i.e., 21% malar area of face and 3. Mandibular i.e, 16% ramus of mandible. Different treatment modalities for Melasma include general measures like avoiding excessive exposure to sunlight and Topical Agents such as phenolic (Hydroquinone, 4-isopropyl catechol, N-acetyl-4-Scysteinylphenol,4-Hidroxianisol) and non-phenolic compounds (Niacinamide, Retinoids, Corticosteroid, Azelaic Acid, L-ascorbic acid) as well as combination therapies like Kligman’s formula 5 and newer approaches like Laser. 6 Original Kligman’s formula is one of the most studied and widely prescribed formulas for Melasma by physicians, which includes Dexamethasone (0.1%), Tretinoin (0.1%) and Hydroquinone(5%)7. This formula was founded by Albert M Kligman and I Willis8. This formula was founded in 19759. Later, it was replaced by a mid-potent topical steroid -Mometasone Furoate 0.1%10. But, out of all the different variations of the triple combination, the one with fluocinolone acetonide 0.01%, Hydroquinone 4%, and Tretinoin 0.05% is the only topical treatment approved by US Food and Drug Administration11. There is a paucity of comparative studies on efficacy and safety of these new-age treatments and various combinations. 7 . Therefore, in this present study, an attempt was made to fill this gap by comparing the clinical efficacy and safety of Fluocinolone Acetonide 0.01%, Vs Mometasone Furoate 0.1 % cream in the treatment of Melasma.

Triple combination cream from the same company (INTAS) containing the same base and content, only the steroid molecule is different [LOMELA containing Mometasone Furoate (0.1%) and GLOMELA containing Fluocinolone acetonide (0.01%)], and same sunscreen (MELAGARD) was used for each patient enrolled in the study.

It was a split-face interventional study, wherein a total of 20 clinically diagnosed patients of Melasma were enrolled as per the inclusion and exclusion criteria. Menstruating women in the age group of 20-45 with melasma were included in the study while pregnant or nursing women, women on contraceptive pills at the time of the study or in the past 6 months, patients on any concurrent therapy, patients with hypersensitivity to the formulations, concurrent illnesses, or having used topical steroids or hydroquinone 2 weeks before study entry and systemic steroids for 1 month were excluded from the study. Informed consent was obtained from all the patients after explaining all the aspects of the study. A complete history (including general medical history, family history, past history and history of previous treatment for the disease) was taken; cutaneous and systemic examinations were done and documented in predesigned study performa. All patients were instructed to apply the Fluocinolone acetonide 0•01% containing TC cream on the right side and Mometasone Furoate 0.1 % containing TC cream on the left side of the face. Patients were instructed to apply every topical agent at night time, applying evenly without excessive rubbing. Patients were instructed to use sunscreen lotion in the daytime. Pre-treatment MASI score was noted and pre-treatment photographic documentation was done. Melasma Area and Severity Index (MASI) score 12 is developed by Kimbrough-green et. Al, for the assessment of Melasma. The severity of Melasama in each of the four regions (forehead, right malar region, left the malar region and chin) is assessed based on the total area involved (A), darkness (D) and homogeneity (H). A numerical value is assigned for the corresponding percentage area involved as follows:0= no involvement; 1 = <10% involvement; 2 = 10-29% involvement; 3 = 30-49% involvement; 4 = 50-69% involvement; 5 = 70-89% involvement; 6= 90-100% involvement. The darkness of melasma (D) is compared to the normal skin and graded on a scale of 0 to 4 as follows: 0=normal skin colour without evidence of hyperpigmentation; 1=barely visible hyperpigmentation; 2=mild hyperpigmentation; 3=moderate hyperpigmentation; 4=severe hyperpigmentation. Homogeneity of the hyperpigmentation (H) is also graded on a scale of 0 to 4 as follows: 0=normal skin colour without evidence of hyperpigmentation; 1=specks of involvement; 2=small patchy areas of involvement <1.5 cm diameter; 3=patches of involvement >2 cm diameter; 4=uniform skin involvement without any clear areas.

To calculate the MASI score, the sum of the severity grade for darkness (D) and homogeneity (H) is multiplied by the numerical value of area (A) involved and by the percentage of the four facial areas (10-30%). MASI = 0.3(Df + Hf)Af + 0.3(Drm + Hrm)Arm + 0.3(Dlm + Hlm)Alm + 0.1(Dc + Hc)Ac(f = Forehead, mr = Right malar, ml = Left malar, c = Chin) Photographic and clinical assessments were carried out at 0, 2, 6, and 12 weeks. Subjects were enquired at each visit about the effect of the drug and signs of improvement. Patients were asked not to interchange the medication. They were not supposed to use any other medication. Nature and type of adverse event were recorded in the performa. Finally, all findings were analysed statistically, and an attempt was made to compare the results of the present study.

The proportion of patients showing improvement has been reported in proportions and mean difference in the MASI score for the two creams has been reported with Mann-Whitney U test. P-value of <0.05 is considered statistically significant.

A total of 20 patients were studied who met the inclusion and exclusion criteria. Out of 20, 15 patients were followed for 12 weeks while five patients were followed up to 6 weeks. The youngest case enrolled in our study was 24 years old and the eldest case was 47 years old.

There is a 79.40% improvement in MASI score when 0.01% Flucinolone acetonide TC applied on right side of the cheek with MASI score 6.63 at 0 week to 1.31 at 12-weeks. (Table 1) In the same manner 0.1% Mometasone Furoate TC when applied on Left side of the cheek shown an improvement of 75.79% in MASI score which is 6.57 at the 0 week to 1.59 at the 12 weeks. When  0.01% Flucinolone Acetonide TC was applied on the Right side of the cheek and 0.1% Mometasone Furoate TC on Left side of the cheek the results are that, there is a 30.82% percentage improvement in MASI score ( from 4.51 at 0 weeks and 3.12 at 6 weeks) on the Right side of the cheek and 29.1% improvement in MASI score ( from 4.57 at 0 week to 3.24 at 6 weeks)on the Left side of the cheek. (Table 2)

Table 1. Pre and Post-treatment Average MASI Score i.e. at 0 week and 12 weeks (i.e. end of treatment) (N=15)

Table 2. Pre and Post-treatment MASI score i.e. at 0 week and 6 week. (N=5)

Figure 1. Difference of MASI score at 0 and 12 weeks in patients put on Mometasone furoate (0.01%) and Fluocinolone acetonide 0.01% (n=15) and 0 and 6 weeks (n=5)

A two sample t-test was performed to compare Mometasone Furoate(0.01%) and Flucinolone acetonide (0.01%).There was not a significant difference between Mometasone Furoate(0.01%) Mean =4.0675 , SD = 3.0697 and  Flucinolone acetonide (0.01%) Mean = 4.1325, SD = 3.0966 , with p = 0.9472.

Table 3. Distribution according to the type of side effects

In this study population, the cutaneous side effects were observed in two patients using Fluocinolone acetonide 0.01% on the right side of the cheek out of 20 patients; while in five patients using Mometasone furoate 0.1% on the left side of the cheek. The most common side effect was erythema in four patients followed by burning in three patients and dryness in two patients. Erythema was seen in only one patient using Fluocinolone acetonide 0.01% TC, while in three patients using Mometasone Furoate 0.1% TC. Burning was seen in two patients using Mometasone Furoate 0.1% TC, while in only one patient using Fluocinolone acetonide 0.01% TC. (Table 3) All side effects were reversible.

Melasma is the most commonly found at any time during the years of reproductive activity. It is the most common pigment disorder in India13. Melasma is very commonly found in pregnant women, about 15% to 50% of pregnant women acquire it. About 1.5% to 33% population has the chance to get it but it happens rarely during puberty and more often during the reproductive years of a woman14.Although, it is more common in women, almost 10% of the cases can occur in men. The clinical and histological features are the same in women and men15. Topical agents are much more effective in the epidermal type of melasma among all available treatment modalities16. Studies have shown that the first line of treatment is sun protection along with topical bleaching agents containing sunscreens. Faster results have been seen in patients who have been treated with a combination of topical agents, oral medications and procedures17. Previous studies have supported that the triple combination of hydroquinone, retinoic acid and corticosteroid is the first-line treatment for this pigment disorder7. Another study has shown that Triple-combination cream was significantly more effective at lightening melasma than hydroquinone alone or the dual combinations of tretinoin and hydroquinone, tretinoin and fluocinolone acetonide or hydroquinone and fluocinolone acetonide18. In a triple combination, the topical steroid decreases the irritation of topical retinoids, topical retinoids increase keratinocytes proliferation and also increase the penetration of hydroquinone while hydroquinone has pigment inhibition effects on its own19. One combination involves 0.05% tretinoin 4.0% hydroquinone and 0.01% flucinolone acetonide. Another study with Tretinoin (0.05%), Hydroquinone (4%) and mometasone furoate (0.1%) as a triple combination has shown effective for Indian skin20. In Indian treatment, hydrocortisone is replaced by a mid-potent topical steroid -Mometasone10. Mometasone furoate is lipophilic and it also has a quality to remain topically in the skin promising fewer systemic side effects21. Fluocinolone has medium strength and a tendency to decrease swelling, itching and redness and can improve melasma10. Many patients with triple combination have shown increased sensitivity to sun exposure, skin atrophy and telangiectasia caused by steroids18.

Mometasone Furoate has been shown to be useful for the Indian skin22 and Fluocinolone acetonide 0.01% also showed good results in a clinical trial23. Keeping this in mind two topical drugs i.e., Fluocinolone acetonide 0.01% TC and Mometasone Furoate 0.1%TC, which are commonly used in melasma with this dosage but with different combinations, are compared in terms of their effectiveness and adverse effects. The MASI score, which expressed effectiveness in the two medications showed good improvement at 0 and 6 weeks as well as at 0 and 12 weeks. The mean difference in the MASI score for both the medications was not statistically significant. Thus, this shows, that in our study, both the medications - Fluocinolone acetonide 0.01% TC and Mometasone Furoate 0.1%TC were equally effective. Thus, either of them can be used. In terms of side effects, the most common side effect was erythema; seen in three patients out of four who were on Mometasone furoate 0.1% TC. However, these were reversible side effects. Therefore, this study concludes that both, Flucinolone acetonide 0.01% TC and Mometasone Furoate 0.1%TC are equal in effectiveness but Mometasone Furoate 0.1%TC has more side effects as compared to Flucinolone Acetonide 0.01%TC.  This study has certain strengths. It was conducted in a tertiary hospital, having patients from varied regions and probably coming for treatment in later stages. Hence, the effectiveness studied would help for a varied population with severe malasma cases. To our knowledge, there have been no studies so far to compare the effectiveness of the two medications Flucinolone acetonide 0.01% TC and Mometasone Furoate 0.1%TC on treatment of melasma.

A limited sample size is the limitation of the study. Further follow up of the same cohort and increasing the sample size for a similar study can help to understand the long-term effectiveness as well as help to study the side effects in greater details. The participants were not supervised during the application of the creams, so there could be an error on the patient's side which is difficult to identify.

1. Melasma [Internet]. [cited 2023 May 21]. Available from: https://dermnetnz.org/topics/melasma
2. Melasma (Chloasma) [Internet]. 2019 [cited 2023 May 21]. Available from: https://www.health.harvard.edu/a_to_z/melasma-chloasma-a-to-z#:~:text=What%20Is%20It%3F,in%20a%20nearly%20identical%20pattern.
3. Griffiths C, Barker J, Bleiker T, Chalmers R, Creamer D. Rook’s Textbook of Dermatology. Chichester, West Sussex: John Wiley &amp; Sons, Ltd; 2016.
4. [Internet]. [cited 2023 May 21]. Available from: https://reference.medscape.com/medline/abstract/6787100
5. [Internet]. [cited 2023 May 28]. Available from: https://cms.galenos.com.tr/Uploads/Article_20221/BAS-6-54-En.pdf
6. Sheth P. Newer and upcoming therapies for Melasma [Internet]. scientific scholar; 2012 [cited 2023 May 29]. Available from: https://ijdvl.com/newer-and-upcoming-therapies-for-melasma/
7. Bandyopadhyay D. Topical treatment of Melasma [Internet]. U.S. National Library of Medicine; 2009 [cited 2023 May 21]. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2807702/
8. I; KA. A new formula for depigmenting human skin [Internet]. U.S. National Library of Medicine; [cited 2023 May 29]. Available from: https://pubmed.ncbi.nlm.nih.gov/1119822/
9. Internet]. [cited 2023 May 28]. Available from: https://www.wcd2019milan-dl.org/abstract-book/documents/abstracts/33-pigmentation/modified-kligman-formula-leading-to-2211.pdf
10. Rendon M;Cardona LM;Bussear EW;Benitez AL;Colón LE;Johnson LA; Successful treatment of moderate to severe melasma with triple-combination cream and glycolic acid peels: A pilot study [Internet]. U.S. National Library of Medicine; [cited 2023 May 29]. Available from: https://pubmed.ncbi.nlm.nih.gov/19090343/#:~:text=Triple%2Dcombination%20(TC)%20cream,the%20topical%20treatment%20of%20melasma
11. Godse KV. Triple combination of hydroquinone, tretinoin and Mometasone furoate with glycolic acid peels in Melasma [Internet]. U.S. National Library of Medicine; 2009 [cited 2023 May 23]. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/ PMC2800888
12. Ogbechie-Godec OA, Elbuluk N. Melasma: An up-to-date comprehensive review [Internet]. U.S. National Library of Medicine; 2017 [cited 2023 May 21]. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5574745/
13. Bhor U, Pande S. Scoring systems in dermatology. Indian Journal of Dermatology, Venereology and Leprology. 2006;72(4):315. doi:10.4103/0378-6323.26722
14. Melasma: Treatment, causes &amp; prevention [Internet]. [cited 2023 May 21]. Available from: https://my.clevelandclinic.org/health/diseases/21454-melasma
15. S; PJB. Pigmentary disorders in India [Internet]. U.S. National Library of Medicine; [cited 2023 May 21]. Available from: https://pubmed.ncbi.nlm.nih.gov/17662900/
16. Vázquez M, Maldonado H, Benmamán C, Sanchez JL. Melasma in men. International Journal of Dermatology. 1988;27(1):25–7. doi:10.1111/j.1365-4362.1988.tb02329.x
17. Cassiano DP, Espósito ACC, Silva CN da, Lima PB, Dias JAF, Hassun K, et al. Update on Melasma-Part II: Treatment - dermatology and therapy [Internet]. Springer Healthcare; 2022 [cited 2023 May 23]. Available from: https://link.springer.com/article/10.1007/s13555-022-00780-4
18. Treatments for Melasma (darker than normal skin occurring in patches) [Internet]. [cited 2023 May 21]. Available from: https://www.cochrane.org/CD003583/SKIN_treatments-for-melasma-darker-than-normal-skin-occurring-in-patches
19. Majid I. Mometasone-based triple combination therapy in Melasma: Is it really safe? Indian Journal of Dermatology. 2010;55(4):359. doi:10.4103/0019-5154.74545
20. Fluocinolone-hydroquinone-tretinoin topical: Uses, side effects, interactions, pictures, warnings &amp; dosing [Internet]. WebMD; [cited 2023 May 23]. Available from: https://www.webmd.com/drugs/2/drug-32574/fluocinolone-hydroquinone-tretinoin-topical/details#:~:text=Fluocinolone is a medium strength,may cause it to return.
21. HM; T. A comprehensive review of the long-term and short-term treatment of Melasma with a triple combination cream [Internet]. U.S. National Library of Medicine; [cited 2023 May 23]. Available from: https://pubmed.ncbi.nlm.nih.gov/16901182/
22. Godse KV. Triple combination of hydroquinone, tretinoin and mometasone furoate with glycolic acid peels in melasma. Indian J Dermatol. 2009;54(1):92-3. doi: 10.4103/0019-5154.49005. PMID: 20049286; PMCID: PMC2800888.
23. Torok HM, Jones T, Rich P, Smith S, Tschen E. Hydroquinone 4%, tretinoin 0.05%, fluocinolone acetonide 0.01%: a safe and efficacious 12-month treatment for melasma. Cutis. 2005;75(1):57-62.