Histopathological evaluation of facial melasma treated with oral tranexamic acid alone and in combination with ketotifen<sup/>

Cruz, Ana Clara Ladeira; Cassiano, Daniel Pinho; Miot, Hélio Amante; Espósito, Ana Cláudia Cavalcante; Hassum, Karime; Brito, Mackerley Bleixuvehl de; Enokihara, Milvia Maria Simões e Silva; Constantino, Maria Carolina Cavalcanti Lima; Bottura, Heitor Raia; Almeida, Joaquim Soares de; Bagatin, Ediléia

doi:10.1016/j.abd.2026.501336

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ORIGINAL ARTICLE • An. Bras. Dermatol. 101 (03) • 2026 • https://doi.org/10.1016/j.abd.2026.501336 linkcopy

Histopathological evaluation of facial melasma treated with oral tranexamic acid alone and in combination with ketotifen^☆

Authorship SCIMAGO INSTITUTIONS RANKINGS

Background: Tranexamic Acid (TA) has demonstrated effectiveness on melasma treatment, and Ketotifen (KET) may inhibit mast cell-mediated melanogenesis. The histologic basis of their depigmenting effects remains unclear.

Objectives: To evaluate histopathological changes from TA with KET over a 3-month treatment. Methods: In this randomized, double-blind trial, 50 women with facial melasma were assigned to KET 1 mg plus TA 250 mg (TA/KET group) or TA 250 mg (TA group), every 12 h for 3-months, with broad-spectrum sunscreen. Skin biopsies were performed at baseline and day-90. Pri-mary outcome was epidermal melanin density reduction; secondary outcomes included stratum corneum compaction, solar elastosis, basement membrane disruptions, and counts of mast cells, melanocytes (including pendulum melanocytes), and upper dermal VEGF density.

Results: Groups were comparable at baseline. Both showed reduced epidermal melanin without intergroup difference, with unchanged VEGF expression, mast cell and melanocyte count, and stratum corneum parameters. The TA/KET-group presented an increase in epidermal thickness, reduction in solar elastosis, pendulum melanocytes counting, and basal membrane disruptions. Study limitations: The short treatment and follow-up may have limited detection of histologic progression. Toluidine blue, while effective in detecting abundant mast cell populations, may lack sensitivity for precise quantification. PAS staining of the basement membrane may occa-sionally produce artifactual discontinuities, even when the membrane is structurally intact. Ketotifen was not tested alone.

Conclusion: Both interventions led to epidermal melanin reduction. The combination TA/KET induced greater dermal and epidermal remodeling changes that surpassed those with TA alone, showing features associated with photoaging reversal and skin homeostasis restoration.

KEYWORDS
Histology; Ketotifen; Melanosis; Tranexamic acid

Variables	TA/KET group	TA group
n	25	25
Age (years), mean (SD)	48 (6)	45 (7)
Phototype, II and III	4 (16)	9 (36)
n IV	11 (44)	9 (36)
(%) V and VI	10 (40)	7 (28)
Pregnancies, median (P₂₅-P₇₅)	2 (1-2)	2 (1-3)
Daily exposition to the sun (min), mean (SD)	95 (79)	73 (68)
Family history of melasma, n (%)	18 (72)	17 (68)
Age of melasma onset (years), mean (SD)	33 (11)	29 (9)
mMASI, mean (SD)	8 (2)	8 (2)
MELASQoL, mean (SD)	47 (12)	53 (12)
Dif-^*L, mean (SD)	4 (2)	4 (2)

Variables	TA D0 Mean (SD)	D90	p (time)	TA/KET D0 Mean (SD)	D90	p (time)	p (time × group)
Epidermal melanin (intensity)a	84 (13)	67 (16)	<0.001	83 (13)	75 (17)	0.005	0.103
Dermal melanin (intensity)a	21 (14)	13 (7)	0.013	19 (14)	18 (12)	0.74	0.183
Mast cellsb	1.7 (1.9)	2.8 (2.9)	0.154	2.7 (2.2)	2.2 (1.5)	0.253	0.424
Basal layer melanocytesc	16 (5)	14 (5)	0.131	17 (6)	15 (4)	0.085	0.480
Pendulum melanocytesc	1 (0.8)	0.8 (1.3)	0.219	1.5 (1.3)	1 (1.2)	0.015	0.54
Melanocytes area (×10)d	68 (19)	63 (12)	0.344	71 (24)	57 (14)	0.034	0.179
BMZ discontinuitiesc	0.9 (0.8)	0.8 (0.8)	0.776	1.3 (0.9)	0.6 (0.6)	<0.001	0.608
Thickness of the stratum corneum [µm]	40 (12)	43 (16)	0.18	44 (16)	47(13)	0.5	0.335
Thickness of the epidermis [µm]	97 (26)	261 (35)	0.156	282 (30)	264 (33)	<0.001	0.191
Compaction of the stratum corneume	n (%)			n (%)
0 (absent)	10 (40)	10 (47)	0.387	12 (48)	16 (66)	0.257	0.323
1 (partial)	11 (44)	9 (42)		11 (44)	6 (25)
2 (diffuse)	4 (16)	2 (9)		2 (8)	2 (8)
Solar elastosisf	n (%)			n (%)
0 (absent)	3 (12)	4 (19)	0.166	4 (16)	5 (20)	0.014	0.636
1 (mild to moderate)	13 (52)	11 (52)		12 (48)	14 (58)
2 (moderate to severe)	9 (36)	6 (28)		9 (36)	5 (20)
VEGF ×103 intensityg	79 (69)	77 (13)	0.465	73 (68)	76(11)	0.276	0.683

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[TFN1] ^a
Mean pixel intensity, as shown in the color histogram, varies between 0 and 255.

[TFN2] ^b
Number of mast cells (calculated as the mean count across five zones at 40× magnification).

[TFN3] ^c
Absolute number of cells at 40× magnification.

[TFN4] ^d
Melanocytes mean area at 40× magnification.

[TFN5] ^e
Visual qualitative scale: 0 (compactation absent, ‘‘basket-weave’’ pattern), 1 (partial corneum compaction, intermixed areas of compact and non-compact stratum corneum) and 2 (diffuse compaction of the stratum corneum).

[TFN6] ^f
Visual qualitative scale for solar elastosis in the upper dermis: 0 (absent), 1 (mild to moderate) and 2 (moderate to intense).

[TFN7] ^g
Vascular Endothelial Growth Factor (VEGF, Dako, 1:50): mean pixel intensity in the upper dermis. Due to the output scale of the deconvolution algorithm, values were no longer restricted to the standard 8-bit range (0-255) and instead ranged between 73,000 and 7.

Histopathological evaluation of facial melasma treated with oral tranexamic acid alone and in combination with ketotifen☆

Histopathological evaluation of facial melasma treated with oral tranexamic acid alone and in combination with ketotifen^☆