By Dominique Butler and Peter Lio, MD

Introduction

Vitiligo is a multifaceted skin disorder, characterized by the loss of pigment in affected regions of the skin, via a gradual decrease in melanocytes¹. Exhibiting a hallmark lesion that is amelanotic, chalk-white, and non-scaly, the disorder commonly affects the face, lips, hands, arms, feet, and genitalia^2,3. This depigmenting autoimmune disease is the most common of the hypopigmentary skin disorders³.

Globally occurring in most populations, vitiligo has an estimated prevalence of 0.5–1%. The disease often commences before age 20, occurring in males and females with approximately equal frequency⁴.

While vitiligo is sometimes viewed as an esthetic concern, it poses some serious mental health consequences. Anxiety and depression represent the leading mental health conditions seen in connection with the disease. These may be the psychological consequences of social embarrassment and/or aggravating factors of vitiligo. Patients affected by vitiligo are also more prone to living a solitary life. This consequently leads to social anxiety, difficulties in both school and the workplace, as well as romantic relationship struggles⁵. Patients who are affected often experience social stigma, which can cause a patient to lose confidence in themselves, thus having the trajectory of their lives impacted in a profound way⁶.

Pathogenesis

Vitiligo is commonly known as a multifactorial polygenic disorder with complex pathogenesis. The underlying pathogenic etiology process remains unclear^3. However, it is possible that the disease may be triggered by certain events, including the exposure to specific chemicals, hormonal changes, including puberty, as well as stressful events, such as childbirth, in addition to skin damage, as seen in severe sunburns or cuts⁷. Despite this uncertainty, there have been many recent advancements. These scientific developments have classified vitiligo as an autoimmune disorder connected with hormonal and hereditary influences¹.

A leading hypothesis for the pathogenesis of vitiligo is the autoimmunity hypothesis, which conveys that patients with the skin condition are more susceptible to oxidative stress. In fact, oxidative stress is considered to play a crucial role in launching autoimmune responses in connection with vitiligo. Specifically, oxidative stress brings about the release of exosomes and inflammatory cytokines, which will then go on to activate the innate immune response. Close behind are the autoreactive cytotoxic CD8+ T cells, which initiate the adaptive immune response. These CD8+ T cells go on to produce interferon-γ (IFN-γ), which promotes disease progression via chemokine secretion from surrounding keratinocytes, enabling the expansion of T cells to the skin via a positive feedback loop mechanism.

Additionally, the neural hypothesis of vitiligo serves as another potential explanation of pathogenic etiology of the disease. It is supported by several findings that illustrate how various neurochemical mediators are responsible for the toxicity towards melanocytes, unfortunately leading to their destruction. Neural factors, as well as emotional, and/or stressful events appear to play a pivotal role in vitiligo onset or exacerbation⁸.

In the intrinsic defect of melanocytes hypothesis, it demonstrates how there is an inherent abnormality that exists, which impedes melanocyte growth and differentiation⁹.

Treatment

Conventional Therapies

Due to its complex pathogenesis, vitiligo presents unique challenges in terms of treatment. Treatment modalities are selected for the individual patient based on disease location and severity, disease activity, patient preference, as well as response evaluation¹⁰.

Recently, novel topical agents targeting Janus kinase (JAK), a family of tyrosine kinases that regulates cytokine signaling, have emerged. JAK inhibitors have demonstrated remarkable efficacy in the management of vitiligo.Ruxolitinib (Opzelura, Incyte) is the first approved JAK inhibitor in vitiligo therapy and has brought more attention to the disease¹¹. While it is an important new addition, it unfortunately carries a boxed warning that can be a cause of concern for patients and families.

Topical corticosteroids have long served as the pillars of localized vitiligo treatment. Although these agents are effective, long-term usage of steroids may cause atrophy, striae, telangiectasias, acneiform eruptions, hypertension, osteoporosis, Cushing’s syndrome, and a host of other conditions¹². Calcineurin inhibitors, such as topical tacrolimus (0.03 or 0.1%) and pimecrolimus (1%) are also commonly employed in treating vitiligo, though they are not specifically approved for this indication. They are particularly preferred to topical corticosteroids for patients with limited vitiligo pertaining to the face or areas at high risk for skin atrophy, such as intertriginous areas and the genitals¹². Narrowband-ultraviolet B (NB-UVB) is used for the treatment of vitiligo, as well. It can be administered as monotherapy or in combination with topical or systemic agents¹³.

Due to the potential safety risks—both real and perceived—that some treatments pose, there is an imperative need to discover additional treatment modalities. Natural and herbal agents offer the potential for both affordability and accessibility with safety¹⁴.

Turmeric and Curcuminoids

 Turmeric is a golden spice, derived from the rhizome of the herb plant Curcuma Longa. Curcuma Longa is a perennial herb that comes from the lineage of the Zingiberaceae family and is indigenous to South Asia’s tropical areas. The yellow-orange powder has been used in Asian cookery, medicine, cosmetics, and fabric coloring for at least the past 2000 years. For centuries, turmeric has been used as a remedy in treating several diseases in the Ayurvedic and Chinese Medicinal Systems^15,16.

Turmeric contains several chemically related compounds, known as curcuminoids. Generally, turmeric rhizomes contain 3-5% of three types of curcuminoid derivatives, including curcumin (75%), demethoxycurcumin (10-20%) and bisdemethoxycurcumin (<5%), curcumin being the most prominent bioactive compound. It is also perhaps the most studied component [16]. Often employed for its taste, appearance, and preservation of food, the crystalline compound also appears to have medicinal healing powers, dating back to ancient civilization ^17.18.

Since the discovery of its antibacterial properties in 1949¹⁸, many studies have ascertained that curcumin possesses an assortment of additional beneficial properties. These include analgesic¹⁸, anti-atherosclerotic^18,19, antithrombotic^19,20, wound healing^18,20,21, immunomodulatory^{19, 22,23,24}, neuroprotective ^{20, 25, 26}, and pulmonoprotective ^{19, 20, 27, 28}properties, among many additional effects, as well.

Numerous animal studies have shown the potential of this spice against inflammatory diseases, cancer, depression, diabetes, and obesity. Further, it has been shown to have an anti-viral effect on several viruses, including HIV, HBV, influenza, and coxsackievirus¹⁸. Importantly, various studies have shown positive results involving turmeric and its associated compounds in treating vitiligo.

In a case reported by Alshaikh et al., a 41-year-old man presented with vitiligo. He was recommended a daily drink consisting of hot water, and he added turmeric powder (curcuma longa) and honey. During his months of treatment, he observed that some of the lesions on his legs and right nipple had begun to show pigment restoration⁶. While only an anecdote, it raises the possibility that turmeric may be useful in this condition.

In an integrative study of 10 patients, conducted by Asawononda et al., researchers evaluated the efficacy of targeted narrowband UVB phototherapy plus topical tetrahydrocurcuminoid cream versus targeted narrowband UVB alone on vitiligo. They found that patients treated with narrowband UVB phototherapy in combination with the tetrahydrocurcuminoid cream showed enhanced repigmentation of vitiligo lesions in comparison to those treated with narrowband UVB monotherapy at 8 and 12 weeks at p=0.078 and 0.158, respectively. Researchers further mentioned how combination treatment began to show effectiveness from week 8 onwards. They believed that extending the duration of treatment may have potentially led to results that were more pronounced²⁹.

In a study by Jalalmanesh et al., 24 patients were treated with both a topical turmeric cream and a placebo vehicle cream. Researchers observed a reduction in lesion size, as well as improvement in the appearance of the lesions in the active treatment group compared to the vehicle group (p < 0.001). Further, the patient satisfaction score was higher following the application of turmeric cream, compared to that of the placebo (p < 0.05)³⁰.

Becatti et al. observed that the application of capsaicin and curcumin each increased the cellular total antioxidant capacity and decreased reactive oxygen species formation, thereby inhibiting keratinocyte apoptosis. Thus, capsaicin and curcumin were shown to prevent and inhibit disease progression and promote repigmentation in vitiligo³¹.  (See Table 1.)

With regards to safety, this medicinal herb is well-tolerated, having negligible systemic toxicity, even when administered at high oral doses^{28, 32, 33, 34}. Studies have designated the safety of curcumin at doses as high as 12g/day over a course of 3-months³⁵.

Although there are many potential benefits in using curcuminoids in the treatment of vitiligo, there are some limitations that exist. Turmeric remains a food/supplement and has not been approved as a drug. Relative bioavailability remains a potential issue. Specifically, due to having poor absorption, rapid metabolism, and rapid systemic elimination, it is likely that only very small amounts of curcumin are able to reach the skin. Thus, the specific formulation and preparation may have much greater impact than with other supplements¹⁹. Moreover, when applied topically, curcumin’s yellow-orange color has the potential to cause cosmetically unappealing skin coloration.

Conclusion

Patients with vitiligo often face social stigma and develop mental health conditions in addition to experiencing challenges in both school and in the workplace. Currently, various treatment modalities exist for vitiligo and continue to expand.  However, alternative methods have been explored including turmeric and associated curcuminoids. These have demonstrated at least some treatment efficacy in the repigmentation of skin lesions seen in vitiligo. These compounds do exhibit some limitations, including potentially low bioavailability, which researchers are continuing to find ways to improve. Overall, turmeric and its associated curcuminoids are a potential alternative or complementary treatment option for vitiligo. Based on various clinical study results of this healing spice, there is hope that patients with vitiligo are able to lead lives that are filled with confidence, peace, and joy.

References:

1. Dutta RR, Kumar T, Ingole N. Diet and Vitiligo: The Story So Far. Cureus. 2022; 28;14(8):e28516. doi: 10.7759/cureus.28516. PMID: 36185835; PMCID: PMC9515252.

2. Picardo, Mauro & Dell’Anna, Maria Lucia & Ezzedine, Khaled & Hamzavi, Iltefat & Harris, John & Parsad, Davinder & Taieb, Alain. (2015). Vitiligo. Nature Reviews Disease Primers. 1. 15011. 10.1038/nrdp.2015.11.

3. Ezzedine K, Lim HW, Suzuki T, et al.Revised classification/nomenclature of vitiligo and related issues: the Vitiligo Global Issues Consensus Conference..Pigment Cell Melanoma Res. 2012;25:0–13.

4. Sawant NS, Vanjari NA, Khopkar U. Gender Differences in Depression, Coping, Stigma, and Quality of Life in Patients of Vitiligo. Dermatol Res Pract. 2019:6879412. doi: 10.1155/2019/6879412. PMID: 31065260; PMCID: PMC6466925.

5. Di Bartolomeo L, Custurone P, Irrera N, et al. Vitiligo and Mental Health: Natural Compounds’ Usefulness. Antioxidants (Basel). 2023;12(1):176. doi: 10.3390/antiox12010176. PMID: 36671038; PMCID: PMC9854903.

6. Alshaikh AA, Bharti RK. Spontaneous Reversal of Vitiligo, a Rare Phenomenon Reported in a Case in Saudi Arabia with an Insight into Metabolic Biochemical Derangements. Medicina (Kaunas). 2023;59(3):427. doi: 10.3390/medicina59030427. PMID: 36984427; PMCID: PMC10053937.

7. (2023, March 22). NHS choices. https://www.nhs.uk/conditions/vitiligo/

8. Diotallevi F, Gioacchini H, De Simoni E, et al. Vitiligo, from Pathogenesis to Therapeutic Advances: State of the Art. Int J Mol Sci. 2023;24(5):4910. doi: 10.3390/ijms24054910. PMID: 36902341; PMCID: PMC10003418.

9. Ahmed jan N, Masood S. Vitiligo. [Updated 2023 Aug 7]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2024 . Available from: https://www.ncbi.nlm.nih.gov/books/NBK559149/

10. Iwanowski T, Kołkowski K, Nowicki RJ, Sokołowska-Wojdyło M. Etiopathogenesis and Emerging Methods for Treatment of Vitiligo. Int J Mol Sci. 2023 ;24(11):9749. doi: 10.3390/ijms24119749. PMID: 37298700; PMCID: PMC10253679.

11. Inoue, S., Katayama, I., Sano, S., & Suzuki, T. (2024, January 10).JAK inhibitors for the treatment of Vitiligo. Journal of Dermatological Science. https://www.jdsjournal.com/article/S0923-1811(23)00271-2/fulltext
12. Bertolani M, Rodighiero E, de Felici Del Giudice MB, et al. Vitiligo: What’s old, what’s new. Dermatol Reports. 2021;13(2):9142. doi: 10.4081/dr.2021.9142. PMID: 34659674; PMCID: PMC8451070.

13. Myers E, Kheradmand S, Miller R. An Update on Narrowband Ultraviolet B Therapy for the Treatment of Skin Diseases. Cureus. 2021;13(11):e19182. doi: 10.7759/cureus.19182. PMID: 34873522; PMCID: PMC8634827.

14. Cohen, B, Elbuluk, N, Mu, E., & Orlow, S. (n.d.). Alternative systemic treatments for Vitiligo: A Review. https://uniderma.info/wp-content/uploads/2020/09/year-2015-Fernblock-Alternative-Systemic-Treatments-for-Vitiligo_-A-Review-Cohen-BE-Am-J-Clin-Dermatol_2831186091.pdf

15. Shirsath SR, Sable SS, Gaikwad SG, et al. Intensification of extraction of curcumin from Curcuma amada using ultrasound assisted approach: Effect of different operating parameters, Ultrasonics Sonochemistry,Volume 38, 2017, Pages 437-445, ISSN 1350-4177, https://doi.org/10.1016/j.ultsonch.2017.03.040. (https://www.sciencedirect.com/science/article/pii/S1350417717301396)

16. Aggarwal BB. Kunnumakkara AB,.Molecular Targets and Therapeutic Uses of Spices: Modern Uses for Ancient Medicine; World Scientific, 2009.

17. Liu Z, Smart JD, Pannala AS.Recent developments in formulation design for improving oral bioavailability of curcumin: a review. Journal of Drug Delivery Science and Technology 2020, 60, 102082 10.1016/j.jddst.2020.102082.

18. Gupta SC, Patchva S, Koh W, et al. Discovery of curcumin, a component of golden spice, and its miraculous biological activities. Clin Exp Pharmacol Physiol. 2012 Mar;39(3):283-99. doi: 10.1111/j.1440-1681.2011.05648.x. PMID: 22118895; PMCID: PMC3288651.

19. Gupta SC, Sung B, Kim JH, et al. Multitargeting by turmeric, the golden spice: From kitchen to clinic. Mol Nutr Food Res. 2013 Sep;57(9):1510-28. doi: 10.1002/mnfr.201100741. Epub 2012 Aug 13. PMID: 22887802.

20. Prakash P, Misra A, Surin WR, et al. Anti-platelet effects of Curcuma oil in experimental models of myocardial ischemia-reperfusion and thrombosis, Thrombosis Research,Volume 127, Issue 2, 2011, Pages 111-118, ISSN 0049-3848, https://doi.org/10.1016/j.thromres.2010.11.007.(https://www.sciencedirect.com/science/article/pii/S0049384810006031)

21. Adamczak A, Ożarowski M, Karpiński TM. Curcumin, a Natural Antimicrobial Agent with Strain-Specific Activity. Pharmaceuticals (Basel). 2020 Jul 16;13(7):153. doi: 10.3390/ph13070153. PMID: 32708619; PMCID: PMC7408453.
22. Singh L, Sharma S, Xu S, et al. Curcumin as a Natural Remedy for Atherosclerosis: A Pharmacological Review. Molecules. 2021 Jul 1;26(13):4036. doi: 10.3390/molecules26134036. PMID: 34279384; PMCID: PMC8272048.

23. Stohs SJ, Chen O, Ray SD, et al. Highly Bioavailable Forms of Curcumin and Promising Avenues for Curcumin-Based Research and Application: A Review. 2020;25(6):1397. doi: 10.3390/molecules25061397. PMID: 32204372; PMCID: PMC7144558.

24. Jamwal R.Bioavailable curcumin formulations: A review of pharmacokinetic studies in healthy volunteers.  Integr Med. 2018, 16 (6), 367–374. 10.1016/j.joim.2018.07.001.

25. Priyadarsini KI.The chemistry of curcumin: from extraction to therapeutic agent. Molecules 2014, 19 (12), 20091–20112. 10.3390/molecules191220091.

26. Kunnumakkara AB, Harsha C, Banik K, et al. Is curcumin bioavailability a problem in humans: lessons from clinical trials. Expert Opin Drug Metab Toxicol 2019, 15(9), 705–733. 10.1080/17425255.2019.1650914.

27. Imaizumi A.Highly bioavailable curcumin (Theracurmin): Its development and clinical application. 2015, 3 (4), 123–130. 10.1016/j.phanu.2015.08.002.

28. Qin S, Huang L, Gong J, et al. Efficacy and safety of turmeric and curcumin in lowering blood lipid levels in patients with cardiovascular risk factors: a meta-analysis of randomized controlled trials. Nutr J. 2017;16(1):68. doi: 10.1186/s12937-017-0293-y. PMID: 29020971; PMCID: PMC5637251.

29. Asawanonda P, Klahan SO. Tetrahydrocurcuminoid cream plus targeted narrowband UVB phototherapy for vitiligo: a preliminary randomized controlled study. Laser Surg. 2010;28:679–684. doi: 10.1089/pho.2009.2637.

30. Jalalmanesh S, Mansouri P, Rajabi M, and Monji , F. (2022, February 1). Therapeutic effects of turmeric topical cream in vitiligo. https://onlinelibrary.wiley.com/doi/10.1111/jocd.14814

31. Becatti, Matteo & Prignano, Francesca & Fiorillo, Claudia & Pescitelli, Leonardo & Nassi, Paolo & Taddei, Niccolò. (2010). The Involvement of Smac/DIABLO, p53, NF-kB, and MAPK Pathways in Apoptosis of Keratinocytes from Perilesional Vitiligo Skin: Protective Effects of Curcumin and Capsaicin. Antioxidants & redox signaling. 13. 1309-21. 10.1089/ars.2009.2779.

32. Lao CD, Ruffin MT,  Normolle D, et al.  Dose escalation of a curcuminoid formulation. BMC Complement Altern Med. 2006, 6, 10. 10.1186/1472-6882-6-10.

33. Sharma RA, Euden SA., Platton SL, et al.Phase I clinical trial of oral curcumin: biomarkers of systemic activity and compliance.  Cancer Res. 2004, 10 (20), 6847–6854. 10.1158/1078-0432.CCR-04-0744.

34. Zheng B. McClements D. J.Formulation of More Efficacious Curcumin Delivery Systems Using Colloid Science: Enhanced Solubility, Stability, and Bioavailability. Molecules 2020, 25 (12), 2791. 10.3390/molecules25122791.

35. Gupta SC, Patchva S, Aggarwal BB. Therapeutic roles of curcumin: lessons learned from clinical trials. AAPS J. 2013 Jan;15(1):195-218. doi: 10.1208/s12248-012-9432-8. Epub 2012 Nov 10. PMID: 23143785; PMCID: PMC3535097.

Table 1. Selected Studies of Turmeric and Curcuminoids in Vitiligo

Citation	Study Type	Participants Recruited	Intervention Treatment modality	Treatment Duration (dose)	Outcome measure(s)	Efficacy	Adverse Effects
Alshaikh et al. Saudi Arabia	Case Report	1 patient Age: 41	Turmeric Powder Saudi Arabia Daily drink of hot water + turmeric powder + honey	¼ tsp; 3 years	Treatment of lesion overall appearance	Restoration of pigment Spontaneous reversal of vitiligo in the form of repigmentation of macular lesions	None reported
Asawononda et al.	Comparative experimental	10 patients, 4 male and 6 female Age: 18 and older, with stable vitiligo	Topical tetrahydro-curcuminoid cream + TNB-UVB   One patch treated with: TNB-UVB + Topical tetrahydrocurcuminoid cream	Twice a week; 12 weeks	To compare efficacy of targeted narrowband UVB phototherapy plus topical tetrahydrocurcuminoid with that of targeted narrowband UVB monotherapy for induction of repigmentation	Repigmentation (More effective than TNB-UVB monotherapy, alone) Statistically significant repigmentation, compared with baseline Overall repigmentation was slightly better in the combination group at 8 and 12 weeks at p= 0.078 and 0.158, respectively	Asymptomatic erythema, itching, burning sensations , and hyperpigmentation at treatment sites in both treatment modalities. It was also noted that adverse effects were minor and well tolerated.
Asawononda et al.	Comparative experimental	10 patients, 4 male and 6 female Age: 18 and older, with stable vitiligo	TNB-UVB Monotherapy Second patch treated with: TNB-UVB Monotherapy	Twice a week; 12 weeks	To compare efficacy of targeted narrowband UVB phototherapy plus topical tetrahydrocurcuminoid with that of targeted narrowband UVB monotherapy for induction of repigmentation	Repigmentation Statistically significant repigmentation, compared with baseline	Asymptomatic erythema, itching, burning sensations, and hyperpigmentation It was also noted that adverse effects were minor and well tolerated.
Jalalmanesh et al.	Double-blind, placebo-controlled experimental	24 Patients completed the trial Age: Majority of patients in their 40s With multiple discrete vitiligo lesions and localized lesions	Turmeric cream, Jalalmanesh et al.   Turmeric cream on one side of lesion	Twice daily; 4 months	Lesion size Vitiligo area scoring index (VASI) Vitiligo noticeability scale (VNS) Physician global assessment (PGA)	Mean vitiligo area scoring index score improved in 14/24 patients   Significant reduction in lesion size of turmeric cream compared to placebo (p < 0.05)   VASI score showed significant improvement following application of turmeric cream in compared to placebo (p < 0.001)   VNS data showed higher treatment success and lesion repigmentation with turmeric cream compared to placebo (p < 0.05)   Increasing trend in mean average PGA score in the categories of moderate and good response following turmeric cream compared to the placebo (p > 0.05)	None reported
Jalalmanesh et al.	Double-blind, placebo-controlled experimental	24 Patients completed the trial Age: Majority of patients in their 40s With multiple discrete vitiligo lesions and localized lesions	Placebo cream, Jalalmanesh et al.   Placebo cream on other side of lesion	Twice daily; 4 months	Lesion size Vitiligo area scoring index (VASI) Vitiligo noticeability scale (VNS) Physician global assessment (PGA)	No relevant change was noted	None reported
Becatti et al.	Comparative experimental	12 patients suffering from nonsegmental vitiligo	Punch-biopsies of 6 mm were taken from patients with nonsegmental vitiligo Keratinocytes were isolated. The expression of cytokeratins was evaluated Cell treatment was induced by adding curcumin or capsaicin at concentrations of 10 mM for 24 h.	24 hours	The intracellular pathways involved in keratinocyte damage and apoptosis and the antioxidant protection of curcumin and capsaicin in these cells were investigated.	In keratinocytes from perilesional vitiligo skin, there were high levels of activated p38, NF-kB p65 subunit, p53, and Smac/DIABLO proteins. Low levels of ERK phosphorylation were present. Curcumin and capsaicin increased ERK phosphorylation, thus inhibiting apoptosis.	None reported

	Peter Lio, MD Peter A. Lio, MD is a Clinical Assistant Professor of Dermatology and Pediatrics at Northwestern University Feinberg School of Medicine and a partner at Medical Dermatology Associates of Chicago.
	Dominique Butler Dominique Butler is a medical student at Meharry Medical College in Nashville, TN.

DISCLOSURE:

Dr. Lio reports research grants/funding from AbbVie, AOBiome, Eczema Foundation, National Eczema Association; is on the speaker’s bureau for AbbVie, Eli Lilly, Galderma, Hyphens Pharma, Incyte, La Roche-Posay/L’Oreal, MyOR Diagnostics, ParentMD, Pfizer, Pierre-Fabre Dermatologie, Regeneron/Sanofi Genzyme; reports consulting/advisory boards for AbbVie, Almirall, Amyris, Arbonne, Arcutis, ASLAN, Boston Skin Science, Bristol-Myers Squibb, Burt’s Bees, Castle Biosciences, Codex Labs, Concerto Biosci, Dermavant, DermVeda, Eli Lilly, Galderma, IntraDerm, Janssen, Johnson & Johnson, Kaleido Biosci, Kimberly Clark, LEO Pharma, Lipidor, L’Oreal, Menlo Therapeutics, Merck, Micreos, MyOR Diagnostics, Regeneron/Sanofi Genzyme, Skinfix, Sonica, Theraplex, UCB, Unilever, Verrica, Yobee Care; stock options: Micreos, Modernizing Medicine, Yobee Care. In addition, Dr. Lio has a patent pending for a Theraplex product with royalties paid and is a Board member and Scientific Advisory Committee Member of the National Eczema Association.