Vitamins for the Management of Nail Disease: A Literature Review

Background: Vitamins have gained popularity among physicians and patients for purported benefits to hair, skin, and nail health. Safe and efficacious therapies for nail disorders, many of which are chronic conditions, are needed. Summary: We conducted a literature review of studies assessing the efficacy of oral, topical, and intralesional vitamin/vitamin derivatives for the treatment of nail disorders, including yellow nail syndrome, brittle nail syndrome, onychomycosis, habit-tic nail deformity, periungual/subungual verruca, and nail psoriasis. Forty-nine articles were reviewed. There is good evidence to support the use of topical tazarotene and vitamin D analogs for nail psoriasis treatment. We found overall limited evidence for treatment of other nail disorders with vitamin/vitamin derivatives, and further research is needed to support their use. Key Messages: Besides topical tazarotene and vitamin D analogs for nail psoriasis treatment, there is limited evidence for treatment of nail disorders with topical, oral, and intralesional vitamin/vitamin derivatives.


Introduction
Safe long-term therapies are needed for the management of nail diseases, many of which may be chronic conditions.Despite limited evidence for treatment with vitamins, in a 2008 survey-based study, 66% of dermatologists reported recommending vitamin supplements to patients for purported skin, hair, and nail health benefits [1], and self-reported hair, skin, and nail supplement use nearly doubled from 2.5% in 2011-2012 to 4.9% in 2017-2020 [2].Therefore, we conducted a literature review on the management of nail disorders, including yellow nail syndrome (YNS), brittle nail syndrome (BNS), onychomycosis, habit-tic nail deformity, periungual/ subungual verruca, and nail psoriasis, with oral, topical, and intralesional vitamins and vitamin derivatives.
A literature search for peer-reviewed articles using the PubMed/MEDLINE database was performed in March 2023 for treatment of nail diseases with vitamins using the following search terms: "nail disease" AND "vitamin;" "nail" AND "vitamin;" "nail condition" AND "vitamin;" "yellow nail syndrome" AND "vitamin;" "brittle nail syndrome" AND "vitamin;" "onychomycosis" AND "vitamin;" "habit-tic deformity" AND "vitamin;" "periungual warts" AND "vitamin;" "subungual warts" AND "vitamin;" "nail psoriasis" AND "vitamin."Full length    YNS is a rare disorder characterized by a clinical trial of yellow nails, respiratory disease, and lower extremity lymphedema [3].The etiology of YNS remains poorly understood, although lymphatic impairment is suspected [4].Nail involvement is characterized by smooth, thick yellow nails with increased transverse curvature, onycholysis, slow nail growth, and loss of cuticles and lunula [5].Most cases are sporadic [6], although there is a weak association with autoimmune diseases and various cancers [4].Spontaneous improvement of nail findings is not associated with improvement of other systemic manifestations [6].
Vitamin E has been used to treat YNS topically and systemically (Table 1) [4,7].Since lipid oxidation of free radicals results in deposition of lipofuscin pigments, causing yellow discoloration, it is theorized that vitamin E protects against free-radical oxidative damage, reversing yellow discoloration [7].
Evidence for treatment with topical vitamin E is limited.In a 64-year-old male patient with YNS treated with topical vitamin E twice daily for 6 months, there was improvement in fingernail thickness, ridging, discoloration, lunula visibility, and nail growth rates [8].Conversely, in a case series of 3 pediatric patients with yellow fingernails since birth, treated with topical vitamin E, there was no significant effect on nail growth rate or clinical appearance [9].
Use of oral vitamin E for YNS has been slightly better studied.In a retrospective cohort study of 25 YNS patients, 56% (14/25) had improvement of yellow nails, of which 35.7% (5/14) were treated with vitamin E (9 untreated) [10].In a case report of a 65-year-old female patient with YNS, there was complete resolution of onychodystrophy with oral alpha-tocopherol acetate 800 IU/day treatment for 6.5 months [11].
Combination regimens of oral vitamin E and pulsedose triazole antifungals have also been studied.Azole antifungals are thought to improve yellow nails by increasing the linear nail growth rate [13,17].In a clinical trial of 13 YNS patients, 84.6% had complete clinical cure with oral vitamin E and pulse-dose fluconazole between 18 months and 2 years [12].In a case series of 3 patients with YNS, fingernail dystrophy resolved after 6 months to 1 year of vitamin E and pulse-dose fluconazole/ itraconazole treatment [14].
BNS affects approximately 20% of the population; women are typically affected twice as frequently as men.Common patient complaints include nail softness, dryness, weakness, breakability, and slow growth rate [18].BNS is characterized by impaired intercellular adhesion with lamellar splitting of the distal nail plate [19].Standard treatment is irritant avoidance, water immersion avoidance, and topical emollients [20].Although there is supporting clinical evidence (Table 2) that biotin is effective for the treatment of BNS, the mechanism of treatment, whether via correction of an underlying deficiency or otherwise, remains unknown [21].
In a clinical trial of 45 patients with BNS of unknown etiology treated with oral biotin 2.5 mg daily, there was improved firmness and hardness of fingernails in 91% (41/45) of patients following a 5.5 ± 2.3month course [22].In a retrospective study of 46 patients with oral biotin 2.5 mg/day for 1-4 months, there was clinical improvement in nails in 63% (22/35) of patients [24].In a case series of 14 patients, clinical improvement and complete resolution were achieved in 66.7% (6/9) and 33.3% (3/9) patients, respectively, at 6 months.At 1 year of therapy, 100% (9/9) of patients had complete resolution [25].In a clinical trial of 50 patients, 80% of patients treated with nail lacquer and oral biotin 10 mg daily had an onychodystrophy global severity score reduction of greater than 50% compared to baseline, in comparison to 53% of patients treated with nail lacquer alone (p = 0.05) [26].A clinical trial of 50 randomized patients to a topical formulation (including vitamin E) arm, an oral biomineral formulation (including vitamins C, E, B6, and B7), and a topical and oral combination arm.After 3 months of treatment, nail hardness improved by 40% in the topical arm (p < 0.01), 43% in the oral arm (p < 0.05), and 50% in the combination arm (p < 0.05) [27].
Use of topical tazarotene for the management of BNS was studied in a clinical trial of 20 patients.After 12 weeks of treatment with tazarotene cream 0.1% twice daily, 100% (18/18) of patients achieved the primary end-point of improvement measured by the physician global improvement assessment of target nails [28].
Onychomycosis is the most common nail disorder seen in clinical practice.A primary obstacle in onychomycosis management is slow nail growth and the nail plate serving as a barrier to drug permeation and diffusion.Therefore, treatment requires long duration of therapy, typically 12 months or longer for toenails [29].The vitamins that have been studied for the management of onychomycosis are topical vitamin E, topical tazarotene, and oral acitretin (Table 3).
Vitamin E has antioxidant properties [36] and is thought to increase tissue growth rate via acceleration of fibroblast and epithelial cellular proliferation [37].The water-soluble derivative of vitamin E, alpha-tocopheryl  polyethylene glycol succinate, is a widely used biomaterial in drug delivery systems [38,39].Use of vitamin E may, therefore, facilitate antifungal delivery to tissues.
In a clinical trial of 20 patients treated with topical vitamin E and essential oils of lime, oregano, and tea tree, there was a 50% complete cure rate and 78.5% complete cure rate after 3 and 6 months, respectively [30].In a case report of a patient treated with topical 400 IU vitamin E, there was complete clinical resolution of toenail onychomycosis after 6 months [31].
Tazarotene is a synthetic third-generation retinoid prodrug derived from vitamin A with immunomodulatory and anti-inflammatory properties.It protects keratinocytes from infection by Propionibacterium acnes and thus may have defensive activity against infective processes [40].Tazarotene reduces hyperkeratinization, resulting in high epidermal penetration [41].
In a clinical trial of 15 patients with toenail onychomycosis treated with topical tazarotene 0.1% gel daily, mycological cure rate was 40% at 1 month, and complete clinical cure and negative cultures were achieved in 100% (15/15) of patients at 3 months.Disk diffusion assay after 48 h of incubation in tazarotene solution showed a central area of inhibition in all in vitro fungal cultures [32].In a comparative cross-sectional study of 40 patients, clinical improvement as assessed by the onychomycosis severity index was 25% in patients treated with tazarotene alone, compared to 50% in patients treated with tazarotene and tioconazole (p = 0.039) after 3 months of therapy [33].In a clinical trial of 102 patients treated with fractional carbon dioxide laser-assisted delivery of topical tazarotene or topical tioconazole, there was no difference in clinical cure between groups (p = 0.33).In the tazarotene group, 91.7 and 100% had negative KOH and cultures, respectively, compared to 78.3 and 95.5% in the tioconazole group (p < 0.001) [34].
Retinoids have immunomodulatory and fungistatic activity against dermatophytes and Candida albicans [42] and increase nail growth rate via increased epidermal   turnover [35].It has been hypothesized that systemic retinoids may serve a therapeutic adjuvant role in the treatment of onychomycosis [35].
In a clinical trial of 135 onychomycosis patients, patients were subdivided into three arms, including itraconazole pulse therapy (400 mg/day for 1 week/month), oral acitretin (25 mg/day), or combined pulsed itraconazole/acitretin (itraconazole 400 mg/day for 1 week/month and oral acitretin 25 mg/day) for 3 months.Mycological and complete cures were achieved in 51.1 and 20% of the itraconazole group, 28.9 and 28.9% of the acitretin group, and 80.0 and 53.3% in the combined itraconazole/acitretin group (mycological cure p ≤ 0.05 and clinical cure p = 0.007), respectively.Cheilitis was reported in 44.4% (20/45) of the oral acitretin group and 57.7% (26/45) of the combined itraconazole/acitretin therapy group [35].
Habit-tic nail deformity occurs due to repeated, habitual self-induced mechanical trauma of the cuticle and proximal nail fold using another digit [43].The thumbnails are most frequently involved.Clinical examination is significant for a longitudinal midline furrow with numerous parallel transverse ridges [44].Treatment includes occlusive dressings, cyanoacrylate adhesives, cognitive behavioral therapy, and psychotropic medications [45].
Evidence for the management of habit-tic nail deformity with oral multivitamins is limited to a single case series (n = 2) (Table 4).Both patients denied a history of trauma or self-manipulation.Both patients had complete resolution of transverse ridging after treatment with an oral multivitamin for 5 and 4 months, respectively [46].
Human papilloma virus is responsible for development of verruca and is the most common nail viral infection.Verruca typically involves the nail fold and less commonly the nail bed.Proximal nail fold verruca may result in longitudinal ridging and nail plate dystrophy, whereas nail bed verruca may cause onycholysis [47].Periungual and subungual verruca are challenging to treat.Local destruction is associated with high recurrence rate and may also cause scarring and permanent onychodystrophy [48].
Vitamin D plays a role in the proliferation and differentiation of keratinocytes and is thought to stimulate cell-mediated immunity.It regulates epidermal cell proliferation/differentiation and modulates cytokine production [48].
Tretinoin is a vitamin A derivative that interrupts epithelial cell differentiation and HPV replication in verruca [52].It promotes cornified cell detachment and enhances shedding.It also increases turnover of loosely adherent corneocytes via increased mitotic activity [53].In a retrospective observational study of 36 patients treated with superficial X-ray therapy or a combination regimen of superficial X-ray therapy (28 days) with topical tretinoin (occluded for 8 h/day for 20 days), clinical cure was achieved in 75 and 92.7% of patients, respectively (p < 0.046) [51].
Nail involvement is estimated to occur in 40% of patients with cutaneous psoriasis, with lifetime prevalence of 80-90% [54].In addition, 5-10% of patients have isolated nail psoriasis, with no or limited skin involvement.Clinical findings include nail pitting, onycholysis, subungual hyperkeratosis, and splinter hemorrhages, all of which may contribute to pain, limited functionality, and poor cosmetic appearance [55,56].Treatment is dichotomized into 3 or fewer nails involved or greater than 3 nails involved and includes intralesional steroid injections, topical steroids, topical vitamin D analogs, systemics, and biologics (Table 6) [57].As nail psoriasis is a chronic condition requiring long-term treatment, effective and safe treatment options are needed [58][59][60][61].
Vitamin A for nail psoriasis treatment is available as tazarotene, a topical vitamin A derivative, and oral synthetic retinoids.Mechanism of action is decreased epidermal hyperproliferation, normalization of cellular differentiation, and inflammatory control [69,80].
Use of topical tazarotene for nail psoriasis has been studied in several trials.In a randomized controlled trial of 31 patients treated with topical tazarotene, there was greater reduction in onycholysis in occluded nails (p ≤ 0.05 at weeks 4 and 12) and greater reduction in onycholysis in nonoccluded nails (p ≤ 0.05 at week 24) compared to vehicle gel [62].In a trial of 46 patients randomized to topical tazarotene or clobetasol propionate, there was improvement in both groups (p < 0.001) in pitting, onycholysis, and hyperkeratosis after 12 weeks (p > 0.05 between groups).At 24 weeks, the group treated with tazarotene showed greater reduction in hyperkeratosis compared to the group treated with clobetasol (p < 0.001) [63].In an open, prospective study of 25 patients treated with topical tazarotene, 76% (19/25) of patients had reduction in onycholysis, hyperkeratosis, oil spots, and pitting (p < 0.0001) at 12 weeks [64].Of note, Piraccini et al. [67] reported pyogenic granuloma formulation in a case series of 2 patients with nail psoriasis treated with topical tazarotene.
In an open, prospective study of 36 nail psoriasis patients treated with oral acitretin 0.2-0.3mg/kg daily, average fingernail psoriasis severity index score decreased from 31.5 to 18.6 (41% mean percent reduction, no p value reported), and 25% (9/36) of patients had clinical resolution at 6 months.One patient developed multiple pyogenic granulomas 2 months after therapy [68].In a prospective, controlled observational study of 41 patients treated with oral acitretin 0.6-0.8mg/kg daily, nail bed and matrix thickness decreased after 6 months, as measured by ultrasound (p = 0.046, p = 0.031, respectively) after 6 months [71].
Vitamin D3 analogs, which have antiproliferative and immunomodulatory effects, have also been studied for the treatment of nail psoriasis [81].Two vitamin D analogs are currently available for the treatment of psoriasis in the USA: calcitriol and calcipotriol (calcipotriene).
In a double-blind trial, 58 nail psoriasis patients were randomized to calcipotriol ointment or betamethasone dipropionate and salicylic acid ointment, with no difference between groups in reduction in subungual hyperkeratosis.For fingernails, subungual hyperkeratosis decreased by 49.2 and 51.7% in the calcipotriol group and betamethasone and salicylic acid group at 5 months, respectively (p < 0.001 from baseline).For toenails, subungual hyperkeratosis decreased by 40.7 and 51.9% in the calcipotriol group and betamethasone and salicylic acid group at 5 months, respectively (p < 0.001 from baseline) [58].In another trial, 40 nail psoriasis patients were randomized to treatment with 0.005% calcipotriol plus, 0.05% betamethasone dipropionate ointment once daily or 0.005% calcipotriol ointment twice daily.At 12 weeks, the nail psoriasis severity index score was reduced in both treatment arms (p < 0.045), with no difference between treatment arms (p = 0.649) [76].
While it is appealing to treat nail diseases with topical and oral vitamin/vitamin derivatives, there is only robust evidence for use of vitamin D3 analogs and retinoids for nail psoriasis treatment.There is a paucity of high-quality studies assessing therapeutic benefit and safety of vitamin/vitamin derivatives for the management of other nail conditions (YNS, BNS, onychomycosis, habit-tic nail deformity, periungual/subungual verruca).
Nail psoriasis had the highest evidence for treatment with vitamin derivatives, with topical vitamin D analogs and topical retinoids included in established treatment algorithms [57].Although combination regimens of topical vitamin D analogs and steroids are typically first line, there is evidence to support equivalent efficacy of topical vitamin D monotherapy.In a randomized controlled trial of 40 patients, Tzung et al. [76] found that topical vitamin D monotherapy was equally effective as a topical vitamin D and steroid combination regimen for the treatment of nail psoriasis.In a double-blind randomized trial of 58 patients, Tosti et al. [58] found that topical vitamin D monotherapy was as efficacious as a topical steroid and salicylic acid regimen for nail psoriasis treatment.Although there is sufficient evidence to support topical tazarotene for nail psoriasis treatment, physicians should caution patients of potential side effects, including periungual skin irritation, proximal nail fold erythema, and proximal nail fold peeling.Evidence for oral acitretin is currently limited, and further trials with standard therapy control arms are needed.More studies are needed to investigate pyogenic granuloma formation associated with topical tazarotene and oral acitretin, which was reported in multiple cases [67,68].
The strongest evidence for YNS treatment is for oral vitamin E with pulse-dose antifungals, which was only supported by one small clinical trial and several case reports.Topical or oral vitamin E monotherapy for YNS was limited to case reports and one small retrospective cohort study.Oral vitamin E for YNS was prescribed at doses ranging from 536 mg/day (800 IU/day) to 804 mg/ day (1,200 IU/day).Although adverse events were not reported, high oral vitamin E intake has known coagulopathic risk due to vitamin K antagonism, hypoprothrombinemic effect, cytochrome p-450 interaction, and antiplatelet activity [82].Toxicity may occur at doses greater than 1,000 mg/day [83].However, there are case reports of coagulopathies in patients with oral vitamin E intake below this threshold and with only marginally elevated serum vitamin E levels [82,84].Therefore, the use of vitamin E should be avoided in older patients, those taking drugs that may increase risk of bleeding, such as oral anticoagulants and NSAIDs, and those with preexisting hypertension [82,84].Topical vitamin E has a more benign side effect profile; however, evidence is limited to case reports.
There is weak evidence to support treatment with oral biotin for brittle nail syndrome, given paucity of studies supporting therapeutic benefit and, moreover, interference with laboratory values, including troponins, thyroid stimulating hormone, N-terminal pro-brain natriuretic peptide, and parathyroid hormone [85,86].Despite a Food and Drug Administration (FDA) warning on biotin's potential for significant interference with laboratory tests [87], in a study examining consumer perception of biotin on Amazon, there was limited consumer awareness of the FDA warning [88].In a survey study of 149 physicians, 43.9% of physicians recommended biotin, primarily for nail and hair disorders, and 45.9% of physicians did not ask patients to discontinue biotin prior to laboratory testing [89].In an assessment of biotin supplementation among 447 patients in an urban outpatient dermatology clinic, 33.7% (152/447) of patients indicated current or past use, of which 28.8% had been recommended biotin by a primary care physician or dermatologist, and of which only 6.6% of users were aware of the FDA warning [90].
Effective alternative therapies for onychomycosis may be needed given poor medicaid coverage for onychomycosis treatment [91] and the patient "fear factor" regarding terbinafine-associated hepatoxicity [92].There was moderate evidence for onychomycosis treatment with topical vitamin E, topical tazarotene, and oral acitretin in several clinical trials.Alessandrini et al.'s [30] study on topical vitamin E yielded promising results with an almost 80% complete cure rate reported following 6 months of treatment.Nasr et al.'s [35] study on oral acitretin similarly yielded promising results with 80.0% mycological cure rate with combination itraconazole/oral acitretin, compared to 28.9 and 51.1% with itraconazole and acitretin alone, respectively (p ≤ 0.05).Acitretin may have innate antifungal activity, and/ or it may have a beneficial effect on onychomycosis treatment by accelerating nail growth.Larger controlled studies are needed to confirm these findings, and currently there are better-studied FDA-approved oral and topical alternatives.
Evidence for periungual verruca treatment with intralesional vitamin D3 included one clinical trial with a small sample size and several case reports.The highest quality study for treatment of verruca with intralesional vitamin D injections was Priya et al.'s [49] clinical trial; however, only about 20% of patients had periungual verruca.In addition, Raghukumar et al.'s [50] study included only about 3% patients with periungual verruca, of which 50% show complete response rate.Adverse events specific to these patients were not reported in

Conclusion
There is limited evidence for treatment of nail disorders with oral, topical, and intralesional vitamins/ vitamin derivatives.Given the rarity of YNS, randomized clinical trials are challenging to perform.Therefore, given the limited treatment options for YNS, treatment topical vitamin E may be reasonable, given that it has a benign side effect profile.Oral vitamin E may be a reasonable YNS treatment option except in older patients, those taking drugs that may increase the risk of bleeding, and those with pre-existing hypertension.We recommend against prescribing oral biotin for BNS, given potential laboratory interactions and lack of high-quality studies proving efficacy.Topical vitamin E may be effective for onychomycosis treatment, however clinical trials are needed to evaluate the efficacy and side effect profile.Topical tazarotene and vitamin D analogs have proven efficacy and may safely be prescribed for nail psoriasis, but pyogenic granuloma formation is a known risk with topical tazarotene.Intralesional vitamin D3 appears to be safe and efficacious for verruca treatment, however further studies dedicated to periungual and subungual verruca are needed.
Vitamins for the Management of Nail Disease: A Literature Review Skin Appendage Disord 2024;10:104-122 DOI: 10.1159/000534972 either study.More clinical trials examining safety and efficacy of periungual and subungual verruca are necessary to draw firm conclusions.

Table 2 .
Brittle nail syndrome studies Vitamins for the Management of Nail Disease: A Literature Review Skin Appendage Disord 2024;10:104-122 DOI: 10.1159/000534972 articles of randomized controlled trials, uncontrolled trials, systematic reviews, cross-sectional studies, cohort studies, case-controlled studies, case reports, and case series were included.Records that were irrelevant, not in English, or did not meet study criteria were excluded.A total of 49 articles were selected for review.