Article

The Comparison

A A 25-year-old man of Hispanic ethnicity with pink papules, pustules, and large keloidal tumors on the occipital scalp characteristic of acne keloidalis nuchae (AKN). There is hair loss and some tufting of remaining hairs.

B A 17-year-old adolescent boy of African descent with small papules on the occipital scalp and some hair loss from AKN.

C A 19-year-old man of African descent with extensive papules and keloidal tumors on the occipital scalp as well as scarring hair loss and tufting of hairs from AKN.

Acne keloidalis nuchae (AKN) is a chronic inflammatory condition commonly affecting the occipital scalp and posterior neck. It causes discrete or extensive fibrosing papules that may coalesce to form pronounced ­tumorlike masses^1,2 with scarring alopecia (Figure, A–C).³ Pustules, hair tufts, secondary bacterial infections, abscesses, and sinus tracts also may occur.¹ The pathogenesis of AKN has been characterized as varying stages of follicular inflammation at the infundibular and isthmus levels followed by fibrotic occlusion of the ­follicular lumen.⁴ Pruritus, pain, bleeding, oozing, and a feeling of scalp tightness may occur.^1,5

Umar et al⁶ performed a retrospective review of 108 men with AKN—58% of African descent, 37% Hispanic, 3% Asian, and 2% Middle Eastern—and proposed a 3-tier classification system for AKN. Tier 1 focused on the distribution and sagittal spread of AKN lesions between the clinical demarcation lines of the occipital notch and posterior hairline. Tier 2 focused on the type of lesions present—discrete papules or nodules, coalescing/abutting lesions, plaques (raised, atrophic, or indurated), or dome-shaped tumoral masses. Tier 3 focused on the presence or absence of co-existing dissecting cellulitis or folliculitis decalvans.⁶

Epidemiology

Acne keloidalis nuchae primarily manifests in adolescent and adult men of African or Afro-Caribbean descent.⁷ Among African American men, the prevalence of AKN ranges from 0.5% to 13.6%.⁸ Similar ranges have been reported among Nigerian, South African, and West African men.¹ Acne keloidalis nuchae also affects Asian and Hispanic men but rarely is seen in non-Hispanic White men or in women of any ethnicity.^9,10 The male to female ratio is 20:1.^1,11 Hair texture, hairstyling practices such as closely shaved or faded haircuts, and genetics likely contribute to development of AKN. Sports and occupations that require the use of headgear or a tight collar may increase the risk for AKN.¹²

Key clinical features in people with darker skin tones

• The lesions of AKN range in color from pink to dark brown or black. Postinflammatory hyperpigmentation or hyperchromia may be present around AKN lesions.
• Chronicity of AKN may lead to extended use of high-potency topical or intralesional corticosteroids, which causes transient or long-lasting hypopigmentation, especially in those with darker skin tones.

Worth noting

• Acne keloidalis nuchae can be disfiguring, which negatively impacts quality of life and self-esteem.¹²
• Some occupations (eg, military, police) have hair policies that may not be favorable to those with or at risk for AKN.
• Patients with AKN are 2 to 3 times more likely to present with metabolic syndrome, hypertension, type 2 diabetes mellitus, or obesity.¹³

Treatment

There are no treatments approved by the US Food and Drug Administration specifically for AKN. Treatment approaches are based on the pathophysiology, secondary impacts on the skin, and disease severity. Growing out the hair may prevent worsening and/or decrease the risk for new lesions.⁶

• Options include but are not limited to topical and systemic therapies (eg, topical corticosteroids, oral or topical antibiotics, isotretinoin, topical retinoids, imiquimod, pimecrolimus), light devices (eg, phototherapy, laser), ablative therapies (eg, laser, cryotherapy, radiotherapy), and surgery (eg, excision, follicular unit excision), often in combination.^6,14,15
• Intralesional triamcinolone injections are considered standard of care. Adotama et al¹⁶ found that injecting ­triamcinolone into the deep dermis in the area of flat or papular AKN yielded better control of inflammation and decreased appearance of lesions compared with injecting individual lesions.
• For extensive AKN lesions that do not respond to ­less-invasive therapies, consider surgical techniques,^6,17 such as follicular unit excision¹⁸ and more extensive surgical excisions building on approaches from pioneers Drs. John Kenney and Harold Pierce.¹⁹ An innovative surgical approach for removal of large AKNs is the bat excision technique—wound shape resembles a bat in a spread-eagled position—with secondary intention healing with or without debridement and/or tension sutures. The resulting linear scar acts as a new posterior hair line.²⁰

Health disparity highlights

Access to a dermatologic or plastic surgeon with expertise in the surgical treatment of large AKNs may be challenging but is needed to reduce risk for recurrence and adverse events.

Close-cropped haircuts on the occipital scalp, which are particularly popular among men of African descent, increase the risk for AKN.⁵ Although this grooming style may be a personal preference, other hairstyles commonly worn by those with tightly coiled hair may be deemed “unprofessional” in society or the workplace,²¹ which leads to hairstyling practices that may increase the risk for AKN.

Acne keloidalis nuchae remains an understudied entity that adversely affects patients with skin of color.

The Comparison

A A 25-year-old man of Hispanic ethnicity with pink papules, pustules, and large keloidal tumors on the occipital scalp characteristic of acne keloidalis nuchae (AKN). There is hair loss and some tufting of remaining hairs.

B A 17-year-old adolescent boy of African descent with small papules on the occipital scalp and some hair loss from AKN.

C A 19-year-old man of African descent with extensive papules and keloidal tumors on the occipital scalp as well as scarring hair loss and tufting of hairs from AKN.

Acne keloidalis nuchae (AKN) is a chronic inflammatory condition commonly affecting the occipital scalp and posterior neck. It causes discrete or extensive fibrosing papules that may coalesce to form pronounced ­tumorlike masses^1,2 with scarring alopecia (Figure, A–C).³ Pustules, hair tufts, secondary bacterial infections, abscesses, and sinus tracts also may occur.¹ The pathogenesis of AKN has been characterized as varying stages of follicular inflammation at the infundibular and isthmus levels followed by fibrotic occlusion of the ­follicular lumen.⁴ Pruritus, pain, bleeding, oozing, and a feeling of scalp tightness may occur.^1,5

Umar et al⁶ performed a retrospective review of 108 men with AKN—58% of African descent, 37% Hispanic, 3% Asian, and 2% Middle Eastern—and proposed a 3-tier classification system for AKN. Tier 1 focused on the distribution and sagittal spread of AKN lesions between the clinical demarcation lines of the occipital notch and posterior hairline. Tier 2 focused on the type of lesions present—discrete papules or nodules, coalescing/abutting lesions, plaques (raised, atrophic, or indurated), or dome-shaped tumoral masses. Tier 3 focused on the presence or absence of co-existing dissecting cellulitis or folliculitis decalvans.⁶

Epidemiology

Acne keloidalis nuchae primarily manifests in adolescent and adult men of African or Afro-Caribbean descent.⁷ Among African American men, the prevalence of AKN ranges from 0.5% to 13.6%.⁸ Similar ranges have been reported among Nigerian, South African, and West African men.¹ Acne keloidalis nuchae also affects Asian and Hispanic men but rarely is seen in non-Hispanic White men or in women of any ethnicity.^9,10 The male to female ratio is 20:1.^1,11 Hair texture, hairstyling practices such as closely shaved or faded haircuts, and genetics likely contribute to development of AKN. Sports and occupations that require the use of headgear or a tight collar may increase the risk for AKN.¹²

Key clinical features in people with darker skin tones

• The lesions of AKN range in color from pink to dark brown or black. Postinflammatory hyperpigmentation or hyperchromia may be present around AKN lesions.
• Chronicity of AKN may lead to extended use of high-potency topical or intralesional corticosteroids, which causes transient or long-lasting hypopigmentation, especially in those with darker skin tones.

Worth noting

• Acne keloidalis nuchae can be disfiguring, which negatively impacts quality of life and self-esteem.¹²
• Some occupations (eg, military, police) have hair policies that may not be favorable to those with or at risk for AKN.
• Patients with AKN are 2 to 3 times more likely to present with metabolic syndrome, hypertension, type 2 diabetes mellitus, or obesity.¹³

Treatment

There are no treatments approved by the US Food and Drug Administration specifically for AKN. Treatment approaches are based on the pathophysiology, secondary impacts on the skin, and disease severity. Growing out the hair may prevent worsening and/or decrease the risk for new lesions.⁶

• Options include but are not limited to topical and systemic therapies (eg, topical corticosteroids, oral or topical antibiotics, isotretinoin, topical retinoids, imiquimod, pimecrolimus), light devices (eg, phototherapy, laser), ablative therapies (eg, laser, cryotherapy, radiotherapy), and surgery (eg, excision, follicular unit excision), often in combination.^6,14,15
• Intralesional triamcinolone injections are considered standard of care. Adotama et al¹⁶ found that injecting ­triamcinolone into the deep dermis in the area of flat or papular AKN yielded better control of inflammation and decreased appearance of lesions compared with injecting individual lesions.
• For extensive AKN lesions that do not respond to ­less-invasive therapies, consider surgical techniques,^6,17 such as follicular unit excision¹⁸ and more extensive surgical excisions building on approaches from pioneers Drs. John Kenney and Harold Pierce.¹⁹ An innovative surgical approach for removal of large AKNs is the bat excision technique—wound shape resembles a bat in a spread-eagled position—with secondary intention healing with or without debridement and/or tension sutures. The resulting linear scar acts as a new posterior hair line.²⁰

Health disparity highlights

Access to a dermatologic or plastic surgeon with expertise in the surgical treatment of large AKNs may be challenging but is needed to reduce risk for recurrence and adverse events.

Close-cropped haircuts on the occipital scalp, which are particularly popular among men of African descent, increase the risk for AKN.⁵ Although this grooming style may be a personal preference, other hairstyles commonly worn by those with tightly coiled hair may be deemed “unprofessional” in society or the workplace,²¹ which leads to hairstyling practices that may increase the risk for AKN.

Acne keloidalis nuchae remains an understudied entity that adversely affects patients with skin of color.

The Comparison

A A 25-year-old man of Hispanic ethnicity with pink papules, pustules, and large keloidal tumors on the occipital scalp characteristic of acne keloidalis nuchae (AKN). There is hair loss and some tufting of remaining hairs.

B A 17-year-old adolescent boy of African descent with small papules on the occipital scalp and some hair loss from AKN.

C A 19-year-old man of African descent with extensive papules and keloidal tumors on the occipital scalp as well as scarring hair loss and tufting of hairs from AKN.

Acne keloidalis nuchae (AKN) is a chronic inflammatory condition commonly affecting the occipital scalp and posterior neck. It causes discrete or extensive fibrosing papules that may coalesce to form pronounced ­tumorlike masses^1,2 with scarring alopecia (Figure, A–C).³ Pustules, hair tufts, secondary bacterial infections, abscesses, and sinus tracts also may occur.¹ The pathogenesis of AKN has been characterized as varying stages of follicular inflammation at the infundibular and isthmus levels followed by fibrotic occlusion of the ­follicular lumen.⁴ Pruritus, pain, bleeding, oozing, and a feeling of scalp tightness may occur.^1,5

Umar et al⁶ performed a retrospective review of 108 men with AKN—58% of African descent, 37% Hispanic, 3% Asian, and 2% Middle Eastern—and proposed a 3-tier classification system for AKN. Tier 1 focused on the distribution and sagittal spread of AKN lesions between the clinical demarcation lines of the occipital notch and posterior hairline. Tier 2 focused on the type of lesions present—discrete papules or nodules, coalescing/abutting lesions, plaques (raised, atrophic, or indurated), or dome-shaped tumoral masses. Tier 3 focused on the presence or absence of co-existing dissecting cellulitis or folliculitis decalvans.⁶

Epidemiology

Acne keloidalis nuchae primarily manifests in adolescent and adult men of African or Afro-Caribbean descent.⁷ Among African American men, the prevalence of AKN ranges from 0.5% to 13.6%.⁸ Similar ranges have been reported among Nigerian, South African, and West African men.¹ Acne keloidalis nuchae also affects Asian and Hispanic men but rarely is seen in non-Hispanic White men or in women of any ethnicity.^9,10 The male to female ratio is 20:1.^1,11 Hair texture, hairstyling practices such as closely shaved or faded haircuts, and genetics likely contribute to development of AKN. Sports and occupations that require the use of headgear or a tight collar may increase the risk for AKN.¹²

Key clinical features in people with darker skin tones

• The lesions of AKN range in color from pink to dark brown or black. Postinflammatory hyperpigmentation or hyperchromia may be present around AKN lesions.
• Chronicity of AKN may lead to extended use of high-potency topical or intralesional corticosteroids, which causes transient or long-lasting hypopigmentation, especially in those with darker skin tones.

Worth noting

• Acne keloidalis nuchae can be disfiguring, which negatively impacts quality of life and self-esteem.¹²
• Some occupations (eg, military, police) have hair policies that may not be favorable to those with or at risk for AKN.
• Patients with AKN are 2 to 3 times more likely to present with metabolic syndrome, hypertension, type 2 diabetes mellitus, or obesity.¹³

Treatment

There are no treatments approved by the US Food and Drug Administration specifically for AKN. Treatment approaches are based on the pathophysiology, secondary impacts on the skin, and disease severity. Growing out the hair may prevent worsening and/or decrease the risk for new lesions.⁶

• Options include but are not limited to topical and systemic therapies (eg, topical corticosteroids, oral or topical antibiotics, isotretinoin, topical retinoids, imiquimod, pimecrolimus), light devices (eg, phototherapy, laser), ablative therapies (eg, laser, cryotherapy, radiotherapy), and surgery (eg, excision, follicular unit excision), often in combination.^6,14,15
• Intralesional triamcinolone injections are considered standard of care. Adotama et al¹⁶ found that injecting ­triamcinolone into the deep dermis in the area of flat or papular AKN yielded better control of inflammation and decreased appearance of lesions compared with injecting individual lesions.
• For extensive AKN lesions that do not respond to ­less-invasive therapies, consider surgical techniques,^6,17 such as follicular unit excision¹⁸ and more extensive surgical excisions building on approaches from pioneers Drs. John Kenney and Harold Pierce.¹⁹ An innovative surgical approach for removal of large AKNs is the bat excision technique—wound shape resembles a bat in a spread-eagled position—with secondary intention healing with or without debridement and/or tension sutures. The resulting linear scar acts as a new posterior hair line.²⁰

Health disparity highlights

Access to a dermatologic or plastic surgeon with expertise in the surgical treatment of large AKNs may be challenging but is needed to reduce risk for recurrence and adverse events.

Close-cropped haircuts on the occipital scalp, which are particularly popular among men of African descent, increase the risk for AKN.⁵ Although this grooming style may be a personal preference, other hairstyles commonly worn by those with tightly coiled hair may be deemed “unprofessional” in society or the workplace,²¹ which leads to hairstyling practices that may increase the risk for AKN.

Acne keloidalis nuchae remains an understudied entity that adversely affects patients with skin of color.

Vitamin D (VD) regulates keratinocyte proliferation and differentiation, modulates inflammatory pathways, and protects against cellular damage in the skin. ¹ In the setting of tissue injury and acute skin inflammation, active vitamin D—1,25(OH) ₂ D—suppresses signaling from pro-inflammatory chemokines and cytokines such as IFN- γ and IL-17. ^2,3 This suppression reduces proliferation of helper T cells (T _H 1, T _H 17) and B cells, decreasing tissue damage from reactive oxygen species release while enhancing secretion of the anti-inflammatory cytokine IL-10 by antigen-presenting cells. ^2-4

Suboptimal VD levels have been associated with numerous health consequences including malignancy, prompting interest in VD supplementation for improving cancer-related outcomes.⁵ Beyond disease prognosis, high-dose VD supplementation has been suggested as a potential therapy for adverse events (AEs) related to cancer treatments. In one study, mice that received oral vitamin D₃ supplementation of 11,500 IU/kg daily had fewer doxorubicin-induced cardiotoxic effects on ejection fraction (P<.0001) and stroke volume (P<.01) than mice that received VD supplementation of 1500 IU/kg daily.⁶

In this review, we examine the impact of chemoradiation on 25(OH)D levels—which more accurately reflects VD stores than 1,25(OH)₂D levels—and the impact of suboptimal VD on cutaneous toxicities related to chemoradiation. To define the suboptimal VD threshold, we used the Endocrine Society’s clinical practice guidelines, which characterize suboptimal 25(OH)D levels as insufficiency (21–29 ng/mL [52.5–72.5 nmol/L]) or deficiency (<20 ng/mL [50 nmol/L])⁷; deficiency can be further categorized as severe deficiency (<12 ng/mL [30 nmol/L]).⁸ This review also evaluates the evidence for vitamin D₃ supplementation to alleviate the cutaneous AEs of chemotherapy and radiation treatments.

Effects of Chemotherapy on Vitamin D Levels

A high prevalence of VD deficiency is seen in various cancers. In a retrospective review of 25(OH)D levels in 2098 adults with solid tumors of any stage (6% had metastatic disease [n=124]), suboptimal levels were found in 69% of patients with breast cancer (n=617), 75% with colorectal cancer (n=84), 72% with gynecologic cancer (n=65), 79% with kidney and bladder cancer (n=145), 83% with pancreatic and upper gastrointestinal tract cancer (n=178), 73% with lung cancer (n=73), 69% with prostate cancer (n=225), 61% with skin cancer (n=399), and 63% with thyroid cancer (n=172).⁵ Suboptimal VD also has been found in hematologic malignancies. In a prospective cohort study, mean serum 25(OH)D levels in 23 patients with recently diagnosed acute myeloid leukemia demonstrated VD deficiency (mean [SD], 18.6 [6.6] nmol/L).⁹ Given that many patients already exhibit a baseline VD deficiency at cancer diagnosis, it is important to understand the relationship between VD and cancer treatment modalities.⁵

In the United States, breast and colorectal cancers were estimated to be the first and fourth most common cancers, with 313,510 and 152,810 predicted new cases in 2024, respectively.¹⁰ This review will focus on breast and colorectal cancer when describing VD variation associated with chemotherapy exposure due to their high prevalence.

Effects of Chemotherapy on Vitamin D Levels in Breast Cancer—Breast cancer studies have shown suboptimal VD levels in 76% of females 75 years or younger with any T1, T2, or T3; N0 or N1; and M0 breast cancer, in which 38.5% (n=197) had insufficient and 37.5% (n=192) had deficient 25(OH)D levels.¹¹ In a study of female patients with primary breast cancer (stage I, II, or III and T1 with high Ki67 expression [≥30%], T2, or T3), VD deficiency was seen in 60% of patients not receiving VD supplementation.^12,13 A systematic review that included 7 studies of different types of breast cancer suggested that circulating 25(OH)D may be associated with improved prognosis.¹⁴ Thus, studies have investigated risk factors associated with poor or worsening VD status in individuals with breast cancer, including exposure to chemotherapy and/or radiation treatment.^12,15-18

A prospective cohort study assessed 25(OH)D levels in 95 patients with any breast cancer (stages I, II, IIIA, IIIB) before and after initiating chemotherapy with docetaxel, doxorubicin, epirubicin, 5-fluorouracil, or cyclophosphamide, compared with a group of 52 females without cancer.¹⁷ In the breast cancer group, approximately 80% (76/95) had suboptimal and 50% (47/95) had deficient VD levels before chemotherapy initiation (mean [SD], 54.1 [22.8] nmol/L). In the comparison group, 60% (31/52) had suboptimal and 30% (15/52) had deficient VD at baseline (mean [SD], 66.1 [23.5] nmol/L), which was higher than the breast cancer group (P=.03). A subgroup analysis excluded participants who started, stopped, or lacked data on dietary supplements containing VD (n=39); in the remaining 56 participants, a significant decrease in 25(OH)D levels was observed shortly after finishing chemotherapy compared with the prechemotherapy baseline value (mean, −7.9 nmol/L; P=.004). Notably, 6 months after chemotherapy completion, 25(OH)D levels increased (mean, +12.8 nmol/L; P<.001). Vitamin D levels remained stable in the comparison group (P=.987).¹⁷

Consistent with these findings, a cross-sectional study assessing VD status in 394 female patients with primary breast cancer (stage I, II, or III and T1 with high Ki67 expression [≥30%], T2, or T3), found that a history of chemotherapy was associated with increased odds of 25(OH)D levels less than 20 ng/mL compared with breast cancer patients with no prior chemotherapy (odds ratio, 1.86; 95% CI, 1.03-3.38).¹² Although the study data included chemotherapy history, no information was provided on specific chemotherapy agents or regimens used in this cohort, limiting the ability to detect the drugs most often implicated.

Both studies indicated a complex interplay between chemotherapy and VD levels in breast cancer patients. Although Kok et al¹⁷ suggested a transient decrease in VD levels during chemotherapy with a subsequent recovery after cessation, Fassio et al¹² highlighted the increased odds of VD deficiency associated with chemotherapy. Ultimately, larger randomized controlled trials are needed to better understand the relationship between chemotherapy and VD status in breast cancer patients.

Effects of Chemotherapy on Vitamin D Levels in Colorectal Cancer—Similar to patterns seen in breast cancer, a systematic review with 6 studies of different types of colorectal cancer suggested that circulating 25(OH)D levels may be associated with prognosis.¹⁴ Studies also have investigated the relationship between colorectal chemotherapy regimens and VD status.^15,16,18,19

A retrospective study assessed 25(OH)D levels in 315 patients with any colorectal cancer (stage I–IV).¹⁵ Patients were included in the analysis if they received less than 400 IU daily of VD supplementation at baseline. For the whole study sample, the mean (SD) VD level was 23.7 (13.71) ng/mL. Patients who had not received chemotherapy within 3 months of the VD level assessment were categorized as the no chemotherapy group, and the others were designated as the chemotherapy group; the latter group was exposed to various chemotherapy regimens, including combinations of irinotecan, oxaliplatin, 5-fluorouracil, leucovorin, bevacizumab, or cetuximab. Multivariate analysis showed that the chemotherapy group was 3.7 times more likely to have very low VD levels (≤15 ng/mL) compared with those in the no chemotherapy group (P<.0001).¹⁵

A separate cross-sectional study examined serum 25(OH)D concentrations in 1201 patients with any newly diagnosed colorectal carcinoma (stage I–III); 91% of cases were adenocarcinoma.¹⁸ In a multivariate analysis, chemotherapy plus surgery was associated with lower VD levels than surgery alone 6 months after diagnosis (mean, −8.74 nmol/L; 95% CI, −11.30 to −6.18 nmol/L), specifically decreasing by a mean of 6.7 nmol/L (95% CI, −9.8 to −3.8 nmol/L) after adjusting for demographic and lifestyle factors.¹⁸ However, a prospective cohort study demonstrated different findings.¹⁹ Comparing 58 patients with newly diagnosed colorectal adenocarcinoma (stages I–IV) who underwent chemotherapy and 36 patients who did not receive chemotherapy, there was no significant change in 25(OH)D levels from the time of diagnosis to 6 months later. Median VD levels decreased by 0.7 ng/mL in those who received chemotherapy, while a minimal (and not significant) increase of 1.6 ng/mL was observed in those without chemotherapy intervention (P=.26). Notably, supplementation was not restricted in this cohort, which may have resulted in higher VD levels in those taking supplements.¹⁹

Since time of year and geographic location can influence VD levels, one prospective cohort study controlled for differential sun exposure due to these factors in their analysis.¹⁶ Assessment of 25(OH)D levels was completed in 81 chemotherapy-naïve cancer patients immediately before beginning chemotherapy as well as 6 and 12 weeks into treatment. More than 8 primary cancer types were represented in this study, with breast (34% [29/81]) and colorectal (14% [12/81]) cancer being the most common, but the cancer stages of the participants were not detailed. Vitamin D levels decreased after commencing chemotherapy, with the largest drop occurring 6 weeks into treatment. From the 6- to 12-week end points, VD increased but remained below the original baseline level (baseline: mean [SD], 49.2 [22.3] nmol/L; 6 weeks: mean [SD], 40.9 [19.0] nmol/L; 12 weeks: mean [SD], 45.9 [19.7] nmol/L; P=.05).¹⁶

Although focused on breast and colorectal cancers, these studies suggest that various chemotherapy regimens may confer a higher risk for VD deficiency compared with VD status at diagnosis and/or prior to chemotherapy treatment. However, most of these studies only discussed stage-based differences, excluding analysis of the variety of cancer subtypes that comprise breast and colorectal malignancies, which may limit our ability to extrapolate from these data. Ultimately, larger randomized controlled trials are needed to better understand the relationship between chemotherapy and VD status across various primary cancer types.

Effects of Radiation Therapy on Vitamin D Levels

Unlike chemotherapy, studies on the association between radiation therapy and VD levels are minimal, with most reports in the literature discussing the use of VD to potentiate the effects of radiation therapy. In one cross-sectional analysis of 1201 patients with newly diagnosed stage I, II, or III colorectal cancer of any type (94% were adenocarcinoma), radiation plus surgery was associated with slightly lower 25(OH)D levels than surgery alone for tumor treatment 6 months after diagnosis (mean, −3.17; 95% CI, −6.07 to −0.28 nmol/L). However, after adjustment for demographic and lifestyle factors, this decrease in VD levels attributable to radiotherapy was not statistically significant compared with the surgery-only cohort (mean, −1.78; 95% CI, −5.07 to 1.52 nmol/L).¹⁸

Similarly, a cross-sectional study assessing VD status in 394 female patients with primary breast cancer (stage I, II, or III and T1 with high Ki67 expression [≥30%], T2, or T3), found that a history of radiotherapy was not associated with a difference in serum 25(OH)D levels compared with those with breast cancer without prior radiotherapy (odds ratio, 0.90; 95% CI, 0.52-1.54).¹² From the limited existing literature specifically addressing variations of VD levels with radiation, radiation therapy does not appear to significantly impact VD levels.

Vitamin D Levels and the Severity of Chemotherapy- or Radiation Therapy–Induced AEs

A prospective cohort of 241 patients did not find an increase in the incidence or severity of chemotherapy-induced cutaneous toxicities in those with suboptimal 1,25(OH)₂D₃ levels (≤75 nmol/L).²⁰ Eight different primary cancer types were represented, including breast and colorectal cancer; the tumor stages of the participants were not detailed. Forty-one patients had normal 1,25(OH)₂D₃ levels, while the remaining 200 had suboptimal levels. There was no significant association between serum VD levels and the following dermatologic toxicities: desquamation (P=.26), xerosis (P=.15), mucositis (P=.30), or painful rash (P=.87). Surprisingly, nail changes and hand-foot reactions occurred with greater frequency in patients with normal VD levels (P=.01 and P=.03, respectively).²⁰ Hand-foot reaction is part of the toxic erythema of chemotherapy (TEC) spectrum, which is comprised of a range of cytotoxic skin injuries that typically manifest within 2 to 3 weeks of exposure to the offending chemotherapeutic agents, often characterized by erythema, pain, swelling, and blistering, particularly in intertriginous and acral areas.^21-23 Recovery from TEC generally takes at least 2 to 4 weeks and may necessitate cessation of the offending chemotherapeutic agent.^21,24 Notably, this study measured 1,25(OH)₂D₃ levels instead of 25(OH)D levels, which may not reliably indicate body stores of VD.^7,20 These results underscore the complex nature between chemotherapy and VD; however, VD levels alone do not appear to be a sufficient biomarker for predicting chemotherapy-associated cutaneous AEs.

Interestingly, radiation therapy–induced AEs may be associated with VD levels. A prospective cohort study of 98 patients with prostate, bladder, or gynecologic cancers (tumor stages were not detailed) undergoing pelvic radiotherapy found that females and males with 25(OH)D levels below a threshold of 35 and 40 nmol/L, respectively, were more likely to experience higher Radiation Therapy Oncology Group (RTOG) grade acute proctitis compared with those with VD above these thresholds.²⁵ Specifically, VD below these thresholds was associated with increased odds of RTOG grade 2 or higher radiation-induced proctitis (OR, 3.07; 95% CI, 1.27-7.50 [P=.013]). Additionally, a weak correlation was noted between VD below these thresholds and the RTOG grade, with a Spearman correlation value of −0.189 (P=.031).²⁵

One prospective cohort study included 28 patients with any cancer of the oral cavity, oropharynx, hypopharynx, or larynx stages II, III, or IVA; 93% (26/28) were stage III or IVA.²⁶ The 20 (71%) patients with suboptimal 25(OH)D levels (≤75 nmol/L) experienced a higher prevalence of grade II radiation dermatitis compared with the 8 (29%) patients with optimal VD levels (χ²₂=5.973; P=.0505). This pattern persisted with the severity of mucositis; patients from the suboptimal VD group presented with higher rates of grades II and III mucositis compared with the VD optimal group (χ²₂=13.627; P=.0011).²⁶ Recognizing the small cohort evaluated in the study, we highlight the importance of further studies to clarify these associations.

Chemotherapy-Induced Cutaneous Events Treated with High-Dose Vitamin D

Chemotherapeutic agents are known to induce cellular damage, resulting in a range of cutaneous AEs that can invoke discontinuation of otherwise effective chemotherapeutic interventions.^27,28 Recent research has explored the potential of high-dose vitamin D₃ as a therapeutic agent to mitigate cutaneous reactions.^29,30

A randomized, double-blind, placebo-controlled trial investigated the use of a single high dose of oral ­25(OH)D to treat topical nitrogen mustard (NM)–induced rash.²⁹ To characterize baseline inflammatory responses from NM injury without intervention, clinical measures, serum studies, and tissue analyses from skin biopsies were performed on 28 healthy adults after exposure to topical NM—a chemotherapeutic agent classified as a DNA alkylator. Two weeks later, participants were exposed to topical NM a second time and were split into 2 groups: 14 patients received a single 200,000-IU dose of oral 25(OH)D while the other 14 participants were given a placebo. Using the inflammatory markers induced from baseline exposure to NM alone, posttreatment analysis revealed that the punch biopsies from the 25(OH)D group expressed fewer NM-induced inflammatory markers compared with the placebo group at both 72 hours and 6 weeks following NM injury (72 hours: 12 vs 17 inflammatory markers; 6 weeks: 4 vs 11 inflammatory markers). Notably, NM inflammatory markers were enriched for IL-17 signaling pathways in the placebo biopsies but not in the 25(OH)D intervention group. This study also identified mild and severe patterns of inflammatory responses to NM that were independent of the 25(OH)D intervention. Biomarkers specific to skin biopsies from participants with the severe response included CCL20, CCL2, and CXCL8 (adjusted P<.05). At 6 weeks posttreatment, the 25(OH)D group showed a 67% reduction in NM injury markers compared with a 35% reduction in the placebo group. Despite a reduction in tissue inflammatory markers, there were no clinically significant changes observed in skin redness, swelling, or histologic structure when comparing the 25(OH)D- supplemented group to the placebo group at any time during the study, necessitating further research into the mechanistic roles of high doses VD supplementation.²⁹

Although Ernst et al²⁹ did not observe any clinically significant improvements with VD treatment, a case series of 6 patients with either glioblastoma multiforme, acute myeloid leukemia, or aplastic anemia did demonstrate clinical improvement of TEC after receiving high-dose vitamin D₃.³⁰ The mean time to onset of TEC was noted at 8.5 days following administration of the inciting chemotherapeutic agent, which included combinations of anthracycline, antimetabolite, kinase inhibitor, B-cell lymphoma 2 inhibitor, purine analogue, and alkylating agents. A combination of clinical and histologic findings was used to diagnose TEC. Baseline 25(OH)D levels were not established prior to treatment. The treatment regimen for 1 patient included 2 doses of 50,000 IU of VD spaced 1 week apart, totaling 100,000 IU, while the remaining 5 patients received a total of 200,000 IU, also split into 2 doses given 1 week apart. All patients received their first dose of VD within a week of the cutaneous eruption. Following the initial VD dose, there was a notable improvement in pain, pruritus, or swelling by the next day. Reduction in erythema also was observed within 1 to 4 days.³⁰

No AEs associated with VD supplementation were reported, suggesting a potential beneficial role of high-dose VD in accelerating recovery from chemotherapy-induced rashes without evident safety concerns.

Radiation Therapy–Induced Cutaneous Events Treated with High-Dose Vitamin D

Radiation dermatitis is a common and often severe complication of radiation therapy that affects more than 90% of patients undergoing treatment, with half of these individuals experiencing grade 2 toxicity, according to the National Cancer Institute’s Common Terminology Criteria for Adverse Events.^31,32 Radiation damage to basal keratinocytes and hair follicle stem cells disrupts the renewal of the skin’s outer layer, while a surge of free radicals causes irreversible DNA damage.³³ Symptoms of radiation dermatitis can vary from mild pink erythema to tissue ulceration and necrosis, typically within 1 to 4 weeks of radiation exposure.³⁴ The resulting dermatitis can take 2 to 4 weeks to heal, notably impacting patient quality of life and often necessitating modifications or interruptions in cancer therapy.³³

Prior studies have demonstrated the use of high-dose VD to improve the healing of UV-irradiated skin. A randomized controlled trial investigated high-dose vitamin D₃ to treat experimentally induced sunburn in 20 healthy adults. Compared with those who received a placebo, participants receiving the oral dose of 200,000 IU of vitamin D₃ demonstrated suppression of the pro-inflammatory mediators tumor necrosis factor α (P=.04) and inducible nitric oxide synthase (P=.02), while expression of tissue repair enhancer arginase 1 was increased (P<.005).³⁵ The mechanism of this enhanced tissue repair was investigated using a mouse model, in which intraperitoneal 25(OH)D was administered following severe UV-induced skin injury. On immunofluorescence microscopy, mice treated with VD showed enhanced autophagy within the macrophages infiltrating UV-irradiated skin.³⁶ The use of high-dose VD to treat UV-irradiated skin in these studies established a precedent for using VD to heal cutaneous injury caused by ionizing radiation therapy.

Some studies have focused on the role of VD for treating acute radiation dermatitis. A study of 23 patients with ductal carcinoma in situ or localized invasive ductal carcinoma breast cancer compared the effectiveness of topical calcipotriol to that of a standard hydrating ointment.³⁷ Participants were randomized to 1 of 2 treatments before starting adjuvant radiotherapy to evaluate their potential in preventing radiation dermatitis. In 87% (20/23) of these patients, no difference in skin reaction was observed between the 2 treatments, suggesting that topical VD application may not offer any advantage over the standard hydrating ointment for the prevention of radiation dermatitis.³⁷

Benefits of high-dose oral VD for treating radiation dermatitis also have been reported. Nguyen et al³⁸ documented 3 cases in which patients with neuroendocrine carcinoma of the pancreas, tonsillar carcinoma, and breast cancer received 200,000 IU of oral ergocalciferol distributed over 2 doses given 7 days apart for radiation dermatitis. These patients experienced substantial improvements in pain, swelling, and redness within a week of the initial dose. Additionally, a case of radiation recall dermatitis, which occurred a week after vinorelbine chemotherapy, was treated with 2 doses totaling 100,000 IU of oral ergocalciferol. This patient also had improvement in pain and swelling but continued to have tumor-related induration and ulceration.³⁹

Although topical VD did not show significant benefits over standard treatments for radiation dermatitis, high-dose oral VD appears promising in improving patient outcomes of pain and swelling more rapidly than current practices. Further research is needed to confirm these findings and establish standardized treatment protocols.

Final Thoughts

Suboptimal VD levels are prevalent in numerous cancer types. Chemotherapy often is associated with acute, potentially transient worsening of VD status in patients with breast and colorectal cancer. Although 25(OH)D levels have not corresponded with increased frequency of ­chemotherapy-related dermatologic AEs, suboptimal 25(OH)D levels appear to be associated with increased severity of radiation-induced mucositis and dermatitis.^20,25,26 The use of high-dose VD as a therapeutic agent shows promise in mitigating chemotherapy-induced and radiation therapy–induced rashes in multiple cancer types with reduction of inflammatory markers and a durable anti-inflammatory impact. Although the mechanisms of cellular injury vary among chemotherapeutic agents, the anti-inflammatory and tissue repair properties of VD may make it an effective treatment for chemotherapy-induced cutaneous damage regardless of injury mechanism.^2-4,35 However, reports of clinical improvement vary, and further objective studies to classify optimal dosing, administration, and outcome measures are needed. The absence of reported AEs associated with high-dose VD supplementation is encouraging, but selection of a safe and optimal dosing regimen can only occur with dedicated clinical trials.

Vitamin D (VD) regulates keratinocyte proliferation and differentiation, modulates inflammatory pathways, and protects against cellular damage in the skin. ¹ In the setting of tissue injury and acute skin inflammation, active vitamin D—1,25(OH) ₂ D—suppresses signaling from pro-inflammatory chemokines and cytokines such as IFN- γ and IL-17. ^2,3 This suppression reduces proliferation of helper T cells (T _H 1, T _H 17) and B cells, decreasing tissue damage from reactive oxygen species release while enhancing secretion of the anti-inflammatory cytokine IL-10 by antigen-presenting cells. ^2-4

Suboptimal VD levels have been associated with numerous health consequences including malignancy, prompting interest in VD supplementation for improving cancer-related outcomes.⁵ Beyond disease prognosis, high-dose VD supplementation has been suggested as a potential therapy for adverse events (AEs) related to cancer treatments. In one study, mice that received oral vitamin D₃ supplementation of 11,500 IU/kg daily had fewer doxorubicin-induced cardiotoxic effects on ejection fraction (P<.0001) and stroke volume (P<.01) than mice that received VD supplementation of 1500 IU/kg daily.⁶

In this review, we examine the impact of chemoradiation on 25(OH)D levels—which more accurately reflects VD stores than 1,25(OH)₂D levels—and the impact of suboptimal VD on cutaneous toxicities related to chemoradiation. To define the suboptimal VD threshold, we used the Endocrine Society’s clinical practice guidelines, which characterize suboptimal 25(OH)D levels as insufficiency (21–29 ng/mL [52.5–72.5 nmol/L]) or deficiency (<20 ng/mL [50 nmol/L])⁷; deficiency can be further categorized as severe deficiency (<12 ng/mL [30 nmol/L]).⁸ This review also evaluates the evidence for vitamin D₃ supplementation to alleviate the cutaneous AEs of chemotherapy and radiation treatments.

Effects of Chemotherapy on Vitamin D Levels

A high prevalence of VD deficiency is seen in various cancers. In a retrospective review of 25(OH)D levels in 2098 adults with solid tumors of any stage (6% had metastatic disease [n=124]), suboptimal levels were found in 69% of patients with breast cancer (n=617), 75% with colorectal cancer (n=84), 72% with gynecologic cancer (n=65), 79% with kidney and bladder cancer (n=145), 83% with pancreatic and upper gastrointestinal tract cancer (n=178), 73% with lung cancer (n=73), 69% with prostate cancer (n=225), 61% with skin cancer (n=399), and 63% with thyroid cancer (n=172).⁵ Suboptimal VD also has been found in hematologic malignancies. In a prospective cohort study, mean serum 25(OH)D levels in 23 patients with recently diagnosed acute myeloid leukemia demonstrated VD deficiency (mean [SD], 18.6 [6.6] nmol/L).⁹ Given that many patients already exhibit a baseline VD deficiency at cancer diagnosis, it is important to understand the relationship between VD and cancer treatment modalities.⁵

In the United States, breast and colorectal cancers were estimated to be the first and fourth most common cancers, with 313,510 and 152,810 predicted new cases in 2024, respectively.¹⁰ This review will focus on breast and colorectal cancer when describing VD variation associated with chemotherapy exposure due to their high prevalence.

Effects of Chemotherapy on Vitamin D Levels in Breast Cancer—Breast cancer studies have shown suboptimal VD levels in 76% of females 75 years or younger with any T1, T2, or T3; N0 or N1; and M0 breast cancer, in which 38.5% (n=197) had insufficient and 37.5% (n=192) had deficient 25(OH)D levels.¹¹ In a study of female patients with primary breast cancer (stage I, II, or III and T1 with high Ki67 expression [≥30%], T2, or T3), VD deficiency was seen in 60% of patients not receiving VD supplementation.^12,13 A systematic review that included 7 studies of different types of breast cancer suggested that circulating 25(OH)D may be associated with improved prognosis.¹⁴ Thus, studies have investigated risk factors associated with poor or worsening VD status in individuals with breast cancer, including exposure to chemotherapy and/or radiation treatment.^12,15-18

A prospective cohort study assessed 25(OH)D levels in 95 patients with any breast cancer (stages I, II, IIIA, IIIB) before and after initiating chemotherapy with docetaxel, doxorubicin, epirubicin, 5-fluorouracil, or cyclophosphamide, compared with a group of 52 females without cancer.¹⁷ In the breast cancer group, approximately 80% (76/95) had suboptimal and 50% (47/95) had deficient VD levels before chemotherapy initiation (mean [SD], 54.1 [22.8] nmol/L). In the comparison group, 60% (31/52) had suboptimal and 30% (15/52) had deficient VD at baseline (mean [SD], 66.1 [23.5] nmol/L), which was higher than the breast cancer group (P=.03). A subgroup analysis excluded participants who started, stopped, or lacked data on dietary supplements containing VD (n=39); in the remaining 56 participants, a significant decrease in 25(OH)D levels was observed shortly after finishing chemotherapy compared with the prechemotherapy baseline value (mean, −7.9 nmol/L; P=.004). Notably, 6 months after chemotherapy completion, 25(OH)D levels increased (mean, +12.8 nmol/L; P<.001). Vitamin D levels remained stable in the comparison group (P=.987).¹⁷

Consistent with these findings, a cross-sectional study assessing VD status in 394 female patients with primary breast cancer (stage I, II, or III and T1 with high Ki67 expression [≥30%], T2, or T3), found that a history of chemotherapy was associated with increased odds of 25(OH)D levels less than 20 ng/mL compared with breast cancer patients with no prior chemotherapy (odds ratio, 1.86; 95% CI, 1.03-3.38).¹² Although the study data included chemotherapy history, no information was provided on specific chemotherapy agents or regimens used in this cohort, limiting the ability to detect the drugs most often implicated.

Both studies indicated a complex interplay between chemotherapy and VD levels in breast cancer patients. Although Kok et al¹⁷ suggested a transient decrease in VD levels during chemotherapy with a subsequent recovery after cessation, Fassio et al¹² highlighted the increased odds of VD deficiency associated with chemotherapy. Ultimately, larger randomized controlled trials are needed to better understand the relationship between chemotherapy and VD status in breast cancer patients.

Effects of Chemotherapy on Vitamin D Levels in Colorectal Cancer—Similar to patterns seen in breast cancer, a systematic review with 6 studies of different types of colorectal cancer suggested that circulating 25(OH)D levels may be associated with prognosis.¹⁴ Studies also have investigated the relationship between colorectal chemotherapy regimens and VD status.^15,16,18,19

A retrospective study assessed 25(OH)D levels in 315 patients with any colorectal cancer (stage I–IV).¹⁵ Patients were included in the analysis if they received less than 400 IU daily of VD supplementation at baseline. For the whole study sample, the mean (SD) VD level was 23.7 (13.71) ng/mL. Patients who had not received chemotherapy within 3 months of the VD level assessment were categorized as the no chemotherapy group, and the others were designated as the chemotherapy group; the latter group was exposed to various chemotherapy regimens, including combinations of irinotecan, oxaliplatin, 5-fluorouracil, leucovorin, bevacizumab, or cetuximab. Multivariate analysis showed that the chemotherapy group was 3.7 times more likely to have very low VD levels (≤15 ng/mL) compared with those in the no chemotherapy group (P<.0001).¹⁵

A separate cross-sectional study examined serum 25(OH)D concentrations in 1201 patients with any newly diagnosed colorectal carcinoma (stage I–III); 91% of cases were adenocarcinoma.¹⁸ In a multivariate analysis, chemotherapy plus surgery was associated with lower VD levels than surgery alone 6 months after diagnosis (mean, −8.74 nmol/L; 95% CI, −11.30 to −6.18 nmol/L), specifically decreasing by a mean of 6.7 nmol/L (95% CI, −9.8 to −3.8 nmol/L) after adjusting for demographic and lifestyle factors.¹⁸ However, a prospective cohort study demonstrated different findings.¹⁹ Comparing 58 patients with newly diagnosed colorectal adenocarcinoma (stages I–IV) who underwent chemotherapy and 36 patients who did not receive chemotherapy, there was no significant change in 25(OH)D levels from the time of diagnosis to 6 months later. Median VD levels decreased by 0.7 ng/mL in those who received chemotherapy, while a minimal (and not significant) increase of 1.6 ng/mL was observed in those without chemotherapy intervention (P=.26). Notably, supplementation was not restricted in this cohort, which may have resulted in higher VD levels in those taking supplements.¹⁹

Since time of year and geographic location can influence VD levels, one prospective cohort study controlled for differential sun exposure due to these factors in their analysis.¹⁶ Assessment of 25(OH)D levels was completed in 81 chemotherapy-naïve cancer patients immediately before beginning chemotherapy as well as 6 and 12 weeks into treatment. More than 8 primary cancer types were represented in this study, with breast (34% [29/81]) and colorectal (14% [12/81]) cancer being the most common, but the cancer stages of the participants were not detailed. Vitamin D levels decreased after commencing chemotherapy, with the largest drop occurring 6 weeks into treatment. From the 6- to 12-week end points, VD increased but remained below the original baseline level (baseline: mean [SD], 49.2 [22.3] nmol/L; 6 weeks: mean [SD], 40.9 [19.0] nmol/L; 12 weeks: mean [SD], 45.9 [19.7] nmol/L; P=.05).¹⁶

Although focused on breast and colorectal cancers, these studies suggest that various chemotherapy regimens may confer a higher risk for VD deficiency compared with VD status at diagnosis and/or prior to chemotherapy treatment. However, most of these studies only discussed stage-based differences, excluding analysis of the variety of cancer subtypes that comprise breast and colorectal malignancies, which may limit our ability to extrapolate from these data. Ultimately, larger randomized controlled trials are needed to better understand the relationship between chemotherapy and VD status across various primary cancer types.

Effects of Radiation Therapy on Vitamin D Levels

Unlike chemotherapy, studies on the association between radiation therapy and VD levels are minimal, with most reports in the literature discussing the use of VD to potentiate the effects of radiation therapy. In one cross-sectional analysis of 1201 patients with newly diagnosed stage I, II, or III colorectal cancer of any type (94% were adenocarcinoma), radiation plus surgery was associated with slightly lower 25(OH)D levels than surgery alone for tumor treatment 6 months after diagnosis (mean, −3.17; 95% CI, −6.07 to −0.28 nmol/L). However, after adjustment for demographic and lifestyle factors, this decrease in VD levels attributable to radiotherapy was not statistically significant compared with the surgery-only cohort (mean, −1.78; 95% CI, −5.07 to 1.52 nmol/L).¹⁸

Similarly, a cross-sectional study assessing VD status in 394 female patients with primary breast cancer (stage I, II, or III and T1 with high Ki67 expression [≥30%], T2, or T3), found that a history of radiotherapy was not associated with a difference in serum 25(OH)D levels compared with those with breast cancer without prior radiotherapy (odds ratio, 0.90; 95% CI, 0.52-1.54).¹² From the limited existing literature specifically addressing variations of VD levels with radiation, radiation therapy does not appear to significantly impact VD levels.

Vitamin D Levels and the Severity of Chemotherapy- or Radiation Therapy–Induced AEs

A prospective cohort of 241 patients did not find an increase in the incidence or severity of chemotherapy-induced cutaneous toxicities in those with suboptimal 1,25(OH)₂D₃ levels (≤75 nmol/L).²⁰ Eight different primary cancer types were represented, including breast and colorectal cancer; the tumor stages of the participants were not detailed. Forty-one patients had normal 1,25(OH)₂D₃ levels, while the remaining 200 had suboptimal levels. There was no significant association between serum VD levels and the following dermatologic toxicities: desquamation (P=.26), xerosis (P=.15), mucositis (P=.30), or painful rash (P=.87). Surprisingly, nail changes and hand-foot reactions occurred with greater frequency in patients with normal VD levels (P=.01 and P=.03, respectively).²⁰ Hand-foot reaction is part of the toxic erythema of chemotherapy (TEC) spectrum, which is comprised of a range of cytotoxic skin injuries that typically manifest within 2 to 3 weeks of exposure to the offending chemotherapeutic agents, often characterized by erythema, pain, swelling, and blistering, particularly in intertriginous and acral areas.^21-23 Recovery from TEC generally takes at least 2 to 4 weeks and may necessitate cessation of the offending chemotherapeutic agent.^21,24 Notably, this study measured 1,25(OH)₂D₃ levels instead of 25(OH)D levels, which may not reliably indicate body stores of VD.^7,20 These results underscore the complex nature between chemotherapy and VD; however, VD levels alone do not appear to be a sufficient biomarker for predicting chemotherapy-associated cutaneous AEs.

Interestingly, radiation therapy–induced AEs may be associated with VD levels. A prospective cohort study of 98 patients with prostate, bladder, or gynecologic cancers (tumor stages were not detailed) undergoing pelvic radiotherapy found that females and males with 25(OH)D levels below a threshold of 35 and 40 nmol/L, respectively, were more likely to experience higher Radiation Therapy Oncology Group (RTOG) grade acute proctitis compared with those with VD above these thresholds.²⁵ Specifically, VD below these thresholds was associated with increased odds of RTOG grade 2 or higher radiation-induced proctitis (OR, 3.07; 95% CI, 1.27-7.50 [P=.013]). Additionally, a weak correlation was noted between VD below these thresholds and the RTOG grade, with a Spearman correlation value of −0.189 (P=.031).²⁵

One prospective cohort study included 28 patients with any cancer of the oral cavity, oropharynx, hypopharynx, or larynx stages II, III, or IVA; 93% (26/28) were stage III or IVA.²⁶ The 20 (71%) patients with suboptimal 25(OH)D levels (≤75 nmol/L) experienced a higher prevalence of grade II radiation dermatitis compared with the 8 (29%) patients with optimal VD levels (χ²₂=5.973; P=.0505). This pattern persisted with the severity of mucositis; patients from the suboptimal VD group presented with higher rates of grades II and III mucositis compared with the VD optimal group (χ²₂=13.627; P=.0011).²⁶ Recognizing the small cohort evaluated in the study, we highlight the importance of further studies to clarify these associations.

Chemotherapy-Induced Cutaneous Events Treated with High-Dose Vitamin D

Chemotherapeutic agents are known to induce cellular damage, resulting in a range of cutaneous AEs that can invoke discontinuation of otherwise effective chemotherapeutic interventions.^27,28 Recent research has explored the potential of high-dose vitamin D₃ as a therapeutic agent to mitigate cutaneous reactions.^29,30

A randomized, double-blind, placebo-controlled trial investigated the use of a single high dose of oral ­25(OH)D to treat topical nitrogen mustard (NM)–induced rash.²⁹ To characterize baseline inflammatory responses from NM injury without intervention, clinical measures, serum studies, and tissue analyses from skin biopsies were performed on 28 healthy adults after exposure to topical NM—a chemotherapeutic agent classified as a DNA alkylator. Two weeks later, participants were exposed to topical NM a second time and were split into 2 groups: 14 patients received a single 200,000-IU dose of oral 25(OH)D while the other 14 participants were given a placebo. Using the inflammatory markers induced from baseline exposure to NM alone, posttreatment analysis revealed that the punch biopsies from the 25(OH)D group expressed fewer NM-induced inflammatory markers compared with the placebo group at both 72 hours and 6 weeks following NM injury (72 hours: 12 vs 17 inflammatory markers; 6 weeks: 4 vs 11 inflammatory markers). Notably, NM inflammatory markers were enriched for IL-17 signaling pathways in the placebo biopsies but not in the 25(OH)D intervention group. This study also identified mild and severe patterns of inflammatory responses to NM that were independent of the 25(OH)D intervention. Biomarkers specific to skin biopsies from participants with the severe response included CCL20, CCL2, and CXCL8 (adjusted P<.05). At 6 weeks posttreatment, the 25(OH)D group showed a 67% reduction in NM injury markers compared with a 35% reduction in the placebo group. Despite a reduction in tissue inflammatory markers, there were no clinically significant changes observed in skin redness, swelling, or histologic structure when comparing the 25(OH)D- supplemented group to the placebo group at any time during the study, necessitating further research into the mechanistic roles of high doses VD supplementation.²⁹

Although Ernst et al²⁹ did not observe any clinically significant improvements with VD treatment, a case series of 6 patients with either glioblastoma multiforme, acute myeloid leukemia, or aplastic anemia did demonstrate clinical improvement of TEC after receiving high-dose vitamin D₃.³⁰ The mean time to onset of TEC was noted at 8.5 days following administration of the inciting chemotherapeutic agent, which included combinations of anthracycline, antimetabolite, kinase inhibitor, B-cell lymphoma 2 inhibitor, purine analogue, and alkylating agents. A combination of clinical and histologic findings was used to diagnose TEC. Baseline 25(OH)D levels were not established prior to treatment. The treatment regimen for 1 patient included 2 doses of 50,000 IU of VD spaced 1 week apart, totaling 100,000 IU, while the remaining 5 patients received a total of 200,000 IU, also split into 2 doses given 1 week apart. All patients received their first dose of VD within a week of the cutaneous eruption. Following the initial VD dose, there was a notable improvement in pain, pruritus, or swelling by the next day. Reduction in erythema also was observed within 1 to 4 days.³⁰

No AEs associated with VD supplementation were reported, suggesting a potential beneficial role of high-dose VD in accelerating recovery from chemotherapy-induced rashes without evident safety concerns.

Radiation Therapy–Induced Cutaneous Events Treated with High-Dose Vitamin D

Radiation dermatitis is a common and often severe complication of radiation therapy that affects more than 90% of patients undergoing treatment, with half of these individuals experiencing grade 2 toxicity, according to the National Cancer Institute’s Common Terminology Criteria for Adverse Events.^31,32 Radiation damage to basal keratinocytes and hair follicle stem cells disrupts the renewal of the skin’s outer layer, while a surge of free radicals causes irreversible DNA damage.³³ Symptoms of radiation dermatitis can vary from mild pink erythema to tissue ulceration and necrosis, typically within 1 to 4 weeks of radiation exposure.³⁴ The resulting dermatitis can take 2 to 4 weeks to heal, notably impacting patient quality of life and often necessitating modifications or interruptions in cancer therapy.³³

Prior studies have demonstrated the use of high-dose VD to improve the healing of UV-irradiated skin. A randomized controlled trial investigated high-dose vitamin D₃ to treat experimentally induced sunburn in 20 healthy adults. Compared with those who received a placebo, participants receiving the oral dose of 200,000 IU of vitamin D₃ demonstrated suppression of the pro-inflammatory mediators tumor necrosis factor α (P=.04) and inducible nitric oxide synthase (P=.02), while expression of tissue repair enhancer arginase 1 was increased (P<.005).³⁵ The mechanism of this enhanced tissue repair was investigated using a mouse model, in which intraperitoneal 25(OH)D was administered following severe UV-induced skin injury. On immunofluorescence microscopy, mice treated with VD showed enhanced autophagy within the macrophages infiltrating UV-irradiated skin.³⁶ The use of high-dose VD to treat UV-irradiated skin in these studies established a precedent for using VD to heal cutaneous injury caused by ionizing radiation therapy.

Some studies have focused on the role of VD for treating acute radiation dermatitis. A study of 23 patients with ductal carcinoma in situ or localized invasive ductal carcinoma breast cancer compared the effectiveness of topical calcipotriol to that of a standard hydrating ointment.³⁷ Participants were randomized to 1 of 2 treatments before starting adjuvant radiotherapy to evaluate their potential in preventing radiation dermatitis. In 87% (20/23) of these patients, no difference in skin reaction was observed between the 2 treatments, suggesting that topical VD application may not offer any advantage over the standard hydrating ointment for the prevention of radiation dermatitis.³⁷

Benefits of high-dose oral VD for treating radiation dermatitis also have been reported. Nguyen et al³⁸ documented 3 cases in which patients with neuroendocrine carcinoma of the pancreas, tonsillar carcinoma, and breast cancer received 200,000 IU of oral ergocalciferol distributed over 2 doses given 7 days apart for radiation dermatitis. These patients experienced substantial improvements in pain, swelling, and redness within a week of the initial dose. Additionally, a case of radiation recall dermatitis, which occurred a week after vinorelbine chemotherapy, was treated with 2 doses totaling 100,000 IU of oral ergocalciferol. This patient also had improvement in pain and swelling but continued to have tumor-related induration and ulceration.³⁹

Although topical VD did not show significant benefits over standard treatments for radiation dermatitis, high-dose oral VD appears promising in improving patient outcomes of pain and swelling more rapidly than current practices. Further research is needed to confirm these findings and establish standardized treatment protocols.

Final Thoughts

Suboptimal VD levels are prevalent in numerous cancer types. Chemotherapy often is associated with acute, potentially transient worsening of VD status in patients with breast and colorectal cancer. Although 25(OH)D levels have not corresponded with increased frequency of ­chemotherapy-related dermatologic AEs, suboptimal 25(OH)D levels appear to be associated with increased severity of radiation-induced mucositis and dermatitis.^20,25,26 The use of high-dose VD as a therapeutic agent shows promise in mitigating chemotherapy-induced and radiation therapy–induced rashes in multiple cancer types with reduction of inflammatory markers and a durable anti-inflammatory impact. Although the mechanisms of cellular injury vary among chemotherapeutic agents, the anti-inflammatory and tissue repair properties of VD may make it an effective treatment for chemotherapy-induced cutaneous damage regardless of injury mechanism.^2-4,35 However, reports of clinical improvement vary, and further objective studies to classify optimal dosing, administration, and outcome measures are needed. The absence of reported AEs associated with high-dose VD supplementation is encouraging, but selection of a safe and optimal dosing regimen can only occur with dedicated clinical trials.

Vitamin D (VD) regulates keratinocyte proliferation and differentiation, modulates inflammatory pathways, and protects against cellular damage in the skin. ¹ In the setting of tissue injury and acute skin inflammation, active vitamin D—1,25(OH) ₂ D—suppresses signaling from pro-inflammatory chemokines and cytokines such as IFN- γ and IL-17. ^2,3 This suppression reduces proliferation of helper T cells (T _H 1, T _H 17) and B cells, decreasing tissue damage from reactive oxygen species release while enhancing secretion of the anti-inflammatory cytokine IL-10 by antigen-presenting cells. ^2-4

Suboptimal VD levels have been associated with numerous health consequences including malignancy, prompting interest in VD supplementation for improving cancer-related outcomes.⁵ Beyond disease prognosis, high-dose VD supplementation has been suggested as a potential therapy for adverse events (AEs) related to cancer treatments. In one study, mice that received oral vitamin D₃ supplementation of 11,500 IU/kg daily had fewer doxorubicin-induced cardiotoxic effects on ejection fraction (P<.0001) and stroke volume (P<.01) than mice that received VD supplementation of 1500 IU/kg daily.⁶

In this review, we examine the impact of chemoradiation on 25(OH)D levels—which more accurately reflects VD stores than 1,25(OH)₂D levels—and the impact of suboptimal VD on cutaneous toxicities related to chemoradiation. To define the suboptimal VD threshold, we used the Endocrine Society’s clinical practice guidelines, which characterize suboptimal 25(OH)D levels as insufficiency (21–29 ng/mL [52.5–72.5 nmol/L]) or deficiency (<20 ng/mL [50 nmol/L])⁷; deficiency can be further categorized as severe deficiency (<12 ng/mL [30 nmol/L]).⁸ This review also evaluates the evidence for vitamin D₃ supplementation to alleviate the cutaneous AEs of chemotherapy and radiation treatments.

Effects of Chemotherapy on Vitamin D Levels

A high prevalence of VD deficiency is seen in various cancers. In a retrospective review of 25(OH)D levels in 2098 adults with solid tumors of any stage (6% had metastatic disease [n=124]), suboptimal levels were found in 69% of patients with breast cancer (n=617), 75% with colorectal cancer (n=84), 72% with gynecologic cancer (n=65), 79% with kidney and bladder cancer (n=145), 83% with pancreatic and upper gastrointestinal tract cancer (n=178), 73% with lung cancer (n=73), 69% with prostate cancer (n=225), 61% with skin cancer (n=399), and 63% with thyroid cancer (n=172).⁵ Suboptimal VD also has been found in hematologic malignancies. In a prospective cohort study, mean serum 25(OH)D levels in 23 patients with recently diagnosed acute myeloid leukemia demonstrated VD deficiency (mean [SD], 18.6 [6.6] nmol/L).⁹ Given that many patients already exhibit a baseline VD deficiency at cancer diagnosis, it is important to understand the relationship between VD and cancer treatment modalities.⁵

In the United States, breast and colorectal cancers were estimated to be the first and fourth most common cancers, with 313,510 and 152,810 predicted new cases in 2024, respectively.¹⁰ This review will focus on breast and colorectal cancer when describing VD variation associated with chemotherapy exposure due to their high prevalence.

Effects of Chemotherapy on Vitamin D Levels in Breast Cancer—Breast cancer studies have shown suboptimal VD levels in 76% of females 75 years or younger with any T1, T2, or T3; N0 or N1; and M0 breast cancer, in which 38.5% (n=197) had insufficient and 37.5% (n=192) had deficient 25(OH)D levels.¹¹ In a study of female patients with primary breast cancer (stage I, II, or III and T1 with high Ki67 expression [≥30%], T2, or T3), VD deficiency was seen in 60% of patients not receiving VD supplementation.^12,13 A systematic review that included 7 studies of different types of breast cancer suggested that circulating 25(OH)D may be associated with improved prognosis.¹⁴ Thus, studies have investigated risk factors associated with poor or worsening VD status in individuals with breast cancer, including exposure to chemotherapy and/or radiation treatment.^12,15-18

A prospective cohort study assessed 25(OH)D levels in 95 patients with any breast cancer (stages I, II, IIIA, IIIB) before and after initiating chemotherapy with docetaxel, doxorubicin, epirubicin, 5-fluorouracil, or cyclophosphamide, compared with a group of 52 females without cancer.¹⁷ In the breast cancer group, approximately 80% (76/95) had suboptimal and 50% (47/95) had deficient VD levels before chemotherapy initiation (mean [SD], 54.1 [22.8] nmol/L). In the comparison group, 60% (31/52) had suboptimal and 30% (15/52) had deficient VD at baseline (mean [SD], 66.1 [23.5] nmol/L), which was higher than the breast cancer group (P=.03). A subgroup analysis excluded participants who started, stopped, or lacked data on dietary supplements containing VD (n=39); in the remaining 56 participants, a significant decrease in 25(OH)D levels was observed shortly after finishing chemotherapy compared with the prechemotherapy baseline value (mean, −7.9 nmol/L; P=.004). Notably, 6 months after chemotherapy completion, 25(OH)D levels increased (mean, +12.8 nmol/L; P<.001). Vitamin D levels remained stable in the comparison group (P=.987).¹⁷

Consistent with these findings, a cross-sectional study assessing VD status in 394 female patients with primary breast cancer (stage I, II, or III and T1 with high Ki67 expression [≥30%], T2, or T3), found that a history of chemotherapy was associated with increased odds of 25(OH)D levels less than 20 ng/mL compared with breast cancer patients with no prior chemotherapy (odds ratio, 1.86; 95% CI, 1.03-3.38).¹² Although the study data included chemotherapy history, no information was provided on specific chemotherapy agents or regimens used in this cohort, limiting the ability to detect the drugs most often implicated.

Both studies indicated a complex interplay between chemotherapy and VD levels in breast cancer patients. Although Kok et al¹⁷ suggested a transient decrease in VD levels during chemotherapy with a subsequent recovery after cessation, Fassio et al¹² highlighted the increased odds of VD deficiency associated with chemotherapy. Ultimately, larger randomized controlled trials are needed to better understand the relationship between chemotherapy and VD status in breast cancer patients.

Effects of Chemotherapy on Vitamin D Levels in Colorectal Cancer—Similar to patterns seen in breast cancer, a systematic review with 6 studies of different types of colorectal cancer suggested that circulating 25(OH)D levels may be associated with prognosis.¹⁴ Studies also have investigated the relationship between colorectal chemotherapy regimens and VD status.^15,16,18,19

A retrospective study assessed 25(OH)D levels in 315 patients with any colorectal cancer (stage I–IV).¹⁵ Patients were included in the analysis if they received less than 400 IU daily of VD supplementation at baseline. For the whole study sample, the mean (SD) VD level was 23.7 (13.71) ng/mL. Patients who had not received chemotherapy within 3 months of the VD level assessment were categorized as the no chemotherapy group, and the others were designated as the chemotherapy group; the latter group was exposed to various chemotherapy regimens, including combinations of irinotecan, oxaliplatin, 5-fluorouracil, leucovorin, bevacizumab, or cetuximab. Multivariate analysis showed that the chemotherapy group was 3.7 times more likely to have very low VD levels (≤15 ng/mL) compared with those in the no chemotherapy group (P<.0001).¹⁵

A separate cross-sectional study examined serum 25(OH)D concentrations in 1201 patients with any newly diagnosed colorectal carcinoma (stage I–III); 91% of cases were adenocarcinoma.¹⁸ In a multivariate analysis, chemotherapy plus surgery was associated with lower VD levels than surgery alone 6 months after diagnosis (mean, −8.74 nmol/L; 95% CI, −11.30 to −6.18 nmol/L), specifically decreasing by a mean of 6.7 nmol/L (95% CI, −9.8 to −3.8 nmol/L) after adjusting for demographic and lifestyle factors.¹⁸ However, a prospective cohort study demonstrated different findings.¹⁹ Comparing 58 patients with newly diagnosed colorectal adenocarcinoma (stages I–IV) who underwent chemotherapy and 36 patients who did not receive chemotherapy, there was no significant change in 25(OH)D levels from the time of diagnosis to 6 months later. Median VD levels decreased by 0.7 ng/mL in those who received chemotherapy, while a minimal (and not significant) increase of 1.6 ng/mL was observed in those without chemotherapy intervention (P=.26). Notably, supplementation was not restricted in this cohort, which may have resulted in higher VD levels in those taking supplements.¹⁹

Since time of year and geographic location can influence VD levels, one prospective cohort study controlled for differential sun exposure due to these factors in their analysis.¹⁶ Assessment of 25(OH)D levels was completed in 81 chemotherapy-naïve cancer patients immediately before beginning chemotherapy as well as 6 and 12 weeks into treatment. More than 8 primary cancer types were represented in this study, with breast (34% [29/81]) and colorectal (14% [12/81]) cancer being the most common, but the cancer stages of the participants were not detailed. Vitamin D levels decreased after commencing chemotherapy, with the largest drop occurring 6 weeks into treatment. From the 6- to 12-week end points, VD increased but remained below the original baseline level (baseline: mean [SD], 49.2 [22.3] nmol/L; 6 weeks: mean [SD], 40.9 [19.0] nmol/L; 12 weeks: mean [SD], 45.9 [19.7] nmol/L; P=.05).¹⁶

Although focused on breast and colorectal cancers, these studies suggest that various chemotherapy regimens may confer a higher risk for VD deficiency compared with VD status at diagnosis and/or prior to chemotherapy treatment. However, most of these studies only discussed stage-based differences, excluding analysis of the variety of cancer subtypes that comprise breast and colorectal malignancies, which may limit our ability to extrapolate from these data. Ultimately, larger randomized controlled trials are needed to better understand the relationship between chemotherapy and VD status across various primary cancer types.

Effects of Radiation Therapy on Vitamin D Levels

Unlike chemotherapy, studies on the association between radiation therapy and VD levels are minimal, with most reports in the literature discussing the use of VD to potentiate the effects of radiation therapy. In one cross-sectional analysis of 1201 patients with newly diagnosed stage I, II, or III colorectal cancer of any type (94% were adenocarcinoma), radiation plus surgery was associated with slightly lower 25(OH)D levels than surgery alone for tumor treatment 6 months after diagnosis (mean, −3.17; 95% CI, −6.07 to −0.28 nmol/L). However, after adjustment for demographic and lifestyle factors, this decrease in VD levels attributable to radiotherapy was not statistically significant compared with the surgery-only cohort (mean, −1.78; 95% CI, −5.07 to 1.52 nmol/L).¹⁸

Similarly, a cross-sectional study assessing VD status in 394 female patients with primary breast cancer (stage I, II, or III and T1 with high Ki67 expression [≥30%], T2, or T3), found that a history of radiotherapy was not associated with a difference in serum 25(OH)D levels compared with those with breast cancer without prior radiotherapy (odds ratio, 0.90; 95% CI, 0.52-1.54).¹² From the limited existing literature specifically addressing variations of VD levels with radiation, radiation therapy does not appear to significantly impact VD levels.

Vitamin D Levels and the Severity of Chemotherapy- or Radiation Therapy–Induced AEs

A prospective cohort of 241 patients did not find an increase in the incidence or severity of chemotherapy-induced cutaneous toxicities in those with suboptimal 1,25(OH)₂D₃ levels (≤75 nmol/L).²⁰ Eight different primary cancer types were represented, including breast and colorectal cancer; the tumor stages of the participants were not detailed. Forty-one patients had normal 1,25(OH)₂D₃ levels, while the remaining 200 had suboptimal levels. There was no significant association between serum VD levels and the following dermatologic toxicities: desquamation (P=.26), xerosis (P=.15), mucositis (P=.30), or painful rash (P=.87). Surprisingly, nail changes and hand-foot reactions occurred with greater frequency in patients with normal VD levels (P=.01 and P=.03, respectively).²⁰ Hand-foot reaction is part of the toxic erythema of chemotherapy (TEC) spectrum, which is comprised of a range of cytotoxic skin injuries that typically manifest within 2 to 3 weeks of exposure to the offending chemotherapeutic agents, often characterized by erythema, pain, swelling, and blistering, particularly in intertriginous and acral areas.^21-23 Recovery from TEC generally takes at least 2 to 4 weeks and may necessitate cessation of the offending chemotherapeutic agent.^21,24 Notably, this study measured 1,25(OH)₂D₃ levels instead of 25(OH)D levels, which may not reliably indicate body stores of VD.^7,20 These results underscore the complex nature between chemotherapy and VD; however, VD levels alone do not appear to be a sufficient biomarker for predicting chemotherapy-associated cutaneous AEs.

Interestingly, radiation therapy–induced AEs may be associated with VD levels. A prospective cohort study of 98 patients with prostate, bladder, or gynecologic cancers (tumor stages were not detailed) undergoing pelvic radiotherapy found that females and males with 25(OH)D levels below a threshold of 35 and 40 nmol/L, respectively, were more likely to experience higher Radiation Therapy Oncology Group (RTOG) grade acute proctitis compared with those with VD above these thresholds.²⁵ Specifically, VD below these thresholds was associated with increased odds of RTOG grade 2 or higher radiation-induced proctitis (OR, 3.07; 95% CI, 1.27-7.50 [P=.013]). Additionally, a weak correlation was noted between VD below these thresholds and the RTOG grade, with a Spearman correlation value of −0.189 (P=.031).²⁵

One prospective cohort study included 28 patients with any cancer of the oral cavity, oropharynx, hypopharynx, or larynx stages II, III, or IVA; 93% (26/28) were stage III or IVA.²⁶ The 20 (71%) patients with suboptimal 25(OH)D levels (≤75 nmol/L) experienced a higher prevalence of grade II radiation dermatitis compared with the 8 (29%) patients with optimal VD levels (χ²₂=5.973; P=.0505). This pattern persisted with the severity of mucositis; patients from the suboptimal VD group presented with higher rates of grades II and III mucositis compared with the VD optimal group (χ²₂=13.627; P=.0011).²⁶ Recognizing the small cohort evaluated in the study, we highlight the importance of further studies to clarify these associations.

Chemotherapy-Induced Cutaneous Events Treated with High-Dose Vitamin D

Chemotherapeutic agents are known to induce cellular damage, resulting in a range of cutaneous AEs that can invoke discontinuation of otherwise effective chemotherapeutic interventions.^27,28 Recent research has explored the potential of high-dose vitamin D₃ as a therapeutic agent to mitigate cutaneous reactions.^29,30

A randomized, double-blind, placebo-controlled trial investigated the use of a single high dose of oral ­25(OH)D to treat topical nitrogen mustard (NM)–induced rash.²⁹ To characterize baseline inflammatory responses from NM injury without intervention, clinical measures, serum studies, and tissue analyses from skin biopsies were performed on 28 healthy adults after exposure to topical NM—a chemotherapeutic agent classified as a DNA alkylator. Two weeks later, participants were exposed to topical NM a second time and were split into 2 groups: 14 patients received a single 200,000-IU dose of oral 25(OH)D while the other 14 participants were given a placebo. Using the inflammatory markers induced from baseline exposure to NM alone, posttreatment analysis revealed that the punch biopsies from the 25(OH)D group expressed fewer NM-induced inflammatory markers compared with the placebo group at both 72 hours and 6 weeks following NM injury (72 hours: 12 vs 17 inflammatory markers; 6 weeks: 4 vs 11 inflammatory markers). Notably, NM inflammatory markers were enriched for IL-17 signaling pathways in the placebo biopsies but not in the 25(OH)D intervention group. This study also identified mild and severe patterns of inflammatory responses to NM that were independent of the 25(OH)D intervention. Biomarkers specific to skin biopsies from participants with the severe response included CCL20, CCL2, and CXCL8 (adjusted P<.05). At 6 weeks posttreatment, the 25(OH)D group showed a 67% reduction in NM injury markers compared with a 35% reduction in the placebo group. Despite a reduction in tissue inflammatory markers, there were no clinically significant changes observed in skin redness, swelling, or histologic structure when comparing the 25(OH)D- supplemented group to the placebo group at any time during the study, necessitating further research into the mechanistic roles of high doses VD supplementation.²⁹

Although Ernst et al²⁹ did not observe any clinically significant improvements with VD treatment, a case series of 6 patients with either glioblastoma multiforme, acute myeloid leukemia, or aplastic anemia did demonstrate clinical improvement of TEC after receiving high-dose vitamin D₃.³⁰ The mean time to onset of TEC was noted at 8.5 days following administration of the inciting chemotherapeutic agent, which included combinations of anthracycline, antimetabolite, kinase inhibitor, B-cell lymphoma 2 inhibitor, purine analogue, and alkylating agents. A combination of clinical and histologic findings was used to diagnose TEC. Baseline 25(OH)D levels were not established prior to treatment. The treatment regimen for 1 patient included 2 doses of 50,000 IU of VD spaced 1 week apart, totaling 100,000 IU, while the remaining 5 patients received a total of 200,000 IU, also split into 2 doses given 1 week apart. All patients received their first dose of VD within a week of the cutaneous eruption. Following the initial VD dose, there was a notable improvement in pain, pruritus, or swelling by the next day. Reduction in erythema also was observed within 1 to 4 days.³⁰

No AEs associated with VD supplementation were reported, suggesting a potential beneficial role of high-dose VD in accelerating recovery from chemotherapy-induced rashes without evident safety concerns.

Radiation Therapy–Induced Cutaneous Events Treated with High-Dose Vitamin D

Radiation dermatitis is a common and often severe complication of radiation therapy that affects more than 90% of patients undergoing treatment, with half of these individuals experiencing grade 2 toxicity, according to the National Cancer Institute’s Common Terminology Criteria for Adverse Events.^31,32 Radiation damage to basal keratinocytes and hair follicle stem cells disrupts the renewal of the skin’s outer layer, while a surge of free radicals causes irreversible DNA damage.³³ Symptoms of radiation dermatitis can vary from mild pink erythema to tissue ulceration and necrosis, typically within 1 to 4 weeks of radiation exposure.³⁴ The resulting dermatitis can take 2 to 4 weeks to heal, notably impacting patient quality of life and often necessitating modifications or interruptions in cancer therapy.³³

Prior studies have demonstrated the use of high-dose VD to improve the healing of UV-irradiated skin. A randomized controlled trial investigated high-dose vitamin D₃ to treat experimentally induced sunburn in 20 healthy adults. Compared with those who received a placebo, participants receiving the oral dose of 200,000 IU of vitamin D₃ demonstrated suppression of the pro-inflammatory mediators tumor necrosis factor α (P=.04) and inducible nitric oxide synthase (P=.02), while expression of tissue repair enhancer arginase 1 was increased (P<.005).³⁵ The mechanism of this enhanced tissue repair was investigated using a mouse model, in which intraperitoneal 25(OH)D was administered following severe UV-induced skin injury. On immunofluorescence microscopy, mice treated with VD showed enhanced autophagy within the macrophages infiltrating UV-irradiated skin.³⁶ The use of high-dose VD to treat UV-irradiated skin in these studies established a precedent for using VD to heal cutaneous injury caused by ionizing radiation therapy.

Some studies have focused on the role of VD for treating acute radiation dermatitis. A study of 23 patients with ductal carcinoma in situ or localized invasive ductal carcinoma breast cancer compared the effectiveness of topical calcipotriol to that of a standard hydrating ointment.³⁷ Participants were randomized to 1 of 2 treatments before starting adjuvant radiotherapy to evaluate their potential in preventing radiation dermatitis. In 87% (20/23) of these patients, no difference in skin reaction was observed between the 2 treatments, suggesting that topical VD application may not offer any advantage over the standard hydrating ointment for the prevention of radiation dermatitis.³⁷

Benefits of high-dose oral VD for treating radiation dermatitis also have been reported. Nguyen et al³⁸ documented 3 cases in which patients with neuroendocrine carcinoma of the pancreas, tonsillar carcinoma, and breast cancer received 200,000 IU of oral ergocalciferol distributed over 2 doses given 7 days apart for radiation dermatitis. These patients experienced substantial improvements in pain, swelling, and redness within a week of the initial dose. Additionally, a case of radiation recall dermatitis, which occurred a week after vinorelbine chemotherapy, was treated with 2 doses totaling 100,000 IU of oral ergocalciferol. This patient also had improvement in pain and swelling but continued to have tumor-related induration and ulceration.³⁹

Although topical VD did not show significant benefits over standard treatments for radiation dermatitis, high-dose oral VD appears promising in improving patient outcomes of pain and swelling more rapidly than current practices. Further research is needed to confirm these findings and establish standardized treatment protocols.

Final Thoughts

Suboptimal VD levels are prevalent in numerous cancer types. Chemotherapy often is associated with acute, potentially transient worsening of VD status in patients with breast and colorectal cancer. Although 25(OH)D levels have not corresponded with increased frequency of ­chemotherapy-related dermatologic AEs, suboptimal 25(OH)D levels appear to be associated with increased severity of radiation-induced mucositis and dermatitis.^20,25,26 The use of high-dose VD as a therapeutic agent shows promise in mitigating chemotherapy-induced and radiation therapy–induced rashes in multiple cancer types with reduction of inflammatory markers and a durable anti-inflammatory impact. Although the mechanisms of cellular injury vary among chemotherapeutic agents, the anti-inflammatory and tissue repair properties of VD may make it an effective treatment for chemotherapy-induced cutaneous damage regardless of injury mechanism.^2-4,35 However, reports of clinical improvement vary, and further objective studies to classify optimal dosing, administration, and outcome measures are needed. The absence of reported AEs associated with high-dose VD supplementation is encouraging, but selection of a safe and optimal dosing regimen can only occur with dedicated clinical trials.

Frontal fibrosing alopecia (FFA) has become increasingly common since it was first described in 1994.¹ A positive correlation between FFA and the use of sunscreens was reported in an observational study.² The geographic distribution of this association has spanned the United Kingdom (UK), Europe, and Asia, though data from the United States are lacking. Various international studies have demonstrated an association between FFA and sunscreen use, further exemplifying this stark contrast.

In the United Kingdom (UK), Aldoori et al² found that women who used sunscreen at least twice weekly had 2 times the likelihood of developing FFA compared with women who did not use sunscreen regularly. Kidambi et al³ found similar results in UK men with FFA who had higher rates of primary sunscreen use and higher rates of at least twice-weekly use of facial moisturizer with unspecified sunscreen content.

These associations between FFA and sunscreen use are not unique to the UK. A study conducted in Spain identified a statistical association between FFA and use of facial sunscreen in women (odds ratio, 1.6 [95% CI, 1.06-2.41]) and men (odds ratio, 1.84 [95% CI, 1.04-3.23]).⁴ In Thailand, FFA was nearly twice as likely to be present in patients with regular sunscreen use compared to controls who did not apply sunscreen regularly.⁵ Interestingly, a Brazilian study showed no connection between sunscreen use and FFA. Instead, FFA was associated with hair straightening with formalin or use of facial soap orfacial moisturizer.⁶ An international systematic review of 1248 patients with FFA and 1459 controls determined that sunscreen users were 2.21 times more likely to develop FFA than their counterparts who did not use sunscreen regularly.⁷

Quite glaring is the lack of data from the United States, which could be used to compare FFA and sunscreen associations to other nations. It is possible that certain regions of the world such as the United States may not have an increased risk for FFA in sunscreen users due to other environmental factors, differing sunscreen application practices, or differing chemical ingredients. At the same time, many other countries cannot afford or lack access to sunscreens or facial moisturizers, which is an additional variable that may complicate this association. These populations need to be studied to determine whether they are as susceptible to FFA as those who use sunscreen regularly around the world.

Another underlying factor supporting this association is the inherent need for sunscreen use. For instance, research has shown that patients with FFA had higher rates of actinic skin damage, which could explain increased sunscreen use.⁸

To make more clear and distinct claims, further studies are needed in regions that are known to use sunscreen extensively (eg, United States) to compare with their European, Asian, and South American counterparts. Moreover, it also is important to study regions where sunscreen access is limited and whether there is FFA development in these populations.

Given the potential association between sunscreen use and FFA, dermatologists can take a cautious approach tailored to the patient by recommending noncomedogenic mineral sunscreens with zinc or titanium oxide, which are less irritating than chemical sunscreens. Avoidance of sunscreen application to the hairline and use of additional sun-protection methods such as broad-brimmed hats also should be emphasized.

Frontal fibrosing alopecia (FFA) has become increasingly common since it was first described in 1994.¹ A positive correlation between FFA and the use of sunscreens was reported in an observational study.² The geographic distribution of this association has spanned the United Kingdom (UK), Europe, and Asia, though data from the United States are lacking. Various international studies have demonstrated an association between FFA and sunscreen use, further exemplifying this stark contrast.

In the United Kingdom (UK), Aldoori et al² found that women who used sunscreen at least twice weekly had 2 times the likelihood of developing FFA compared with women who did not use sunscreen regularly. Kidambi et al³ found similar results in UK men with FFA who had higher rates of primary sunscreen use and higher rates of at least twice-weekly use of facial moisturizer with unspecified sunscreen content.

These associations between FFA and sunscreen use are not unique to the UK. A study conducted in Spain identified a statistical association between FFA and use of facial sunscreen in women (odds ratio, 1.6 [95% CI, 1.06-2.41]) and men (odds ratio, 1.84 [95% CI, 1.04-3.23]).⁴ In Thailand, FFA was nearly twice as likely to be present in patients with regular sunscreen use compared to controls who did not apply sunscreen regularly.⁵ Interestingly, a Brazilian study showed no connection between sunscreen use and FFA. Instead, FFA was associated with hair straightening with formalin or use of facial soap orfacial moisturizer.⁶ An international systematic review of 1248 patients with FFA and 1459 controls determined that sunscreen users were 2.21 times more likely to develop FFA than their counterparts who did not use sunscreen regularly.⁷

Quite glaring is the lack of data from the United States, which could be used to compare FFA and sunscreen associations to other nations. It is possible that certain regions of the world such as the United States may not have an increased risk for FFA in sunscreen users due to other environmental factors, differing sunscreen application practices, or differing chemical ingredients. At the same time, many other countries cannot afford or lack access to sunscreens or facial moisturizers, which is an additional variable that may complicate this association. These populations need to be studied to determine whether they are as susceptible to FFA as those who use sunscreen regularly around the world.

Another underlying factor supporting this association is the inherent need for sunscreen use. For instance, research has shown that patients with FFA had higher rates of actinic skin damage, which could explain increased sunscreen use.⁸

To make more clear and distinct claims, further studies are needed in regions that are known to use sunscreen extensively (eg, United States) to compare with their European, Asian, and South American counterparts. Moreover, it also is important to study regions where sunscreen access is limited and whether there is FFA development in these populations.

Given the potential association between sunscreen use and FFA, dermatologists can take a cautious approach tailored to the patient by recommending noncomedogenic mineral sunscreens with zinc or titanium oxide, which are less irritating than chemical sunscreens. Avoidance of sunscreen application to the hairline and use of additional sun-protection methods such as broad-brimmed hats also should be emphasized.

Frontal fibrosing alopecia (FFA) has become increasingly common since it was first described in 1994.¹ A positive correlation between FFA and the use of sunscreens was reported in an observational study.² The geographic distribution of this association has spanned the United Kingdom (UK), Europe, and Asia, though data from the United States are lacking. Various international studies have demonstrated an association between FFA and sunscreen use, further exemplifying this stark contrast.

In the United Kingdom (UK), Aldoori et al² found that women who used sunscreen at least twice weekly had 2 times the likelihood of developing FFA compared with women who did not use sunscreen regularly. Kidambi et al³ found similar results in UK men with FFA who had higher rates of primary sunscreen use and higher rates of at least twice-weekly use of facial moisturizer with unspecified sunscreen content.

These associations between FFA and sunscreen use are not unique to the UK. A study conducted in Spain identified a statistical association between FFA and use of facial sunscreen in women (odds ratio, 1.6 [95% CI, 1.06-2.41]) and men (odds ratio, 1.84 [95% CI, 1.04-3.23]).⁴ In Thailand, FFA was nearly twice as likely to be present in patients with regular sunscreen use compared to controls who did not apply sunscreen regularly.⁵ Interestingly, a Brazilian study showed no connection between sunscreen use and FFA. Instead, FFA was associated with hair straightening with formalin or use of facial soap orfacial moisturizer.⁶ An international systematic review of 1248 patients with FFA and 1459 controls determined that sunscreen users were 2.21 times more likely to develop FFA than their counterparts who did not use sunscreen regularly.⁷

Quite glaring is the lack of data from the United States, which could be used to compare FFA and sunscreen associations to other nations. It is possible that certain regions of the world such as the United States may not have an increased risk for FFA in sunscreen users due to other environmental factors, differing sunscreen application practices, or differing chemical ingredients. At the same time, many other countries cannot afford or lack access to sunscreens or facial moisturizers, which is an additional variable that may complicate this association. These populations need to be studied to determine whether they are as susceptible to FFA as those who use sunscreen regularly around the world.

Another underlying factor supporting this association is the inherent need for sunscreen use. For instance, research has shown that patients with FFA had higher rates of actinic skin damage, which could explain increased sunscreen use.⁸

To make more clear and distinct claims, further studies are needed in regions that are known to use sunscreen extensively (eg, United States) to compare with their European, Asian, and South American counterparts. Moreover, it also is important to study regions where sunscreen access is limited and whether there is FFA development in these populations.

Given the potential association between sunscreen use and FFA, dermatologists can take a cautious approach tailored to the patient by recommending noncomedogenic mineral sunscreens with zinc or titanium oxide, which are less irritating than chemical sunscreens. Avoidance of sunscreen application to the hairline and use of additional sun-protection methods such as broad-brimmed hats also should be emphasized.

To the Editor:

We read with interest the case reported by Yanovsky et al¹ (Cutis. 2023;112:E23-E25). We thank the authors for updating our knowledge about atopic dermatitis (AD) and omalizumab and improving our understanding of the various wanted and unwanted effects that may manifest with omalizumab. We wish to clarify a few points on omalizumab use.

First, Yanovsky et al¹ reported that their patient’s AD flares occurred within a few days after omalizumab injections to control asthma, possibly because omalizumab may have caused a paradoxical increase in sensitivity to other cytokines such as IL-33 in basophils and increased IL-4/IL-13 production in the skin. The authors cited Imai² to explain that IL-33 plays a role in the pathogenesis of AD, increases itching, and disrupts the skin barrier. However, Imai² did not discuss a relationship with omalizumab. As a recombinant humanized IgG1 monoclonal anti-IgE antibody, omalizumab works by interacting with the high-affinity receptor Fc epsilon RI that typically is found on eosinophils, mast cells, and basophils and plays a critical role in preventing the allergic cascade.³ We could not find any studies in the literature regarding omalizumab having a specific effect on the skin, causing cytokine imbalance, or increasing IL-4/IL-13 levels.

Second, the case report indicated that AD lesions improved with the biologic dupilumab,¹ which seems amazing. Dupilumab is a monoclonal antibody used in patients with moderate to severe AD that blocks IL-4/IL-13 signaling and thus inhibits receptor signaling downstream of the Janus kinase signal transducer and activator of transcription protein pathway.⁴ It also has been shown to be beneficial in children with moderate to severe uncontrolled asthma.⁵ In vivo studies are needed to learn about the effects of these biologics on asthma and AD, whose complex immunologic effects are increasingly well understood by real patient experience.

Third, omalizumab has been found to relieve AD, not exacerbate it, in our own experience with 7 patients (unpublished data, 2024) and randomized controlled trials.⁶

Fourth, Yanovsky et al¹ reported that the patient’s lesions flared up within a few days after taking omalizumab, which suggests a non-IgE delayed reaction. Could this reaction be related to polysorbate 20 used as an excipient in the commercial preparation? When we examined both preparations, the presence of polysorbate 80 in dupilumab was noteworthy,⁷ unlike omalizumab. We suggest the authors perform a patch test including polysorbate 20 and polysorbate 80.

Finally, the authors mentioned that omalizumab may cause a paradoxical exacerbation of AD in certain patients, as in tumor necrosis factor α inhibitor–induced psoriasis.⁸ This has been reported,⁸ but tumor necrosis factor α inhibitors are cytokine inhibitors and can lead to cytokine imbalance, while omalizumab is an IgE inhibitor.

Yanovsky et al¹ described AD flares as “triggered by omalizumab,” which we believe was not the case. Because this patient had chronic AD, other causes of AD exacerbation in this patient could include stress or infection. Also, when they say that AD is triggered or induced, it implies that they are attributing the occurrence/development of AD in this patient to omalizumab. Of course, this also is not true.

Author’s Response

Thank you for your thoughtful comments. Although we agree that we cannot prove omalizumab was the cause of our patient’s AD flares, the new onset of severely worsening disease that was exacerbated by each dose of omalizumab as well as subsequent resolution upon switching to dupilumab was highly suggestive for a causal relationship. Our goal was to alert physicians to the possibility of this phenomenon and to encourage further study.

Karen A. Chernoff, MD
From the Department of Dermatology, Weill Cornell Medical College, New York, New York.
The author has no relevant financial disclosures to report.

To the Editor:

We read with interest the case reported by Yanovsky et al¹ (Cutis. 2023;112:E23-E25). We thank the authors for updating our knowledge about atopic dermatitis (AD) and omalizumab and improving our understanding of the various wanted and unwanted effects that may manifest with omalizumab. We wish to clarify a few points on omalizumab use.

First, Yanovsky et al¹ reported that their patient’s AD flares occurred within a few days after omalizumab injections to control asthma, possibly because omalizumab may have caused a paradoxical increase in sensitivity to other cytokines such as IL-33 in basophils and increased IL-4/IL-13 production in the skin. The authors cited Imai² to explain that IL-33 plays a role in the pathogenesis of AD, increases itching, and disrupts the skin barrier. However, Imai² did not discuss a relationship with omalizumab. As a recombinant humanized IgG1 monoclonal anti-IgE antibody, omalizumab works by interacting with the high-affinity receptor Fc epsilon RI that typically is found on eosinophils, mast cells, and basophils and plays a critical role in preventing the allergic cascade.³ We could not find any studies in the literature regarding omalizumab having a specific effect on the skin, causing cytokine imbalance, or increasing IL-4/IL-13 levels.

Second, the case report indicated that AD lesions improved with the biologic dupilumab,¹ which seems amazing. Dupilumab is a monoclonal antibody used in patients with moderate to severe AD that blocks IL-4/IL-13 signaling and thus inhibits receptor signaling downstream of the Janus kinase signal transducer and activator of transcription protein pathway.⁴ It also has been shown to be beneficial in children with moderate to severe uncontrolled asthma.⁵ In vivo studies are needed to learn about the effects of these biologics on asthma and AD, whose complex immunologic effects are increasingly well understood by real patient experience.

Third, omalizumab has been found to relieve AD, not exacerbate it, in our own experience with 7 patients (unpublished data, 2024) and randomized controlled trials.⁶

Fourth, Yanovsky et al¹ reported that the patient’s lesions flared up within a few days after taking omalizumab, which suggests a non-IgE delayed reaction. Could this reaction be related to polysorbate 20 used as an excipient in the commercial preparation? When we examined both preparations, the presence of polysorbate 80 in dupilumab was noteworthy,⁷ unlike omalizumab. We suggest the authors perform a patch test including polysorbate 20 and polysorbate 80.

Finally, the authors mentioned that omalizumab may cause a paradoxical exacerbation of AD in certain patients, as in tumor necrosis factor α inhibitor–induced psoriasis.⁸ This has been reported,⁸ but tumor necrosis factor α inhibitors are cytokine inhibitors and can lead to cytokine imbalance, while omalizumab is an IgE inhibitor.

Yanovsky et al¹ described AD flares as “triggered by omalizumab,” which we believe was not the case. Because this patient had chronic AD, other causes of AD exacerbation in this patient could include stress or infection. Also, when they say that AD is triggered or induced, it implies that they are attributing the occurrence/development of AD in this patient to omalizumab. Of course, this also is not true.

Author’s Response

Thank you for your thoughtful comments. Although we agree that we cannot prove omalizumab was the cause of our patient’s AD flares, the new onset of severely worsening disease that was exacerbated by each dose of omalizumab as well as subsequent resolution upon switching to dupilumab was highly suggestive for a causal relationship. Our goal was to alert physicians to the possibility of this phenomenon and to encourage further study.

Karen A. Chernoff, MD
From the Department of Dermatology, Weill Cornell Medical College, New York, New York.
The author has no relevant financial disclosures to report.

To the Editor:

We read with interest the case reported by Yanovsky et al¹ (Cutis. 2023;112:E23-E25). We thank the authors for updating our knowledge about atopic dermatitis (AD) and omalizumab and improving our understanding of the various wanted and unwanted effects that may manifest with omalizumab. We wish to clarify a few points on omalizumab use.

First, Yanovsky et al¹ reported that their patient’s AD flares occurred within a few days after omalizumab injections to control asthma, possibly because omalizumab may have caused a paradoxical increase in sensitivity to other cytokines such as IL-33 in basophils and increased IL-4/IL-13 production in the skin. The authors cited Imai² to explain that IL-33 plays a role in the pathogenesis of AD, increases itching, and disrupts the skin barrier. However, Imai² did not discuss a relationship with omalizumab. As a recombinant humanized IgG1 monoclonal anti-IgE antibody, omalizumab works by interacting with the high-affinity receptor Fc epsilon RI that typically is found on eosinophils, mast cells, and basophils and plays a critical role in preventing the allergic cascade.³ We could not find any studies in the literature regarding omalizumab having a specific effect on the skin, causing cytokine imbalance, or increasing IL-4/IL-13 levels.

Second, the case report indicated that AD lesions improved with the biologic dupilumab,¹ which seems amazing. Dupilumab is a monoclonal antibody used in patients with moderate to severe AD that blocks IL-4/IL-13 signaling and thus inhibits receptor signaling downstream of the Janus kinase signal transducer and activator of transcription protein pathway.⁴ It also has been shown to be beneficial in children with moderate to severe uncontrolled asthma.⁵ In vivo studies are needed to learn about the effects of these biologics on asthma and AD, whose complex immunologic effects are increasingly well understood by real patient experience.

Third, omalizumab has been found to relieve AD, not exacerbate it, in our own experience with 7 patients (unpublished data, 2024) and randomized controlled trials.⁶

Fourth, Yanovsky et al¹ reported that the patient’s lesions flared up within a few days after taking omalizumab, which suggests a non-IgE delayed reaction. Could this reaction be related to polysorbate 20 used as an excipient in the commercial preparation? When we examined both preparations, the presence of polysorbate 80 in dupilumab was noteworthy,⁷ unlike omalizumab. We suggest the authors perform a patch test including polysorbate 20 and polysorbate 80.

Finally, the authors mentioned that omalizumab may cause a paradoxical exacerbation of AD in certain patients, as in tumor necrosis factor α inhibitor–induced psoriasis.⁸ This has been reported,⁸ but tumor necrosis factor α inhibitors are cytokine inhibitors and can lead to cytokine imbalance, while omalizumab is an IgE inhibitor.

Yanovsky et al¹ described AD flares as “triggered by omalizumab,” which we believe was not the case. Because this patient had chronic AD, other causes of AD exacerbation in this patient could include stress or infection. Also, when they say that AD is triggered or induced, it implies that they are attributing the occurrence/development of AD in this patient to omalizumab. Of course, this also is not true.

Author’s Response

Thank you for your thoughtful comments. Although we agree that we cannot prove omalizumab was the cause of our patient’s AD flares, the new onset of severely worsening disease that was exacerbated by each dose of omalizumab as well as subsequent resolution upon switching to dupilumab was highly suggestive for a causal relationship. Our goal was to alert physicians to the possibility of this phenomenon and to encourage further study.

Karen A. Chernoff, MD
From the Department of Dermatology, Weill Cornell Medical College, New York, New York.
The author has no relevant financial disclosures to report.

There is a well-established connection between the mind and the skin, and it is clear that this relationship is bidirectional—not only does skin disease increase the risk for depression, anxiety, sleep disturbance, and suicidality, but psychologic stress actually can worsen skin disease through multiple mechanisms, including direct damage to the skin barrier.^1,2 Psychologic stress also impacts the microbiome, another critical driver of skin disease.^3,4 The concept of the itch-scratch cycle vividly illustrates the vicious interplay between the mind and body in atopic dermatitis (AD).

However, patients with AD are not the only ones impacted—caregivers also experience psychologic stress. Remarkably, one study of patients with AD and their caregivers found that the caregivers actually reported significantly worse mental health and anxiety (P=.01 and P=.03, respectively) than patients themselves, even when controlling for the severity of disease.⁵

Thus, it would seem obvious for mental health to be a central component of AD care—to improve patient and caregiver quality of life while also improving symptoms. Research has actually borne this out, with one systematic review and meta-analysis concluding that psychological intervention has a beneficial effect on AD,⁶ and another that the addition of psychological and educational interventions to conventional treatment provided better therapeutic results in alleviating eczema severity and psychological symptoms.⁷ One study demonstrated that patients with AD who received cognitive behavioral therapy via the internet displayed a statistically significant improvement in their disease (P<.001) as measured by the Patient-Oriented Eczema Measure compared with those in the control group who received standard care alone. They also reported improvements in perceived stress, sleep problems, and depression in the intervention group that were sustained at 1-year follow-up.⁸ These findings are particularly impactful because clinical results were achieved while leveraging an internet-based approach to therapy.

Regrettably, despite the preponderance of evidence supporting the connection between mental health and AD, there remain considerable unmet needs. A recent cross-sectional survey of 954 adults with AD and caregivers of children with AD (N=954) conducted by the National Eczema Association found that half of patients were never asked about mental health during any of their visits, and of those referred for mental health resources, only 57% utilized the recommended services.⁹ Importantly, patients aged 18 to 34 years reported wanting to be asked about mental health. Of those who did receive referrals, most were for counseling services (23%), followed by alternative mental health therapy such as music or art therapy (15%), cognitive behavioral therapy (13%), or peer/social support groups (12%). Approximately 10% reported receiving a pamphlet or a brochure only.⁹

Physicians who treat patients with AD can and must do better, but first we must explore why these referral rates are so low. As with many complex problems, there is unlikely to be one simple unifying reason. As expected, the answer is nuanced and multifaceted, and—most importantly—staggeringly incomplete.

For starters, mental health interventions rarely are as easy as applying a cream or taking a pill. Hedman-Lagerlöf et al⁸ specifically pointed out that although their approach—using internet-based cognitive behavioral therapy—was explicitly designed to be more accessible with fewer resources, it required approximately 35 hours of treatment over 12 weeks, requiring both substantial time and commitment from patients who often are already burned out and exhausted due to AD. They even underscored that the most commonly reported adverse effect of therapy was increased stress or worry, making it a difficult sell.⁸

Even before most patients have a chance to consider the time required and the potential adverse effects of mental health interventions for AD, greater hurdles exist. Finances, medical insurance, and wait times were highlighted as barriers to care in a systematic review.¹⁰ These are deep-seated problems in the United States; while they may be surmountable in certain geo­graphic areas, the frequency with which these concerns arise means that it does not take too many failed attempts at referring patients for mental health services before clinicians just give up—similar to any form of operant conditioning.

A more elusive concept is stigmatization. Although it may not be quantifiable, the idea is that patients may encounter additional challenges when seeking mental health care, either because the interactions themselves may worsen their symptoms (eg, increased anxiety) or they may be more likely to have a negative perception of the experience.¹¹ A 2020 systematic review of barriers to addressing common mental health problems found that stigma was the most prominent barrier in adolescents, with the second most prominent being negative attitudes and beliefs about mental health services and professionals.¹² As a clinician, I can attest that I have sometimes detected skepticism when I have suggested mental health services to patients and have even been asked outright if I thought the problem was all in their head. My patients with AD generally have been much more open to the idea of mental health support, especially after I explain the powerful mind-body connection, than patients with other conditions—most notably delusions of parasitosis—who have been much more dismissive of such overtures. An oft-cited paper from 1976 frames the problem perfectly, describing what can happen after a referral for mental health services.¹³ The authors stated that the suggestion of mental health makes patients feel that the dermatologist does not believe them in the first place. Beyond this, the authors pointed out that referring the patient elsewhere reduces their hopes for dermatologic treatment.¹³

Knowing now—perhaps more than ever before—that the mind and skin are intimately connected compels us to solve these problems and find ways around these obstacles. Selecting the optimal forms of mental health services for each patient, having the structural support of the health care system, and winning the trust of patients and caregivers while combating stigma are undoubtedly tall orders; however, understanding the stakes for patients with AD, their caregivers, and society as a whole should inspire us to keep pushing forward.

There is a well-established connection between the mind and the skin, and it is clear that this relationship is bidirectional—not only does skin disease increase the risk for depression, anxiety, sleep disturbance, and suicidality, but psychologic stress actually can worsen skin disease through multiple mechanisms, including direct damage to the skin barrier.^1,2 Psychologic stress also impacts the microbiome, another critical driver of skin disease.^3,4 The concept of the itch-scratch cycle vividly illustrates the vicious interplay between the mind and body in atopic dermatitis (AD).

However, patients with AD are not the only ones impacted—caregivers also experience psychologic stress. Remarkably, one study of patients with AD and their caregivers found that the caregivers actually reported significantly worse mental health and anxiety (P=.01 and P=.03, respectively) than patients themselves, even when controlling for the severity of disease.⁵

Thus, it would seem obvious for mental health to be a central component of AD care—to improve patient and caregiver quality of life while also improving symptoms. Research has actually borne this out, with one systematic review and meta-analysis concluding that psychological intervention has a beneficial effect on AD,⁶ and another that the addition of psychological and educational interventions to conventional treatment provided better therapeutic results in alleviating eczema severity and psychological symptoms.⁷ One study demonstrated that patients with AD who received cognitive behavioral therapy via the internet displayed a statistically significant improvement in their disease (P<.001) as measured by the Patient-Oriented Eczema Measure compared with those in the control group who received standard care alone. They also reported improvements in perceived stress, sleep problems, and depression in the intervention group that were sustained at 1-year follow-up.⁸ These findings are particularly impactful because clinical results were achieved while leveraging an internet-based approach to therapy.

Regrettably, despite the preponderance of evidence supporting the connection between mental health and AD, there remain considerable unmet needs. A recent cross-sectional survey of 954 adults with AD and caregivers of children with AD (N=954) conducted by the National Eczema Association found that half of patients were never asked about mental health during any of their visits, and of those referred for mental health resources, only 57% utilized the recommended services.⁹ Importantly, patients aged 18 to 34 years reported wanting to be asked about mental health. Of those who did receive referrals, most were for counseling services (23%), followed by alternative mental health therapy such as music or art therapy (15%), cognitive behavioral therapy (13%), or peer/social support groups (12%). Approximately 10% reported receiving a pamphlet or a brochure only.⁹

Physicians who treat patients with AD can and must do better, but first we must explore why these referral rates are so low. As with many complex problems, there is unlikely to be one simple unifying reason. As expected, the answer is nuanced and multifaceted, and—most importantly—staggeringly incomplete.

For starters, mental health interventions rarely are as easy as applying a cream or taking a pill. Hedman-Lagerlöf et al⁸ specifically pointed out that although their approach—using internet-based cognitive behavioral therapy—was explicitly designed to be more accessible with fewer resources, it required approximately 35 hours of treatment over 12 weeks, requiring both substantial time and commitment from patients who often are already burned out and exhausted due to AD. They even underscored that the most commonly reported adverse effect of therapy was increased stress or worry, making it a difficult sell.⁸

Even before most patients have a chance to consider the time required and the potential adverse effects of mental health interventions for AD, greater hurdles exist. Finances, medical insurance, and wait times were highlighted as barriers to care in a systematic review.¹⁰ These are deep-seated problems in the United States; while they may be surmountable in certain geo­graphic areas, the frequency with which these concerns arise means that it does not take too many failed attempts at referring patients for mental health services before clinicians just give up—similar to any form of operant conditioning.

A more elusive concept is stigmatization. Although it may not be quantifiable, the idea is that patients may encounter additional challenges when seeking mental health care, either because the interactions themselves may worsen their symptoms (eg, increased anxiety) or they may be more likely to have a negative perception of the experience.¹¹ A 2020 systematic review of barriers to addressing common mental health problems found that stigma was the most prominent barrier in adolescents, with the second most prominent being negative attitudes and beliefs about mental health services and professionals.¹² As a clinician, I can attest that I have sometimes detected skepticism when I have suggested mental health services to patients and have even been asked outright if I thought the problem was all in their head. My patients with AD generally have been much more open to the idea of mental health support, especially after I explain the powerful mind-body connection, than patients with other conditions—most notably delusions of parasitosis—who have been much more dismissive of such overtures. An oft-cited paper from 1976 frames the problem perfectly, describing what can happen after a referral for mental health services.¹³ The authors stated that the suggestion of mental health makes patients feel that the dermatologist does not believe them in the first place. Beyond this, the authors pointed out that referring the patient elsewhere reduces their hopes for dermatologic treatment.¹³

Knowing now—perhaps more than ever before—that the mind and skin are intimately connected compels us to solve these problems and find ways around these obstacles. Selecting the optimal forms of mental health services for each patient, having the structural support of the health care system, and winning the trust of patients and caregivers while combating stigma are undoubtedly tall orders; however, understanding the stakes for patients with AD, their caregivers, and society as a whole should inspire us to keep pushing forward.

There is a well-established connection between the mind and the skin, and it is clear that this relationship is bidirectional—not only does skin disease increase the risk for depression, anxiety, sleep disturbance, and suicidality, but psychologic stress actually can worsen skin disease through multiple mechanisms, including direct damage to the skin barrier.^1,2 Psychologic stress also impacts the microbiome, another critical driver of skin disease.^3,4 The concept of the itch-scratch cycle vividly illustrates the vicious interplay between the mind and body in atopic dermatitis (AD).

However, patients with AD are not the only ones impacted—caregivers also experience psychologic stress. Remarkably, one study of patients with AD and their caregivers found that the caregivers actually reported significantly worse mental health and anxiety (P=.01 and P=.03, respectively) than patients themselves, even when controlling for the severity of disease.⁵

Thus, it would seem obvious for mental health to be a central component of AD care—to improve patient and caregiver quality of life while also improving symptoms. Research has actually borne this out, with one systematic review and meta-analysis concluding that psychological intervention has a beneficial effect on AD,⁶ and another that the addition of psychological and educational interventions to conventional treatment provided better therapeutic results in alleviating eczema severity and psychological symptoms.⁷ One study demonstrated that patients with AD who received cognitive behavioral therapy via the internet displayed a statistically significant improvement in their disease (P<.001) as measured by the Patient-Oriented Eczema Measure compared with those in the control group who received standard care alone. They also reported improvements in perceived stress, sleep problems, and depression in the intervention group that were sustained at 1-year follow-up.⁸ These findings are particularly impactful because clinical results were achieved while leveraging an internet-based approach to therapy.

Regrettably, despite the preponderance of evidence supporting the connection between mental health and AD, there remain considerable unmet needs. A recent cross-sectional survey of 954 adults with AD and caregivers of children with AD (N=954) conducted by the National Eczema Association found that half of patients were never asked about mental health during any of their visits, and of those referred for mental health resources, only 57% utilized the recommended services.⁹ Importantly, patients aged 18 to 34 years reported wanting to be asked about mental health. Of those who did receive referrals, most were for counseling services (23%), followed by alternative mental health therapy such as music or art therapy (15%), cognitive behavioral therapy (13%), or peer/social support groups (12%). Approximately 10% reported receiving a pamphlet or a brochure only.⁹

Physicians who treat patients with AD can and must do better, but first we must explore why these referral rates are so low. As with many complex problems, there is unlikely to be one simple unifying reason. As expected, the answer is nuanced and multifaceted, and—most importantly—staggeringly incomplete.

For starters, mental health interventions rarely are as easy as applying a cream or taking a pill. Hedman-Lagerlöf et al⁸ specifically pointed out that although their approach—using internet-based cognitive behavioral therapy—was explicitly designed to be more accessible with fewer resources, it required approximately 35 hours of treatment over 12 weeks, requiring both substantial time and commitment from patients who often are already burned out and exhausted due to AD. They even underscored that the most commonly reported adverse effect of therapy was increased stress or worry, making it a difficult sell.⁸

Even before most patients have a chance to consider the time required and the potential adverse effects of mental health interventions for AD, greater hurdles exist. Finances, medical insurance, and wait times were highlighted as barriers to care in a systematic review.¹⁰ These are deep-seated problems in the United States; while they may be surmountable in certain geo­graphic areas, the frequency with which these concerns arise means that it does not take too many failed attempts at referring patients for mental health services before clinicians just give up—similar to any form of operant conditioning.

A more elusive concept is stigmatization. Although it may not be quantifiable, the idea is that patients may encounter additional challenges when seeking mental health care, either because the interactions themselves may worsen their symptoms (eg, increased anxiety) or they may be more likely to have a negative perception of the experience.¹¹ A 2020 systematic review of barriers to addressing common mental health problems found that stigma was the most prominent barrier in adolescents, with the second most prominent being negative attitudes and beliefs about mental health services and professionals.¹² As a clinician, I can attest that I have sometimes detected skepticism when I have suggested mental health services to patients and have even been asked outright if I thought the problem was all in their head. My patients with AD generally have been much more open to the idea of mental health support, especially after I explain the powerful mind-body connection, than patients with other conditions—most notably delusions of parasitosis—who have been much more dismissive of such overtures. An oft-cited paper from 1976 frames the problem perfectly, describing what can happen after a referral for mental health services.¹³ The authors stated that the suggestion of mental health makes patients feel that the dermatologist does not believe them in the first place. Beyond this, the authors pointed out that referring the patient elsewhere reduces their hopes for dermatologic treatment.¹³

Knowing now—perhaps more than ever before—that the mind and skin are intimately connected compels us to solve these problems and find ways around these obstacles. Selecting the optimal forms of mental health services for each patient, having the structural support of the health care system, and winning the trust of patients and caregivers while combating stigma are undoubtedly tall orders; however, understanding the stakes for patients with AD, their caregivers, and society as a whole should inspire us to keep pushing forward.