Article

The benefit of immunotherapy in combination with chemotherapy for programmed death–ligand 1–positive (PD-L1+) metastatic triple-negative breast cancer (mTNBC) has been shown in both the IMpassion130 and KEYNOTE-355 trials.^[2,3] However, the IMpassion131 trial, which evaluated atezolizumab plus paclitaxel, did not show a progression-free survival (PFS) or overall survival (OS) benefit vs paclitaxel alone in PD-L1+ mTNBC.^[4] Various explanations for these divergent results have been proposed, including the inherent properties of the chemotherapy backbone, patient populations, and the heterogenous nature of TNBC, which can affect response to immunotherapy. Of present, the various KEYNOTE-355 regimens (pembrolizumab plus investigator's choice chemotherapy [nab-paclitaxel, paclitaxel, or gemcitabine-carboplatin]) are US Food and Drug Administration approved for PD-L1+ mTNBC in the first-line setting. The phase 2 randomized TBCRC 043 trial investigated the effect of atezolizumab with carboplatin in patients with mTNBC and further looked at clinical and molecular correlates of response (Lehmann et al). A total of 106 patients were randomly assigned to carboplatin or carboplatin plus atezolizumab; the combination improved PFS (median PFS, 4.1 vs 2.2 mo; hazard ratio [HR] 0.66; P = .05) and OS (12.6 vs 8.6 mo; HR 0.60; P = .03). Grade 3/4 serious adverse events were more common with carboplatin-atezolizumab vs carboplatin alone (41% vs 8%). In addition, an association of better responses with PD-L1 immunotherapy was seen in patients with obesity, uncontrolled blood glucose levels, high tumor mutation burden, and increased tumor infiltrating lymphocytes. These data support the role of immunotherapy in mTNBC, highlight tumor heterogeneity within this subtype and encourage correlative studies to better define which patients benefit from immunotherapy.

Various studies have demonstrated the favorable impact of physical activity on breast cancer risk in postmenopausal women.^[5] However, data in premenopausal women is less clear. Various mechanisms connecting physical activity to premenopausal breast cancer risk have been proposed including the effect of exercise on sex steroid hormones, fasting insulin levels, and inflammation.^[6] A pooled analysis from 19 cohort studies including 547,601 premenopausal women, with 10,231 incident cases of breast cancer, aimed to examine the relationship between leisure-time physical activity (sports, exercise, recreational walking) and breast cancer risk in young women (Timmins et al). Higher (90th percentile) vs lower (10th percentile) levels of leisure-time physical activity were associated with a 10% reduction in breast cancer risk after adjustment for body mass index (BMI; adjusted HR 0.90; 95% CI 0.85-0.95; P < .001). They also found a significant reduction in risk: 32% (HR 0.68; P = .01) and 9% (HR 0.91; P = .005) for women with underweight (BMI < 18.5) and with average weight (BMI 18.5-24.9), respectively. Further, the effect of physical activity was most pronounced in the human epidermal growth factor receptor 2 (HER2)–enriched breast cancer subtype, wherein higher vs lower levels of activity were associated with an estimated 45% reduction in breast cancer risk (adjusted HR 0.55; 95% CI 0.37-0.82). These findings support the beneficial role of aerobic exercise and healthy body weight on breast cancer risk among premenopausal women and highlight the value of incorporating this information into counseling for our patients.

Additional References

1. Figueroa JD, Gierach GL, Duggan MA, et al. Risk factors for breast cancer development by tumor characteristics among women with benign breast disease. Breast Cancer Res. 2021;23:34. doi: 10.1186/s13058-021-01410-1 Source
2. Schmid P, Adams S, Rugo HS, et al, for the IMpassion130 Trial Investigators. Atezolizumab and nab-paclitaxel in advanced triple-negative breast cancer. N Engl J Med. 2018;379:2108-2121. doi: 10.1056/nejmoa1809615 Source
3. Cortes J, Rugo HS, Cescon DW, et al, for the KEYNOTE-355 Investigators. Pembrolizumab plus chemotherapy in advanced triple-negative breast cancer. N Engl J Med. 2022;387:217-226. doi: 10.1056/NEJMoa2202809 Source
4. Miles D, Gligorov J, André F, et al, on behalf of the IMpassion131 investigators. Primary results from IMpassion131, a double-blind, placebo-controlled, randomised phase III trial of first-line paclitaxel with or without atezolizumab for unresectable locally advanced/metastatic triple-negative breast cancer. Ann Oncol. 2021;32:994-1004. doi: 10.1016/j.annonc.2021.05.801 Source
5. Eliassen AH, Hankinson SE, Rosner B, et al. Physical activity and risk of breast cancer among postmenopausal women. Arch Intern Med. 2010;170:1758-1764. doi: 10.1001/archinternmed.2010.363 Source
6. Swain CTV, Drummond AE, Boing L, et al. Linking physical activity to breast cancer via sex hormones, part 1: The effect of physical activity on sex steroid hormones. Cancer Epidemiol Biomarkers Prev. 2022;31:16-27. doi: 10.1158/1055-9965.EPI-21-0437 Source

The benefit of immunotherapy in combination with chemotherapy for programmed death–ligand 1–positive (PD-L1+) metastatic triple-negative breast cancer (mTNBC) has been shown in both the IMpassion130 and KEYNOTE-355 trials.^[2,3] However, the IMpassion131 trial, which evaluated atezolizumab plus paclitaxel, did not show a progression-free survival (PFS) or overall survival (OS) benefit vs paclitaxel alone in PD-L1+ mTNBC.^[4] Various explanations for these divergent results have been proposed, including the inherent properties of the chemotherapy backbone, patient populations, and the heterogenous nature of TNBC, which can affect response to immunotherapy. Of present, the various KEYNOTE-355 regimens (pembrolizumab plus investigator's choice chemotherapy [nab-paclitaxel, paclitaxel, or gemcitabine-carboplatin]) are US Food and Drug Administration approved for PD-L1+ mTNBC in the first-line setting. The phase 2 randomized TBCRC 043 trial investigated the effect of atezolizumab with carboplatin in patients with mTNBC and further looked at clinical and molecular correlates of response (Lehmann et al). A total of 106 patients were randomly assigned to carboplatin or carboplatin plus atezolizumab; the combination improved PFS (median PFS, 4.1 vs 2.2 mo; hazard ratio [HR] 0.66; P = .05) and OS (12.6 vs 8.6 mo; HR 0.60; P = .03). Grade 3/4 serious adverse events were more common with carboplatin-atezolizumab vs carboplatin alone (41% vs 8%). In addition, an association of better responses with PD-L1 immunotherapy was seen in patients with obesity, uncontrolled blood glucose levels, high tumor mutation burden, and increased tumor infiltrating lymphocytes. These data support the role of immunotherapy in mTNBC, highlight tumor heterogeneity within this subtype and encourage correlative studies to better define which patients benefit from immunotherapy.

Various studies have demonstrated the favorable impact of physical activity on breast cancer risk in postmenopausal women.^[5] However, data in premenopausal women is less clear. Various mechanisms connecting physical activity to premenopausal breast cancer risk have been proposed including the effect of exercise on sex steroid hormones, fasting insulin levels, and inflammation.^[6] A pooled analysis from 19 cohort studies including 547,601 premenopausal women, with 10,231 incident cases of breast cancer, aimed to examine the relationship between leisure-time physical activity (sports, exercise, recreational walking) and breast cancer risk in young women (Timmins et al). Higher (90th percentile) vs lower (10th percentile) levels of leisure-time physical activity were associated with a 10% reduction in breast cancer risk after adjustment for body mass index (BMI; adjusted HR 0.90; 95% CI 0.85-0.95; P < .001). They also found a significant reduction in risk: 32% (HR 0.68; P = .01) and 9% (HR 0.91; P = .005) for women with underweight (BMI < 18.5) and with average weight (BMI 18.5-24.9), respectively. Further, the effect of physical activity was most pronounced in the human epidermal growth factor receptor 2 (HER2)–enriched breast cancer subtype, wherein higher vs lower levels of activity were associated with an estimated 45% reduction in breast cancer risk (adjusted HR 0.55; 95% CI 0.37-0.82). These findings support the beneficial role of aerobic exercise and healthy body weight on breast cancer risk among premenopausal women and highlight the value of incorporating this information into counseling for our patients.

Additional References

1. Figueroa JD, Gierach GL, Duggan MA, et al. Risk factors for breast cancer development by tumor characteristics among women with benign breast disease. Breast Cancer Res. 2021;23:34. doi: 10.1186/s13058-021-01410-1 Source
2. Schmid P, Adams S, Rugo HS, et al, for the IMpassion130 Trial Investigators. Atezolizumab and nab-paclitaxel in advanced triple-negative breast cancer. N Engl J Med. 2018;379:2108-2121. doi: 10.1056/nejmoa1809615 Source
3. Cortes J, Rugo HS, Cescon DW, et al, for the KEYNOTE-355 Investigators. Pembrolizumab plus chemotherapy in advanced triple-negative breast cancer. N Engl J Med. 2022;387:217-226. doi: 10.1056/NEJMoa2202809 Source
4. Miles D, Gligorov J, André F, et al, on behalf of the IMpassion131 investigators. Primary results from IMpassion131, a double-blind, placebo-controlled, randomised phase III trial of first-line paclitaxel with or without atezolizumab for unresectable locally advanced/metastatic triple-negative breast cancer. Ann Oncol. 2021;32:994-1004. doi: 10.1016/j.annonc.2021.05.801 Source
5. Eliassen AH, Hankinson SE, Rosner B, et al. Physical activity and risk of breast cancer among postmenopausal women. Arch Intern Med. 2010;170:1758-1764. doi: 10.1001/archinternmed.2010.363 Source
6. Swain CTV, Drummond AE, Boing L, et al. Linking physical activity to breast cancer via sex hormones, part 1: The effect of physical activity on sex steroid hormones. Cancer Epidemiol Biomarkers Prev. 2022;31:16-27. doi: 10.1158/1055-9965.EPI-21-0437 Source

The benefit of immunotherapy in combination with chemotherapy for programmed death–ligand 1–positive (PD-L1+) metastatic triple-negative breast cancer (mTNBC) has been shown in both the IMpassion130 and KEYNOTE-355 trials.^[2,3] However, the IMpassion131 trial, which evaluated atezolizumab plus paclitaxel, did not show a progression-free survival (PFS) or overall survival (OS) benefit vs paclitaxel alone in PD-L1+ mTNBC.^[4] Various explanations for these divergent results have been proposed, including the inherent properties of the chemotherapy backbone, patient populations, and the heterogenous nature of TNBC, which can affect response to immunotherapy. Of present, the various KEYNOTE-355 regimens (pembrolizumab plus investigator's choice chemotherapy [nab-paclitaxel, paclitaxel, or gemcitabine-carboplatin]) are US Food and Drug Administration approved for PD-L1+ mTNBC in the first-line setting. The phase 2 randomized TBCRC 043 trial investigated the effect of atezolizumab with carboplatin in patients with mTNBC and further looked at clinical and molecular correlates of response (Lehmann et al). A total of 106 patients were randomly assigned to carboplatin or carboplatin plus atezolizumab; the combination improved PFS (median PFS, 4.1 vs 2.2 mo; hazard ratio [HR] 0.66; P = .05) and OS (12.6 vs 8.6 mo; HR 0.60; P = .03). Grade 3/4 serious adverse events were more common with carboplatin-atezolizumab vs carboplatin alone (41% vs 8%). In addition, an association of better responses with PD-L1 immunotherapy was seen in patients with obesity, uncontrolled blood glucose levels, high tumor mutation burden, and increased tumor infiltrating lymphocytes. These data support the role of immunotherapy in mTNBC, highlight tumor heterogeneity within this subtype and encourage correlative studies to better define which patients benefit from immunotherapy.

Various studies have demonstrated the favorable impact of physical activity on breast cancer risk in postmenopausal women.^[5] However, data in premenopausal women is less clear. Various mechanisms connecting physical activity to premenopausal breast cancer risk have been proposed including the effect of exercise on sex steroid hormones, fasting insulin levels, and inflammation.^[6] A pooled analysis from 19 cohort studies including 547,601 premenopausal women, with 10,231 incident cases of breast cancer, aimed to examine the relationship between leisure-time physical activity (sports, exercise, recreational walking) and breast cancer risk in young women (Timmins et al). Higher (90th percentile) vs lower (10th percentile) levels of leisure-time physical activity were associated with a 10% reduction in breast cancer risk after adjustment for body mass index (BMI; adjusted HR 0.90; 95% CI 0.85-0.95; P < .001). They also found a significant reduction in risk: 32% (HR 0.68; P = .01) and 9% (HR 0.91; P = .005) for women with underweight (BMI < 18.5) and with average weight (BMI 18.5-24.9), respectively. Further, the effect of physical activity was most pronounced in the human epidermal growth factor receptor 2 (HER2)–enriched breast cancer subtype, wherein higher vs lower levels of activity were associated with an estimated 45% reduction in breast cancer risk (adjusted HR 0.55; 95% CI 0.37-0.82). These findings support the beneficial role of aerobic exercise and healthy body weight on breast cancer risk among premenopausal women and highlight the value of incorporating this information into counseling for our patients.

Additional References

1. Figueroa JD, Gierach GL, Duggan MA, et al. Risk factors for breast cancer development by tumor characteristics among women with benign breast disease. Breast Cancer Res. 2021;23:34. doi: 10.1186/s13058-021-01410-1 Source
2. Schmid P, Adams S, Rugo HS, et al, for the IMpassion130 Trial Investigators. Atezolizumab and nab-paclitaxel in advanced triple-negative breast cancer. N Engl J Med. 2018;379:2108-2121. doi: 10.1056/nejmoa1809615 Source
3. Cortes J, Rugo HS, Cescon DW, et al, for the KEYNOTE-355 Investigators. Pembrolizumab plus chemotherapy in advanced triple-negative breast cancer. N Engl J Med. 2022;387:217-226. doi: 10.1056/NEJMoa2202809 Source
4. Miles D, Gligorov J, André F, et al, on behalf of the IMpassion131 investigators. Primary results from IMpassion131, a double-blind, placebo-controlled, randomised phase III trial of first-line paclitaxel with or without atezolizumab for unresectable locally advanced/metastatic triple-negative breast cancer. Ann Oncol. 2021;32:994-1004. doi: 10.1016/j.annonc.2021.05.801 Source
5. Eliassen AH, Hankinson SE, Rosner B, et al. Physical activity and risk of breast cancer among postmenopausal women. Arch Intern Med. 2010;170:1758-1764. doi: 10.1001/archinternmed.2010.363 Source
6. Swain CTV, Drummond AE, Boing L, et al. Linking physical activity to breast cancer via sex hormones, part 1: The effect of physical activity on sex steroid hormones. Cancer Epidemiol Biomarkers Prev. 2022;31:16-27. doi: 10.1158/1055-9965.EPI-21-0437 Source

The Diagnosis: Giant Apocrine Hidrocystoma

Histopathology of the noduloplaque revealed an unremarkable epidermis with multilocular cystic spaces centered in the dermis. The cysts had a double-lined epithelium with inner columnar to cuboidal cells and outer myoepithelial cells (bottom quiz image). Columnar cells showing decapitation secretion could be appreciated at places indicating apocrine secretion (Figure). A final diagnosis of apocrine hidrocystoma was made.

Hidrocystomas are rare, benign, cystic lesions derived either from apocrine or eccrine glands.¹ Apocrine hidrocystoma usually manifests as asymptomatic, solitary, dome-shaped papules or nodules with a predilection for the head and neck region. Hidrocystomas can vary from flesh colored to blue, brown, or black. Pigmentation in hidrocystoma is seen in 5% to 80% of cases and is attributed to the Tyndall effect.¹ The tumor usually is less than 20 mm in diameter; larger lesions are termed giant apocrine hidrocystoma.² Apocrine hidrocystoma manifesting with multiple lesions and a size greater than 10 mm, as seen in our case, is uncommon.

Zaballos et al³ described dermoscopy of apocrine hidrocystoma in 22 patients. Hallmark dermoscopic findings were the presence of a homogeneous flesh-colored, yellowish, blue to pinkish-blue area involving the entire lesion with arborizing vessels and whitish structures.³ Similar dermoscopic findings were present in our patient. The homogeneous area histologically correlates to the multiloculated cysts located in the dermis. The exact reason for white structures is unknown; however, their visualization in apocrine hidrocystoma could be attributed to the alternation in collagen orientation secondary to the presence of large or multiple cysts in the dermis.

The presence of shiny white dots arranged in a square resembling a four-leaf clover (also known as white rosettes) was a unique dermoscopic finding in our patient. These rosettes can be appreciated only with polarized dermoscopy, and they have been described in actinic keratosis, seborrheic keratosis, squamous cell carcinoma, and basal cell carcinoma.⁴ The exact morphologic correlate of white rosettes is unknown but is postulated to be secondary to material inside adnexal openings in small rosettes and concentric perifollicular fibrosis in larger rosettes.⁴ In our patient, we believe the white rosettes can be attributed to the accumulated secretions in the dermal glands, which also were seen via histopathology. Dermoscopy also revealed increased peripheral, brown, networklike pigmentation, which was unique and could be secondary to the patient’s darker skin phenotype.

Differential diagnoses of apocrine hidrocystoma include both melanocytic and nonmelanocytic conditions such as epidermal cyst, nodular melanoma, nodular hidradenoma, syringoma, blue nevus, pilomatricoma, eccrine poroma, nodular Kaposi sarcoma, and venous lake.1 Histopathology showing large unilocular or multilocular dermal cysts with double lining comprising outer myoepithelial cells and inner columnar or cuboidal cell with decapitation secretion is paramount in confirming the diagnosis of apocrine hidrocystoma.

Dermoscopy can act as a valuable noninvasive modality in differentiating apocrine hidrocystoma from its melanocytic and nonmelanocytic differential diagnoses (Table).^5-8 In our patient, the presence of a homogeneous pink to bluish area involving the entire lesion, linear branched vessels, and whitish structures on dermoscopy pointed to the diagnosis of apocrine hidrocystoma, which was further confirmed by characteristic histopathologic findings.

The treatment of apocrine hidrocystoma includes surgical excision for solitary lesions, with electrodesiccation and curettage, chemical cautery, and CO₂ laser ablation employed for multiple lesions.¹ Our patient was scheduled for CO₂ laser ablation, considering the multiple lesions and size of the apocrine hidrocystoma but was subsequently lost to follow-up.

The Diagnosis: Giant Apocrine Hidrocystoma

Histopathology of the noduloplaque revealed an unremarkable epidermis with multilocular cystic spaces centered in the dermis. The cysts had a double-lined epithelium with inner columnar to cuboidal cells and outer myoepithelial cells (bottom quiz image). Columnar cells showing decapitation secretion could be appreciated at places indicating apocrine secretion (Figure). A final diagnosis of apocrine hidrocystoma was made.

Hidrocystomas are rare, benign, cystic lesions derived either from apocrine or eccrine glands.¹ Apocrine hidrocystoma usually manifests as asymptomatic, solitary, dome-shaped papules or nodules with a predilection for the head and neck region. Hidrocystomas can vary from flesh colored to blue, brown, or black. Pigmentation in hidrocystoma is seen in 5% to 80% of cases and is attributed to the Tyndall effect.¹ The tumor usually is less than 20 mm in diameter; larger lesions are termed giant apocrine hidrocystoma.² Apocrine hidrocystoma manifesting with multiple lesions and a size greater than 10 mm, as seen in our case, is uncommon.

Zaballos et al³ described dermoscopy of apocrine hidrocystoma in 22 patients. Hallmark dermoscopic findings were the presence of a homogeneous flesh-colored, yellowish, blue to pinkish-blue area involving the entire lesion with arborizing vessels and whitish structures.³ Similar dermoscopic findings were present in our patient. The homogeneous area histologically correlates to the multiloculated cysts located in the dermis. The exact reason for white structures is unknown; however, their visualization in apocrine hidrocystoma could be attributed to the alternation in collagen orientation secondary to the presence of large or multiple cysts in the dermis.

The presence of shiny white dots arranged in a square resembling a four-leaf clover (also known as white rosettes) was a unique dermoscopic finding in our patient. These rosettes can be appreciated only with polarized dermoscopy, and they have been described in actinic keratosis, seborrheic keratosis, squamous cell carcinoma, and basal cell carcinoma.⁴ The exact morphologic correlate of white rosettes is unknown but is postulated to be secondary to material inside adnexal openings in small rosettes and concentric perifollicular fibrosis in larger rosettes.⁴ In our patient, we believe the white rosettes can be attributed to the accumulated secretions in the dermal glands, which also were seen via histopathology. Dermoscopy also revealed increased peripheral, brown, networklike pigmentation, which was unique and could be secondary to the patient’s darker skin phenotype.

Differential diagnoses of apocrine hidrocystoma include both melanocytic and nonmelanocytic conditions such as epidermal cyst, nodular melanoma, nodular hidradenoma, syringoma, blue nevus, pilomatricoma, eccrine poroma, nodular Kaposi sarcoma, and venous lake.1 Histopathology showing large unilocular or multilocular dermal cysts with double lining comprising outer myoepithelial cells and inner columnar or cuboidal cell with decapitation secretion is paramount in confirming the diagnosis of apocrine hidrocystoma.

Dermoscopy can act as a valuable noninvasive modality in differentiating apocrine hidrocystoma from its melanocytic and nonmelanocytic differential diagnoses (Table).^5-8 In our patient, the presence of a homogeneous pink to bluish area involving the entire lesion, linear branched vessels, and whitish structures on dermoscopy pointed to the diagnosis of apocrine hidrocystoma, which was further confirmed by characteristic histopathologic findings.

The treatment of apocrine hidrocystoma includes surgical excision for solitary lesions, with electrodesiccation and curettage, chemical cautery, and CO₂ laser ablation employed for multiple lesions.¹ Our patient was scheduled for CO₂ laser ablation, considering the multiple lesions and size of the apocrine hidrocystoma but was subsequently lost to follow-up.

The Diagnosis: Giant Apocrine Hidrocystoma

Histopathology of the noduloplaque revealed an unremarkable epidermis with multilocular cystic spaces centered in the dermis. The cysts had a double-lined epithelium with inner columnar to cuboidal cells and outer myoepithelial cells (bottom quiz image). Columnar cells showing decapitation secretion could be appreciated at places indicating apocrine secretion (Figure). A final diagnosis of apocrine hidrocystoma was made.

Hidrocystomas are rare, benign, cystic lesions derived either from apocrine or eccrine glands.¹ Apocrine hidrocystoma usually manifests as asymptomatic, solitary, dome-shaped papules or nodules with a predilection for the head and neck region. Hidrocystomas can vary from flesh colored to blue, brown, or black. Pigmentation in hidrocystoma is seen in 5% to 80% of cases and is attributed to the Tyndall effect.¹ The tumor usually is less than 20 mm in diameter; larger lesions are termed giant apocrine hidrocystoma.² Apocrine hidrocystoma manifesting with multiple lesions and a size greater than 10 mm, as seen in our case, is uncommon.

Zaballos et al³ described dermoscopy of apocrine hidrocystoma in 22 patients. Hallmark dermoscopic findings were the presence of a homogeneous flesh-colored, yellowish, blue to pinkish-blue area involving the entire lesion with arborizing vessels and whitish structures.³ Similar dermoscopic findings were present in our patient. The homogeneous area histologically correlates to the multiloculated cysts located in the dermis. The exact reason for white structures is unknown; however, their visualization in apocrine hidrocystoma could be attributed to the alternation in collagen orientation secondary to the presence of large or multiple cysts in the dermis.

The presence of shiny white dots arranged in a square resembling a four-leaf clover (also known as white rosettes) was a unique dermoscopic finding in our patient. These rosettes can be appreciated only with polarized dermoscopy, and they have been described in actinic keratosis, seborrheic keratosis, squamous cell carcinoma, and basal cell carcinoma.⁴ The exact morphologic correlate of white rosettes is unknown but is postulated to be secondary to material inside adnexal openings in small rosettes and concentric perifollicular fibrosis in larger rosettes.⁴ In our patient, we believe the white rosettes can be attributed to the accumulated secretions in the dermal glands, which also were seen via histopathology. Dermoscopy also revealed increased peripheral, brown, networklike pigmentation, which was unique and could be secondary to the patient’s darker skin phenotype.

Differential diagnoses of apocrine hidrocystoma include both melanocytic and nonmelanocytic conditions such as epidermal cyst, nodular melanoma, nodular hidradenoma, syringoma, blue nevus, pilomatricoma, eccrine poroma, nodular Kaposi sarcoma, and venous lake.1 Histopathology showing large unilocular or multilocular dermal cysts with double lining comprising outer myoepithelial cells and inner columnar or cuboidal cell with decapitation secretion is paramount in confirming the diagnosis of apocrine hidrocystoma.

Dermoscopy can act as a valuable noninvasive modality in differentiating apocrine hidrocystoma from its melanocytic and nonmelanocytic differential diagnoses (Table).^5-8 In our patient, the presence of a homogeneous pink to bluish area involving the entire lesion, linear branched vessels, and whitish structures on dermoscopy pointed to the diagnosis of apocrine hidrocystoma, which was further confirmed by characteristic histopathologic findings.

The treatment of apocrine hidrocystoma includes surgical excision for solitary lesions, with electrodesiccation and curettage, chemical cautery, and CO₂ laser ablation employed for multiple lesions.¹ Our patient was scheduled for CO₂ laser ablation, considering the multiple lesions and size of the apocrine hidrocystoma but was subsequently lost to follow-up.

The Diagnosis: Coral Dermatitis

At 3-week follow-up, the patient demonstrated remarkable improvement in the intensity and size of the erythematous cerebriform plaques following daily application of triamcinolone acetonide cream 0.1% (Figure). The lesion disappeared after several months and did not recur. The delayed presentation of symptoms with a history of incidental coral contact during snorkeling most likely represents the type IV hypersensitivity reaction seen in the diagnosis of coral dermatitis, an extraordinarily rare form of contact dermatitis.¹ Not all coral trigger skin reactions. Species of coral that contain nematocysts in their tentacles (aptly named stinging capsules) are responsible for the sting preceding coral dermatitis, as the nematocysts eject a coiled filament in response to human tactile stimulation that injects toxins into the epidermis.²

Acute, delayed, or chronic cutaneous changes follow envenomation. Acute responses arise immediately to a few hours after initial contact and are considered an irritant contact dermatitis.³ Local tissue histamine release and cascades of cytotoxic reactions often result in the characteristic urticarial or vesiculobullous plaques in addition to necrosis, piloerection, and localized lymphadenopathy.^2-4 Although relatively uncommon, there may be rapid onset of systemic symptoms such as fever, malaise, hives, nausea, or emesis. Cardiopulmonary events, hepatotoxicity, renal failure, or anaphylaxis are rare.² Histopathology of biopsy specimens reveals epidermal spongiosis with microvesicles and papillary dermal edema.^1,5 In comparison, delayed reactions occur within days to weeks and exhibit epidermal parakeratosis, spongiosis, basal layer vacuolization, focal necrosis, lymphocyte exocytosis, and papillary dermal edema with extravasated erythrocytes.1,6 Clinically, it may present as linear rows of erythematous papules with burning and pruritus.⁶ Chronic reactions manifest after months as difficult-to-treat, persistent lichenoid dermatitis occasionally accompanied by granulomatous changes.^1,2,4 Primary prevention measures after initial contact include an acetic acid rinse and cold compression to wash away residual nematocysts in the affected area.^4,7,8 If a rash develops, topical steroids are the mainstay of treatment.^3,8

In tandem with toxic nematocysts, the rigid calcified bodies of coral provide an additional self-defense mechanism against human contact.^2,4 The irregular haphazard nature of coral may catch novice divers off guard and lead to laceration of a mispositioned limb, thereby increasing the risk for secondary infections due to the introduction of calcium carbonate and toxic mucinous deposits at the wound site, warranting antibiotic treatment.^2,4,7 Because tropical locales are home to other natural dangers that inflict disease and mimic early signs of coral dermatitis, reaching an accurate diagnosis can be difficult, particularly for lower limb lesions. In summary, the diagnosis of coral dermatitis can be rendered based on morphology of the lesion and clinical context (exposure to corals and delayed symptoms) as well as response to topical steroids.

The differential diagnosis includes accidental trauma. Variations in impact force and patient skin integrity lead to a number of possible cutaneous manifestations seen in accidental trauma,⁹ which includes contusions resulting from burst capillaries underneath intact skin, abrasions due to the superficial epidermis scuffing away, and lacerations caused by enough force to rip and split the skin, leaving subcutaneous tissue between the intact tissue.^9,10 Typically, the pattern of injury can provide hints to match what object or organism caused the wound.⁹ However, delayed response and worsening symptoms, as seen in coral dermatitis, would be unusual in accidental trauma unless it is complicated by secondary infection (infectious dermatitis), which does not respond to topical steroids and requires antibiotic treatment.

Another differential diagnosis includes cutaneous larva migrans, which infests domesticated and stray animals. For example, hookworm larvae propagate their eggs inside the intestines of their host before fecal-soil transmission in sandy locales.¹¹ Unexpecting beachgoers travel barefoot on this contaminated soil, offering ample opportunity for the parasite to burrow into the upper dermis.^11,12 The clinical presentation includes signs and symptoms of creeping eruption such as pruritic, linear, serpiginous tracks. Topical treatment with thiabendazole requires application 3 times daily for 15 days, which increases the risk for nonadherence, yet this therapy proves advantageous if a patient does not tolerate oral agents due to systemic adverse effects.^11,12 Oral agents (eg, ivermectin, albendazole) offer improved adherence with a single dose^11,13; the cure rate was higher with a single dose of ivermectin 12 mg vs a single dose of albendazole 400 mg.13 The current suggested treatment is ivermectin 200 μg/kg by mouth daily for 1 or 2 days.¹⁴

The incidence of seabather’s eruption (also known as chinkui dermatitis) is highest during the summer season and fluctuates between epidemic and nonepidemic years.^15,16 It occurs sporadically worldwide mostly in tropical climates due to trapping of larvae spawn of sea animals such as crustaceans in swimwear. Initially, it presents as a pruritic and burning sensation after exiting the water, manifesting as a macular, papular, or maculopapular rash on areas covered by the swimsuit.^15,16 The sensation is worse in areas that are tightly banded on the swimsuit, including the waistband and elastic straps.¹⁵ Commonly, the affected individual will seek relief via a shower, which intensifies the burning, especially if the swimsuit has not been removed. The contaminated swimwear should be immediately discarded, as the trapped sea larvae’s nematocysts activate with the pressure and friction of movement.¹⁵ Seabather’s eruption typically resolves spontaneously within a week, but symptom management can be achieved with topical steroids (triamcinolone 0.1% or clobetasol 0.05%).^15,16 Unlike coral dermatitis, in seabather’s eruption the symptoms are immediate and the location of the eruption coincides with areas covered by the swimsuit.

The Diagnosis: Coral Dermatitis

At 3-week follow-up, the patient demonstrated remarkable improvement in the intensity and size of the erythematous cerebriform plaques following daily application of triamcinolone acetonide cream 0.1% (Figure). The lesion disappeared after several months and did not recur. The delayed presentation of symptoms with a history of incidental coral contact during snorkeling most likely represents the type IV hypersensitivity reaction seen in the diagnosis of coral dermatitis, an extraordinarily rare form of contact dermatitis.¹ Not all coral trigger skin reactions. Species of coral that contain nematocysts in their tentacles (aptly named stinging capsules) are responsible for the sting preceding coral dermatitis, as the nematocysts eject a coiled filament in response to human tactile stimulation that injects toxins into the epidermis.²

Acute, delayed, or chronic cutaneous changes follow envenomation. Acute responses arise immediately to a few hours after initial contact and are considered an irritant contact dermatitis.³ Local tissue histamine release and cascades of cytotoxic reactions often result in the characteristic urticarial or vesiculobullous plaques in addition to necrosis, piloerection, and localized lymphadenopathy.^2-4 Although relatively uncommon, there may be rapid onset of systemic symptoms such as fever, malaise, hives, nausea, or emesis. Cardiopulmonary events, hepatotoxicity, renal failure, or anaphylaxis are rare.² Histopathology of biopsy specimens reveals epidermal spongiosis with microvesicles and papillary dermal edema.^1,5 In comparison, delayed reactions occur within days to weeks and exhibit epidermal parakeratosis, spongiosis, basal layer vacuolization, focal necrosis, lymphocyte exocytosis, and papillary dermal edema with extravasated erythrocytes.1,6 Clinically, it may present as linear rows of erythematous papules with burning and pruritus.⁶ Chronic reactions manifest after months as difficult-to-treat, persistent lichenoid dermatitis occasionally accompanied by granulomatous changes.^1,2,4 Primary prevention measures after initial contact include an acetic acid rinse and cold compression to wash away residual nematocysts in the affected area.^4,7,8 If a rash develops, topical steroids are the mainstay of treatment.^3,8

In tandem with toxic nematocysts, the rigid calcified bodies of coral provide an additional self-defense mechanism against human contact.^2,4 The irregular haphazard nature of coral may catch novice divers off guard and lead to laceration of a mispositioned limb, thereby increasing the risk for secondary infections due to the introduction of calcium carbonate and toxic mucinous deposits at the wound site, warranting antibiotic treatment.^2,4,7 Because tropical locales are home to other natural dangers that inflict disease and mimic early signs of coral dermatitis, reaching an accurate diagnosis can be difficult, particularly for lower limb lesions. In summary, the diagnosis of coral dermatitis can be rendered based on morphology of the lesion and clinical context (exposure to corals and delayed symptoms) as well as response to topical steroids.

The differential diagnosis includes accidental trauma. Variations in impact force and patient skin integrity lead to a number of possible cutaneous manifestations seen in accidental trauma,⁹ which includes contusions resulting from burst capillaries underneath intact skin, abrasions due to the superficial epidermis scuffing away, and lacerations caused by enough force to rip and split the skin, leaving subcutaneous tissue between the intact tissue.^9,10 Typically, the pattern of injury can provide hints to match what object or organism caused the wound.⁹ However, delayed response and worsening symptoms, as seen in coral dermatitis, would be unusual in accidental trauma unless it is complicated by secondary infection (infectious dermatitis), which does not respond to topical steroids and requires antibiotic treatment.

Another differential diagnosis includes cutaneous larva migrans, which infests domesticated and stray animals. For example, hookworm larvae propagate their eggs inside the intestines of their host before fecal-soil transmission in sandy locales.¹¹ Unexpecting beachgoers travel barefoot on this contaminated soil, offering ample opportunity for the parasite to burrow into the upper dermis.^11,12 The clinical presentation includes signs and symptoms of creeping eruption such as pruritic, linear, serpiginous tracks. Topical treatment with thiabendazole requires application 3 times daily for 15 days, which increases the risk for nonadherence, yet this therapy proves advantageous if a patient does not tolerate oral agents due to systemic adverse effects.^11,12 Oral agents (eg, ivermectin, albendazole) offer improved adherence with a single dose^11,13; the cure rate was higher with a single dose of ivermectin 12 mg vs a single dose of albendazole 400 mg.13 The current suggested treatment is ivermectin 200 μg/kg by mouth daily for 1 or 2 days.¹⁴

The incidence of seabather’s eruption (also known as chinkui dermatitis) is highest during the summer season and fluctuates between epidemic and nonepidemic years.^15,16 It occurs sporadically worldwide mostly in tropical climates due to trapping of larvae spawn of sea animals such as crustaceans in swimwear. Initially, it presents as a pruritic and burning sensation after exiting the water, manifesting as a macular, papular, or maculopapular rash on areas covered by the swimsuit.^15,16 The sensation is worse in areas that are tightly banded on the swimsuit, including the waistband and elastic straps.¹⁵ Commonly, the affected individual will seek relief via a shower, which intensifies the burning, especially if the swimsuit has not been removed. The contaminated swimwear should be immediately discarded, as the trapped sea larvae’s nematocysts activate with the pressure and friction of movement.¹⁵ Seabather’s eruption typically resolves spontaneously within a week, but symptom management can be achieved with topical steroids (triamcinolone 0.1% or clobetasol 0.05%).^15,16 Unlike coral dermatitis, in seabather’s eruption the symptoms are immediate and the location of the eruption coincides with areas covered by the swimsuit.

The Diagnosis: Coral Dermatitis

At 3-week follow-up, the patient demonstrated remarkable improvement in the intensity and size of the erythematous cerebriform plaques following daily application of triamcinolone acetonide cream 0.1% (Figure). The lesion disappeared after several months and did not recur. The delayed presentation of symptoms with a history of incidental coral contact during snorkeling most likely represents the type IV hypersensitivity reaction seen in the diagnosis of coral dermatitis, an extraordinarily rare form of contact dermatitis.¹ Not all coral trigger skin reactions. Species of coral that contain nematocysts in their tentacles (aptly named stinging capsules) are responsible for the sting preceding coral dermatitis, as the nematocysts eject a coiled filament in response to human tactile stimulation that injects toxins into the epidermis.²

Acute, delayed, or chronic cutaneous changes follow envenomation. Acute responses arise immediately to a few hours after initial contact and are considered an irritant contact dermatitis.³ Local tissue histamine release and cascades of cytotoxic reactions often result in the characteristic urticarial or vesiculobullous plaques in addition to necrosis, piloerection, and localized lymphadenopathy.^2-4 Although relatively uncommon, there may be rapid onset of systemic symptoms such as fever, malaise, hives, nausea, or emesis. Cardiopulmonary events, hepatotoxicity, renal failure, or anaphylaxis are rare.² Histopathology of biopsy specimens reveals epidermal spongiosis with microvesicles and papillary dermal edema.^1,5 In comparison, delayed reactions occur within days to weeks and exhibit epidermal parakeratosis, spongiosis, basal layer vacuolization, focal necrosis, lymphocyte exocytosis, and papillary dermal edema with extravasated erythrocytes.1,6 Clinically, it may present as linear rows of erythematous papules with burning and pruritus.⁶ Chronic reactions manifest after months as difficult-to-treat, persistent lichenoid dermatitis occasionally accompanied by granulomatous changes.^1,2,4 Primary prevention measures after initial contact include an acetic acid rinse and cold compression to wash away residual nematocysts in the affected area.^4,7,8 If a rash develops, topical steroids are the mainstay of treatment.^3,8

In tandem with toxic nematocysts, the rigid calcified bodies of coral provide an additional self-defense mechanism against human contact.^2,4 The irregular haphazard nature of coral may catch novice divers off guard and lead to laceration of a mispositioned limb, thereby increasing the risk for secondary infections due to the introduction of calcium carbonate and toxic mucinous deposits at the wound site, warranting antibiotic treatment.^2,4,7 Because tropical locales are home to other natural dangers that inflict disease and mimic early signs of coral dermatitis, reaching an accurate diagnosis can be difficult, particularly for lower limb lesions. In summary, the diagnosis of coral dermatitis can be rendered based on morphology of the lesion and clinical context (exposure to corals and delayed symptoms) as well as response to topical steroids.

The differential diagnosis includes accidental trauma. Variations in impact force and patient skin integrity lead to a number of possible cutaneous manifestations seen in accidental trauma,⁹ which includes contusions resulting from burst capillaries underneath intact skin, abrasions due to the superficial epidermis scuffing away, and lacerations caused by enough force to rip and split the skin, leaving subcutaneous tissue between the intact tissue.^9,10 Typically, the pattern of injury can provide hints to match what object or organism caused the wound.⁹ However, delayed response and worsening symptoms, as seen in coral dermatitis, would be unusual in accidental trauma unless it is complicated by secondary infection (infectious dermatitis), which does not respond to topical steroids and requires antibiotic treatment.

Another differential diagnosis includes cutaneous larva migrans, which infests domesticated and stray animals. For example, hookworm larvae propagate their eggs inside the intestines of their host before fecal-soil transmission in sandy locales.¹¹ Unexpecting beachgoers travel barefoot on this contaminated soil, offering ample opportunity for the parasite to burrow into the upper dermis.^11,12 The clinical presentation includes signs and symptoms of creeping eruption such as pruritic, linear, serpiginous tracks. Topical treatment with thiabendazole requires application 3 times daily for 15 days, which increases the risk for nonadherence, yet this therapy proves advantageous if a patient does not tolerate oral agents due to systemic adverse effects.^11,12 Oral agents (eg, ivermectin, albendazole) offer improved adherence with a single dose^11,13; the cure rate was higher with a single dose of ivermectin 12 mg vs a single dose of albendazole 400 mg.13 The current suggested treatment is ivermectin 200 μg/kg by mouth daily for 1 or 2 days.¹⁴

The incidence of seabather’s eruption (also known as chinkui dermatitis) is highest during the summer season and fluctuates between epidemic and nonepidemic years.^15,16 It occurs sporadically worldwide mostly in tropical climates due to trapping of larvae spawn of sea animals such as crustaceans in swimwear. Initially, it presents as a pruritic and burning sensation after exiting the water, manifesting as a macular, papular, or maculopapular rash on areas covered by the swimsuit.^15,16 The sensation is worse in areas that are tightly banded on the swimsuit, including the waistband and elastic straps.¹⁵ Commonly, the affected individual will seek relief via a shower, which intensifies the burning, especially if the swimsuit has not been removed. The contaminated swimwear should be immediately discarded, as the trapped sea larvae’s nematocysts activate with the pressure and friction of movement.¹⁵ Seabather’s eruption typically resolves spontaneously within a week, but symptom management can be achieved with topical steroids (triamcinolone 0.1% or clobetasol 0.05%).^15,16 Unlike coral dermatitis, in seabather’s eruption the symptoms are immediate and the location of the eruption coincides with areas covered by the swimsuit.

The Diagnosis: Granuloma Annulare

The biopsies revealed palisading granulomatous dermatitis consistent with granuloma annulare (GA). This diagnosis was supported by the clinical presentation and histopathologic findings. Although the pathogenesis of GA is unclear, it is a benign, self-limiting condition. Primarily affected sites include the trunk and forearms. Generalized GA (or GA with ≥10 lesions) may warrant workup for malignancy, as it may represent a paraneoplastic process.¹ Histopathology reveals granulomas comprising a dermal lymphohistiocytic infiltrate as well as central mucin and nuclear debris. There are a few histologic subtypes of GA, including palisading and interstitial, which refer to the distribution of the histiocytic infiltrate.^2,3 This case—with palisading histiocytes lining the collection of necrobiosis and mucin (bottom quiz image)—features palisading GA. Notably, GA exhibits central rather than diffuse mucin.⁴

Erythema gyratum repens is a paraneoplastic arcuate erythema that manifests as erythematous figurate, gyrate, or annular plaques exhibiting a trailing scale. Clinically, erythema gyratum repens spreads rapidly—as quickly as 1 cm/d—and can be extensive (as in this case). Histopathology ruled out this diagnosis in our patient. Nonspecific findings of acanthosis, parakeratosis, and superficial spongiosis can be found in erythema gyratum repens. A superficial and deep perivascular lymphohistiocytic infiltrate may be seen in figurate erythemas (Figure 1).⁵ Unlike GA, this infiltrate does not form granulomas, is more superficial, and does not contain mucin.

Histopathology also can help establish the diagnosis of leprosy and its specific subtype, as leprosy exists on a spectrum from tuberculoid to lepromatous, with a great deal of overlap in between.⁶ Lepromatous leprosy has many cutaneous clinical presentations but typically manifests as erythematous papules or nodules. It is multibacillary, and these mycobacteria form clumps known as globi that can be seen on Fite stain.⁷ In lepromatous leprosy, there is a characteristic dense lymphohistiocytic infiltrate (Figure 2) above which a Grenz zone can be seen.^4,8 There are no well-formed granulomas in lepromatous leprosy, unlike in tuberculoid leprosy, which is paucibacillary and creates a granulomatous response surrounding nerves and adnexal structures.⁶

Mycosis fungoides (MF) is the most common cutaneous lymphoma. There are patch, plaque, and tumor stages of MF, each of which exhibits various histopathologic findings.⁹ In early patch-stage MF, lymphocytes have perinuclear clearing, and the degree of lymphocytic infiltrate is out of proportion to the spongiosis present. Epidermotropism and Pautrier microabscesses often are present in the epidermis (Figure 3). In the plaque stage, there is a denser lymphoid infiltrate in a lichenoid pattern with epidermotropism and Pautrier microabscesses. The tumor stage shows a dense dermal lymphoid infiltrate with more atypia and typically a lack of epidermotropism. Rarely, MF can exhibit a granulomatous variant in which epithelioid histiocytes collect to form granulomas along with atypical lymphocytes.¹⁰

The diagnosis of cutaneous sarcoidosis requires clinicopathologic corroboration. Histopathology demonstrates epithelioid histiocytes forming noncaseating granulomas with little to no lymphocytic infiltrate (Figure 4). There typically is no necrosis or necrobiosis as there is in GA. The diagnosis of sarcoidosis can be challenging histopathologically, and stains should be used to rule out infectious processes.⁴ Asteroid bodies— star-shaped eosinophilic inclusions within giant cells—may be present but are nonspecific for sarcoidosis.¹¹ Schaumann bodies—inclusions of calcifications within giant cells—also may be present and can aid in diagnosis.¹²

The Diagnosis: Granuloma Annulare

The biopsies revealed palisading granulomatous dermatitis consistent with granuloma annulare (GA). This diagnosis was supported by the clinical presentation and histopathologic findings. Although the pathogenesis of GA is unclear, it is a benign, self-limiting condition. Primarily affected sites include the trunk and forearms. Generalized GA (or GA with ≥10 lesions) may warrant workup for malignancy, as it may represent a paraneoplastic process.¹ Histopathology reveals granulomas comprising a dermal lymphohistiocytic infiltrate as well as central mucin and nuclear debris. There are a few histologic subtypes of GA, including palisading and interstitial, which refer to the distribution of the histiocytic infiltrate.^2,3 This case—with palisading histiocytes lining the collection of necrobiosis and mucin (bottom quiz image)—features palisading GA. Notably, GA exhibits central rather than diffuse mucin.⁴

Erythema gyratum repens is a paraneoplastic arcuate erythema that manifests as erythematous figurate, gyrate, or annular plaques exhibiting a trailing scale. Clinically, erythema gyratum repens spreads rapidly—as quickly as 1 cm/d—and can be extensive (as in this case). Histopathology ruled out this diagnosis in our patient. Nonspecific findings of acanthosis, parakeratosis, and superficial spongiosis can be found in erythema gyratum repens. A superficial and deep perivascular lymphohistiocytic infiltrate may be seen in figurate erythemas (Figure 1).⁵ Unlike GA, this infiltrate does not form granulomas, is more superficial, and does not contain mucin.

Histopathology also can help establish the diagnosis of leprosy and its specific subtype, as leprosy exists on a spectrum from tuberculoid to lepromatous, with a great deal of overlap in between.⁶ Lepromatous leprosy has many cutaneous clinical presentations but typically manifests as erythematous papules or nodules. It is multibacillary, and these mycobacteria form clumps known as globi that can be seen on Fite stain.⁷ In lepromatous leprosy, there is a characteristic dense lymphohistiocytic infiltrate (Figure 2) above which a Grenz zone can be seen.^4,8 There are no well-formed granulomas in lepromatous leprosy, unlike in tuberculoid leprosy, which is paucibacillary and creates a granulomatous response surrounding nerves and adnexal structures.⁶

Mycosis fungoides (MF) is the most common cutaneous lymphoma. There are patch, plaque, and tumor stages of MF, each of which exhibits various histopathologic findings.⁹ In early patch-stage MF, lymphocytes have perinuclear clearing, and the degree of lymphocytic infiltrate is out of proportion to the spongiosis present. Epidermotropism and Pautrier microabscesses often are present in the epidermis (Figure 3). In the plaque stage, there is a denser lymphoid infiltrate in a lichenoid pattern with epidermotropism and Pautrier microabscesses. The tumor stage shows a dense dermal lymphoid infiltrate with more atypia and typically a lack of epidermotropism. Rarely, MF can exhibit a granulomatous variant in which epithelioid histiocytes collect to form granulomas along with atypical lymphocytes.¹⁰

The diagnosis of cutaneous sarcoidosis requires clinicopathologic corroboration. Histopathology demonstrates epithelioid histiocytes forming noncaseating granulomas with little to no lymphocytic infiltrate (Figure 4). There typically is no necrosis or necrobiosis as there is in GA. The diagnosis of sarcoidosis can be challenging histopathologically, and stains should be used to rule out infectious processes.⁴ Asteroid bodies— star-shaped eosinophilic inclusions within giant cells—may be present but are nonspecific for sarcoidosis.¹¹ Schaumann bodies—inclusions of calcifications within giant cells—also may be present and can aid in diagnosis.¹²

The Diagnosis: Granuloma Annulare

The biopsies revealed palisading granulomatous dermatitis consistent with granuloma annulare (GA). This diagnosis was supported by the clinical presentation and histopathologic findings. Although the pathogenesis of GA is unclear, it is a benign, self-limiting condition. Primarily affected sites include the trunk and forearms. Generalized GA (or GA with ≥10 lesions) may warrant workup for malignancy, as it may represent a paraneoplastic process.¹ Histopathology reveals granulomas comprising a dermal lymphohistiocytic infiltrate as well as central mucin and nuclear debris. There are a few histologic subtypes of GA, including palisading and interstitial, which refer to the distribution of the histiocytic infiltrate.^2,3 This case—with palisading histiocytes lining the collection of necrobiosis and mucin (bottom quiz image)—features palisading GA. Notably, GA exhibits central rather than diffuse mucin.⁴

Erythema gyratum repens is a paraneoplastic arcuate erythema that manifests as erythematous figurate, gyrate, or annular plaques exhibiting a trailing scale. Clinically, erythema gyratum repens spreads rapidly—as quickly as 1 cm/d—and can be extensive (as in this case). Histopathology ruled out this diagnosis in our patient. Nonspecific findings of acanthosis, parakeratosis, and superficial spongiosis can be found in erythema gyratum repens. A superficial and deep perivascular lymphohistiocytic infiltrate may be seen in figurate erythemas (Figure 1).⁵ Unlike GA, this infiltrate does not form granulomas, is more superficial, and does not contain mucin.

Histopathology also can help establish the diagnosis of leprosy and its specific subtype, as leprosy exists on a spectrum from tuberculoid to lepromatous, with a great deal of overlap in between.⁶ Lepromatous leprosy has many cutaneous clinical presentations but typically manifests as erythematous papules or nodules. It is multibacillary, and these mycobacteria form clumps known as globi that can be seen on Fite stain.⁷ In lepromatous leprosy, there is a characteristic dense lymphohistiocytic infiltrate (Figure 2) above which a Grenz zone can be seen.^4,8 There are no well-formed granulomas in lepromatous leprosy, unlike in tuberculoid leprosy, which is paucibacillary and creates a granulomatous response surrounding nerves and adnexal structures.⁶

Mycosis fungoides (MF) is the most common cutaneous lymphoma. There are patch, plaque, and tumor stages of MF, each of which exhibits various histopathologic findings.⁹ In early patch-stage MF, lymphocytes have perinuclear clearing, and the degree of lymphocytic infiltrate is out of proportion to the spongiosis present. Epidermotropism and Pautrier microabscesses often are present in the epidermis (Figure 3). In the plaque stage, there is a denser lymphoid infiltrate in a lichenoid pattern with epidermotropism and Pautrier microabscesses. The tumor stage shows a dense dermal lymphoid infiltrate with more atypia and typically a lack of epidermotropism. Rarely, MF can exhibit a granulomatous variant in which epithelioid histiocytes collect to form granulomas along with atypical lymphocytes.¹⁰

The diagnosis of cutaneous sarcoidosis requires clinicopathologic corroboration. Histopathology demonstrates epithelioid histiocytes forming noncaseating granulomas with little to no lymphocytic infiltrate (Figure 4). There typically is no necrosis or necrobiosis as there is in GA. The diagnosis of sarcoidosis can be challenging histopathologically, and stains should be used to rule out infectious processes.⁴ Asteroid bodies— star-shaped eosinophilic inclusions within giant cells—may be present but are nonspecific for sarcoidosis.¹¹ Schaumann bodies—inclusions of calcifications within giant cells—also may be present and can aid in diagnosis.¹²

Psoriasis is a chronic inflammatory skin disease for which several lifestyle factors—smoking, alcohol use, and psychological stress—are associated with higher incidence and more severe disease.^1-3 Diet also has been implicated as a factor that can affect psoriasis,⁴ and many patients have shown interest in possible dietary interventions to help their disease.⁵

In 2018, the National Psoriasis Foundation (NPF) presented dietary recommendations for patients based on results from a systematic review. From the available literature, only dietary weight reduction with hypocaloric diets in overweight or obese patients could be strongly recommended, and it has been proven that obesity is associated with worse psoriasis severity.⁶ Other more recent studies have shown that dietary modifications such as intermittent fasting and the ketogenic diet also led to weight loss and improved psoriasis severity in overweight patients; however, it is difficult to discern if the improvement was due to weight loss alone or if the dietary patterns themselves played a role.^7,8 The paucity of well-designed studies evaluating the effects of other dietary changes has prevented further guidelines from being written. We propose that dietary patterns such as the Mediterranean diet (MeD) and vegan/vegetarian diets—even without strong data showing benefits in skin disease—may help to decrease systemic inflammation, improve gut dysbiosis, and help decrease the risk for cardiometabolic comorbidities that are associated with psoriasis.

Mediterranean Diet

The MeD is based on the dietary tendencies of inhabitants from the regions surrounding the Mediterranean Sea and is centered around nutrient-rich foods such as vegetables, olive oil, and legumes while limiting meat and dairy.⁹ The NPF recommended considering a trial of the MeD based on low-quality evidence.⁶ Observational studies have indicated that psoriasis patients are less likely to adhere to the MeD, but those who do have less severe disease.⁸ However, a search of PubMed articles indexed for MEDLINE using the terms Mediterranean diet and psoriasis yielded no prospective interventional studies. Given the association of the MeD with less severe disease, it is important to understand which specific foods in the MeD could be beneficial. Intake of omega-3 fatty acids, such as those found in fatty fish, are important for modulation of systemic inflammation.⁷ High intake of polyphenols—found in fruits and vegetables, extra-virgin olive oil, and wine—also have been implicated in improving inflammatory diseases due to potent antioxidant and anti-inflammatory properties. Individually, fruits, vegetables, whole grains, and sea fish have been associated with lowering C-reactive protein levels, which also is indicative of the benefits of these foods on systemic inflammation.⁷

Vegan/Vegetarian Diets

Although fruits, vegetables, legumes, and whole grains are a substantial component of the MeD, there are limited data on vegetarian or purely vegan plant-based diets. An observational study from the NPF found that only 48.4% (15/31) of patients on the MeD vs 69.0% (20/29) on a vegan diet reported a favorable skin response.⁵ Two case reports also have shown beneficial results of a strict vegan diet for psoriasis and psoriatic arthritis, where whole-food plant-based diets also improved joint symptoms.^10-12 As with any diet, those who pursue a plant-based diet should strive to consume a variety of foods to avoid nutrient deficiencies. A recent systematic meta-analysis of 141 studies evaluated nutrient status of vegan and vegetarian diets compared to pescovegetarians and those who consume meat. All dietary patterns showed varying degrees of low levels of different nutrients.¹³ Of note, the researchers found that vitamin B₁₂, vitamin D, iron, zinc, iodine, calcium, and docosahexaenoic acid were lower in plant-based diets. In contrast, folate; vitamins B₁, B₆, C, and E; polyunsaturated fatty acids; α-linolenic acid; and magnesium intake were higher. Those who consumed meat were at risk for inadequate intake of fiber, polyunsaturated fatty acids, α-linolenic acid, folate, vitamin E, calcium, magnesium, and vitamin D, though vitamin D intake was higher than in vegans/vegetarians.¹³ The results of this meta-analysis indicated the importance of educating patients on what constitutes a well-rounded, micronutrient-rich diet or appropriate supplementation for any diet.

Effects on Gut Microbiome

Any changes in diet can lead to alterations in the gut microbiome, which may impact skin disease, as evidence indicates a bidirectional relationship between gut and skin health.¹⁰ A metagenomic analysis of the gut microbiota in patients with untreated plaque psoriasis revealed a signature dysbiosis for which the researchers developed a psoriasis microbiota index, suggesting the gut microbiota may play a role in psoriasis pathophysiology.¹⁴ Research shows that both the MeD and vegan/vegetarian diets, which are relatively rich in fiber and omega-3 fatty acids and low in saturated fat and animal protein compared to many diets, cause increases in dietary fiber–metabolizing bacteria that produce short-chain fatty acids. These short-chain fatty acids improve gut epithelial integrity and alleviate both gut and systemic inflammation.¹⁰

The changes to the gut microbiome induced by a high-fat diet also are concerning. In contrast to the MeD or vegan/vegetarian diets, consumption of a high-fat diet induces alterations in the composition of the gut microbiota that in turn increase the release of proinflammatory cytokines and promote higher intestinal permeability.¹⁰ Similarly, high sugar consumption promotes increased intestinal permeability and shifts the gut microbiota to organisms that can rapidly utilize simple carbohydrates at the expense of other beneficial organisms, reducing bacterial diversity.¹⁵ The Western diet, which is notable for both high fat and high sugar content, is sometimes referred to as a proinflammatory diet and has been shown to worsen psoriasiformlike lesions in mice.¹⁶ Importantly, most research indicates that high fat and high sugar consumption appear to be more prevalent in psoriasis patients,⁸ but the type of fat consumed in the diet matters. The Western diet includes abundant saturated fat found in meat, dairy products, palm and coconut oils, and processed foods, as well as omega-6 fatty acids that are found in meat, poultry, and eggs. Saturated fat has been shown to promote helper T cell (T_H17) accumulation in the skin, and omega-6 fatty acids serve as precursors to various inflammatory lipid mediators.⁴ This distinction of sources of fat between the Western diet and MeD is important in understanding the diets’ different effects on psoriasis and overall health. As previously discussed, the high intake of omega-3 acids in the MeD is one of the ways it may exert its anti-inflammatory benefits.⁷

Next Steps in Advising Psoriasis Patients

A major limitation of the data for MeD and vegan/vegetarian diets is limited randomized controlled trials evaluating the impact of these diets on psoriasis. Thus, dietary recommendations for psoriasis are not as strong as for other diseases for which more conclusive data exist.⁸ Although the data on diet and psoriasis are not definitive, perhaps dermatologists should shift the question from “Does this diet definitely improve psoriasis?” to “Does this diet definitely improve my patient’s health as a whole and maybe also their psoriasis?” For instance, the MeD has been shown to reduce the risk for type 2 diabetes mellitus and cardiovascular disease as well as to slow cognitive decline.¹⁷ Vegan/vegetarian diets focusing on whole vs processed foods have been shown to be highly effective in combatting obesity, type 2 diabetes mellitus, coronary artery disease including severe atherosclerosis, and hypertension.¹⁸ Psoriasis patients are at increased risk for many of the ailments that the MeD and plant-based diets protect against, making these diets potentially even more impactful than for someone without psoriasis.¹⁹ Dietary recommendations should still be made in conjunction with continuing traditional therapies for psoriasis and in consultation with the patient’s primary care physician and/or dietitian; however, rather than waiting for more randomized controlled trials before making health-promoting recommendations, what would be the downside of starting now? At worst, the dietary change decreases their risk for several metabolic conditions, and at best they may even see an improvement in their psoriasis.

Psoriasis is a chronic inflammatory skin disease for which several lifestyle factors—smoking, alcohol use, and psychological stress—are associated with higher incidence and more severe disease.^1-3 Diet also has been implicated as a factor that can affect psoriasis,⁴ and many patients have shown interest in possible dietary interventions to help their disease.⁵

In 2018, the National Psoriasis Foundation (NPF) presented dietary recommendations for patients based on results from a systematic review. From the available literature, only dietary weight reduction with hypocaloric diets in overweight or obese patients could be strongly recommended, and it has been proven that obesity is associated with worse psoriasis severity.⁶ Other more recent studies have shown that dietary modifications such as intermittent fasting and the ketogenic diet also led to weight loss and improved psoriasis severity in overweight patients; however, it is difficult to discern if the improvement was due to weight loss alone or if the dietary patterns themselves played a role.^7,8 The paucity of well-designed studies evaluating the effects of other dietary changes has prevented further guidelines from being written. We propose that dietary patterns such as the Mediterranean diet (MeD) and vegan/vegetarian diets—even without strong data showing benefits in skin disease—may help to decrease systemic inflammation, improve gut dysbiosis, and help decrease the risk for cardiometabolic comorbidities that are associated with psoriasis.

Mediterranean Diet

The MeD is based on the dietary tendencies of inhabitants from the regions surrounding the Mediterranean Sea and is centered around nutrient-rich foods such as vegetables, olive oil, and legumes while limiting meat and dairy.⁹ The NPF recommended considering a trial of the MeD based on low-quality evidence.⁶ Observational studies have indicated that psoriasis patients are less likely to adhere to the MeD, but those who do have less severe disease.⁸ However, a search of PubMed articles indexed for MEDLINE using the terms Mediterranean diet and psoriasis yielded no prospective interventional studies. Given the association of the MeD with less severe disease, it is important to understand which specific foods in the MeD could be beneficial. Intake of omega-3 fatty acids, such as those found in fatty fish, are important for modulation of systemic inflammation.⁷ High intake of polyphenols—found in fruits and vegetables, extra-virgin olive oil, and wine—also have been implicated in improving inflammatory diseases due to potent antioxidant and anti-inflammatory properties. Individually, fruits, vegetables, whole grains, and sea fish have been associated with lowering C-reactive protein levels, which also is indicative of the benefits of these foods on systemic inflammation.⁷

Vegan/Vegetarian Diets

Although fruits, vegetables, legumes, and whole grains are a substantial component of the MeD, there are limited data on vegetarian or purely vegan plant-based diets. An observational study from the NPF found that only 48.4% (15/31) of patients on the MeD vs 69.0% (20/29) on a vegan diet reported a favorable skin response.⁵ Two case reports also have shown beneficial results of a strict vegan diet for psoriasis and psoriatic arthritis, where whole-food plant-based diets also improved joint symptoms.^10-12 As with any diet, those who pursue a plant-based diet should strive to consume a variety of foods to avoid nutrient deficiencies. A recent systematic meta-analysis of 141 studies evaluated nutrient status of vegan and vegetarian diets compared to pescovegetarians and those who consume meat. All dietary patterns showed varying degrees of low levels of different nutrients.¹³ Of note, the researchers found that vitamin B₁₂, vitamin D, iron, zinc, iodine, calcium, and docosahexaenoic acid were lower in plant-based diets. In contrast, folate; vitamins B₁, B₆, C, and E; polyunsaturated fatty acids; α-linolenic acid; and magnesium intake were higher. Those who consumed meat were at risk for inadequate intake of fiber, polyunsaturated fatty acids, α-linolenic acid, folate, vitamin E, calcium, magnesium, and vitamin D, though vitamin D intake was higher than in vegans/vegetarians.¹³ The results of this meta-analysis indicated the importance of educating patients on what constitutes a well-rounded, micronutrient-rich diet or appropriate supplementation for any diet.

Effects on Gut Microbiome

Any changes in diet can lead to alterations in the gut microbiome, which may impact skin disease, as evidence indicates a bidirectional relationship between gut and skin health.¹⁰ A metagenomic analysis of the gut microbiota in patients with untreated plaque psoriasis revealed a signature dysbiosis for which the researchers developed a psoriasis microbiota index, suggesting the gut microbiota may play a role in psoriasis pathophysiology.¹⁴ Research shows that both the MeD and vegan/vegetarian diets, which are relatively rich in fiber and omega-3 fatty acids and low in saturated fat and animal protein compared to many diets, cause increases in dietary fiber–metabolizing bacteria that produce short-chain fatty acids. These short-chain fatty acids improve gut epithelial integrity and alleviate both gut and systemic inflammation.¹⁰

The changes to the gut microbiome induced by a high-fat diet also are concerning. In contrast to the MeD or vegan/vegetarian diets, consumption of a high-fat diet induces alterations in the composition of the gut microbiota that in turn increase the release of proinflammatory cytokines and promote higher intestinal permeability.¹⁰ Similarly, high sugar consumption promotes increased intestinal permeability and shifts the gut microbiota to organisms that can rapidly utilize simple carbohydrates at the expense of other beneficial organisms, reducing bacterial diversity.¹⁵ The Western diet, which is notable for both high fat and high sugar content, is sometimes referred to as a proinflammatory diet and has been shown to worsen psoriasiformlike lesions in mice.¹⁶ Importantly, most research indicates that high fat and high sugar consumption appear to be more prevalent in psoriasis patients,⁸ but the type of fat consumed in the diet matters. The Western diet includes abundant saturated fat found in meat, dairy products, palm and coconut oils, and processed foods, as well as omega-6 fatty acids that are found in meat, poultry, and eggs. Saturated fat has been shown to promote helper T cell (T_H17) accumulation in the skin, and omega-6 fatty acids serve as precursors to various inflammatory lipid mediators.⁴ This distinction of sources of fat between the Western diet and MeD is important in understanding the diets’ different effects on psoriasis and overall health. As previously discussed, the high intake of omega-3 acids in the MeD is one of the ways it may exert its anti-inflammatory benefits.⁷

Next Steps in Advising Psoriasis Patients

A major limitation of the data for MeD and vegan/vegetarian diets is limited randomized controlled trials evaluating the impact of these diets on psoriasis. Thus, dietary recommendations for psoriasis are not as strong as for other diseases for which more conclusive data exist.⁸ Although the data on diet and psoriasis are not definitive, perhaps dermatologists should shift the question from “Does this diet definitely improve psoriasis?” to “Does this diet definitely improve my patient’s health as a whole and maybe also their psoriasis?” For instance, the MeD has been shown to reduce the risk for type 2 diabetes mellitus and cardiovascular disease as well as to slow cognitive decline.¹⁷ Vegan/vegetarian diets focusing on whole vs processed foods have been shown to be highly effective in combatting obesity, type 2 diabetes mellitus, coronary artery disease including severe atherosclerosis, and hypertension.¹⁸ Psoriasis patients are at increased risk for many of the ailments that the MeD and plant-based diets protect against, making these diets potentially even more impactful than for someone without psoriasis.¹⁹ Dietary recommendations should still be made in conjunction with continuing traditional therapies for psoriasis and in consultation with the patient’s primary care physician and/or dietitian; however, rather than waiting for more randomized controlled trials before making health-promoting recommendations, what would be the downside of starting now? At worst, the dietary change decreases their risk for several metabolic conditions, and at best they may even see an improvement in their psoriasis.

Psoriasis is a chronic inflammatory skin disease for which several lifestyle factors—smoking, alcohol use, and psychological stress—are associated with higher incidence and more severe disease.^1-3 Diet also has been implicated as a factor that can affect psoriasis,⁴ and many patients have shown interest in possible dietary interventions to help their disease.⁵

In 2018, the National Psoriasis Foundation (NPF) presented dietary recommendations for patients based on results from a systematic review. From the available literature, only dietary weight reduction with hypocaloric diets in overweight or obese patients could be strongly recommended, and it has been proven that obesity is associated with worse psoriasis severity.⁶ Other more recent studies have shown that dietary modifications such as intermittent fasting and the ketogenic diet also led to weight loss and improved psoriasis severity in overweight patients; however, it is difficult to discern if the improvement was due to weight loss alone or if the dietary patterns themselves played a role.^7,8 The paucity of well-designed studies evaluating the effects of other dietary changes has prevented further guidelines from being written. We propose that dietary patterns such as the Mediterranean diet (MeD) and vegan/vegetarian diets—even without strong data showing benefits in skin disease—may help to decrease systemic inflammation, improve gut dysbiosis, and help decrease the risk for cardiometabolic comorbidities that are associated with psoriasis.

Mediterranean Diet

The MeD is based on the dietary tendencies of inhabitants from the regions surrounding the Mediterranean Sea and is centered around nutrient-rich foods such as vegetables, olive oil, and legumes while limiting meat and dairy.⁹ The NPF recommended considering a trial of the MeD based on low-quality evidence.⁶ Observational studies have indicated that psoriasis patients are less likely to adhere to the MeD, but those who do have less severe disease.⁸ However, a search of PubMed articles indexed for MEDLINE using the terms Mediterranean diet and psoriasis yielded no prospective interventional studies. Given the association of the MeD with less severe disease, it is important to understand which specific foods in the MeD could be beneficial. Intake of omega-3 fatty acids, such as those found in fatty fish, are important for modulation of systemic inflammation.⁷ High intake of polyphenols—found in fruits and vegetables, extra-virgin olive oil, and wine—also have been implicated in improving inflammatory diseases due to potent antioxidant and anti-inflammatory properties. Individually, fruits, vegetables, whole grains, and sea fish have been associated with lowering C-reactive protein levels, which also is indicative of the benefits of these foods on systemic inflammation.⁷

Vegan/Vegetarian Diets

Although fruits, vegetables, legumes, and whole grains are a substantial component of the MeD, there are limited data on vegetarian or purely vegan plant-based diets. An observational study from the NPF found that only 48.4% (15/31) of patients on the MeD vs 69.0% (20/29) on a vegan diet reported a favorable skin response.⁵ Two case reports also have shown beneficial results of a strict vegan diet for psoriasis and psoriatic arthritis, where whole-food plant-based diets also improved joint symptoms.^10-12 As with any diet, those who pursue a plant-based diet should strive to consume a variety of foods to avoid nutrient deficiencies. A recent systematic meta-analysis of 141 studies evaluated nutrient status of vegan and vegetarian diets compared to pescovegetarians and those who consume meat. All dietary patterns showed varying degrees of low levels of different nutrients.¹³ Of note, the researchers found that vitamin B₁₂, vitamin D, iron, zinc, iodine, calcium, and docosahexaenoic acid were lower in plant-based diets. In contrast, folate; vitamins B₁, B₆, C, and E; polyunsaturated fatty acids; α-linolenic acid; and magnesium intake were higher. Those who consumed meat were at risk for inadequate intake of fiber, polyunsaturated fatty acids, α-linolenic acid, folate, vitamin E, calcium, magnesium, and vitamin D, though vitamin D intake was higher than in vegans/vegetarians.¹³ The results of this meta-analysis indicated the importance of educating patients on what constitutes a well-rounded, micronutrient-rich diet or appropriate supplementation for any diet.

Effects on Gut Microbiome

Any changes in diet can lead to alterations in the gut microbiome, which may impact skin disease, as evidence indicates a bidirectional relationship between gut and skin health.¹⁰ A metagenomic analysis of the gut microbiota in patients with untreated plaque psoriasis revealed a signature dysbiosis for which the researchers developed a psoriasis microbiota index, suggesting the gut microbiota may play a role in psoriasis pathophysiology.¹⁴ Research shows that both the MeD and vegan/vegetarian diets, which are relatively rich in fiber and omega-3 fatty acids and low in saturated fat and animal protein compared to many diets, cause increases in dietary fiber–metabolizing bacteria that produce short-chain fatty acids. These short-chain fatty acids improve gut epithelial integrity and alleviate both gut and systemic inflammation.¹⁰

The changes to the gut microbiome induced by a high-fat diet also are concerning. In contrast to the MeD or vegan/vegetarian diets, consumption of a high-fat diet induces alterations in the composition of the gut microbiota that in turn increase the release of proinflammatory cytokines and promote higher intestinal permeability.¹⁰ Similarly, high sugar consumption promotes increased intestinal permeability and shifts the gut microbiota to organisms that can rapidly utilize simple carbohydrates at the expense of other beneficial organisms, reducing bacterial diversity.¹⁵ The Western diet, which is notable for both high fat and high sugar content, is sometimes referred to as a proinflammatory diet and has been shown to worsen psoriasiformlike lesions in mice.¹⁶ Importantly, most research indicates that high fat and high sugar consumption appear to be more prevalent in psoriasis patients,⁸ but the type of fat consumed in the diet matters. The Western diet includes abundant saturated fat found in meat, dairy products, palm and coconut oils, and processed foods, as well as omega-6 fatty acids that are found in meat, poultry, and eggs. Saturated fat has been shown to promote helper T cell (T_H17) accumulation in the skin, and omega-6 fatty acids serve as precursors to various inflammatory lipid mediators.⁴ This distinction of sources of fat between the Western diet and MeD is important in understanding the diets’ different effects on psoriasis and overall health. As previously discussed, the high intake of omega-3 acids in the MeD is one of the ways it may exert its anti-inflammatory benefits.⁷

Next Steps in Advising Psoriasis Patients

A major limitation of the data for MeD and vegan/vegetarian diets is limited randomized controlled trials evaluating the impact of these diets on psoriasis. Thus, dietary recommendations for psoriasis are not as strong as for other diseases for which more conclusive data exist.⁸ Although the data on diet and psoriasis are not definitive, perhaps dermatologists should shift the question from “Does this diet definitely improve psoriasis?” to “Does this diet definitely improve my patient’s health as a whole and maybe also their psoriasis?” For instance, the MeD has been shown to reduce the risk for type 2 diabetes mellitus and cardiovascular disease as well as to slow cognitive decline.¹⁷ Vegan/vegetarian diets focusing on whole vs processed foods have been shown to be highly effective in combatting obesity, type 2 diabetes mellitus, coronary artery disease including severe atherosclerosis, and hypertension.¹⁸ Psoriasis patients are at increased risk for many of the ailments that the MeD and plant-based diets protect against, making these diets potentially even more impactful than for someone without psoriasis.¹⁹ Dietary recommendations should still be made in conjunction with continuing traditional therapies for psoriasis and in consultation with the patient’s primary care physician and/or dietitian; however, rather than waiting for more randomized controlled trials before making health-promoting recommendations, what would be the downside of starting now? At worst, the dietary change decreases their risk for several metabolic conditions, and at best they may even see an improvement in their psoriasis.

According to Electronic Residency Application Service (ERAS) statistics, there were more than 1400 dermatology applicants in 2022, with an average of almost 560 applications received per program.^1,2 With the goal to expand the diversity of board-certified dermatologists, there is increasing emphasis on the holistic review of applications, forgoing filtering by discrete metrics such as AOA (American Osteopathic Association) membership and US Medical Licensing Examination (USMLE) scores.³ According to the Association of American Medical Colleges, holistic review focuses on an individual applicant’s experience and unique attributes in addition to their academic achievements.⁴ Recent strategies to enhance the residency recruitment process have included the introduction of standardized letters of recommendation, preference signaling, and supplemental applications.^5,6

Because it has become increasingly important to include applicant factors and achievements that extend beyond academics, the number of data points that are required for holistic review has expanded. If each application required 20 minutes to review, this would result in 166 total hours for complete holistic review of 500 applications. Tools that can facilitate holistic review of candidates and select applicants whose interests and career goals align with individual residency programs have the potential to optimize review. Artificial intelligence (AI) may aid in this process. This column highlights some of the published research on novel AI strategies that have the potential to impact dermatology residency recruitment.

Machine Learning to Screen Applicants

Artificial intelligence involves a machine-based system that can make decisions, predictions, and recommendations when provided a given set of human-defined objectives.⁷ Autonomous systems, machine learning (ML), and generative AI are examples of AI models.⁸ Machine learning has been explored to shorten and streamline the application review process and decrease bias. Because ML is a model in which the computer learns patterns based on large amounts of input data,⁹ it is possible that models could be developed and used in future cycles. Some studies found that applicants were discovered who traditionally would not have made it to the next stage of consideration based primarily on academic metrics.^10,11 Burk-Rafel et al¹⁰ developed and validated an ML-based decision support tool for residency program directors to use for interview invitation decisions. The tool utilized 61 variables from ERAS data from more than 8000 applications in 3 prior application cycles at a single internal medicine residency program. An interview invitation was designated as the target outcome. Ultimately, the model would output a probability score for an interview invitation. The authors were able to tune the model to a 91% sensitivity and 85% specificity; for a pool of 2000 applicants and an invite rate of 15%, 1475 applicants would be screened out with a negative predictive value of 98% with maintenance of performance, even with removal of USMLE Step 1 examination scores. Their ML model was prospectively validated during an ongoing resident selection cycle, and when compared with human review, the AI model found an additional 20 applicants to invite for interviews. They concluded that this tool could potentially augment the human review process and reveal applicants who may have otherwise been overlooked.¹⁰

Rees and Ryder¹¹ utilized another ML screening approach with the target outcome of ranked and matriculated compared with ranked applicants based on ERAS data using 72 unique variables for more than 5000 applicants. Their model was able to identify ranked candidates from the overall applicant pool with high accuracy; identification of ranked applicants that matriculated at the program was more modest but better than random probability.¹¹Both the Burk-Rafel et al¹⁰ and Rees and Ryder¹¹ models excluded some unstructured data components of the residency application, such as personal statements, medical student performance evaluation letters, transcripts, and letters of reference, that some may consider strongly in the holistic review process. Drum et al¹² explored the value of extraction of this type of data. They created a program to extract “snippets” of text that pertained to values of successful residents for their internal medicine–pediatrics residency program that they previously validated via a modified Delphi method, which then were annotated by expert reviewers. Natural language processing was used to train an ML algorithm (MLA) to classify snippets into 11 value categories. Four values had more than 66% agreement with human annotation: academic strength; leadership; communication; and justice, equity, diversity, and inclusion. Although this MLA has not reached high enough levels of agreement for all the predetermined success values, the authors hope to generate a model that could produce a quantitative score to use as an initial screening tool to select applicants for interview.¹² This type of analysis also could be incorporated into other MLAs for further refinement of the mentoring and application process.

Knapke et al¹³ evaluated the use of a natural language modeling platform to look for semantic patterns in medical school applications that could predict which students would be more likely to pursue family medicine residency, thus beginning the recruitment process even before residency application. This strategy could be particularly valuable for specialties for which there may be greater need in the workforce.

AI for Administrative Purposes

Artificial intelligence also has been used for nonapplication aspects of the residency recruitment process, such as interview scheduling. In the absence of coordinated interview release dates (as was implemented in dermatology starting in the 2020-2021 application cycle), a deluge of responses to schedule an interview comes flooding in as soon as invitations for interviewees are sent out, which can produce anxiety both for applicants and residency program staff as the schedule is sorted out and can create delays at both ends. Stephens et al¹⁴ utilized a computerized scheduling program for pediatric surgery fellowship applicants. It was used in 2016 to schedule 26 interviews, and it was found to reduce the average time to schedule an interview from 14.4 hours to 1.7 hours. It also reduced the number of email exchanges needed to finalize scheduling.¹⁴

Another aspect of residency recruitment that is amenable to AI is information gathering. Many would-be applicants turn to the internet and social media to learn about residency programs—their unique qualities, assets, and potential alignment of career goals.¹⁵ This exchange often is unidirectional, as the applicant clicks through the website searching for information. Yi et al¹⁶ explored the use of a chatbot, which mimics human conversation and exchange, on their institution’s pain fellowship website. Fellowship applicants could create specific prompts, such as “Show me faculty that trained at <applicant’s home program>,” and the chatbot would reply with the answer. The researchers sent a survey to all 258 applicants to the pain fellowship program that was completed by 48 applicants. Of these respondents, more than 70% (35/48) utilized the chatbot, and 84% (40/48) stated that they had found the information that was requested. The respondents overall found the chatbot to be a useful and positive experience.¹⁶

Specific Tools to Consider

There are some tools that are publicly available for programs and applicants to use that rely on AI.

In collaboration with ERAS and the Association of American Medical Colleges, Cortex powered by Thalamus (SJ MedConnect Inc)(https://thalamusgme.com/cortex-application-screening/) offers technology-assisted holistic review of residency and fellowship applications by utilizing natural language processing and optical character recognition to aggregate data from ERAS.

Tools also are being leveraged by applicants to help them find residency programs that fit their criteria, prepare for interviews, and complete portions of the application. Match A Resident (https://www.matcharesident.com/) is a resource for the international medical graduate community. As part of the service, the “Learn More with MARai” feature uses AI to generate information on residency programs to increase applicants’ confidence going into the interview process.¹⁷ Big Interview Medical (https://www.biginterviewmedical.com/ai-feedback), a paid interview preparation system developed by interview experts, utilizes AI to provide feedback to residents practicing for the interview process by measuring the amount of natural eye contact, language used, and pace of speech. A “Power Word” score is provided that incorporates aspects such as using filler words (“umm,” “uhh”). A Pace of Speech Tool provides rate of speaking feedback presuming that there is an ideal pace to decrease the impression that the applicant is nervous. Johnstone et al¹⁸ used ChatGPT (https://chat.openai.com/auth/login) to generate 2 personal statements for anesthesia residency applicants. Based on survey responses from 31 program directors, 22 rated the statements as good or excellent.¹⁸

Ethnical Concerns and Limitations of AI

The potential use of AI tools by residency applicants inevitably brings forth consideration of biases, ethics, and current limitations. These tools are highly dependent on the quality and quantity of data used for training and validation. Information considered valuable in the holistic review of applications includes unstructured data such as personal statements and letters of recommendation, and incorporating this information can be challenging in ML models, in contrast to discrete structured data such as grades, test scores, and awards. In addition, MLAs depend on large quantities of data to optimize performance.¹⁹ Depending on the size of the applicant pool and the amount of data available, this can present a limitation for smaller programs in developing ML tools for residency recruitment. Studies evaluating the use of AI in the residency application process often are from single institutions, and therefore generalizability is uncertain. The risk for latent bias—whereby a historical or pre-existing stereotype gets perpetuated through the system—must be considered, with the development of tools to detect and address this if found. Choosing which data to use to train the model can be tricky as well as choosing the outcome of interest. For these interventions to become more resilient, programs need to self-examine what defines their criteria for a successful match to their program to incorporate this data into their ML studies. The previously described models in this overview focused on outcomes such as whether an applicant was invited to interview, whether the applicant was ranked, and whether the applicant matriculated to their program.^10,11 For supervised ML models that rely on outcomes to develop a prediction, continued research as to what outcomes represent resident success (eg, passing board certification examinations, correlation with clinical performance) would be important. There also is the possibility of applicants restructuring their applications to align with goals of an AI-assisted search and using AI to generate part or all of their application. The use of ChatGPT and other AI tools in the preparation of personal statements and curriculum vitae may provide benefits such as improved efficiency and grammar support.²⁰ However, as use becomes more widespread, there is the potential increased similarity of personal statements and likely varied opinions on the use of such tools as writing aids.^21,22 Continued efforts to develop guidance on generative AI use cases is ongoing; an example is the launch of VALID AI (https://validai.health/), a collaboration among health systems, health plans, and AI research organizations and nonprofits.²³

Final Thoughts

Artificial intelligence tools may be a promising resource for residency and fellowship programs seeking to find meaningful ways to select applicants who are good matches for their training environment. Prioritizing the holistic review of applications has been promoted as a method to evaluate the applicant beyond their test scores and grades. The use of MLAs may streamline this review process, aid in scheduling interviews, and help discover trends in successful matriculants.

According to Electronic Residency Application Service (ERAS) statistics, there were more than 1400 dermatology applicants in 2022, with an average of almost 560 applications received per program.^1,2 With the goal to expand the diversity of board-certified dermatologists, there is increasing emphasis on the holistic review of applications, forgoing filtering by discrete metrics such as AOA (American Osteopathic Association) membership and US Medical Licensing Examination (USMLE) scores.³ According to the Association of American Medical Colleges, holistic review focuses on an individual applicant’s experience and unique attributes in addition to their academic achievements.⁴ Recent strategies to enhance the residency recruitment process have included the introduction of standardized letters of recommendation, preference signaling, and supplemental applications.^5,6

Because it has become increasingly important to include applicant factors and achievements that extend beyond academics, the number of data points that are required for holistic review has expanded. If each application required 20 minutes to review, this would result in 166 total hours for complete holistic review of 500 applications. Tools that can facilitate holistic review of candidates and select applicants whose interests and career goals align with individual residency programs have the potential to optimize review. Artificial intelligence (AI) may aid in this process. This column highlights some of the published research on novel AI strategies that have the potential to impact dermatology residency recruitment.

Machine Learning to Screen Applicants

Artificial intelligence involves a machine-based system that can make decisions, predictions, and recommendations when provided a given set of human-defined objectives.⁷ Autonomous systems, machine learning (ML), and generative AI are examples of AI models.⁸ Machine learning has been explored to shorten and streamline the application review process and decrease bias. Because ML is a model in which the computer learns patterns based on large amounts of input data,⁹ it is possible that models could be developed and used in future cycles. Some studies found that applicants were discovered who traditionally would not have made it to the next stage of consideration based primarily on academic metrics.^10,11 Burk-Rafel et al¹⁰ developed and validated an ML-based decision support tool for residency program directors to use for interview invitation decisions. The tool utilized 61 variables from ERAS data from more than 8000 applications in 3 prior application cycles at a single internal medicine residency program. An interview invitation was designated as the target outcome. Ultimately, the model would output a probability score for an interview invitation. The authors were able to tune the model to a 91% sensitivity and 85% specificity; for a pool of 2000 applicants and an invite rate of 15%, 1475 applicants would be screened out with a negative predictive value of 98% with maintenance of performance, even with removal of USMLE Step 1 examination scores. Their ML model was prospectively validated during an ongoing resident selection cycle, and when compared with human review, the AI model found an additional 20 applicants to invite for interviews. They concluded that this tool could potentially augment the human review process and reveal applicants who may have otherwise been overlooked.¹⁰

Rees and Ryder¹¹ utilized another ML screening approach with the target outcome of ranked and matriculated compared with ranked applicants based on ERAS data using 72 unique variables for more than 5000 applicants. Their model was able to identify ranked candidates from the overall applicant pool with high accuracy; identification of ranked applicants that matriculated at the program was more modest but better than random probability.¹¹Both the Burk-Rafel et al¹⁰ and Rees and Ryder¹¹ models excluded some unstructured data components of the residency application, such as personal statements, medical student performance evaluation letters, transcripts, and letters of reference, that some may consider strongly in the holistic review process. Drum et al¹² explored the value of extraction of this type of data. They created a program to extract “snippets” of text that pertained to values of successful residents for their internal medicine–pediatrics residency program that they previously validated via a modified Delphi method, which then were annotated by expert reviewers. Natural language processing was used to train an ML algorithm (MLA) to classify snippets into 11 value categories. Four values had more than 66% agreement with human annotation: academic strength; leadership; communication; and justice, equity, diversity, and inclusion. Although this MLA has not reached high enough levels of agreement for all the predetermined success values, the authors hope to generate a model that could produce a quantitative score to use as an initial screening tool to select applicants for interview.¹² This type of analysis also could be incorporated into other MLAs for further refinement of the mentoring and application process.

Knapke et al¹³ evaluated the use of a natural language modeling platform to look for semantic patterns in medical school applications that could predict which students would be more likely to pursue family medicine residency, thus beginning the recruitment process even before residency application. This strategy could be particularly valuable for specialties for which there may be greater need in the workforce.

AI for Administrative Purposes

Artificial intelligence also has been used for nonapplication aspects of the residency recruitment process, such as interview scheduling. In the absence of coordinated interview release dates (as was implemented in dermatology starting in the 2020-2021 application cycle), a deluge of responses to schedule an interview comes flooding in as soon as invitations for interviewees are sent out, which can produce anxiety both for applicants and residency program staff as the schedule is sorted out and can create delays at both ends. Stephens et al¹⁴ utilized a computerized scheduling program for pediatric surgery fellowship applicants. It was used in 2016 to schedule 26 interviews, and it was found to reduce the average time to schedule an interview from 14.4 hours to 1.7 hours. It also reduced the number of email exchanges needed to finalize scheduling.¹⁴

Another aspect of residency recruitment that is amenable to AI is information gathering. Many would-be applicants turn to the internet and social media to learn about residency programs—their unique qualities, assets, and potential alignment of career goals.¹⁵ This exchange often is unidirectional, as the applicant clicks through the website searching for information. Yi et al¹⁶ explored the use of a chatbot, which mimics human conversation and exchange, on their institution’s pain fellowship website. Fellowship applicants could create specific prompts, such as “Show me faculty that trained at <applicant’s home program>,” and the chatbot would reply with the answer. The researchers sent a survey to all 258 applicants to the pain fellowship program that was completed by 48 applicants. Of these respondents, more than 70% (35/48) utilized the chatbot, and 84% (40/48) stated that they had found the information that was requested. The respondents overall found the chatbot to be a useful and positive experience.¹⁶

Specific Tools to Consider

There are some tools that are publicly available for programs and applicants to use that rely on AI.

In collaboration with ERAS and the Association of American Medical Colleges, Cortex powered by Thalamus (SJ MedConnect Inc)(https://thalamusgme.com/cortex-application-screening/) offers technology-assisted holistic review of residency and fellowship applications by utilizing natural language processing and optical character recognition to aggregate data from ERAS.

Tools also are being leveraged by applicants to help them find residency programs that fit their criteria, prepare for interviews, and complete portions of the application. Match A Resident (https://www.matcharesident.com/) is a resource for the international medical graduate community. As part of the service, the “Learn More with MARai” feature uses AI to generate information on residency programs to increase applicants’ confidence going into the interview process.¹⁷ Big Interview Medical (https://www.biginterviewmedical.com/ai-feedback), a paid interview preparation system developed by interview experts, utilizes AI to provide feedback to residents practicing for the interview process by measuring the amount of natural eye contact, language used, and pace of speech. A “Power Word” score is provided that incorporates aspects such as using filler words (“umm,” “uhh”). A Pace of Speech Tool provides rate of speaking feedback presuming that there is an ideal pace to decrease the impression that the applicant is nervous. Johnstone et al¹⁸ used ChatGPT (https://chat.openai.com/auth/login) to generate 2 personal statements for anesthesia residency applicants. Based on survey responses from 31 program directors, 22 rated the statements as good or excellent.¹⁸

Ethnical Concerns and Limitations of AI

The potential use of AI tools by residency applicants inevitably brings forth consideration of biases, ethics, and current limitations. These tools are highly dependent on the quality and quantity of data used for training and validation. Information considered valuable in the holistic review of applications includes unstructured data such as personal statements and letters of recommendation, and incorporating this information can be challenging in ML models, in contrast to discrete structured data such as grades, test scores, and awards. In addition, MLAs depend on large quantities of data to optimize performance.¹⁹ Depending on the size of the applicant pool and the amount of data available, this can present a limitation for smaller programs in developing ML tools for residency recruitment. Studies evaluating the use of AI in the residency application process often are from single institutions, and therefore generalizability is uncertain. The risk for latent bias—whereby a historical or pre-existing stereotype gets perpetuated through the system—must be considered, with the development of tools to detect and address this if found. Choosing which data to use to train the model can be tricky as well as choosing the outcome of interest. For these interventions to become more resilient, programs need to self-examine what defines their criteria for a successful match to their program to incorporate this data into their ML studies. The previously described models in this overview focused on outcomes such as whether an applicant was invited to interview, whether the applicant was ranked, and whether the applicant matriculated to their program.^10,11 For supervised ML models that rely on outcomes to develop a prediction, continued research as to what outcomes represent resident success (eg, passing board certification examinations, correlation with clinical performance) would be important. There also is the possibility of applicants restructuring their applications to align with goals of an AI-assisted search and using AI to generate part or all of their application. The use of ChatGPT and other AI tools in the preparation of personal statements and curriculum vitae may provide benefits such as improved efficiency and grammar support.²⁰ However, as use becomes more widespread, there is the potential increased similarity of personal statements and likely varied opinions on the use of such tools as writing aids.^21,22 Continued efforts to develop guidance on generative AI use cases is ongoing; an example is the launch of VALID AI (https://validai.health/), a collaboration among health systems, health plans, and AI research organizations and nonprofits.²³

Final Thoughts

Artificial intelligence tools may be a promising resource for residency and fellowship programs seeking to find meaningful ways to select applicants who are good matches for their training environment. Prioritizing the holistic review of applications has been promoted as a method to evaluate the applicant beyond their test scores and grades. The use of MLAs may streamline this review process, aid in scheduling interviews, and help discover trends in successful matriculants.

According to Electronic Residency Application Service (ERAS) statistics, there were more than 1400 dermatology applicants in 2022, with an average of almost 560 applications received per program.^1,2 With the goal to expand the diversity of board-certified dermatologists, there is increasing emphasis on the holistic review of applications, forgoing filtering by discrete metrics such as AOA (American Osteopathic Association) membership and US Medical Licensing Examination (USMLE) scores.³ According to the Association of American Medical Colleges, holistic review focuses on an individual applicant’s experience and unique attributes in addition to their academic achievements.⁴ Recent strategies to enhance the residency recruitment process have included the introduction of standardized letters of recommendation, preference signaling, and supplemental applications.^5,6

Because it has become increasingly important to include applicant factors and achievements that extend beyond academics, the number of data points that are required for holistic review has expanded. If each application required 20 minutes to review, this would result in 166 total hours for complete holistic review of 500 applications. Tools that can facilitate holistic review of candidates and select applicants whose interests and career goals align with individual residency programs have the potential to optimize review. Artificial intelligence (AI) may aid in this process. This column highlights some of the published research on novel AI strategies that have the potential to impact dermatology residency recruitment.

Machine Learning to Screen Applicants

Artificial intelligence involves a machine-based system that can make decisions, predictions, and recommendations when provided a given set of human-defined objectives.⁷ Autonomous systems, machine learning (ML), and generative AI are examples of AI models.⁸ Machine learning has been explored to shorten and streamline the application review process and decrease bias. Because ML is a model in which the computer learns patterns based on large amounts of input data,⁹ it is possible that models could be developed and used in future cycles. Some studies found that applicants were discovered who traditionally would not have made it to the next stage of consideration based primarily on academic metrics.^10,11 Burk-Rafel et al¹⁰ developed and validated an ML-based decision support tool for residency program directors to use for interview invitation decisions. The tool utilized 61 variables from ERAS data from more than 8000 applications in 3 prior application cycles at a single internal medicine residency program. An interview invitation was designated as the target outcome. Ultimately, the model would output a probability score for an interview invitation. The authors were able to tune the model to a 91% sensitivity and 85% specificity; for a pool of 2000 applicants and an invite rate of 15%, 1475 applicants would be screened out with a negative predictive value of 98% with maintenance of performance, even with removal of USMLE Step 1 examination scores. Their ML model was prospectively validated during an ongoing resident selection cycle, and when compared with human review, the AI model found an additional 20 applicants to invite for interviews. They concluded that this tool could potentially augment the human review process and reveal applicants who may have otherwise been overlooked.¹⁰

Rees and Ryder¹¹ utilized another ML screening approach with the target outcome of ranked and matriculated compared with ranked applicants based on ERAS data using 72 unique variables for more than 5000 applicants. Their model was able to identify ranked candidates from the overall applicant pool with high accuracy; identification of ranked applicants that matriculated at the program was more modest but better than random probability.¹¹Both the Burk-Rafel et al¹⁰ and Rees and Ryder¹¹ models excluded some unstructured data components of the residency application, such as personal statements, medical student performance evaluation letters, transcripts, and letters of reference, that some may consider strongly in the holistic review process. Drum et al¹² explored the value of extraction of this type of data. They created a program to extract “snippets” of text that pertained to values of successful residents for their internal medicine–pediatrics residency program that they previously validated via a modified Delphi method, which then were annotated by expert reviewers. Natural language processing was used to train an ML algorithm (MLA) to classify snippets into 11 value categories. Four values had more than 66% agreement with human annotation: academic strength; leadership; communication; and justice, equity, diversity, and inclusion. Although this MLA has not reached high enough levels of agreement for all the predetermined success values, the authors hope to generate a model that could produce a quantitative score to use as an initial screening tool to select applicants for interview.¹² This type of analysis also could be incorporated into other MLAs for further refinement of the mentoring and application process.

Knapke et al¹³ evaluated the use of a natural language modeling platform to look for semantic patterns in medical school applications that could predict which students would be more likely to pursue family medicine residency, thus beginning the recruitment process even before residency application. This strategy could be particularly valuable for specialties for which there may be greater need in the workforce.

AI for Administrative Purposes

Artificial intelligence also has been used for nonapplication aspects of the residency recruitment process, such as interview scheduling. In the absence of coordinated interview release dates (as was implemented in dermatology starting in the 2020-2021 application cycle), a deluge of responses to schedule an interview comes flooding in as soon as invitations for interviewees are sent out, which can produce anxiety both for applicants and residency program staff as the schedule is sorted out and can create delays at both ends. Stephens et al¹⁴ utilized a computerized scheduling program for pediatric surgery fellowship applicants. It was used in 2016 to schedule 26 interviews, and it was found to reduce the average time to schedule an interview from 14.4 hours to 1.7 hours. It also reduced the number of email exchanges needed to finalize scheduling.¹⁴

Another aspect of residency recruitment that is amenable to AI is information gathering. Many would-be applicants turn to the internet and social media to learn about residency programs—their unique qualities, assets, and potential alignment of career goals.¹⁵ This exchange often is unidirectional, as the applicant clicks through the website searching for information. Yi et al¹⁶ explored the use of a chatbot, which mimics human conversation and exchange, on their institution’s pain fellowship website. Fellowship applicants could create specific prompts, such as “Show me faculty that trained at <applicant’s home program>,” and the chatbot would reply with the answer. The researchers sent a survey to all 258 applicants to the pain fellowship program that was completed by 48 applicants. Of these respondents, more than 70% (35/48) utilized the chatbot, and 84% (40/48) stated that they had found the information that was requested. The respondents overall found the chatbot to be a useful and positive experience.¹⁶

Specific Tools to Consider

There are some tools that are publicly available for programs and applicants to use that rely on AI.

In collaboration with ERAS and the Association of American Medical Colleges, Cortex powered by Thalamus (SJ MedConnect Inc)(https://thalamusgme.com/cortex-application-screening/) offers technology-assisted holistic review of residency and fellowship applications by utilizing natural language processing and optical character recognition to aggregate data from ERAS.

Tools also are being leveraged by applicants to help them find residency programs that fit their criteria, prepare for interviews, and complete portions of the application. Match A Resident (https://www.matcharesident.com/) is a resource for the international medical graduate community. As part of the service, the “Learn More with MARai” feature uses AI to generate information on residency programs to increase applicants’ confidence going into the interview process.¹⁷ Big Interview Medical (https://www.biginterviewmedical.com/ai-feedback), a paid interview preparation system developed by interview experts, utilizes AI to provide feedback to residents practicing for the interview process by measuring the amount of natural eye contact, language used, and pace of speech. A “Power Word” score is provided that incorporates aspects such as using filler words (“umm,” “uhh”). A Pace of Speech Tool provides rate of speaking feedback presuming that there is an ideal pace to decrease the impression that the applicant is nervous. Johnstone et al¹⁸ used ChatGPT (https://chat.openai.com/auth/login) to generate 2 personal statements for anesthesia residency applicants. Based on survey responses from 31 program directors, 22 rated the statements as good or excellent.¹⁸

Ethnical Concerns and Limitations of AI

The potential use of AI tools by residency applicants inevitably brings forth consideration of biases, ethics, and current limitations. These tools are highly dependent on the quality and quantity of data used for training and validation. Information considered valuable in the holistic review of applications includes unstructured data such as personal statements and letters of recommendation, and incorporating this information can be challenging in ML models, in contrast to discrete structured data such as grades, test scores, and awards. In addition, MLAs depend on large quantities of data to optimize performance.¹⁹ Depending on the size of the applicant pool and the amount of data available, this can present a limitation for smaller programs in developing ML tools for residency recruitment. Studies evaluating the use of AI in the residency application process often are from single institutions, and therefore generalizability is uncertain. The risk for latent bias—whereby a historical or pre-existing stereotype gets perpetuated through the system—must be considered, with the development of tools to detect and address this if found. Choosing which data to use to train the model can be tricky as well as choosing the outcome of interest. For these interventions to become more resilient, programs need to self-examine what defines their criteria for a successful match to their program to incorporate this data into their ML studies. The previously described models in this overview focused on outcomes such as whether an applicant was invited to interview, whether the applicant was ranked, and whether the applicant matriculated to their program.^10,11 For supervised ML models that rely on outcomes to develop a prediction, continued research as to what outcomes represent resident success (eg, passing board certification examinations, correlation with clinical performance) would be important. There also is the possibility of applicants restructuring their applications to align with goals of an AI-assisted search and using AI to generate part or all of their application. The use of ChatGPT and other AI tools in the preparation of personal statements and curriculum vitae may provide benefits such as improved efficiency and grammar support.²⁰ However, as use becomes more widespread, there is the potential increased similarity of personal statements and likely varied opinions on the use of such tools as writing aids.^21,22 Continued efforts to develop guidance on generative AI use cases is ongoing; an example is the launch of VALID AI (https://validai.health/), a collaboration among health systems, health plans, and AI research organizations and nonprofits.²³

Final Thoughts

Artificial intelligence tools may be a promising resource for residency and fellowship programs seeking to find meaningful ways to select applicants who are good matches for their training environment. Prioritizing the holistic review of applications has been promoted as a method to evaluate the applicant beyond their test scores and grades. The use of MLAs may streamline this review process, aid in scheduling interviews, and help discover trends in successful matriculants.

Psoriasis is a chronic autoimmune skin condition that affects approximately 2% to 4% of the US population and notably impacts overall quality of life.^1,2 There is no cure for this long-lasting condition. Fortunately, recent developments in research have led to more targeted therapies, paving the way for a more promising transformative landscape of psoriasis management. Herein, we explore the most up-to-date advancements and developments in the realm of psoriasis care.

Emerging Systemic Therapies

Biologics are cutting-edge treatments available for moderate to severe plaque psoriasis, as IL-17A, IL-23, and tumor necrosis factor α (TNF-α) have been recognized as key targets.³

IL-17—Bimekizumab is a unique monoclonal antibody that inhibits the activity of both IL-17A and IL-17F cytokines.³ This treatment was approved by the US Food and Drug Administration (FDA) in October 2023 for patients with moderate to severe plaque psoriasis who are candidates for systemic therapy or phototherapy.⁴

Bimekizumab outperformed ustekinumab in the BE VIVID phase 3 trial, with 273 of 321 patients (85%) receiving bimekizumab vs 81 of 163 patients (50%) receiving ustekinumab experiencing at least 90% improvement in psoriasis area and severity index (PASI) score at week 16.⁴ In a 2020 observational study (PSO-BIO-REAL), the efficacy rate of skin clearance after 6 months of treatment with biologics was only 25% (1/4).⁵ Aside from moderate to severe plaque psoriasis, bimekizumab demonstrated notable improvement in patients with psoriatic arthritis who had inadequate response or intolerance to TNF-α inhibitors compared to a placebo group in the BE COMPLETE phase 3 trial.⁶

IL-23—Guselkumab, risankizumab, and tildrakizumab are injectable therapies approved by the FDA in 2017 for moderate to severe plaque psoriasis.³ They inhibit IL-23 signaling by targeting the p19 subunit in addition to sparing IL-12.^3,7

A novel oral therapeutic peptide, JNJ-2113—the first oral IL-23 receptor antagonist peptide that blocks IL-23 signaling—has been developed, offering a new way to treat moderate to severe plaque psoriasis. Trial results from a phase 2 study (FRONTIER1) have supported JNJ-2113’s advancement into phase 3.^7,8 Patients who received JNJ-2113 successfully achieved PASI75 in addition to surpassing PASI90 and PASI100 at greater proportions compared to placebo at week 16.⁷

The promising early results of JNJ-2113 provide patients with greater flexibility and convenience for treatment options to address the manifestations of psoriasis. Although a considerable number of patients with moderate to severe plaque psoriasis qualify for advanced therapies, a substantial proportion remain untreated. Introducing an oral route of medication administration may help overcome barriers to therapy access due to a greater preference for pills over injections.⁹

TNF-α Inhibitors—Adalimumab is a TNF-α inhibitor that is used to treat moderate to severe chronic plaque psoriasis in adults who are candidates for systemic phototherapy.^1,10 However, one of the main barriers to initiating treatment has been cost. Biosimilars contribute to market competition, thus allowing the possibility of lower drug prices.¹⁰

There are 9 FDA-approved biosimilar products for adalimumab, with 2 having interchangeable designation. The first interchangeable biosimilar to enter the US market, adalimumab-adbm, became available in July 2023. In October 2023, adalimumab-afzb was granted interchangeable designation,¹¹ which enables pharmacists to swiftly substitute brand products for lower-cost biosimilars, providing patients with equally safe and effective alternatives without the delay of involving the prescribing clinician.¹² Pricing information indicates an initial 5% discount, which may later increase to 60%, from brand name adalimumab. Hopefully, reduced drug costs due to market competition will allow more patients to overcome barriers to therapy access.

IL-12/IL-23—Ustekinumab is a monoclonal antibody that targets IL-12 and IL-23. The FDA recently approved ustekinumab-auub as the first interchangeable ustekinumab biosimilar for the treatment of various inflammatory diseases, including moderate to severe plaque psoriasis and psoriatic arthritis.^12,13 The approval of ustekinumab-auub expands therapeutic options for the treatment of diverse inflammatory diseases. As the first interchangeable biosimilar in its category, this development underscores the importance of biosimilars in providing effective and accessible treatment.^12,14

Topical Innovations

In October 2023, the FDA approved an expanded indication for roflumilast cream 0.3% to treat children as young as 6 years for plaque psoriasis, even for use in intertriginous areas,¹⁵ which is a milestone given the lack of treatment options for the pediatric population because topical steroids, the most common treatment option for plaque psoriasis, can have safety concerns related to long-term use. With the advent of this steroid-free topical agent, pediatric patients have a safe and well-tolerated option for managing plaque psoriasis.¹⁶ This promising effort will now expand to trials in children as young as 2 years to test efficacy.¹⁶

Engel et al¹⁷ proposed a new algorithmic approach to the topical management of psoriasis with roflumilast cream and tapinarof cream as first-line treatments for mild disease due to their novelty in treating intertriginous areas, whereas traditional topical steroids in these areas would be inapt.¹⁷ The latest indication for roflumilast cream suggests that this proposed recommendation could be a promising and convenient enhancement to psoriasis management, potentially outperforming traditional topical corticosteroids.^15,17

Final Thoughts

Innovative targeted therapies ranging from new biologic agents to broader applications of topical treatments hold the potential to transform conventional psoriasis management with greater efficacy and safety, which can help create a more effective and personalized approach with greater patient satisfaction, ultimately enhancing overall quality of life. The choice of treatment is dependent not only on the severity of the disease but also on accessibility considerations such as cost. Overall, these innovative therapies add substantial value to the treatment armamentarium for psoriasis.

Psoriasis is a chronic autoimmune skin condition that affects approximately 2% to 4% of the US population and notably impacts overall quality of life.^1,2 There is no cure for this long-lasting condition. Fortunately, recent developments in research have led to more targeted therapies, paving the way for a more promising transformative landscape of psoriasis management. Herein, we explore the most up-to-date advancements and developments in the realm of psoriasis care.

Emerging Systemic Therapies

Biologics are cutting-edge treatments available for moderate to severe plaque psoriasis, as IL-17A, IL-23, and tumor necrosis factor α (TNF-α) have been recognized as key targets.³

IL-17—Bimekizumab is a unique monoclonal antibody that inhibits the activity of both IL-17A and IL-17F cytokines.³ This treatment was approved by the US Food and Drug Administration (FDA) in October 2023 for patients with moderate to severe plaque psoriasis who are candidates for systemic therapy or phototherapy.⁴

Bimekizumab outperformed ustekinumab in the BE VIVID phase 3 trial, with 273 of 321 patients (85%) receiving bimekizumab vs 81 of 163 patients (50%) receiving ustekinumab experiencing at least 90% improvement in psoriasis area and severity index (PASI) score at week 16.⁴ In a 2020 observational study (PSO-BIO-REAL), the efficacy rate of skin clearance after 6 months of treatment with biologics was only 25% (1/4).⁵ Aside from moderate to severe plaque psoriasis, bimekizumab demonstrated notable improvement in patients with psoriatic arthritis who had inadequate response or intolerance to TNF-α inhibitors compared to a placebo group in the BE COMPLETE phase 3 trial.⁶

IL-23—Guselkumab, risankizumab, and tildrakizumab are injectable therapies approved by the FDA in 2017 for moderate to severe plaque psoriasis.³ They inhibit IL-23 signaling by targeting the p19 subunit in addition to sparing IL-12.^3,7

A novel oral therapeutic peptide, JNJ-2113—the first oral IL-23 receptor antagonist peptide that blocks IL-23 signaling—has been developed, offering a new way to treat moderate to severe plaque psoriasis. Trial results from a phase 2 study (FRONTIER1) have supported JNJ-2113’s advancement into phase 3.^7,8 Patients who received JNJ-2113 successfully achieved PASI75 in addition to surpassing PASI90 and PASI100 at greater proportions compared to placebo at week 16.⁷

The promising early results of JNJ-2113 provide patients with greater flexibility and convenience for treatment options to address the manifestations of psoriasis. Although a considerable number of patients with moderate to severe plaque psoriasis qualify for advanced therapies, a substantial proportion remain untreated. Introducing an oral route of medication administration may help overcome barriers to therapy access due to a greater preference for pills over injections.⁹

TNF-α Inhibitors—Adalimumab is a TNF-α inhibitor that is used to treat moderate to severe chronic plaque psoriasis in adults who are candidates for systemic phototherapy.^1,10 However, one of the main barriers to initiating treatment has been cost. Biosimilars contribute to market competition, thus allowing the possibility of lower drug prices.¹⁰

There are 9 FDA-approved biosimilar products for adalimumab, with 2 having interchangeable designation. The first interchangeable biosimilar to enter the US market, adalimumab-adbm, became available in July 2023. In October 2023, adalimumab-afzb was granted interchangeable designation,¹¹ which enables pharmacists to swiftly substitute brand products for lower-cost biosimilars, providing patients with equally safe and effective alternatives without the delay of involving the prescribing clinician.¹² Pricing information indicates an initial 5% discount, which may later increase to 60%, from brand name adalimumab. Hopefully, reduced drug costs due to market competition will allow more patients to overcome barriers to therapy access.

IL-12/IL-23—Ustekinumab is a monoclonal antibody that targets IL-12 and IL-23. The FDA recently approved ustekinumab-auub as the first interchangeable ustekinumab biosimilar for the treatment of various inflammatory diseases, including moderate to severe plaque psoriasis and psoriatic arthritis.^12,13 The approval of ustekinumab-auub expands therapeutic options for the treatment of diverse inflammatory diseases. As the first interchangeable biosimilar in its category, this development underscores the importance of biosimilars in providing effective and accessible treatment.^12,14

Topical Innovations

In October 2023, the FDA approved an expanded indication for roflumilast cream 0.3% to treat children as young as 6 years for plaque psoriasis, even for use in intertriginous areas,¹⁵ which is a milestone given the lack of treatment options for the pediatric population because topical steroids, the most common treatment option for plaque psoriasis, can have safety concerns related to long-term use. With the advent of this steroid-free topical agent, pediatric patients have a safe and well-tolerated option for managing plaque psoriasis.¹⁶ This promising effort will now expand to trials in children as young as 2 years to test efficacy.¹⁶

Engel et al¹⁷ proposed a new algorithmic approach to the topical management of psoriasis with roflumilast cream and tapinarof cream as first-line treatments for mild disease due to their novelty in treating intertriginous areas, whereas traditional topical steroids in these areas would be inapt.¹⁷ The latest indication for roflumilast cream suggests that this proposed recommendation could be a promising and convenient enhancement to psoriasis management, potentially outperforming traditional topical corticosteroids.^15,17

Final Thoughts

Innovative targeted therapies ranging from new biologic agents to broader applications of topical treatments hold the potential to transform conventional psoriasis management with greater efficacy and safety, which can help create a more effective and personalized approach with greater patient satisfaction, ultimately enhancing overall quality of life. The choice of treatment is dependent not only on the severity of the disease but also on accessibility considerations such as cost. Overall, these innovative therapies add substantial value to the treatment armamentarium for psoriasis.

Psoriasis is a chronic autoimmune skin condition that affects approximately 2% to 4% of the US population and notably impacts overall quality of life.^1,2 There is no cure for this long-lasting condition. Fortunately, recent developments in research have led to more targeted therapies, paving the way for a more promising transformative landscape of psoriasis management. Herein, we explore the most up-to-date advancements and developments in the realm of psoriasis care.

Emerging Systemic Therapies

Biologics are cutting-edge treatments available for moderate to severe plaque psoriasis, as IL-17A, IL-23, and tumor necrosis factor α (TNF-α) have been recognized as key targets.³

IL-17—Bimekizumab is a unique monoclonal antibody that inhibits the activity of both IL-17A and IL-17F cytokines.³ This treatment was approved by the US Food and Drug Administration (FDA) in October 2023 for patients with moderate to severe plaque psoriasis who are candidates for systemic therapy or phototherapy.⁴

Bimekizumab outperformed ustekinumab in the BE VIVID phase 3 trial, with 273 of 321 patients (85%) receiving bimekizumab vs 81 of 163 patients (50%) receiving ustekinumab experiencing at least 90% improvement in psoriasis area and severity index (PASI) score at week 16.⁴ In a 2020 observational study (PSO-BIO-REAL), the efficacy rate of skin clearance after 6 months of treatment with biologics was only 25% (1/4).⁵ Aside from moderate to severe plaque psoriasis, bimekizumab demonstrated notable improvement in patients with psoriatic arthritis who had inadequate response or intolerance to TNF-α inhibitors compared to a placebo group in the BE COMPLETE phase 3 trial.⁶

IL-23—Guselkumab, risankizumab, and tildrakizumab are injectable therapies approved by the FDA in 2017 for moderate to severe plaque psoriasis.³ They inhibit IL-23 signaling by targeting the p19 subunit in addition to sparing IL-12.^3,7

A novel oral therapeutic peptide, JNJ-2113—the first oral IL-23 receptor antagonist peptide that blocks IL-23 signaling—has been developed, offering a new way to treat moderate to severe plaque psoriasis. Trial results from a phase 2 study (FRONTIER1) have supported JNJ-2113’s advancement into phase 3.^7,8 Patients who received JNJ-2113 successfully achieved PASI75 in addition to surpassing PASI90 and PASI100 at greater proportions compared to placebo at week 16.⁷

The promising early results of JNJ-2113 provide patients with greater flexibility and convenience for treatment options to address the manifestations of psoriasis. Although a considerable number of patients with moderate to severe plaque psoriasis qualify for advanced therapies, a substantial proportion remain untreated. Introducing an oral route of medication administration may help overcome barriers to therapy access due to a greater preference for pills over injections.⁹

TNF-α Inhibitors—Adalimumab is a TNF-α inhibitor that is used to treat moderate to severe chronic plaque psoriasis in adults who are candidates for systemic phototherapy.^1,10 However, one of the main barriers to initiating treatment has been cost. Biosimilars contribute to market competition, thus allowing the possibility of lower drug prices.¹⁰

There are 9 FDA-approved biosimilar products for adalimumab, with 2 having interchangeable designation. The first interchangeable biosimilar to enter the US market, adalimumab-adbm, became available in July 2023. In October 2023, adalimumab-afzb was granted interchangeable designation,¹¹ which enables pharmacists to swiftly substitute brand products for lower-cost biosimilars, providing patients with equally safe and effective alternatives without the delay of involving the prescribing clinician.¹² Pricing information indicates an initial 5% discount, which may later increase to 60%, from brand name adalimumab. Hopefully, reduced drug costs due to market competition will allow more patients to overcome barriers to therapy access.

IL-12/IL-23—Ustekinumab is a monoclonal antibody that targets IL-12 and IL-23. The FDA recently approved ustekinumab-auub as the first interchangeable ustekinumab biosimilar for the treatment of various inflammatory diseases, including moderate to severe plaque psoriasis and psoriatic arthritis.^12,13 The approval of ustekinumab-auub expands therapeutic options for the treatment of diverse inflammatory diseases. As the first interchangeable biosimilar in its category, this development underscores the importance of biosimilars in providing effective and accessible treatment.^12,14

Topical Innovations

In October 2023, the FDA approved an expanded indication for roflumilast cream 0.3% to treat children as young as 6 years for plaque psoriasis, even for use in intertriginous areas,¹⁵ which is a milestone given the lack of treatment options for the pediatric population because topical steroids, the most common treatment option for plaque psoriasis, can have safety concerns related to long-term use. With the advent of this steroid-free topical agent, pediatric patients have a safe and well-tolerated option for managing plaque psoriasis.¹⁶ This promising effort will now expand to trials in children as young as 2 years to test efficacy.¹⁶

Engel et al¹⁷ proposed a new algorithmic approach to the topical management of psoriasis with roflumilast cream and tapinarof cream as first-line treatments for mild disease due to their novelty in treating intertriginous areas, whereas traditional topical steroids in these areas would be inapt.¹⁷ The latest indication for roflumilast cream suggests that this proposed recommendation could be a promising and convenient enhancement to psoriasis management, potentially outperforming traditional topical corticosteroids.^15,17

Final Thoughts

Innovative targeted therapies ranging from new biologic agents to broader applications of topical treatments hold the potential to transform conventional psoriasis management with greater efficacy and safety, which can help create a more effective and personalized approach with greater patient satisfaction, ultimately enhancing overall quality of life. The choice of treatment is dependent not only on the severity of the disease but also on accessibility considerations such as cost. Overall, these innovative therapies add substantial value to the treatment armamentarium for psoriasis.

In April 2023, the US Preventive Services Task Force (USPSTF) issued a controversial recommendation that the current evidence is insufficient to assess the benefits vs harms of visual skin examination by clinicians for skin cancer screening in adolescents and adults who do not have signs or symptoms of skin cancer.^1,2 This recommendation by the USPSTF has not changed in a quarter century,³ but a recent study described an interesting paradox that should trigger wide evaluation and debate.

Patel et al⁴ analyzed data from the National Cancer Institute’s Surveillance, Epidemiology, and End Results Program from January 2000 to December 2018 to identify adults with a diagnosis of first primary melanoma in situ (MIS). Overall mortality was then determined through the National Vital Statistics System, which provides cause-of-death information for all deaths in the United States. The authors found 137,872 patients who had 1—and only 1—MIS discovered over the observation period. These patients predominantly were White (96.7%), and the mean (SD) age at diagnosis was 61.9 (16.5) years. During 910,308 total person-years of follow-up (mean [SD], 6.6 [5.1] years), 893 (0.6%) patients died of melanoma and 17,327 (12.6%) died of any cause. The 15-year melanoma-specific standardized mortality rate (SMR) was 1.89 (95% CI, 1.77-2.02), yet the 15-year overall survival relative to matched population controls was 112.4% (95% CI, 112.0%-112.8%), thus all-cause SMR was significantly lower at 0.68 (95% CI, 0.67-0.7). Although MIS was associated with a small increase in cohort melanoma mortality, overall mortality was actually lower than in the general population.⁴

Patel et al⁴ did a further broader search that included an additional 18,379 patients who also experienced a second primary melanoma, of which 6751 (36.7%) were invasive and 11,628 (63.3%) were in situ, with a melanoma-specific survival of 98.2% (95% CI, 97.6%-98.5%). Yet relative all-cause survival was significantly higher at 126.7% (95% CI, 125.5%-128.0%). Even among patients in whom a second primary melanoma was invasive, melanoma-specific survival was reduced to 91.1% (95% CI, 90.0%-92.1%), but relative all-cause survival was 116.7% (95% CI, 115%-118.4%). These data in the overall cohort of 155,251 patients showed a discordance between melanoma mortality, which was 4.27-times higher than in the general population (SMR, 4.27; 95% CI, 4.07-4.48), and a lower risk for death from all causes that was approximately 27% lower than in the general population (SMR, 0.73; 95% CI, 0.72-0.74). The authors showed that their findings were not associated with socioeconomic status.⁴

The analysis by Patel et al⁴ is now the second study in the literature to show this discordant melanoma survival pattern. In an earlier Australian study of 2452 melanoma patients, Watts et al⁵ reported that melanoma detection during routine skin checks was associated with a 25% lower all-cause mortality (hazard ratio, 0.75; 95% CI, 0.63-0.90) but not melanoma-specific mortality after multivariable adjustment for a variety of factors including socioeconomic status.These analyses by 2 different groups of investigators have broad implications. Both groups suggested that the improved life span in melanoma patients may be due to health-seeking behavior, which has been defined as “any action undertaken by individuals who perceive themselves to have a health problem or to be ill for the purpose of finding an appropriate remedy.”⁶

Once treated for melanoma, it is clear that patients are likely to return at regular intervals for thorough full-body skin examinations, but this activity alone could not be responsible for improved all-cause mortality in the face of increased melanoma-specific mortality. It seems the authors are implying a broader concept of good health behavior, originally defined by MacKian⁷ as encompassing “activities undertaken to maintain good health, to prevent ill health, as well as dealing with any departure from a good state of health,” such as overt behavioral patterns, actions, and habits with the goal of maintenance, restoration, and improvement of one’s health. A variety of behaviors fall within such a definition including smoking cessation, decreased alcohol use, good diet, more physical activity, safe sexual behavior, scheduling physician visits, medication adherence, vaccination, and yes—screening examinations for health problems.⁸

The concept that individuals who are diagnosed with melanoma fall into a pattern of good health behavior is an interesting hypothesis that must remain speculative until the multiple aspects of good health behavior are rigorously studied. This concept coexists with the hypothesis of melanoma “overdiagnosis”—the idea that many melanomas are detected that will never lead to death.⁹ Both concepts deserve further analysis. Unquestionably, a randomized controlled trial could never recruit patients willing to undergo long-term untreated observation of their melanomas to test the hypothesis that their melanoma diagnosis would eventually lead to death. Furthermore, Patel et al⁴ do suggest that even MIS carries a small but measurable increased risk for death from the disease, which is not particularly supportive of the overdiagnosis hypothesis; however, analysis of the concept that improved individual health behavior is at least in part responsible for the first discovery of melanomas is certainly approachable. Here is the key question: Did the melanoma diagnosis trigger a sudden change in multiple aspects of health behavior that led to significant all-cause mortality benefits? The average age of the population studied by Patel et al⁴ was approximately 62 years. One wonders whether the consequences of a lifetime of established health behavior patterns can be rapidly ­modified—certainly possible but again remains to be proven by further studies.

Conversely, the alternative hypothesis is that discovery of MIS was the result of active pursuit of self-examination and screening procedures as part of individually ingrained good health behavior over a lifetime. Goodwin et al¹⁰ carried out a study in a sample of the Medicare population aged 69 to 90 years looking at men who had prostate cancer screening via prostate-specific antigen measurement and women who had undergone mammography in older age, compared to the contrast population who had not had these screening procedures. They tracked date of death in Medicare enrollment files. They identified 543,970 women and 362,753 men who were aged 69 to 90 years as of January 1, 2003. Patients were stratified by life expectancy based on age and comorbidity. Within each stratum, the patients with cancer screening had higher actual median survival than those who were not screened, with differences ranging from 1.7 to 2.1 years for women and 0.9 to 1.1 years for men.¹⁰ These results were not the result of lower prostate or breast cancer mortality. Rather, one surmises that other health factors yielded lower mortality in the screened cohorts.

A full-body skin examination is a time-consuming process. Patients who come to their physician for a routine annual physical don’t expect a skin examination and very few physicians have the time for a long detailed full-body skin examination. When the patient presents to a dermatologist for an examination, it often is because they have real concerns; for example, they may have had a family member who died of skin cancer, or the patient themself may have noticed a worrisome lesion. Patients, not physicians, are the drivers of skin cancer screening, a fact that often is dismissed by those who are not necessarily supportive of the practice.

In light of the findings of Patel et al,⁴ it is essential that the USPSTF reviews be reanalyzed to compare skin cancer–specific mortality, all-cause mortality, and lifespan in individuals who pursue skin cancer screening; the reanalysis also should not be exclusively limited to survival. With the advent of the immune checkpoint inhibitors, patients with metastatic melanoma are living much longer.¹¹ The burden of living with metastatic cancer must be characterized and measured to have a complete picture and a valid analysis.

After the release of the USPSTF recommendation, there have been calls for large-scale studies to prove the benefits of skin cancer screening.¹² Such studies may be valuable; however, if the hypothesis that overall healthy behavior as the major outcome determinant is substantiated, it may prove quite challenging to perform tests of association with specific interventions. It has been shown that skin cancer screening does lead to discovery of more melanomas,¹³ yet in light of the paradox described by Patel et al,⁴ it also is likely that causes of death other than melanoma impact overall mortality. Patients who pursue skin examinations may engage in multiple different health activities that are beneficial in the long term, making it difficult to analyze the specific benefit of skin cancer screening in isolation. It may prove difficult to ask patients to omit selected aspects of healthy behavior to try to prove the point. At this time, there is much more work to be done prior to offering opinions on the importance of skin cancer examination in isolation to improve overall health care. In the meantime, dermatologists owe it to our patients to continue to diligently pursue thorough and detailed skin examinations.

In April 2023, the US Preventive Services Task Force (USPSTF) issued a controversial recommendation that the current evidence is insufficient to assess the benefits vs harms of visual skin examination by clinicians for skin cancer screening in adolescents and adults who do not have signs or symptoms of skin cancer.^1,2 This recommendation by the USPSTF has not changed in a quarter century,³ but a recent study described an interesting paradox that should trigger wide evaluation and debate.

Patel et al⁴ analyzed data from the National Cancer Institute’s Surveillance, Epidemiology, and End Results Program from January 2000 to December 2018 to identify adults with a diagnosis of first primary melanoma in situ (MIS). Overall mortality was then determined through the National Vital Statistics System, which provides cause-of-death information for all deaths in the United States. The authors found 137,872 patients who had 1—and only 1—MIS discovered over the observation period. These patients predominantly were White (96.7%), and the mean (SD) age at diagnosis was 61.9 (16.5) years. During 910,308 total person-years of follow-up (mean [SD], 6.6 [5.1] years), 893 (0.6%) patients died of melanoma and 17,327 (12.6%) died of any cause. The 15-year melanoma-specific standardized mortality rate (SMR) was 1.89 (95% CI, 1.77-2.02), yet the 15-year overall survival relative to matched population controls was 112.4% (95% CI, 112.0%-112.8%), thus all-cause SMR was significantly lower at 0.68 (95% CI, 0.67-0.7). Although MIS was associated with a small increase in cohort melanoma mortality, overall mortality was actually lower than in the general population.⁴

Patel et al⁴ did a further broader search that included an additional 18,379 patients who also experienced a second primary melanoma, of which 6751 (36.7%) were invasive and 11,628 (63.3%) were in situ, with a melanoma-specific survival of 98.2% (95% CI, 97.6%-98.5%). Yet relative all-cause survival was significantly higher at 126.7% (95% CI, 125.5%-128.0%). Even among patients in whom a second primary melanoma was invasive, melanoma-specific survival was reduced to 91.1% (95% CI, 90.0%-92.1%), but relative all-cause survival was 116.7% (95% CI, 115%-118.4%). These data in the overall cohort of 155,251 patients showed a discordance between melanoma mortality, which was 4.27-times higher than in the general population (SMR, 4.27; 95% CI, 4.07-4.48), and a lower risk for death from all causes that was approximately 27% lower than in the general population (SMR, 0.73; 95% CI, 0.72-0.74). The authors showed that their findings were not associated with socioeconomic status.⁴

The analysis by Patel et al⁴ is now the second study in the literature to show this discordant melanoma survival pattern. In an earlier Australian study of 2452 melanoma patients, Watts et al⁵ reported that melanoma detection during routine skin checks was associated with a 25% lower all-cause mortality (hazard ratio, 0.75; 95% CI, 0.63-0.90) but not melanoma-specific mortality after multivariable adjustment for a variety of factors including socioeconomic status.These analyses by 2 different groups of investigators have broad implications. Both groups suggested that the improved life span in melanoma patients may be due to health-seeking behavior, which has been defined as “any action undertaken by individuals who perceive themselves to have a health problem or to be ill for the purpose of finding an appropriate remedy.”⁶

Once treated for melanoma, it is clear that patients are likely to return at regular intervals for thorough full-body skin examinations, but this activity alone could not be responsible for improved all-cause mortality in the face of increased melanoma-specific mortality. It seems the authors are implying a broader concept of good health behavior, originally defined by MacKian⁷ as encompassing “activities undertaken to maintain good health, to prevent ill health, as well as dealing with any departure from a good state of health,” such as overt behavioral patterns, actions, and habits with the goal of maintenance, restoration, and improvement of one’s health. A variety of behaviors fall within such a definition including smoking cessation, decreased alcohol use, good diet, more physical activity, safe sexual behavior, scheduling physician visits, medication adherence, vaccination, and yes—screening examinations for health problems.⁸

The concept that individuals who are diagnosed with melanoma fall into a pattern of good health behavior is an interesting hypothesis that must remain speculative until the multiple aspects of good health behavior are rigorously studied. This concept coexists with the hypothesis of melanoma “overdiagnosis”—the idea that many melanomas are detected that will never lead to death.⁹ Both concepts deserve further analysis. Unquestionably, a randomized controlled trial could never recruit patients willing to undergo long-term untreated observation of their melanomas to test the hypothesis that their melanoma diagnosis would eventually lead to death. Furthermore, Patel et al⁴ do suggest that even MIS carries a small but measurable increased risk for death from the disease, which is not particularly supportive of the overdiagnosis hypothesis; however, analysis of the concept that improved individual health behavior is at least in part responsible for the first discovery of melanomas is certainly approachable. Here is the key question: Did the melanoma diagnosis trigger a sudden change in multiple aspects of health behavior that led to significant all-cause mortality benefits? The average age of the population studied by Patel et al⁴ was approximately 62 years. One wonders whether the consequences of a lifetime of established health behavior patterns can be rapidly ­modified—certainly possible but again remains to be proven by further studies.

Conversely, the alternative hypothesis is that discovery of MIS was the result of active pursuit of self-examination and screening procedures as part of individually ingrained good health behavior over a lifetime. Goodwin et al¹⁰ carried out a study in a sample of the Medicare population aged 69 to 90 years looking at men who had prostate cancer screening via prostate-specific antigen measurement and women who had undergone mammography in older age, compared to the contrast population who had not had these screening procedures. They tracked date of death in Medicare enrollment files. They identified 543,970 women and 362,753 men who were aged 69 to 90 years as of January 1, 2003. Patients were stratified by life expectancy based on age and comorbidity. Within each stratum, the patients with cancer screening had higher actual median survival than those who were not screened, with differences ranging from 1.7 to 2.1 years for women and 0.9 to 1.1 years for men.¹⁰ These results were not the result of lower prostate or breast cancer mortality. Rather, one surmises that other health factors yielded lower mortality in the screened cohorts.

A full-body skin examination is a time-consuming process. Patients who come to their physician for a routine annual physical don’t expect a skin examination and very few physicians have the time for a long detailed full-body skin examination. When the patient presents to a dermatologist for an examination, it often is because they have real concerns; for example, they may have had a family member who died of skin cancer, or the patient themself may have noticed a worrisome lesion. Patients, not physicians, are the drivers of skin cancer screening, a fact that often is dismissed by those who are not necessarily supportive of the practice.

In light of the findings of Patel et al,⁴ it is essential that the USPSTF reviews be reanalyzed to compare skin cancer–specific mortality, all-cause mortality, and lifespan in individuals who pursue skin cancer screening; the reanalysis also should not be exclusively limited to survival. With the advent of the immune checkpoint inhibitors, patients with metastatic melanoma are living much longer.¹¹ The burden of living with metastatic cancer must be characterized and measured to have a complete picture and a valid analysis.

After the release of the USPSTF recommendation, there have been calls for large-scale studies to prove the benefits of skin cancer screening.¹² Such studies may be valuable; however, if the hypothesis that overall healthy behavior as the major outcome determinant is substantiated, it may prove quite challenging to perform tests of association with specific interventions. It has been shown that skin cancer screening does lead to discovery of more melanomas,¹³ yet in light of the paradox described by Patel et al,⁴ it also is likely that causes of death other than melanoma impact overall mortality. Patients who pursue skin examinations may engage in multiple different health activities that are beneficial in the long term, making it difficult to analyze the specific benefit of skin cancer screening in isolation. It may prove difficult to ask patients to omit selected aspects of healthy behavior to try to prove the point. At this time, there is much more work to be done prior to offering opinions on the importance of skin cancer examination in isolation to improve overall health care. In the meantime, dermatologists owe it to our patients to continue to diligently pursue thorough and detailed skin examinations.

In April 2023, the US Preventive Services Task Force (USPSTF) issued a controversial recommendation that the current evidence is insufficient to assess the benefits vs harms of visual skin examination by clinicians for skin cancer screening in adolescents and adults who do not have signs or symptoms of skin cancer.^1,2 This recommendation by the USPSTF has not changed in a quarter century,³ but a recent study described an interesting paradox that should trigger wide evaluation and debate.

Patel et al⁴ analyzed data from the National Cancer Institute’s Surveillance, Epidemiology, and End Results Program from January 2000 to December 2018 to identify adults with a diagnosis of first primary melanoma in situ (MIS). Overall mortality was then determined through the National Vital Statistics System, which provides cause-of-death information for all deaths in the United States. The authors found 137,872 patients who had 1—and only 1—MIS discovered over the observation period. These patients predominantly were White (96.7%), and the mean (SD) age at diagnosis was 61.9 (16.5) years. During 910,308 total person-years of follow-up (mean [SD], 6.6 [5.1] years), 893 (0.6%) patients died of melanoma and 17,327 (12.6%) died of any cause. The 15-year melanoma-specific standardized mortality rate (SMR) was 1.89 (95% CI, 1.77-2.02), yet the 15-year overall survival relative to matched population controls was 112.4% (95% CI, 112.0%-112.8%), thus all-cause SMR was significantly lower at 0.68 (95% CI, 0.67-0.7). Although MIS was associated with a small increase in cohort melanoma mortality, overall mortality was actually lower than in the general population.⁴

Patel et al⁴ did a further broader search that included an additional 18,379 patients who also experienced a second primary melanoma, of which 6751 (36.7%) were invasive and 11,628 (63.3%) were in situ, with a melanoma-specific survival of 98.2% (95% CI, 97.6%-98.5%). Yet relative all-cause survival was significantly higher at 126.7% (95% CI, 125.5%-128.0%). Even among patients in whom a second primary melanoma was invasive, melanoma-specific survival was reduced to 91.1% (95% CI, 90.0%-92.1%), but relative all-cause survival was 116.7% (95% CI, 115%-118.4%). These data in the overall cohort of 155,251 patients showed a discordance between melanoma mortality, which was 4.27-times higher than in the general population (SMR, 4.27; 95% CI, 4.07-4.48), and a lower risk for death from all causes that was approximately 27% lower than in the general population (SMR, 0.73; 95% CI, 0.72-0.74). The authors showed that their findings were not associated with socioeconomic status.⁴

The analysis by Patel et al⁴ is now the second study in the literature to show this discordant melanoma survival pattern. In an earlier Australian study of 2452 melanoma patients, Watts et al⁵ reported that melanoma detection during routine skin checks was associated with a 25% lower all-cause mortality (hazard ratio, 0.75; 95% CI, 0.63-0.90) but not melanoma-specific mortality after multivariable adjustment for a variety of factors including socioeconomic status.These analyses by 2 different groups of investigators have broad implications. Both groups suggested that the improved life span in melanoma patients may be due to health-seeking behavior, which has been defined as “any action undertaken by individuals who perceive themselves to have a health problem or to be ill for the purpose of finding an appropriate remedy.”⁶

Once treated for melanoma, it is clear that patients are likely to return at regular intervals for thorough full-body skin examinations, but this activity alone could not be responsible for improved all-cause mortality in the face of increased melanoma-specific mortality. It seems the authors are implying a broader concept of good health behavior, originally defined by MacKian⁷ as encompassing “activities undertaken to maintain good health, to prevent ill health, as well as dealing with any departure from a good state of health,” such as overt behavioral patterns, actions, and habits with the goal of maintenance, restoration, and improvement of one’s health. A variety of behaviors fall within such a definition including smoking cessation, decreased alcohol use, good diet, more physical activity, safe sexual behavior, scheduling physician visits, medication adherence, vaccination, and yes—screening examinations for health problems.⁸

The concept that individuals who are diagnosed with melanoma fall into a pattern of good health behavior is an interesting hypothesis that must remain speculative until the multiple aspects of good health behavior are rigorously studied. This concept coexists with the hypothesis of melanoma “overdiagnosis”—the idea that many melanomas are detected that will never lead to death.⁹ Both concepts deserve further analysis. Unquestionably, a randomized controlled trial could never recruit patients willing to undergo long-term untreated observation of their melanomas to test the hypothesis that their melanoma diagnosis would eventually lead to death. Furthermore, Patel et al⁴ do suggest that even MIS carries a small but measurable increased risk for death from the disease, which is not particularly supportive of the overdiagnosis hypothesis; however, analysis of the concept that improved individual health behavior is at least in part responsible for the first discovery of melanomas is certainly approachable. Here is the key question: Did the melanoma diagnosis trigger a sudden change in multiple aspects of health behavior that led to significant all-cause mortality benefits? The average age of the population studied by Patel et al⁴ was approximately 62 years. One wonders whether the consequences of a lifetime of established health behavior patterns can be rapidly ­modified—certainly possible but again remains to be proven by further studies.

Conversely, the alternative hypothesis is that discovery of MIS was the result of active pursuit of self-examination and screening procedures as part of individually ingrained good health behavior over a lifetime. Goodwin et al¹⁰ carried out a study in a sample of the Medicare population aged 69 to 90 years looking at men who had prostate cancer screening via prostate-specific antigen measurement and women who had undergone mammography in older age, compared to the contrast population who had not had these screening procedures. They tracked date of death in Medicare enrollment files. They identified 543,970 women and 362,753 men who were aged 69 to 90 years as of January 1, 2003. Patients were stratified by life expectancy based on age and comorbidity. Within each stratum, the patients with cancer screening had higher actual median survival than those who were not screened, with differences ranging from 1.7 to 2.1 years for women and 0.9 to 1.1 years for men.¹⁰ These results were not the result of lower prostate or breast cancer mortality. Rather, one surmises that other health factors yielded lower mortality in the screened cohorts.

A full-body skin examination is a time-consuming process. Patients who come to their physician for a routine annual physical don’t expect a skin examination and very few physicians have the time for a long detailed full-body skin examination. When the patient presents to a dermatologist for an examination, it often is because they have real concerns; for example, they may have had a family member who died of skin cancer, or the patient themself may have noticed a worrisome lesion. Patients, not physicians, are the drivers of skin cancer screening, a fact that often is dismissed by those who are not necessarily supportive of the practice.

In light of the findings of Patel et al,⁴ it is essential that the USPSTF reviews be reanalyzed to compare skin cancer–specific mortality, all-cause mortality, and lifespan in individuals who pursue skin cancer screening; the reanalysis also should not be exclusively limited to survival. With the advent of the immune checkpoint inhibitors, patients with metastatic melanoma are living much longer.¹¹ The burden of living with metastatic cancer must be characterized and measured to have a complete picture and a valid analysis.

After the release of the USPSTF recommendation, there have been calls for large-scale studies to prove the benefits of skin cancer screening.¹² Such studies may be valuable; however, if the hypothesis that overall healthy behavior as the major outcome determinant is substantiated, it may prove quite challenging to perform tests of association with specific interventions. It has been shown that skin cancer screening does lead to discovery of more melanomas,¹³ yet in light of the paradox described by Patel et al,⁴ it also is likely that causes of death other than melanoma impact overall mortality. Patients who pursue skin examinations may engage in multiple different health activities that are beneficial in the long term, making it difficult to analyze the specific benefit of skin cancer screening in isolation. It may prove difficult to ask patients to omit selected aspects of healthy behavior to try to prove the point. At this time, there is much more work to be done prior to offering opinions on the importance of skin cancer examination in isolation to improve overall health care. In the meantime, dermatologists owe it to our patients to continue to diligently pursue thorough and detailed skin examinations.

Inflammatory skin conditions often have a relapsing and remitting course and represent a large proportion of chronic skin diseases. Common inflammatory skin disorders include acne, psoriasis, hidradenitis suppurativa (HS), atopic dermatitis (AD), and seborrheic dermatitis (SD).¹ Although each of these conditions has a unique pathogenesis, they all are driven by a background of chronic inflammation. It has been reported that diets with high levels of refined carbohydrates and saturated or trans-fatty acids may exacerbate existing inflammation.² Consequently, dietary interventions, such as the ketogenic and low-glycemic diets, have potential anti-inflammatory and metabolic effects that are being assessed as stand-alone or adjunctive therapies for dermatologic diseases.

Diet may partially influence systemic inflammation through its effect on weight. Higher body mass index and obesity are linked to a low-grade inflammatory state and higher levels of circulating inflammatory markers. Therefore, weight loss leads to decreases in inflammatory cytokines, including C-reactive protein, tumor necrosis factor α, and IL-6.³ These cytokines and metabolic effects overlap with inflammatory skin condition pathways. It also is posited that decreased insulin release associated with weight loss results in decreased sebaceous lipogenesis and androgens, which drive keratinocyte proliferation and acne development.^4,5 For instance, in a 2015 meta-analysis of 5 randomized controlled trials on psoriasis, patients in the weight loss intervention group had more substantial reductions in psoriasis area and severity index (PASI) scores compared with controls receiving usual care (P=.004).⁶ However, in a systematic review of 35 studies on acne vulgaris, overweight and obese patients (defined by a body mass index of ≥23 kg/m²) had similar odds of having acne compared with normal-weight individuals (P=.671).⁷

Similar to weight loss, ketogenesis acts as a negative feedback mechanism to reduce insulin release, leading to decreased inflammation and androgens that often exacerbate inflammatory skin diseases.⁸ Ketogenesis ensues when daily carbohydrate intake is limited to less than 50 g, and long-term adherence to a ketogenic diet results in metabolic reliance on ketone bodies such as acetoacetate, β-hydroxybutyrate, and acetone.⁹ These metabolites may decrease free radical damage and consequently improve signs and symptoms of acne, psoriasis, and other inflammatory skin diseases.^10-12 Similarly, increased ketones also may decrease activation of the NLRP3 (NOD-, LRR-, and Pyrin domain-containing protein 3) inflammasome and therefore reduce inflammatory markers such as IL-1β and IL-1.^4,13 Several proposed mechanisms are outlined in the Table.

Collectively, low-glycemic and ketogenic diets have been proposed as potential interventions for reducing inflammatory skin conditions. These dietary approaches are hypothesized to exert their effects by facilitating weight loss, elevating ketone levels, and reducing systemic inflammation. The current review summarizes the existing evidence on ketogenic and low-glycemic diets as treatments for inflammatory skin conditions and evaluates the potential benefits of these dietary interventions in managing and improving outcomes for individuals with inflammatory skin conditions.

Methods

Using PubMed for articles indexed for MEDLINE and Google Scholar, a review of the literature was conducted with a combination of the following search terms: low-glycemic diet, inflammatory, dermatologic, ketogenic diet, inflammation, dermatology, acne, psoriasis, eczema, seborrheic dermatitis, and hidradenitis suppurativa. Reference citations in identified works also were reviewed. Interventional (experimental studies or clinical trials), survey-based, and observational studies that investigated the effects of low-glycemic or ketogenic diets for the treatment of inflammatory skin conditions were included. Inclusion criteria were studies assessing acne, psoriasis, SD, AD, and HS. Exclusion criteria were studies published before 1965; those written in languages other than English; and those analyzing other diets, such as the Mediterranean or low-fat diets. The search yielded a total of 11 observational studies and 4 controlled studies published between 1966 and January 2023. Because this analysis utilized publicly available data and did not qualify as human subject research, institutional review board approval was not required.

Results

Acne Vulgaris—Acne vulgaris is a disease of chronic pilosebaceous inflammation and follicular epithelial proliferation associated with Propionibacterium acnes. The association between acne and low-glycemic diets has been examined in several studies. Diet quality is measured and assessed using the glycemic index (GI), which is the effect of a single food on postprandial blood glucose, and the glycemic load, which is the GI adjusted for carbohydrates per serving.¹⁴ High levels of GI and glycemic load are associated with hyperinsulinemia and an increase in insulinlike growth factor 1 concentration that promotes mechanistic target of rapamycin (mTOR) complex 1–mediated follicular lipogenesis, sebum fatty acid production, and androgen synthesis.¹⁵Propionibacterium acnes directly activates toll-like receptor 2 on monocytes through damage-associated molecular patterns and indirectly through products of triglyceride catalysis, causing release of IL-12, IL-6, tumor necrosis factor α, and other proinflammatory cytokines.¹⁶ Therefore, lifestyle modifications focused on strict glucose control have been postulated to reduce acne severity via modulation of lipogenesis, androgen concentration, and inflammation.

Six survey-based studies evaluated sugar intake in patients with acne compared to healthy matched controls (eTable). Among these studies, 5 reported higher glycemic loads or daily sugar intake in acne patients compared to individuals without acne.^{12,19,20,26,28} The remaining study was conducted in 1967 and enrolled 16 acne patients and 32 matched controls. It reported no significant difference in sugar intake between the groups (P>.05).¹⁷

Smith et al¹⁸ randomized 43 male patients aged 15 to 25 years with facial acne into 2 cohorts for 12 weeks, each consuming either a low-glycemic diet (25% protein, 45% low-glycemic food [fruits, whole grains], and 30% fat) or a carbohydrate-dense diet of foods with medium to high GI based on prior documentation of the original diet. Patients were instructed to use a noncomedogenic cleanser as their only acne treatment. At 12 weeks, patients consuming the low-glycemic diet had an average of 23.5 fewer inflammatory lesions, while those in the intervention group had 12.0 fewer lesions (P=.03).¹⁸

In another controlled study by Kwon et al,²¹ 32 male and female acne patients were randomized to a low-glycemic diet (25% protein, 45% low-glycemic food, and 30% fat) or a standard diet for 10 weeks. Patients on the low-glycemic diet experienced a 70.9% reduction in inflammatory lesions (P<.05). Hematoxylin and eosin staining and image analysis were performed to measure sebaceous gland surface area in the low-glycemic diet group, which decreased from 0.32 to 0.24 mm² (P=.03). The sebaceous gland surface area in the control group was not reported. Moreover, patients on the low-glycemic diet had reduced IL-8 immunohistochemical staining (decreasing from 2.9 to 1.7 [P=.03]) and sterol regulatory element-binding protein 1 levels (decreasing from 2.6 to 1.3 [P=.03]), suggesting suppression of ongoing inflammation. Patients on the low-glycemic diet had no significant difference in transforming growth factor β1(P=.83). In the control group, there was no difference in IL-8, sterol regulatory element binding protein 1, or transforming growth factor β1 (P>.05) on immunohistochemical staining.²¹

Psoriasis—Psoriasis is a systemic inflammatory disease characterized by hyperproliferation and aberrant keratinocyte plaque formation. The innate immune response of keratinocytes in response to epidermal damage or infection begins with neutrophil recruitment and dendritic cell activation. Dendritic cell secretion of IL-23 promotes T-cell differentiation into helper T cells (T_H1) that subsequently secrete IL-17 and IL-22, thereby stimulating keratinocyte proliferation and eventual plaque formation. The relationship between diet and psoriasis is poorly understood; however, hyperinsulinemia is associated with greater severity of psoriasis.³¹ 

Four observational studies examined sugar intake in psoriasis patients. Barrea et al²³ conducted a survey-based study of 82 male participants (41 with psoriasis and 41 healthy controls), reporting that PASI score was correlated with intake of simple carbohydrates (percentage of total kilocalorie)(r=0.564, P<.001). Another study by Yamashita et al²⁷ found higher sugar intake in psoriasis patients than controls (P=.003) based on surveys from 70 patients with psoriasis and 70 matched healthy controls.

These findings contrast with 2 survey-based studies by Johnson et al²² and Afifi et al²⁵ of sugar intake in psoriasis patients using the National Health and Nutrition Examination Survey. Johnson et al²² reported reduced sugar intake among 156 psoriasis patients compared with 6104 unmatched controls (odds ratio, 0.998; CI, 0.996-1 [P=.04]) from 2003 to 2006. Similarly, Afifi et al²⁵ reported decreased sugar intake in 1206 psoriasis patients compared with sex- and age-matched controls (P<.0001) in 2009 and 2010. When patients were asked about dietary triggers, 13.8% of psoriasis patients reported sugar as the most common trigger, which was more frequent than alcohol (13.6%), gluten (7.2%), and dairy (6%).²⁵

Castaldo et al^29,30 published 2 nonrandomized clinical intervention studies in 2020 and 2021 evaluating the impact of the ketogenic diet on psoriasis. In the first study, 37 psoriasis patients followed a 10-week diet consisting of 4 weeks on a ketogenic diet (500 kcal/d) followed by 6 weeks on a low-caloric Mediterranean diet.²⁹ At the end of the intervention, there was a 17.4% reduction in PASI score, a 33.2-point reduction in itch severity score, and a 13.4-point reduction in the dermatology life quality index score; however, this study did not include a control diet group for comparison.²⁹ The second study included 30 psoriasis patients on a ketogenic diet and 30 control patients without psoriasis on a regular diet.³⁰ The ketogenic diet consisted of 400 to 500 g of vegetables, 20 to 30 g of fat, and a proportion of protein based on body weight with at least 12 g of whey protein and various amino acids. Patients on the ketogenic diet had significant reduction in PASI scores (value relative to clinical features, 1.4916 [P=.007]). Furthermore, concentrations of cytokines IL-2 (P=.04) and IL-1β (P=.006) decreased following the ketogenic diet but were not measured in the control group.³⁰

Seborrheic Dermatitis—Seborrheic dermatitis is associated with overcolonization of Malassezia species near lipid-rich sebaceous glands. Malassezia hydrolyzes free fatty acids, yielding oleic acids and leading to T-cell release of IL-8 and IL-17.³² Literature is sparse regarding how dietary modifications may play a role in disease severity. In a survey study, Bett et al¹⁷ compared 16 SD patients to 1:2 matched controls (N=29) to investigate the relationship between sugar consumption and presence of disease. Two control cohorts were selected, 1 from clinic patients diagnosed with verruca and 1 matched by age and sex from a survey-based study at a facility in London, England. Sugar intake was measured both in total grams per day and in “beverage sugar” per day, defined as sugar taken in tea and coffee. There was higher total sugar and higher beverage sugar intake among the SD group compared with both control groups (P<.05).¹⁷

Atopic Dermatitis—Atopic dermatitis is a disease of epidermal barrier dysfunction and IgE-mediated allergic sensitization.³³ There are several mechanisms by which skin structure may be disrupted. It is well established that filaggrin mutations inhibit stratum corneum maturation and lamellar matrix deposition.³⁴ Upregulation of IL-4–, IL-13–, and IL-17–secreting T_H2 cells also is associated with disruption of tight junctions and reduction of filaggrin.^35,36 Given that a T cell–mediated inflammatory response is involved in disease pathogenesis, glycemic control is hypothesized to have therapeutic potential.

Nosrati et al²⁴ surveyed 169 AD patients about their perceived dietary triggers through a 61-question survey based on the National Health and Nutrition Examination Survey. Respondents were queried about their perceptions and dietary changes, such as removal or addition of specific food groups and trial of specific diets. Overall, 16.5% of patients reported sugar being a trigger, making it the fourth most common among those surveyed and less common than dairy (24.8%), gluten (18.3%), and alcohol (17.1%).²⁴

Hidradenitis Suppurativa—Hidradenitis suppurativa is driven by hyperkeratosis, dilatation, and occlusion of pilosebaceous follicular ducts, whose eventual rupture evokes a local acute inflammatory response.³⁷ The inciting event for both acne and HS involves mTOR complex–mediated follicular hyperproliferation andinsulinlike growth factor 1 stimulation of androgen receptors in pilosebaceous glands. Given the similarities between the pathogenesis of acne and HS, it is hypothesized that lifestyle changes, including diet modification, may have a beneficial effect on HS.^38-40

Comment

Acne—Overall, there is strong evidence supporting the efficacy of a low-glycemic diet in the treatment of acne. Notably, among the 6 observational studies identified, there was 1 conflicting study by Bett et al¹⁷ that did not find a statistically significant difference in glucose intake between acne and control patients. However, this study included only 16 acne patients, whereas the other 5 observational studies included 32 to 2255 patients.¹⁷ The strongest evidence supporting low-glycemic dietary interventions in acne treatment is from 2 rigorous randomized clinical trials by Kwon et al²¹ and Smith et al.¹⁸ These trials used intention-to-treat models and maintained consistency in gender, age, and acne treatment protocols across both control and treatment groups. To ensure compliance with dietary interventions, daily telephone calls, food logs, and 24-hour urea sampling were utilized. Acne outcomes were assessed by a dermatologist who remained blinded with well-defined outcome measures. An important limitation of these studies is the difficulty in attributing the observed results solely to reduced glucose intake, as low-glycemic diets often lead to other dietary changes, including reduced fat intake and increased nutrient consumption.^18,21

A 2022 systematic review of acne by Meixiong et al⁴¹ further reinforced the beneficial effects of low-glycemic diets in the management of acne patients. The group reviewed 6 interventional studies and 28 observational studies to investigate the relationship among acne, dairy, and glycemic content and found an association between decreased glucose and dairy on reduction of acne.⁴¹

It is likely that the ketogenic diet, which limits glucose, would be beneficial for acne patients. There may be added benefit through elevated ketone bodies and substantially reduced insulin secretion. However, because there are no observational or interventional studies, further research is needed to draw firm conclusions regarding diet for acne treatment. A randomized clinical trial investigating the effects of the ketogenic diet compared to the low-glycemic diet compared to a regular diet would be valuable.

Psoriasis—Among psoriasis studies, there was a lack of consensus regarding glucose intake and correlation with disease. Among the 4 observational studies, 2 reported increased glucose intake among psoriasis patients and 2 reported decreased glucose intake. It is plausible that the variability in studies is due to differences in sample size and diet heterogeneity among study populations. More specifically, Johnson et al²² and Afifi et al²⁵ analyzed large sample sizes of 6260 and 2412 US participants, respectively, and found decreased sugar intake among psoriasis patients compared to controls. In comparison, Barrea et al²³ and Yamashita et al²⁷ analyzed substantially smaller and more specific populations consisting of 82 Italian and 140 Japanese participants, respectively; both reported increased glucose intake among psoriasis patients compared to controls. These seemingly antithetical results may be explained by regional dietary differences, with varying proportions of meats, vegetables, antioxidants, and vitamins.

Moreover, the variation among studies may be further explained by the high prevalence of comorbidities among psoriasis patients. In the study by Barrea et al,²³ psoriasis patients had higher fasting glucose (P=.004) and insulin (P=.022) levels than healthy patients. After adjusting for body mass index and metabolic syndrome, the correlation coefficient measuring the relationship between the PASI score and intake of simple carbohydrates changed from r=0.564 (P<.001) to r=0.352 (P=.028). The confounding impact of these comorbidities was further highlighted by Yamashita et al,²⁷ who found statistically significant differences in glucose intake between psoriasis and healthy patients (P=.003). However, they reported diminished significance on additional subgroup analysis accounting for potential comorbidities (P=.994).²⁷ Johnson et al²² and Afifi et al²⁵ did not account for comorbidities; therefore, the 4 observational study results must be interpreted cautiously.

The 2 randomized clinical trials by Castaldo et al^29,30 weakly suggest that a ketogenic diet may be beneficial for psoriasis patients. The studies have several notable limitations, including insufficient sample sizes and control groups. Thus, the decreased PASI scores reported in psoriasis patients on the ketogenic diets are challenging to interpret. Additionally, both studies placed patients on highly restrictive diets of 500 kcal/d for 4 weeks. The feasibility of recommending such a diet to patients in clinical practice is questionable. Diets of less than 500 kcal/d may be dangerous for patients with underlying comorbidities and are unlikely to serve as long-term solutions.²³ To contextualize our findings, a 2022 review by Chung et al⁴² examined the impact of various diets—low-caloric, gluten-free, Mediterranean, Western, and ketogenic—on psoriasis and reported insufficient evidence to suggest a benefit to the ketogenic diet for psoriasis patients, though the Mediterranean diet may be well suited for psoriasis patients because of improved cardiovascular health and reduced mortality.

Seborrheic Dermatitis—Sanders et al⁴³ found that patients with a high-fruit diet had lower odds of having SD, while those on a Western diet had higher odds of having SD. Although the study did not measure glycemic load, it is conceivable that the high glycemic load characteristic of the Western diet contributed to these findings.⁴³ However, no studies have investigated the direct link between low-glycemic or ketogenic diets and SD, leaving this area open for further study.

Atopic Dermatitis—It has been hypothesized that mitigating T cell–mediated inflammation via glucose control may contribute to the improvement in AD.^35,36 However, in one study, 16.5% of AD patients self-identified sugar as a dietary trigger, ranking fourth among other dietary triggers.²⁴ Thus, the connection between glucose levels and AD warrants further exploration.

Hidradenitis Suppurativa—Given the role of metabolic and hormonal influence in HS as well as the overlapping pathophysiology with acne, it is possible that low-glycemic and ketogenic diets may have a role in improving HS.^38-40 However, there is a gap in observation and controlled studies investigating the link between low-glycemic or ketogenic diets and HS.

Conclusion

Our analysis focused on interventional and observational research exploring the effects of low-glycemic and ketogenic diets on associations and treatment of inflammatory skin conditions. There is sufficient evidence to counsel acne patients on the benefits of a low-glycemic diet as an adjunctive treatment for acne. Currently, there is insufficient evidence to recommend a low-glycemic or ketogenic diet as a treatment for patients with any other inflammatory skin disease. Prospective and controlled clinical trials are needed to clarify the utility of dietary interventions for treating inflammatory skin conditions.

Inflammatory skin conditions often have a relapsing and remitting course and represent a large proportion of chronic skin diseases. Common inflammatory skin disorders include acne, psoriasis, hidradenitis suppurativa (HS), atopic dermatitis (AD), and seborrheic dermatitis (SD).¹ Although each of these conditions has a unique pathogenesis, they all are driven by a background of chronic inflammation. It has been reported that diets with high levels of refined carbohydrates and saturated or trans-fatty acids may exacerbate existing inflammation.² Consequently, dietary interventions, such as the ketogenic and low-glycemic diets, have potential anti-inflammatory and metabolic effects that are being assessed as stand-alone or adjunctive therapies for dermatologic diseases.

Diet may partially influence systemic inflammation through its effect on weight. Higher body mass index and obesity are linked to a low-grade inflammatory state and higher levels of circulating inflammatory markers. Therefore, weight loss leads to decreases in inflammatory cytokines, including C-reactive protein, tumor necrosis factor α, and IL-6.³ These cytokines and metabolic effects overlap with inflammatory skin condition pathways. It also is posited that decreased insulin release associated with weight loss results in decreased sebaceous lipogenesis and androgens, which drive keratinocyte proliferation and acne development.^4,5 For instance, in a 2015 meta-analysis of 5 randomized controlled trials on psoriasis, patients in the weight loss intervention group had more substantial reductions in psoriasis area and severity index (PASI) scores compared with controls receiving usual care (P=.004).⁶ However, in a systematic review of 35 studies on acne vulgaris, overweight and obese patients (defined by a body mass index of ≥23 kg/m²) had similar odds of having acne compared with normal-weight individuals (P=.671).⁷

Similar to weight loss, ketogenesis acts as a negative feedback mechanism to reduce insulin release, leading to decreased inflammation and androgens that often exacerbate inflammatory skin diseases.⁸ Ketogenesis ensues when daily carbohydrate intake is limited to less than 50 g, and long-term adherence to a ketogenic diet results in metabolic reliance on ketone bodies such as acetoacetate, β-hydroxybutyrate, and acetone.⁹ These metabolites may decrease free radical damage and consequently improve signs and symptoms of acne, psoriasis, and other inflammatory skin diseases.^10-12 Similarly, increased ketones also may decrease activation of the NLRP3 (NOD-, LRR-, and Pyrin domain-containing protein 3) inflammasome and therefore reduce inflammatory markers such as IL-1β and IL-1.^4,13 Several proposed mechanisms are outlined in the Table.

Collectively, low-glycemic and ketogenic diets have been proposed as potential interventions for reducing inflammatory skin conditions. These dietary approaches are hypothesized to exert their effects by facilitating weight loss, elevating ketone levels, and reducing systemic inflammation. The current review summarizes the existing evidence on ketogenic and low-glycemic diets as treatments for inflammatory skin conditions and evaluates the potential benefits of these dietary interventions in managing and improving outcomes for individuals with inflammatory skin conditions.

Methods

Using PubMed for articles indexed for MEDLINE and Google Scholar, a review of the literature was conducted with a combination of the following search terms: low-glycemic diet, inflammatory, dermatologic, ketogenic diet, inflammation, dermatology, acne, psoriasis, eczema, seborrheic dermatitis, and hidradenitis suppurativa. Reference citations in identified works also were reviewed. Interventional (experimental studies or clinical trials), survey-based, and observational studies that investigated the effects of low-glycemic or ketogenic diets for the treatment of inflammatory skin conditions were included. Inclusion criteria were studies assessing acne, psoriasis, SD, AD, and HS. Exclusion criteria were studies published before 1965; those written in languages other than English; and those analyzing other diets, such as the Mediterranean or low-fat diets. The search yielded a total of 11 observational studies and 4 controlled studies published between 1966 and January 2023. Because this analysis utilized publicly available data and did not qualify as human subject research, institutional review board approval was not required.

Results

Acne Vulgaris—Acne vulgaris is a disease of chronic pilosebaceous inflammation and follicular epithelial proliferation associated with Propionibacterium acnes. The association between acne and low-glycemic diets has been examined in several studies. Diet quality is measured and assessed using the glycemic index (GI), which is the effect of a single food on postprandial blood glucose, and the glycemic load, which is the GI adjusted for carbohydrates per serving.¹⁴ High levels of GI and glycemic load are associated with hyperinsulinemia and an increase in insulinlike growth factor 1 concentration that promotes mechanistic target of rapamycin (mTOR) complex 1–mediated follicular lipogenesis, sebum fatty acid production, and androgen synthesis.¹⁵Propionibacterium acnes directly activates toll-like receptor 2 on monocytes through damage-associated molecular patterns and indirectly through products of triglyceride catalysis, causing release of IL-12, IL-6, tumor necrosis factor α, and other proinflammatory cytokines.¹⁶ Therefore, lifestyle modifications focused on strict glucose control have been postulated to reduce acne severity via modulation of lipogenesis, androgen concentration, and inflammation.

Six survey-based studies evaluated sugar intake in patients with acne compared to healthy matched controls (eTable). Among these studies, 5 reported higher glycemic loads or daily sugar intake in acne patients compared to individuals without acne.^{12,19,20,26,28} The remaining study was conducted in 1967 and enrolled 16 acne patients and 32 matched controls. It reported no significant difference in sugar intake between the groups (P>.05).¹⁷

Smith et al¹⁸ randomized 43 male patients aged 15 to 25 years with facial acne into 2 cohorts for 12 weeks, each consuming either a low-glycemic diet (25% protein, 45% low-glycemic food [fruits, whole grains], and 30% fat) or a carbohydrate-dense diet of foods with medium to high GI based on prior documentation of the original diet. Patients were instructed to use a noncomedogenic cleanser as their only acne treatment. At 12 weeks, patients consuming the low-glycemic diet had an average of 23.5 fewer inflammatory lesions, while those in the intervention group had 12.0 fewer lesions (P=.03).¹⁸

In another controlled study by Kwon et al,²¹ 32 male and female acne patients were randomized to a low-glycemic diet (25% protein, 45% low-glycemic food, and 30% fat) or a standard diet for 10 weeks. Patients on the low-glycemic diet experienced a 70.9% reduction in inflammatory lesions (P<.05). Hematoxylin and eosin staining and image analysis were performed to measure sebaceous gland surface area in the low-glycemic diet group, which decreased from 0.32 to 0.24 mm² (P=.03). The sebaceous gland surface area in the control group was not reported. Moreover, patients on the low-glycemic diet had reduced IL-8 immunohistochemical staining (decreasing from 2.9 to 1.7 [P=.03]) and sterol regulatory element-binding protein 1 levels (decreasing from 2.6 to 1.3 [P=.03]), suggesting suppression of ongoing inflammation. Patients on the low-glycemic diet had no significant difference in transforming growth factor β1(P=.83). In the control group, there was no difference in IL-8, sterol regulatory element binding protein 1, or transforming growth factor β1 (P>.05) on immunohistochemical staining.²¹

Psoriasis—Psoriasis is a systemic inflammatory disease characterized by hyperproliferation and aberrant keratinocyte plaque formation. The innate immune response of keratinocytes in response to epidermal damage or infection begins with neutrophil recruitment and dendritic cell activation. Dendritic cell secretion of IL-23 promotes T-cell differentiation into helper T cells (T_H1) that subsequently secrete IL-17 and IL-22, thereby stimulating keratinocyte proliferation and eventual plaque formation. The relationship between diet and psoriasis is poorly understood; however, hyperinsulinemia is associated with greater severity of psoriasis.³¹ 

Four observational studies examined sugar intake in psoriasis patients. Barrea et al²³ conducted a survey-based study of 82 male participants (41 with psoriasis and 41 healthy controls), reporting that PASI score was correlated with intake of simple carbohydrates (percentage of total kilocalorie)(r=0.564, P<.001). Another study by Yamashita et al²⁷ found higher sugar intake in psoriasis patients than controls (P=.003) based on surveys from 70 patients with psoriasis and 70 matched healthy controls.

These findings contrast with 2 survey-based studies by Johnson et al²² and Afifi et al²⁵ of sugar intake in psoriasis patients using the National Health and Nutrition Examination Survey. Johnson et al²² reported reduced sugar intake among 156 psoriasis patients compared with 6104 unmatched controls (odds ratio, 0.998; CI, 0.996-1 [P=.04]) from 2003 to 2006. Similarly, Afifi et al²⁵ reported decreased sugar intake in 1206 psoriasis patients compared with sex- and age-matched controls (P<.0001) in 2009 and 2010. When patients were asked about dietary triggers, 13.8% of psoriasis patients reported sugar as the most common trigger, which was more frequent than alcohol (13.6%), gluten (7.2%), and dairy (6%).²⁵

Castaldo et al^29,30 published 2 nonrandomized clinical intervention studies in 2020 and 2021 evaluating the impact of the ketogenic diet on psoriasis. In the first study, 37 psoriasis patients followed a 10-week diet consisting of 4 weeks on a ketogenic diet (500 kcal/d) followed by 6 weeks on a low-caloric Mediterranean diet.²⁹ At the end of the intervention, there was a 17.4% reduction in PASI score, a 33.2-point reduction in itch severity score, and a 13.4-point reduction in the dermatology life quality index score; however, this study did not include a control diet group for comparison.²⁹ The second study included 30 psoriasis patients on a ketogenic diet and 30 control patients without psoriasis on a regular diet.³⁰ The ketogenic diet consisted of 400 to 500 g of vegetables, 20 to 30 g of fat, and a proportion of protein based on body weight with at least 12 g of whey protein and various amino acids. Patients on the ketogenic diet had significant reduction in PASI scores (value relative to clinical features, 1.4916 [P=.007]). Furthermore, concentrations of cytokines IL-2 (P=.04) and IL-1β (P=.006) decreased following the ketogenic diet but were not measured in the control group.³⁰

Seborrheic Dermatitis—Seborrheic dermatitis is associated with overcolonization of Malassezia species near lipid-rich sebaceous glands. Malassezia hydrolyzes free fatty acids, yielding oleic acids and leading to T-cell release of IL-8 and IL-17.³² Literature is sparse regarding how dietary modifications may play a role in disease severity. In a survey study, Bett et al¹⁷ compared 16 SD patients to 1:2 matched controls (N=29) to investigate the relationship between sugar consumption and presence of disease. Two control cohorts were selected, 1 from clinic patients diagnosed with verruca and 1 matched by age and sex from a survey-based study at a facility in London, England. Sugar intake was measured both in total grams per day and in “beverage sugar” per day, defined as sugar taken in tea and coffee. There was higher total sugar and higher beverage sugar intake among the SD group compared with both control groups (P<.05).¹⁷

Atopic Dermatitis—Atopic dermatitis is a disease of epidermal barrier dysfunction and IgE-mediated allergic sensitization.³³ There are several mechanisms by which skin structure may be disrupted. It is well established that filaggrin mutations inhibit stratum corneum maturation and lamellar matrix deposition.³⁴ Upregulation of IL-4–, IL-13–, and IL-17–secreting T_H2 cells also is associated with disruption of tight junctions and reduction of filaggrin.^35,36 Given that a T cell–mediated inflammatory response is involved in disease pathogenesis, glycemic control is hypothesized to have therapeutic potential.

Nosrati et al²⁴ surveyed 169 AD patients about their perceived dietary triggers through a 61-question survey based on the National Health and Nutrition Examination Survey. Respondents were queried about their perceptions and dietary changes, such as removal or addition of specific food groups and trial of specific diets. Overall, 16.5% of patients reported sugar being a trigger, making it the fourth most common among those surveyed and less common than dairy (24.8%), gluten (18.3%), and alcohol (17.1%).²⁴

Hidradenitis Suppurativa—Hidradenitis suppurativa is driven by hyperkeratosis, dilatation, and occlusion of pilosebaceous follicular ducts, whose eventual rupture evokes a local acute inflammatory response.³⁷ The inciting event for both acne and HS involves mTOR complex–mediated follicular hyperproliferation andinsulinlike growth factor 1 stimulation of androgen receptors in pilosebaceous glands. Given the similarities between the pathogenesis of acne and HS, it is hypothesized that lifestyle changes, including diet modification, may have a beneficial effect on HS.^38-40

Comment

Acne—Overall, there is strong evidence supporting the efficacy of a low-glycemic diet in the treatment of acne. Notably, among the 6 observational studies identified, there was 1 conflicting study by Bett et al¹⁷ that did not find a statistically significant difference in glucose intake between acne and control patients. However, this study included only 16 acne patients, whereas the other 5 observational studies included 32 to 2255 patients.¹⁷ The strongest evidence supporting low-glycemic dietary interventions in acne treatment is from 2 rigorous randomized clinical trials by Kwon et al²¹ and Smith et al.¹⁸ These trials used intention-to-treat models and maintained consistency in gender, age, and acne treatment protocols across both control and treatment groups. To ensure compliance with dietary interventions, daily telephone calls, food logs, and 24-hour urea sampling were utilized. Acne outcomes were assessed by a dermatologist who remained blinded with well-defined outcome measures. An important limitation of these studies is the difficulty in attributing the observed results solely to reduced glucose intake, as low-glycemic diets often lead to other dietary changes, including reduced fat intake and increased nutrient consumption.^18,21

A 2022 systematic review of acne by Meixiong et al⁴¹ further reinforced the beneficial effects of low-glycemic diets in the management of acne patients. The group reviewed 6 interventional studies and 28 observational studies to investigate the relationship among acne, dairy, and glycemic content and found an association between decreased glucose and dairy on reduction of acne.⁴¹

It is likely that the ketogenic diet, which limits glucose, would be beneficial for acne patients. There may be added benefit through elevated ketone bodies and substantially reduced insulin secretion. However, because there are no observational or interventional studies, further research is needed to draw firm conclusions regarding diet for acne treatment. A randomized clinical trial investigating the effects of the ketogenic diet compared to the low-glycemic diet compared to a regular diet would be valuable.

Psoriasis—Among psoriasis studies, there was a lack of consensus regarding glucose intake and correlation with disease. Among the 4 observational studies, 2 reported increased glucose intake among psoriasis patients and 2 reported decreased glucose intake. It is plausible that the variability in studies is due to differences in sample size and diet heterogeneity among study populations. More specifically, Johnson et al²² and Afifi et al²⁵ analyzed large sample sizes of 6260 and 2412 US participants, respectively, and found decreased sugar intake among psoriasis patients compared to controls. In comparison, Barrea et al²³ and Yamashita et al²⁷ analyzed substantially smaller and more specific populations consisting of 82 Italian and 140 Japanese participants, respectively; both reported increased glucose intake among psoriasis patients compared to controls. These seemingly antithetical results may be explained by regional dietary differences, with varying proportions of meats, vegetables, antioxidants, and vitamins.

Moreover, the variation among studies may be further explained by the high prevalence of comorbidities among psoriasis patients. In the study by Barrea et al,²³ psoriasis patients had higher fasting glucose (P=.004) and insulin (P=.022) levels than healthy patients. After adjusting for body mass index and metabolic syndrome, the correlation coefficient measuring the relationship between the PASI score and intake of simple carbohydrates changed from r=0.564 (P<.001) to r=0.352 (P=.028). The confounding impact of these comorbidities was further highlighted by Yamashita et al,²⁷ who found statistically significant differences in glucose intake between psoriasis and healthy patients (P=.003). However, they reported diminished significance on additional subgroup analysis accounting for potential comorbidities (P=.994).²⁷ Johnson et al²² and Afifi et al²⁵ did not account for comorbidities; therefore, the 4 observational study results must be interpreted cautiously.

The 2 randomized clinical trials by Castaldo et al^29,30 weakly suggest that a ketogenic diet may be beneficial for psoriasis patients. The studies have several notable limitations, including insufficient sample sizes and control groups. Thus, the decreased PASI scores reported in psoriasis patients on the ketogenic diets are challenging to interpret. Additionally, both studies placed patients on highly restrictive diets of 500 kcal/d for 4 weeks. The feasibility of recommending such a diet to patients in clinical practice is questionable. Diets of less than 500 kcal/d may be dangerous for patients with underlying comorbidities and are unlikely to serve as long-term solutions.²³ To contextualize our findings, a 2022 review by Chung et al⁴² examined the impact of various diets—low-caloric, gluten-free, Mediterranean, Western, and ketogenic—on psoriasis and reported insufficient evidence to suggest a benefit to the ketogenic diet for psoriasis patients, though the Mediterranean diet may be well suited for psoriasis patients because of improved cardiovascular health and reduced mortality.

Seborrheic Dermatitis—Sanders et al⁴³ found that patients with a high-fruit diet had lower odds of having SD, while those on a Western diet had higher odds of having SD. Although the study did not measure glycemic load, it is conceivable that the high glycemic load characteristic of the Western diet contributed to these findings.⁴³ However, no studies have investigated the direct link between low-glycemic or ketogenic diets and SD, leaving this area open for further study.

Atopic Dermatitis—It has been hypothesized that mitigating T cell–mediated inflammation via glucose control may contribute to the improvement in AD.^35,36 However, in one study, 16.5% of AD patients self-identified sugar as a dietary trigger, ranking fourth among other dietary triggers.²⁴ Thus, the connection between glucose levels and AD warrants further exploration.

Hidradenitis Suppurativa—Given the role of metabolic and hormonal influence in HS as well as the overlapping pathophysiology with acne, it is possible that low-glycemic and ketogenic diets may have a role in improving HS.^38-40 However, there is a gap in observation and controlled studies investigating the link between low-glycemic or ketogenic diets and HS.

Conclusion

Our analysis focused on interventional and observational research exploring the effects of low-glycemic and ketogenic diets on associations and treatment of inflammatory skin conditions. There is sufficient evidence to counsel acne patients on the benefits of a low-glycemic diet as an adjunctive treatment for acne. Currently, there is insufficient evidence to recommend a low-glycemic or ketogenic diet as a treatment for patients with any other inflammatory skin disease. Prospective and controlled clinical trials are needed to clarify the utility of dietary interventions for treating inflammatory skin conditions.

Inflammatory skin conditions often have a relapsing and remitting course and represent a large proportion of chronic skin diseases. Common inflammatory skin disorders include acne, psoriasis, hidradenitis suppurativa (HS), atopic dermatitis (AD), and seborrheic dermatitis (SD).¹ Although each of these conditions has a unique pathogenesis, they all are driven by a background of chronic inflammation. It has been reported that diets with high levels of refined carbohydrates and saturated or trans-fatty acids may exacerbate existing inflammation.² Consequently, dietary interventions, such as the ketogenic and low-glycemic diets, have potential anti-inflammatory and metabolic effects that are being assessed as stand-alone or adjunctive therapies for dermatologic diseases.

Diet may partially influence systemic inflammation through its effect on weight. Higher body mass index and obesity are linked to a low-grade inflammatory state and higher levels of circulating inflammatory markers. Therefore, weight loss leads to decreases in inflammatory cytokines, including C-reactive protein, tumor necrosis factor α, and IL-6.³ These cytokines and metabolic effects overlap with inflammatory skin condition pathways. It also is posited that decreased insulin release associated with weight loss results in decreased sebaceous lipogenesis and androgens, which drive keratinocyte proliferation and acne development.^4,5 For instance, in a 2015 meta-analysis of 5 randomized controlled trials on psoriasis, patients in the weight loss intervention group had more substantial reductions in psoriasis area and severity index (PASI) scores compared with controls receiving usual care (P=.004).⁶ However, in a systematic review of 35 studies on acne vulgaris, overweight and obese patients (defined by a body mass index of ≥23 kg/m²) had similar odds of having acne compared with normal-weight individuals (P=.671).⁷

Similar to weight loss, ketogenesis acts as a negative feedback mechanism to reduce insulin release, leading to decreased inflammation and androgens that often exacerbate inflammatory skin diseases.⁸ Ketogenesis ensues when daily carbohydrate intake is limited to less than 50 g, and long-term adherence to a ketogenic diet results in metabolic reliance on ketone bodies such as acetoacetate, β-hydroxybutyrate, and acetone.⁹ These metabolites may decrease free radical damage and consequently improve signs and symptoms of acne, psoriasis, and other inflammatory skin diseases.^10-12 Similarly, increased ketones also may decrease activation of the NLRP3 (NOD-, LRR-, and Pyrin domain-containing protein 3) inflammasome and therefore reduce inflammatory markers such as IL-1β and IL-1.^4,13 Several proposed mechanisms are outlined in the Table.

Collectively, low-glycemic and ketogenic diets have been proposed as potential interventions for reducing inflammatory skin conditions. These dietary approaches are hypothesized to exert their effects by facilitating weight loss, elevating ketone levels, and reducing systemic inflammation. The current review summarizes the existing evidence on ketogenic and low-glycemic diets as treatments for inflammatory skin conditions and evaluates the potential benefits of these dietary interventions in managing and improving outcomes for individuals with inflammatory skin conditions.

Methods

Using PubMed for articles indexed for MEDLINE and Google Scholar, a review of the literature was conducted with a combination of the following search terms: low-glycemic diet, inflammatory, dermatologic, ketogenic diet, inflammation, dermatology, acne, psoriasis, eczema, seborrheic dermatitis, and hidradenitis suppurativa. Reference citations in identified works also were reviewed. Interventional (experimental studies or clinical trials), survey-based, and observational studies that investigated the effects of low-glycemic or ketogenic diets for the treatment of inflammatory skin conditions were included. Inclusion criteria were studies assessing acne, psoriasis, SD, AD, and HS. Exclusion criteria were studies published before 1965; those written in languages other than English; and those analyzing other diets, such as the Mediterranean or low-fat diets. The search yielded a total of 11 observational studies and 4 controlled studies published between 1966 and January 2023. Because this analysis utilized publicly available data and did not qualify as human subject research, institutional review board approval was not required.

Results

Acne Vulgaris—Acne vulgaris is a disease of chronic pilosebaceous inflammation and follicular epithelial proliferation associated with Propionibacterium acnes. The association between acne and low-glycemic diets has been examined in several studies. Diet quality is measured and assessed using the glycemic index (GI), which is the effect of a single food on postprandial blood glucose, and the glycemic load, which is the GI adjusted for carbohydrates per serving.¹⁴ High levels of GI and glycemic load are associated with hyperinsulinemia and an increase in insulinlike growth factor 1 concentration that promotes mechanistic target of rapamycin (mTOR) complex 1–mediated follicular lipogenesis, sebum fatty acid production, and androgen synthesis.¹⁵Propionibacterium acnes directly activates toll-like receptor 2 on monocytes through damage-associated molecular patterns and indirectly through products of triglyceride catalysis, causing release of IL-12, IL-6, tumor necrosis factor α, and other proinflammatory cytokines.¹⁶ Therefore, lifestyle modifications focused on strict glucose control have been postulated to reduce acne severity via modulation of lipogenesis, androgen concentration, and inflammation.

Six survey-based studies evaluated sugar intake in patients with acne compared to healthy matched controls (eTable). Among these studies, 5 reported higher glycemic loads or daily sugar intake in acne patients compared to individuals without acne.^{12,19,20,26,28} The remaining study was conducted in 1967 and enrolled 16 acne patients and 32 matched controls. It reported no significant difference in sugar intake between the groups (P>.05).¹⁷

Smith et al¹⁸ randomized 43 male patients aged 15 to 25 years with facial acne into 2 cohorts for 12 weeks, each consuming either a low-glycemic diet (25% protein, 45% low-glycemic food [fruits, whole grains], and 30% fat) or a carbohydrate-dense diet of foods with medium to high GI based on prior documentation of the original diet. Patients were instructed to use a noncomedogenic cleanser as their only acne treatment. At 12 weeks, patients consuming the low-glycemic diet had an average of 23.5 fewer inflammatory lesions, while those in the intervention group had 12.0 fewer lesions (P=.03).¹⁸

In another controlled study by Kwon et al,²¹ 32 male and female acne patients were randomized to a low-glycemic diet (25% protein, 45% low-glycemic food, and 30% fat) or a standard diet for 10 weeks. Patients on the low-glycemic diet experienced a 70.9% reduction in inflammatory lesions (P<.05). Hematoxylin and eosin staining and image analysis were performed to measure sebaceous gland surface area in the low-glycemic diet group, which decreased from 0.32 to 0.24 mm² (P=.03). The sebaceous gland surface area in the control group was not reported. Moreover, patients on the low-glycemic diet had reduced IL-8 immunohistochemical staining (decreasing from 2.9 to 1.7 [P=.03]) and sterol regulatory element-binding protein 1 levels (decreasing from 2.6 to 1.3 [P=.03]), suggesting suppression of ongoing inflammation. Patients on the low-glycemic diet had no significant difference in transforming growth factor β1(P=.83). In the control group, there was no difference in IL-8, sterol regulatory element binding protein 1, or transforming growth factor β1 (P>.05) on immunohistochemical staining.²¹

Psoriasis—Psoriasis is a systemic inflammatory disease characterized by hyperproliferation and aberrant keratinocyte plaque formation. The innate immune response of keratinocytes in response to epidermal damage or infection begins with neutrophil recruitment and dendritic cell activation. Dendritic cell secretion of IL-23 promotes T-cell differentiation into helper T cells (T_H1) that subsequently secrete IL-17 and IL-22, thereby stimulating keratinocyte proliferation and eventual plaque formation. The relationship between diet and psoriasis is poorly understood; however, hyperinsulinemia is associated with greater severity of psoriasis.³¹ 

Four observational studies examined sugar intake in psoriasis patients. Barrea et al²³ conducted a survey-based study of 82 male participants (41 with psoriasis and 41 healthy controls), reporting that PASI score was correlated with intake of simple carbohydrates (percentage of total kilocalorie)(r=0.564, P<.001). Another study by Yamashita et al²⁷ found higher sugar intake in psoriasis patients than controls (P=.003) based on surveys from 70 patients with psoriasis and 70 matched healthy controls.

These findings contrast with 2 survey-based studies by Johnson et al²² and Afifi et al²⁵ of sugar intake in psoriasis patients using the National Health and Nutrition Examination Survey. Johnson et al²² reported reduced sugar intake among 156 psoriasis patients compared with 6104 unmatched controls (odds ratio, 0.998; CI, 0.996-1 [P=.04]) from 2003 to 2006. Similarly, Afifi et al²⁵ reported decreased sugar intake in 1206 psoriasis patients compared with sex- and age-matched controls (P<.0001) in 2009 and 2010. When patients were asked about dietary triggers, 13.8% of psoriasis patients reported sugar as the most common trigger, which was more frequent than alcohol (13.6%), gluten (7.2%), and dairy (6%).²⁵

Castaldo et al^29,30 published 2 nonrandomized clinical intervention studies in 2020 and 2021 evaluating the impact of the ketogenic diet on psoriasis. In the first study, 37 psoriasis patients followed a 10-week diet consisting of 4 weeks on a ketogenic diet (500 kcal/d) followed by 6 weeks on a low-caloric Mediterranean diet.²⁹ At the end of the intervention, there was a 17.4% reduction in PASI score, a 33.2-point reduction in itch severity score, and a 13.4-point reduction in the dermatology life quality index score; however, this study did not include a control diet group for comparison.²⁹ The second study included 30 psoriasis patients on a ketogenic diet and 30 control patients without psoriasis on a regular diet.³⁰ The ketogenic diet consisted of 400 to 500 g of vegetables, 20 to 30 g of fat, and a proportion of protein based on body weight with at least 12 g of whey protein and various amino acids. Patients on the ketogenic diet had significant reduction in PASI scores (value relative to clinical features, 1.4916 [P=.007]). Furthermore, concentrations of cytokines IL-2 (P=.04) and IL-1β (P=.006) decreased following the ketogenic diet but were not measured in the control group.³⁰

Seborrheic Dermatitis—Seborrheic dermatitis is associated with overcolonization of Malassezia species near lipid-rich sebaceous glands. Malassezia hydrolyzes free fatty acids, yielding oleic acids and leading to T-cell release of IL-8 and IL-17.³² Literature is sparse regarding how dietary modifications may play a role in disease severity. In a survey study, Bett et al¹⁷ compared 16 SD patients to 1:2 matched controls (N=29) to investigate the relationship between sugar consumption and presence of disease. Two control cohorts were selected, 1 from clinic patients diagnosed with verruca and 1 matched by age and sex from a survey-based study at a facility in London, England. Sugar intake was measured both in total grams per day and in “beverage sugar” per day, defined as sugar taken in tea and coffee. There was higher total sugar and higher beverage sugar intake among the SD group compared with both control groups (P<.05).¹⁷

Atopic Dermatitis—Atopic dermatitis is a disease of epidermal barrier dysfunction and IgE-mediated allergic sensitization.³³ There are several mechanisms by which skin structure may be disrupted. It is well established that filaggrin mutations inhibit stratum corneum maturation and lamellar matrix deposition.³⁴ Upregulation of IL-4–, IL-13–, and IL-17–secreting T_H2 cells also is associated with disruption of tight junctions and reduction of filaggrin.^35,36 Given that a T cell–mediated inflammatory response is involved in disease pathogenesis, glycemic control is hypothesized to have therapeutic potential.

Nosrati et al²⁴ surveyed 169 AD patients about their perceived dietary triggers through a 61-question survey based on the National Health and Nutrition Examination Survey. Respondents were queried about their perceptions and dietary changes, such as removal or addition of specific food groups and trial of specific diets. Overall, 16.5% of patients reported sugar being a trigger, making it the fourth most common among those surveyed and less common than dairy (24.8%), gluten (18.3%), and alcohol (17.1%).²⁴

Hidradenitis Suppurativa—Hidradenitis suppurativa is driven by hyperkeratosis, dilatation, and occlusion of pilosebaceous follicular ducts, whose eventual rupture evokes a local acute inflammatory response.³⁷ The inciting event for both acne and HS involves mTOR complex–mediated follicular hyperproliferation andinsulinlike growth factor 1 stimulation of androgen receptors in pilosebaceous glands. Given the similarities between the pathogenesis of acne and HS, it is hypothesized that lifestyle changes, including diet modification, may have a beneficial effect on HS.^38-40

Comment

Acne—Overall, there is strong evidence supporting the efficacy of a low-glycemic diet in the treatment of acne. Notably, among the 6 observational studies identified, there was 1 conflicting study by Bett et al¹⁷ that did not find a statistically significant difference in glucose intake between acne and control patients. However, this study included only 16 acne patients, whereas the other 5 observational studies included 32 to 2255 patients.¹⁷ The strongest evidence supporting low-glycemic dietary interventions in acne treatment is from 2 rigorous randomized clinical trials by Kwon et al²¹ and Smith et al.¹⁸ These trials used intention-to-treat models and maintained consistency in gender, age, and acne treatment protocols across both control and treatment groups. To ensure compliance with dietary interventions, daily telephone calls, food logs, and 24-hour urea sampling were utilized. Acne outcomes were assessed by a dermatologist who remained blinded with well-defined outcome measures. An important limitation of these studies is the difficulty in attributing the observed results solely to reduced glucose intake, as low-glycemic diets often lead to other dietary changes, including reduced fat intake and increased nutrient consumption.^18,21

A 2022 systematic review of acne by Meixiong et al⁴¹ further reinforced the beneficial effects of low-glycemic diets in the management of acne patients. The group reviewed 6 interventional studies and 28 observational studies to investigate the relationship among acne, dairy, and glycemic content and found an association between decreased glucose and dairy on reduction of acne.⁴¹

It is likely that the ketogenic diet, which limits glucose, would be beneficial for acne patients. There may be added benefit through elevated ketone bodies and substantially reduced insulin secretion. However, because there are no observational or interventional studies, further research is needed to draw firm conclusions regarding diet for acne treatment. A randomized clinical trial investigating the effects of the ketogenic diet compared to the low-glycemic diet compared to a regular diet would be valuable.

Psoriasis—Among psoriasis studies, there was a lack of consensus regarding glucose intake and correlation with disease. Among the 4 observational studies, 2 reported increased glucose intake among psoriasis patients and 2 reported decreased glucose intake. It is plausible that the variability in studies is due to differences in sample size and diet heterogeneity among study populations. More specifically, Johnson et al²² and Afifi et al²⁵ analyzed large sample sizes of 6260 and 2412 US participants, respectively, and found decreased sugar intake among psoriasis patients compared to controls. In comparison, Barrea et al²³ and Yamashita et al²⁷ analyzed substantially smaller and more specific populations consisting of 82 Italian and 140 Japanese participants, respectively; both reported increased glucose intake among psoriasis patients compared to controls. These seemingly antithetical results may be explained by regional dietary differences, with varying proportions of meats, vegetables, antioxidants, and vitamins.

Moreover, the variation among studies may be further explained by the high prevalence of comorbidities among psoriasis patients. In the study by Barrea et al,²³ psoriasis patients had higher fasting glucose (P=.004) and insulin (P=.022) levels than healthy patients. After adjusting for body mass index and metabolic syndrome, the correlation coefficient measuring the relationship between the PASI score and intake of simple carbohydrates changed from r=0.564 (P<.001) to r=0.352 (P=.028). The confounding impact of these comorbidities was further highlighted by Yamashita et al,²⁷ who found statistically significant differences in glucose intake between psoriasis and healthy patients (P=.003). However, they reported diminished significance on additional subgroup analysis accounting for potential comorbidities (P=.994).²⁷ Johnson et al²² and Afifi et al²⁵ did not account for comorbidities; therefore, the 4 observational study results must be interpreted cautiously.

The 2 randomized clinical trials by Castaldo et al^29,30 weakly suggest that a ketogenic diet may be beneficial for psoriasis patients. The studies have several notable limitations, including insufficient sample sizes and control groups. Thus, the decreased PASI scores reported in psoriasis patients on the ketogenic diets are challenging to interpret. Additionally, both studies placed patients on highly restrictive diets of 500 kcal/d for 4 weeks. The feasibility of recommending such a diet to patients in clinical practice is questionable. Diets of less than 500 kcal/d may be dangerous for patients with underlying comorbidities and are unlikely to serve as long-term solutions.²³ To contextualize our findings, a 2022 review by Chung et al⁴² examined the impact of various diets—low-caloric, gluten-free, Mediterranean, Western, and ketogenic—on psoriasis and reported insufficient evidence to suggest a benefit to the ketogenic diet for psoriasis patients, though the Mediterranean diet may be well suited for psoriasis patients because of improved cardiovascular health and reduced mortality.

Seborrheic Dermatitis—Sanders et al⁴³ found that patients with a high-fruit diet had lower odds of having SD, while those on a Western diet had higher odds of having SD. Although the study did not measure glycemic load, it is conceivable that the high glycemic load characteristic of the Western diet contributed to these findings.⁴³ However, no studies have investigated the direct link between low-glycemic or ketogenic diets and SD, leaving this area open for further study.

Atopic Dermatitis—It has been hypothesized that mitigating T cell–mediated inflammation via glucose control may contribute to the improvement in AD.^35,36 However, in one study, 16.5% of AD patients self-identified sugar as a dietary trigger, ranking fourth among other dietary triggers.²⁴ Thus, the connection between glucose levels and AD warrants further exploration.

Hidradenitis Suppurativa—Given the role of metabolic and hormonal influence in HS as well as the overlapping pathophysiology with acne, it is possible that low-glycemic and ketogenic diets may have a role in improving HS.^38-40 However, there is a gap in observation and controlled studies investigating the link between low-glycemic or ketogenic diets and HS.

Conclusion

Our analysis focused on interventional and observational research exploring the effects of low-glycemic and ketogenic diets on associations and treatment of inflammatory skin conditions. There is sufficient evidence to counsel acne patients on the benefits of a low-glycemic diet as an adjunctive treatment for acne. Currently, there is insufficient evidence to recommend a low-glycemic or ketogenic diet as a treatment for patients with any other inflammatory skin disease. Prospective and controlled clinical trials are needed to clarify the utility of dietary interventions for treating inflammatory skin conditions.

Practice Gap

Punch biopsies are utilized frequently by dermatologists to aid in the diagnosis of various skin diseases.¹ When performing a punch biopsy, dermatologists are taught to use either forceps or skin hooks in addition to scissors to extract the tissue from the skin.² However, the use of these sterile instruments for a simple biopsy adds extra costs to the procedure. Herein, a cheaper and often faster method of obtaining the specimen from the patient is described.

The Technique

A 3- or 4-mm disposable punch biopsy tool is employed for this method. After locally anesthetizing the skin, the skin is punched to a subcutaneous depth utilizing the full length of the blade and a little extra pressure is applied downward while stretching the skin around (Figure, A). This may be helpful to dislodge the punch specimen from the surrounding skin. The specimen now can be easily removed by gently grasping it with the thumb and index finger (Figure, B and C). It then can be transferred immediately to the formalin container.

Practice Implications

This technique saves time as well as financial and environmental costs associated with the use of sterile instruments. An additional advantage to this simple method is avoiding specimen crush injuries, which are common when using forceps. This solution works in most cases but may not be suitable for certain special anatomic locations such as the scalp, nose, and ears.

Practice Gap

Punch biopsies are utilized frequently by dermatologists to aid in the diagnosis of various skin diseases.¹ When performing a punch biopsy, dermatologists are taught to use either forceps or skin hooks in addition to scissors to extract the tissue from the skin.² However, the use of these sterile instruments for a simple biopsy adds extra costs to the procedure. Herein, a cheaper and often faster method of obtaining the specimen from the patient is described.

The Technique

A 3- or 4-mm disposable punch biopsy tool is employed for this method. After locally anesthetizing the skin, the skin is punched to a subcutaneous depth utilizing the full length of the blade and a little extra pressure is applied downward while stretching the skin around (Figure, A). This may be helpful to dislodge the punch specimen from the surrounding skin. The specimen now can be easily removed by gently grasping it with the thumb and index finger (Figure, B and C). It then can be transferred immediately to the formalin container.

Practice Implications

This technique saves time as well as financial and environmental costs associated with the use of sterile instruments. An additional advantage to this simple method is avoiding specimen crush injuries, which are common when using forceps. This solution works in most cases but may not be suitable for certain special anatomic locations such as the scalp, nose, and ears.

Practice Gap

Punch biopsies are utilized frequently by dermatologists to aid in the diagnosis of various skin diseases.¹ When performing a punch biopsy, dermatologists are taught to use either forceps or skin hooks in addition to scissors to extract the tissue from the skin.² However, the use of these sterile instruments for a simple biopsy adds extra costs to the procedure. Herein, a cheaper and often faster method of obtaining the specimen from the patient is described.

The Technique

A 3- or 4-mm disposable punch biopsy tool is employed for this method. After locally anesthetizing the skin, the skin is punched to a subcutaneous depth utilizing the full length of the blade and a little extra pressure is applied downward while stretching the skin around (Figure, A). This may be helpful to dislodge the punch specimen from the surrounding skin. The specimen now can be easily removed by gently grasping it with the thumb and index finger (Figure, B and C). It then can be transferred immediately to the formalin container.

Practice Implications

This technique saves time as well as financial and environmental costs associated with the use of sterile instruments. An additional advantage to this simple method is avoiding specimen crush injuries, which are common when using forceps. This solution works in most cases but may not be suitable for certain special anatomic locations such as the scalp, nose, and ears.