MDedge Dermatology

The results of a large French study comparing the cancer risk in children conceived through assisted reproductive technology (ART) with that of naturally conceived children were published recently in JAMA Network Open. This study is one of the largest to date on this subject: It included 8,526,306 children born in France between 2010 and 2021, of whom 260,236 (3%) were conceived through ART, and followed them up to a median age of 6.7 years.

Motivations for the Study

ART (including artificial insemination, in vitro fertilization [IVF], or intracytoplasmic sperm injection [ICSI] with fresh or frozen embryo transfer) accounts for about 1 in 30 births in France. However, limited and heterogeneous data have suggested an increased risk for certain health disorders, including cancer, among children conceived through ART. Therefore, a large-scale evaluation of cancer risk in these children is important.

No Overall Increase

In all, 9256 children developed cancer, including 292 who were conceived through ART. Thus, this study did not show an increased risk for cancer (of all types combined) in children conceived through ART. Nevertheless, a slight increase in the risk for leukemia was observed in children conceived through IVF or ICSI. The investigators observed approximately one additional case for every 5000 newborns conceived through IVF or ICSI who reached age 10 years.

Epidemiological monitoring should be continued to better evaluate long-term risks and see whether the risk for leukemia is confirmed. If it is, then it will be useful to investigate the mechanisms related to ART techniques or the fertility disorders of parents that could lead to an increased risk for leukemia.

This story was translated from Univadis France, which is part of the Medscape Professional Network, using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article appeared on Medscape.com.

The results of a large French study comparing the cancer risk in children conceived through assisted reproductive technology (ART) with that of naturally conceived children were published recently in JAMA Network Open. This study is one of the largest to date on this subject: It included 8,526,306 children born in France between 2010 and 2021, of whom 260,236 (3%) were conceived through ART, and followed them up to a median age of 6.7 years.

Motivations for the Study

ART (including artificial insemination, in vitro fertilization [IVF], or intracytoplasmic sperm injection [ICSI] with fresh or frozen embryo transfer) accounts for about 1 in 30 births in France. However, limited and heterogeneous data have suggested an increased risk for certain health disorders, including cancer, among children conceived through ART. Therefore, a large-scale evaluation of cancer risk in these children is important.

No Overall Increase

In all, 9256 children developed cancer, including 292 who were conceived through ART. Thus, this study did not show an increased risk for cancer (of all types combined) in children conceived through ART. Nevertheless, a slight increase in the risk for leukemia was observed in children conceived through IVF or ICSI. The investigators observed approximately one additional case for every 5000 newborns conceived through IVF or ICSI who reached age 10 years.

Epidemiological monitoring should be continued to better evaluate long-term risks and see whether the risk for leukemia is confirmed. If it is, then it will be useful to investigate the mechanisms related to ART techniques or the fertility disorders of parents that could lead to an increased risk for leukemia.

This story was translated from Univadis France, which is part of the Medscape Professional Network, using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article appeared on Medscape.com.

The results of a large French study comparing the cancer risk in children conceived through assisted reproductive technology (ART) with that of naturally conceived children were published recently in JAMA Network Open. This study is one of the largest to date on this subject: It included 8,526,306 children born in France between 2010 and 2021, of whom 260,236 (3%) were conceived through ART, and followed them up to a median age of 6.7 years.

Motivations for the Study

ART (including artificial insemination, in vitro fertilization [IVF], or intracytoplasmic sperm injection [ICSI] with fresh or frozen embryo transfer) accounts for about 1 in 30 births in France. However, limited and heterogeneous data have suggested an increased risk for certain health disorders, including cancer, among children conceived through ART. Therefore, a large-scale evaluation of cancer risk in these children is important.

No Overall Increase

In all, 9256 children developed cancer, including 292 who were conceived through ART. Thus, this study did not show an increased risk for cancer (of all types combined) in children conceived through ART. Nevertheless, a slight increase in the risk for leukemia was observed in children conceived through IVF or ICSI. The investigators observed approximately one additional case for every 5000 newborns conceived through IVF or ICSI who reached age 10 years.

Epidemiological monitoring should be continued to better evaluate long-term risks and see whether the risk for leukemia is confirmed. If it is, then it will be useful to investigate the mechanisms related to ART techniques or the fertility disorders of parents that could lead to an increased risk for leukemia.

This story was translated from Univadis France, which is part of the Medscape Professional Network, using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article appeared on Medscape.com.

Melasma is an acquired hyperpigmentation disorder characterized by irregular brown macules and patches that usually appear on sun-exposed areas of the skin. The term melasma originates from the Greek word melas meaning black.¹ Facial melasma is divided into 2 groups according to its clinical distribution: centrofacial lesions are located in the center of the face (eg, the glabellar, frontal, nasal, zygomatic, upper lip, chin areas), and peripheral lesions manifest on the frontotemporal, preauricular, and mandibular regions.^1,2 There is debate on the categorization of zygomatic (or malar) melasma; some researchers argue it should be categorized independent of other areas, while others include malar melasma in the centrofacial group because of its frequent association with the centrofacial type, especially with glabellar lesions.² Mandibular melasma is rare and occurs mostly in postmenopausal women after intense sun exposure.^1,2 Although the etiopathogenesis of the disease is not clearly known, increased melanogenesis, extracellular matrix alterations, inflammation, and angiogenesis are assumed to play a role.³ Various risk factors such as genetic predisposition, UV radiation (UVR) exposure, pregnancy, thyroid dysfunction, and exogenous hormones (eg, oral contraceptives, hormone replacement therapy) have been identified; phototoxic drugs, anticonvulsants, and some cosmetics also have been implicated.^4,5 Exposure to UVR is thought to be the main triggering environmental factor by inducing both melanin production and oxidative stress.⁵ However, it also has been shown that visible light can induce hyperpigmentation in darker skin types.⁶

The presence of oxidative stress in melasma recently has become an intriguing topic of interest. First, the presence of oxidative stress in the etiopathogenesis of melasma was thought to be based on the effectiveness of antioxidants in treatment. A few studies also have confirmed the presence of oxidative stress in melasma.^7-10 Classically, oxidative stress can be described as a disturbance in the balance between oxidants and antioxidants. Reactive oxygen species (ROS) are highly reactive molecules due to the unpaired electrons in their structure. Although ROS are present at low levels in physiologic conditions and are involved in critical physiologic events, they damage cellular components such as fat, protein, and nucleic acid at high concentrations.⁵

Dynamic thiol/disulfide homeostasis is one of the most important markers of oxidative stress in biological systems. Thiols are organic compounds containing a sulfhydryl (-SH) group. Thiols are considered highly potent antioxidants because they reduce unstable free radicals by donating electrons. They are the first antioxidants to be depleted in an oxidative environment.^11,12 In case of oxidative stress, they transform into reversible forms called disulfide bridges between 2 thiol groups. Disulfide bridges can be reduced back to thiol groups, which is how dynamic thiol/disulfide homeostasis is maintained. Dynamic thiol/disulfide homeostasis is responsible for cellular events such as antioxidant defense, signal transduction, regulation of enzyme function, and apoptosis.^11,12

The aim of this study was to evaluate the presence of oxidative stress in melasma by comparing dynamic thiol/disulfide homeostasis in patients with melasma compared with age- and sex-matched healthy controls.

Materials and Methods

Participants and Eligibility Criteria—We conducted a prospective study in a tertiary-care hospital (Ankara Bilkent City Hospital [Ankara, Turkey]) of patients with melasma who were followed from October 2021 to October 2022 compared with age- and sex-matched healthy volunteers. Ethics committee approval was obtained from Ankara Bilkent City Hospital before the study (E2-21-881)(13.10.2021). Written informed consent was obtained from all participants, and all were older than 18 years. Patients were excluded if there was the presence of any systemic disease or dermatologic disease other than melasma; smoking or alcohol use; any use of vitamins, food supplements, or any medication in the last 3 months; or pregnancy.

Melasma Severity—The modified melasma area and severity index (mMASI) score was used to determine the severity of melasma. The score is calculated from assessments of the darkness of the pigmentation and the percentage of affected area on the face. The mMASI score is the sum of the darkness score (D); area score (A); and separate fixed coefficients for the forehead, as well as the right malar, left malar, and chin regions.¹³ The mMASI score, with a range of 0 to 24, is a reliable and objective marker in the calculation of melasma severity.⁴

Biochemical Analysis of Samples—The 6-cc peripheral fasting venous blood samples obtained from the study participants were centrifuged at 1500 g for 10 minutes, and the separated sera were stored in a freezer at −80 °C until the time of analysis. When the study was completed, the disulfide and thiol values were analyzed. Serum native and total thiol concentrations indicating thiol/disulfide homeostasis were calculated by a new fully automatic colorimetric method developed by Erel and Neselioglu.¹⁴ Using this method, short disulfide bonds are first reduced with sodium borohydride solution to form free-functional thiol groups, and then the unused sodium borohydride is removed using formaldehyde. Finally, all thiol groups are reacted with 5,5’-dithiobis-(2-nitrobenzoic) acid (Ellman reagent), and all thiol groups are detected after reaction with 5,5’-dithiobis-(2-nitrobenzoic) acid. When a disulfide bond (−S−S−) is reduced, 2 thiol groups are formed. For this reason, half of the difference between total thiol (-SH + the amount of thiol formed by the reduction of disulfides) and native thiol (-SH) corresponds to the dynamic disulfide amount (total thiol − native thiol/2).¹⁴

Statistical Analysis—Statistical analysis was performed using SPSS software (version 24.0). Descriptive statistics were presented as numbers and percentages for categorical variables, and numerical variables were presented as mean, SD, median, minimum, maximum, 25th quartile, and 75th quartile. The conformity of the variables to normal distribution was examined using visual (histograms and probability plots) and analytical methods (Kolmogorov-Smirnov/Shapiro-Wilk tests). In pairwise group comparisons for numerical variables, a Mann-Whitney U test was used when normal distribution was not met, and a t test was used when normal distribution was met. The statistical significance level was accepted as P<.05.

Results

Our study included 67 patients with melasma and 41 healthy age- and sex-matched controls. Of the participants with melasma, 60 (89.5%) were female and 7 (10.5%) were male. The control group was similar to the melasma group in terms of sex (87.8% female vs 12.2% male [P=.59]). The mean age (SD) was 33.1 (6.7) years in the melasma group and 31.9 (6.7) years in the control group. Age was similar across both groups (P=.41). All participants were of Asian race, and Fitzpatrick skin types (types II–IV) were similar across both groups.

Fifty-four (80.6%) participants had centrofacial melasma and 13 (19.4%) had mixed-type melasma. The mMASI score ranged from 3 to 20; the mean (SD) mMASI score was 11.28 (3.2). Disease duration ranged from 2 to 72 months; the mean (SD) disease duration was 12.26 (6.3) months. The demographics and clinical characteristics of the study group are shown in eTable 1.

eTable 2 provides a summary of disulfide, native thiol, and total thiol levels, as well as disulfide/native thiol, disulfide/total thiol, and native thiol/total thiol ratios in the study population. Disulfide/native thiol and disulfide/total thiol ratios were higher in melasma patients (Figure 1), whereas the native thiol/total thiol ratio was higher in the control group (P=.025, P=.025, and P=.026, respectively).

All correlations between age, disease duration, and mMASI scores and disulfide, native thiol, and total thiol levels, as well as disulfide/native thiol, disulfide/total thiol, and native thiol/total thiol ratios, are summarized in eTable 3. No significant correlation was observed between age and disease duration and disulfide, native thiol, and total thiol levels or disulfide/native thiol, disulfide/total thiol, and native thiol/total thiol ratios.

We independently assessed whether Fitzpatrick skin types II, III, and IV exhibited distinct levels of oxidative stress in clinical melasma. There were no significant correlations with Fitzpatrick skin type (disulfide/native thiol, P=.25; disulfide/total thiol, P=.19). We further evaluated if the thiol/disulfide parameters were correlated with duration of melasma by dividing the melasma patients into 3 groups (<6 months [n=12], 6–18 months [n=32], >18 months [n=23]), but there was not any significant correlation (disulfide/native thiol, P=.15; disulfide/total thiol, P=.15). We also divided our patients into 3 groups according to age (<27 years [n=14], 27–36 years [n=33], >36 years [n=20]). There was no correlation of the parameters with age (disulfide/native thiol, P=.15; disulfide/total thiol, P=.14).

There was a positive correlation between mMASI score and disulfide, native thiol, and total thiol levels and disulfide/native thiol and disulfide/total thiol ratios, as well as a negative correlation between mMASI score and native thiol/total thiol ratio. The correlations between mMASI scores and disulfide/native thiol and disulfide/total thiol ratios are shown in Figure 2 and eTable 3.

Comment

Melasma is a common condition that may cause psychosocial problems in affected patients and negatively affect quality of life.¹ It occurs in all races but is more common in individuals with darker skin types (eg, Fitzpatrick skin types III and IV). Although melasma is more common in women during reproductive years (50%–70%), it also has been observed in 10% to 30% of men.⁵

Treatment options include topical bleaching agents, chemical peels, and laser therapy, as well as discontinuation of medications that may potentially trigger melasma; use of broad-spectrum sunscreens also is recommended.⁴ Vitamins A, C, and E, as well as niacinamide, are used in the treatment of melasma, especially for their antioxidant properties. The key role of antioxidants in the treatment of melasma supports the importance of oxidative stress in the pathogenesis.⁷ Melasma often is challenging to treat, particularly the mixed or dermal types, due to their stubborn nature. This condition poses a considerable therapeutic challenge for dermatologists.⁴

Oxidative stress and oxidant-antioxidant imbalance previously have been studied in various diseases, but research investigating the presence of oxidative stress in melasma are limited.^7-10 Exposure of the skin to polluted air and intense UVR, as well as some food by-products, cosmetics, and drugs (eg, oral contraceptives), can directly or indirectly cause ROS production in the skin. Reactive oxygen species are thought to be involved in the pathophysiology of melasma by affecting apoptotic pathways and causing cell proliferation. The intermediate heme pathway has pro-oxidant effects and produces ROS and metabolites such as redox-active quinines. Exposure to UVR leads to the generation of ROS, highlighting the role of oxidative stress in the onset of melasma. ⁵

In any cutaneous disease in which oxidative stress plays a role, oxidant and antioxidant levels may be expected to vary both locally and systemically; however, measurement of oxidative stress markers in serum instead of skin is technically and economically more advantageous.⁸ Firstly, serum collection is less invasive and technically simpler than skin biopsies. Drawing blood is a routine procedure that requires minimal specialized equipment and training compared to the extraction and processing of skin samples. Secondly, analyzing serum samples generally is less expensive than processing skin tissue.⁸

In our study, we evaluated dynamic thiol/disulfide homeostasis in serum to investigate the presence of oxidative stress in the setting of melasma. Functional sulfhydryl (-SH) groups in thiols act as substrates for antioxidant enzymes and as free-radical scavengers. They constitute one of the most powerful defense systems against the unwanted effects of ROS. Thiols, which become the main target of ROS under oxidative stress, oxidize with oxidant molecules and form disulfide bridges.¹⁵

Thiol/disulfide homeostasis has been studied many times in dermatologic diseases,^16-19 and the results obtained from these studies are heterogenous depending on the extent of oxidative damage. It has been shown that thiol/disulfide homeostasis plays a role in oxidative stress in conditions such as psoriasis,¹⁷ seborrheic dermatitis,¹¹ atopic dermatitits,¹⁸ and rosacea.¹⁹ In our study, disulfide/native thiol and disulfide/total thiol levels were significantly higher (both P=.025) in the melasma group compared with the control group, which indicates that the thiol/disulfide balance in patients with melasma is shifted to disulfide formation and thiols are oxidized to disulfide bonds in the presence of oxidative stress.

Seçkin et al⁷ evaluated the role of oxidative stress in the pathogenesis of melasma and found that the serum levels of the antioxidants superoxide dismutase and glutathione peroxidase were significantly higher in the patient group compared with the control group (both P<.001). They also found that the levels of nitric oxide (another antioxidant) were increased in the patient group and the levels of protein carbonyl (an oxidative metabolite) were significantly lower (both P<.001). These findings indicated that free-radical damage may be involved in the pathogenesis of melasma.⁷

In a study of 75 patients with melasma, serum levels of the antioxidants melatonin and catalase were significantly (P<.001 and P=.001, respectively) lower in the melasma group compared with the control group, while serum levels of the oxidants protein carbonyl and nitric oxide were significantly higher (P=.002 and P=.001, respectively). No significant correlation was found between oxidative stress parameters and melasma severity.⁸

Choubey et al⁹ found that serum malondialdehyde (an end product of lipid peroxidation), superoxide dismutase, and glutathione peroxidase levels were significantly higher in the melasma group (n=50) compared with the control group (n=50)(all P<.001). In addition, a significant positive correlation (correlation coefficient, +0.307; P<.05) was found between serum malondialdehyde levels and melasma severity. The mean age (SD) of the patients was 32.22 (6.377) years, and the female (n=41) to male (n=9) ratio was 4.55:1. The most common melasma pattern was centrofacial, followed by malar.⁹

In a study with 50 melasma patients and 50 controls, Rahimi et al¹⁰ examined bilirubin and uric acid levels, which are major extracellular antioxidants. The mean age (SD) at disease onset was 32.6 (6.7) years, and the mean MASI score (SD) was 18.1 (9). Serum bilirubin levels were found to be higher in the melasma group than in the control group and were correlated with disease severity. No significant difference in uric acid levels was found between the groups, and no correlation was found between MASI score and bilirubin and uric acid levels.¹⁰

In our study, the melasma group was similar to those in other reportsin the literature regarding gender distribution, mean age, and melasma pattern.^7-10 Additionally, the correlation of mMASI score with disulfide/native thiol and disulfide/total thiol values in the melasma group suggested that oxidative stress also is correlated with melasma severity.

Thiol-based treatments such as n-acetyl cysteine, which contains a thiol compound, may be helpful in melasma.²⁰ In a double-blind, placebo-controlled study, topical n-acetyl cysteine combined with hydroquinone 2% was used in 10 female patients with melasma. Mild to strong bleaching of the skin was observed in 90% (9/10) of the patients.²¹ Systemic use of n-acetyl cysteine in melasma also may be a potential research topic.

Major limitations of our study were the small sample size and lack of measurement of oxidative stress parameters in the skin concurrently with serum.

Conclusion

In our study, the presence of oxidative stress in melasma was demonstrated by evaluating thiol/disulfide homeostasis—one of the strongest markers of oxidative stress. Oxidative stress also correlated with melasma disease severity in our analysis. The data obtained in this study may contribute to understanding the etiopathogenesis of melasma and may open new horizons in treatment; however, more comprehensive studies should be conducted to support our findings.

Melasma is an acquired hyperpigmentation disorder characterized by irregular brown macules and patches that usually appear on sun-exposed areas of the skin. The term melasma originates from the Greek word melas meaning black.¹ Facial melasma is divided into 2 groups according to its clinical distribution: centrofacial lesions are located in the center of the face (eg, the glabellar, frontal, nasal, zygomatic, upper lip, chin areas), and peripheral lesions manifest on the frontotemporal, preauricular, and mandibular regions.^1,2 There is debate on the categorization of zygomatic (or malar) melasma; some researchers argue it should be categorized independent of other areas, while others include malar melasma in the centrofacial group because of its frequent association with the centrofacial type, especially with glabellar lesions.² Mandibular melasma is rare and occurs mostly in postmenopausal women after intense sun exposure.^1,2 Although the etiopathogenesis of the disease is not clearly known, increased melanogenesis, extracellular matrix alterations, inflammation, and angiogenesis are assumed to play a role.³ Various risk factors such as genetic predisposition, UV radiation (UVR) exposure, pregnancy, thyroid dysfunction, and exogenous hormones (eg, oral contraceptives, hormone replacement therapy) have been identified; phototoxic drugs, anticonvulsants, and some cosmetics also have been implicated.^4,5 Exposure to UVR is thought to be the main triggering environmental factor by inducing both melanin production and oxidative stress.⁵ However, it also has been shown that visible light can induce hyperpigmentation in darker skin types.⁶

The presence of oxidative stress in melasma recently has become an intriguing topic of interest. First, the presence of oxidative stress in the etiopathogenesis of melasma was thought to be based on the effectiveness of antioxidants in treatment. A few studies also have confirmed the presence of oxidative stress in melasma.^7-10 Classically, oxidative stress can be described as a disturbance in the balance between oxidants and antioxidants. Reactive oxygen species (ROS) are highly reactive molecules due to the unpaired electrons in their structure. Although ROS are present at low levels in physiologic conditions and are involved in critical physiologic events, they damage cellular components such as fat, protein, and nucleic acid at high concentrations.⁵

Dynamic thiol/disulfide homeostasis is one of the most important markers of oxidative stress in biological systems. Thiols are organic compounds containing a sulfhydryl (-SH) group. Thiols are considered highly potent antioxidants because they reduce unstable free radicals by donating electrons. They are the first antioxidants to be depleted in an oxidative environment.^11,12 In case of oxidative stress, they transform into reversible forms called disulfide bridges between 2 thiol groups. Disulfide bridges can be reduced back to thiol groups, which is how dynamic thiol/disulfide homeostasis is maintained. Dynamic thiol/disulfide homeostasis is responsible for cellular events such as antioxidant defense, signal transduction, regulation of enzyme function, and apoptosis.^11,12

The aim of this study was to evaluate the presence of oxidative stress in melasma by comparing dynamic thiol/disulfide homeostasis in patients with melasma compared with age- and sex-matched healthy controls.

Materials and Methods

Participants and Eligibility Criteria—We conducted a prospective study in a tertiary-care hospital (Ankara Bilkent City Hospital [Ankara, Turkey]) of patients with melasma who were followed from October 2021 to October 2022 compared with age- and sex-matched healthy volunteers. Ethics committee approval was obtained from Ankara Bilkent City Hospital before the study (E2-21-881)(13.10.2021). Written informed consent was obtained from all participants, and all were older than 18 years. Patients were excluded if there was the presence of any systemic disease or dermatologic disease other than melasma; smoking or alcohol use; any use of vitamins, food supplements, or any medication in the last 3 months; or pregnancy.

Melasma Severity—The modified melasma area and severity index (mMASI) score was used to determine the severity of melasma. The score is calculated from assessments of the darkness of the pigmentation and the percentage of affected area on the face. The mMASI score is the sum of the darkness score (D); area score (A); and separate fixed coefficients for the forehead, as well as the right malar, left malar, and chin regions.¹³ The mMASI score, with a range of 0 to 24, is a reliable and objective marker in the calculation of melasma severity.⁴

Biochemical Analysis of Samples—The 6-cc peripheral fasting venous blood samples obtained from the study participants were centrifuged at 1500 g for 10 minutes, and the separated sera were stored in a freezer at −80 °C until the time of analysis. When the study was completed, the disulfide and thiol values were analyzed. Serum native and total thiol concentrations indicating thiol/disulfide homeostasis were calculated by a new fully automatic colorimetric method developed by Erel and Neselioglu.¹⁴ Using this method, short disulfide bonds are first reduced with sodium borohydride solution to form free-functional thiol groups, and then the unused sodium borohydride is removed using formaldehyde. Finally, all thiol groups are reacted with 5,5’-dithiobis-(2-nitrobenzoic) acid (Ellman reagent), and all thiol groups are detected after reaction with 5,5’-dithiobis-(2-nitrobenzoic) acid. When a disulfide bond (−S−S−) is reduced, 2 thiol groups are formed. For this reason, half of the difference between total thiol (-SH + the amount of thiol formed by the reduction of disulfides) and native thiol (-SH) corresponds to the dynamic disulfide amount (total thiol − native thiol/2).¹⁴

Statistical Analysis—Statistical analysis was performed using SPSS software (version 24.0). Descriptive statistics were presented as numbers and percentages for categorical variables, and numerical variables were presented as mean, SD, median, minimum, maximum, 25th quartile, and 75th quartile. The conformity of the variables to normal distribution was examined using visual (histograms and probability plots) and analytical methods (Kolmogorov-Smirnov/Shapiro-Wilk tests). In pairwise group comparisons for numerical variables, a Mann-Whitney U test was used when normal distribution was not met, and a t test was used when normal distribution was met. The statistical significance level was accepted as P<.05.

Results

Our study included 67 patients with melasma and 41 healthy age- and sex-matched controls. Of the participants with melasma, 60 (89.5%) were female and 7 (10.5%) were male. The control group was similar to the melasma group in terms of sex (87.8% female vs 12.2% male [P=.59]). The mean age (SD) was 33.1 (6.7) years in the melasma group and 31.9 (6.7) years in the control group. Age was similar across both groups (P=.41). All participants were of Asian race, and Fitzpatrick skin types (types II–IV) were similar across both groups.

Fifty-four (80.6%) participants had centrofacial melasma and 13 (19.4%) had mixed-type melasma. The mMASI score ranged from 3 to 20; the mean (SD) mMASI score was 11.28 (3.2). Disease duration ranged from 2 to 72 months; the mean (SD) disease duration was 12.26 (6.3) months. The demographics and clinical characteristics of the study group are shown in eTable 1.

eTable 2 provides a summary of disulfide, native thiol, and total thiol levels, as well as disulfide/native thiol, disulfide/total thiol, and native thiol/total thiol ratios in the study population. Disulfide/native thiol and disulfide/total thiol ratios were higher in melasma patients (Figure 1), whereas the native thiol/total thiol ratio was higher in the control group (P=.025, P=.025, and P=.026, respectively).

All correlations between age, disease duration, and mMASI scores and disulfide, native thiol, and total thiol levels, as well as disulfide/native thiol, disulfide/total thiol, and native thiol/total thiol ratios, are summarized in eTable 3. No significant correlation was observed between age and disease duration and disulfide, native thiol, and total thiol levels or disulfide/native thiol, disulfide/total thiol, and native thiol/total thiol ratios.

We independently assessed whether Fitzpatrick skin types II, III, and IV exhibited distinct levels of oxidative stress in clinical melasma. There were no significant correlations with Fitzpatrick skin type (disulfide/native thiol, P=.25; disulfide/total thiol, P=.19). We further evaluated if the thiol/disulfide parameters were correlated with duration of melasma by dividing the melasma patients into 3 groups (<6 months [n=12], 6–18 months [n=32], >18 months [n=23]), but there was not any significant correlation (disulfide/native thiol, P=.15; disulfide/total thiol, P=.15). We also divided our patients into 3 groups according to age (<27 years [n=14], 27–36 years [n=33], >36 years [n=20]). There was no correlation of the parameters with age (disulfide/native thiol, P=.15; disulfide/total thiol, P=.14).

There was a positive correlation between mMASI score and disulfide, native thiol, and total thiol levels and disulfide/native thiol and disulfide/total thiol ratios, as well as a negative correlation between mMASI score and native thiol/total thiol ratio. The correlations between mMASI scores and disulfide/native thiol and disulfide/total thiol ratios are shown in Figure 2 and eTable 3.

Comment

Melasma is a common condition that may cause psychosocial problems in affected patients and negatively affect quality of life.¹ It occurs in all races but is more common in individuals with darker skin types (eg, Fitzpatrick skin types III and IV). Although melasma is more common in women during reproductive years (50%–70%), it also has been observed in 10% to 30% of men.⁵

Treatment options include topical bleaching agents, chemical peels, and laser therapy, as well as discontinuation of medications that may potentially trigger melasma; use of broad-spectrum sunscreens also is recommended.⁴ Vitamins A, C, and E, as well as niacinamide, are used in the treatment of melasma, especially for their antioxidant properties. The key role of antioxidants in the treatment of melasma supports the importance of oxidative stress in the pathogenesis.⁷ Melasma often is challenging to treat, particularly the mixed or dermal types, due to their stubborn nature. This condition poses a considerable therapeutic challenge for dermatologists.⁴

Oxidative stress and oxidant-antioxidant imbalance previously have been studied in various diseases, but research investigating the presence of oxidative stress in melasma are limited.^7-10 Exposure of the skin to polluted air and intense UVR, as well as some food by-products, cosmetics, and drugs (eg, oral contraceptives), can directly or indirectly cause ROS production in the skin. Reactive oxygen species are thought to be involved in the pathophysiology of melasma by affecting apoptotic pathways and causing cell proliferation. The intermediate heme pathway has pro-oxidant effects and produces ROS and metabolites such as redox-active quinines. Exposure to UVR leads to the generation of ROS, highlighting the role of oxidative stress in the onset of melasma. ⁵

In any cutaneous disease in which oxidative stress plays a role, oxidant and antioxidant levels may be expected to vary both locally and systemically; however, measurement of oxidative stress markers in serum instead of skin is technically and economically more advantageous.⁸ Firstly, serum collection is less invasive and technically simpler than skin biopsies. Drawing blood is a routine procedure that requires minimal specialized equipment and training compared to the extraction and processing of skin samples. Secondly, analyzing serum samples generally is less expensive than processing skin tissue.⁸

In our study, we evaluated dynamic thiol/disulfide homeostasis in serum to investigate the presence of oxidative stress in the setting of melasma. Functional sulfhydryl (-SH) groups in thiols act as substrates for antioxidant enzymes and as free-radical scavengers. They constitute one of the most powerful defense systems against the unwanted effects of ROS. Thiols, which become the main target of ROS under oxidative stress, oxidize with oxidant molecules and form disulfide bridges.¹⁵

Thiol/disulfide homeostasis has been studied many times in dermatologic diseases,^16-19 and the results obtained from these studies are heterogenous depending on the extent of oxidative damage. It has been shown that thiol/disulfide homeostasis plays a role in oxidative stress in conditions such as psoriasis,¹⁷ seborrheic dermatitis,¹¹ atopic dermatitits,¹⁸ and rosacea.¹⁹ In our study, disulfide/native thiol and disulfide/total thiol levels were significantly higher (both P=.025) in the melasma group compared with the control group, which indicates that the thiol/disulfide balance in patients with melasma is shifted to disulfide formation and thiols are oxidized to disulfide bonds in the presence of oxidative stress.

Seçkin et al⁷ evaluated the role of oxidative stress in the pathogenesis of melasma and found that the serum levels of the antioxidants superoxide dismutase and glutathione peroxidase were significantly higher in the patient group compared with the control group (both P<.001). They also found that the levels of nitric oxide (another antioxidant) were increased in the patient group and the levels of protein carbonyl (an oxidative metabolite) were significantly lower (both P<.001). These findings indicated that free-radical damage may be involved in the pathogenesis of melasma.⁷

In a study of 75 patients with melasma, serum levels of the antioxidants melatonin and catalase were significantly (P<.001 and P=.001, respectively) lower in the melasma group compared with the control group, while serum levels of the oxidants protein carbonyl and nitric oxide were significantly higher (P=.002 and P=.001, respectively). No significant correlation was found between oxidative stress parameters and melasma severity.⁸

Choubey et al⁹ found that serum malondialdehyde (an end product of lipid peroxidation), superoxide dismutase, and glutathione peroxidase levels were significantly higher in the melasma group (n=50) compared with the control group (n=50)(all P<.001). In addition, a significant positive correlation (correlation coefficient, +0.307; P<.05) was found between serum malondialdehyde levels and melasma severity. The mean age (SD) of the patients was 32.22 (6.377) years, and the female (n=41) to male (n=9) ratio was 4.55:1. The most common melasma pattern was centrofacial, followed by malar.⁹

In a study with 50 melasma patients and 50 controls, Rahimi et al¹⁰ examined bilirubin and uric acid levels, which are major extracellular antioxidants. The mean age (SD) at disease onset was 32.6 (6.7) years, and the mean MASI score (SD) was 18.1 (9). Serum bilirubin levels were found to be higher in the melasma group than in the control group and were correlated with disease severity. No significant difference in uric acid levels was found between the groups, and no correlation was found between MASI score and bilirubin and uric acid levels.¹⁰

In our study, the melasma group was similar to those in other reportsin the literature regarding gender distribution, mean age, and melasma pattern.^7-10 Additionally, the correlation of mMASI score with disulfide/native thiol and disulfide/total thiol values in the melasma group suggested that oxidative stress also is correlated with melasma severity.

Thiol-based treatments such as n-acetyl cysteine, which contains a thiol compound, may be helpful in melasma.²⁰ In a double-blind, placebo-controlled study, topical n-acetyl cysteine combined with hydroquinone 2% was used in 10 female patients with melasma. Mild to strong bleaching of the skin was observed in 90% (9/10) of the patients.²¹ Systemic use of n-acetyl cysteine in melasma also may be a potential research topic.

Major limitations of our study were the small sample size and lack of measurement of oxidative stress parameters in the skin concurrently with serum.

Conclusion

In our study, the presence of oxidative stress in melasma was demonstrated by evaluating thiol/disulfide homeostasis—one of the strongest markers of oxidative stress. Oxidative stress also correlated with melasma disease severity in our analysis. The data obtained in this study may contribute to understanding the etiopathogenesis of melasma and may open new horizons in treatment; however, more comprehensive studies should be conducted to support our findings.

Melasma is an acquired hyperpigmentation disorder characterized by irregular brown macules and patches that usually appear on sun-exposed areas of the skin. The term melasma originates from the Greek word melas meaning black.¹ Facial melasma is divided into 2 groups according to its clinical distribution: centrofacial lesions are located in the center of the face (eg, the glabellar, frontal, nasal, zygomatic, upper lip, chin areas), and peripheral lesions manifest on the frontotemporal, preauricular, and mandibular regions.^1,2 There is debate on the categorization of zygomatic (or malar) melasma; some researchers argue it should be categorized independent of other areas, while others include malar melasma in the centrofacial group because of its frequent association with the centrofacial type, especially with glabellar lesions.² Mandibular melasma is rare and occurs mostly in postmenopausal women after intense sun exposure.^1,2 Although the etiopathogenesis of the disease is not clearly known, increased melanogenesis, extracellular matrix alterations, inflammation, and angiogenesis are assumed to play a role.³ Various risk factors such as genetic predisposition, UV radiation (UVR) exposure, pregnancy, thyroid dysfunction, and exogenous hormones (eg, oral contraceptives, hormone replacement therapy) have been identified; phototoxic drugs, anticonvulsants, and some cosmetics also have been implicated.^4,5 Exposure to UVR is thought to be the main triggering environmental factor by inducing both melanin production and oxidative stress.⁵ However, it also has been shown that visible light can induce hyperpigmentation in darker skin types.⁶

The presence of oxidative stress in melasma recently has become an intriguing topic of interest. First, the presence of oxidative stress in the etiopathogenesis of melasma was thought to be based on the effectiveness of antioxidants in treatment. A few studies also have confirmed the presence of oxidative stress in melasma.^7-10 Classically, oxidative stress can be described as a disturbance in the balance between oxidants and antioxidants. Reactive oxygen species (ROS) are highly reactive molecules due to the unpaired electrons in their structure. Although ROS are present at low levels in physiologic conditions and are involved in critical physiologic events, they damage cellular components such as fat, protein, and nucleic acid at high concentrations.⁵

Dynamic thiol/disulfide homeostasis is one of the most important markers of oxidative stress in biological systems. Thiols are organic compounds containing a sulfhydryl (-SH) group. Thiols are considered highly potent antioxidants because they reduce unstable free radicals by donating electrons. They are the first antioxidants to be depleted in an oxidative environment.^11,12 In case of oxidative stress, they transform into reversible forms called disulfide bridges between 2 thiol groups. Disulfide bridges can be reduced back to thiol groups, which is how dynamic thiol/disulfide homeostasis is maintained. Dynamic thiol/disulfide homeostasis is responsible for cellular events such as antioxidant defense, signal transduction, regulation of enzyme function, and apoptosis.^11,12

The aim of this study was to evaluate the presence of oxidative stress in melasma by comparing dynamic thiol/disulfide homeostasis in patients with melasma compared with age- and sex-matched healthy controls.

Materials and Methods

Participants and Eligibility Criteria—We conducted a prospective study in a tertiary-care hospital (Ankara Bilkent City Hospital [Ankara, Turkey]) of patients with melasma who were followed from October 2021 to October 2022 compared with age- and sex-matched healthy volunteers. Ethics committee approval was obtained from Ankara Bilkent City Hospital before the study (E2-21-881)(13.10.2021). Written informed consent was obtained from all participants, and all were older than 18 years. Patients were excluded if there was the presence of any systemic disease or dermatologic disease other than melasma; smoking or alcohol use; any use of vitamins, food supplements, or any medication in the last 3 months; or pregnancy.

Melasma Severity—The modified melasma area and severity index (mMASI) score was used to determine the severity of melasma. The score is calculated from assessments of the darkness of the pigmentation and the percentage of affected area on the face. The mMASI score is the sum of the darkness score (D); area score (A); and separate fixed coefficients for the forehead, as well as the right malar, left malar, and chin regions.¹³ The mMASI score, with a range of 0 to 24, is a reliable and objective marker in the calculation of melasma severity.⁴

Biochemical Analysis of Samples—The 6-cc peripheral fasting venous blood samples obtained from the study participants were centrifuged at 1500 g for 10 minutes, and the separated sera were stored in a freezer at −80 °C until the time of analysis. When the study was completed, the disulfide and thiol values were analyzed. Serum native and total thiol concentrations indicating thiol/disulfide homeostasis were calculated by a new fully automatic colorimetric method developed by Erel and Neselioglu.¹⁴ Using this method, short disulfide bonds are first reduced with sodium borohydride solution to form free-functional thiol groups, and then the unused sodium borohydride is removed using formaldehyde. Finally, all thiol groups are reacted with 5,5’-dithiobis-(2-nitrobenzoic) acid (Ellman reagent), and all thiol groups are detected after reaction with 5,5’-dithiobis-(2-nitrobenzoic) acid. When a disulfide bond (−S−S−) is reduced, 2 thiol groups are formed. For this reason, half of the difference between total thiol (-SH + the amount of thiol formed by the reduction of disulfides) and native thiol (-SH) corresponds to the dynamic disulfide amount (total thiol − native thiol/2).¹⁴

Statistical Analysis—Statistical analysis was performed using SPSS software (version 24.0). Descriptive statistics were presented as numbers and percentages for categorical variables, and numerical variables were presented as mean, SD, median, minimum, maximum, 25th quartile, and 75th quartile. The conformity of the variables to normal distribution was examined using visual (histograms and probability plots) and analytical methods (Kolmogorov-Smirnov/Shapiro-Wilk tests). In pairwise group comparisons for numerical variables, a Mann-Whitney U test was used when normal distribution was not met, and a t test was used when normal distribution was met. The statistical significance level was accepted as P<.05.

Results

Our study included 67 patients with melasma and 41 healthy age- and sex-matched controls. Of the participants with melasma, 60 (89.5%) were female and 7 (10.5%) were male. The control group was similar to the melasma group in terms of sex (87.8% female vs 12.2% male [P=.59]). The mean age (SD) was 33.1 (6.7) years in the melasma group and 31.9 (6.7) years in the control group. Age was similar across both groups (P=.41). All participants were of Asian race, and Fitzpatrick skin types (types II–IV) were similar across both groups.

Fifty-four (80.6%) participants had centrofacial melasma and 13 (19.4%) had mixed-type melasma. The mMASI score ranged from 3 to 20; the mean (SD) mMASI score was 11.28 (3.2). Disease duration ranged from 2 to 72 months; the mean (SD) disease duration was 12.26 (6.3) months. The demographics and clinical characteristics of the study group are shown in eTable 1.

eTable 2 provides a summary of disulfide, native thiol, and total thiol levels, as well as disulfide/native thiol, disulfide/total thiol, and native thiol/total thiol ratios in the study population. Disulfide/native thiol and disulfide/total thiol ratios were higher in melasma patients (Figure 1), whereas the native thiol/total thiol ratio was higher in the control group (P=.025, P=.025, and P=.026, respectively).

All correlations between age, disease duration, and mMASI scores and disulfide, native thiol, and total thiol levels, as well as disulfide/native thiol, disulfide/total thiol, and native thiol/total thiol ratios, are summarized in eTable 3. No significant correlation was observed between age and disease duration and disulfide, native thiol, and total thiol levels or disulfide/native thiol, disulfide/total thiol, and native thiol/total thiol ratios.

We independently assessed whether Fitzpatrick skin types II, III, and IV exhibited distinct levels of oxidative stress in clinical melasma. There were no significant correlations with Fitzpatrick skin type (disulfide/native thiol, P=.25; disulfide/total thiol, P=.19). We further evaluated if the thiol/disulfide parameters were correlated with duration of melasma by dividing the melasma patients into 3 groups (<6 months [n=12], 6–18 months [n=32], >18 months [n=23]), but there was not any significant correlation (disulfide/native thiol, P=.15; disulfide/total thiol, P=.15). We also divided our patients into 3 groups according to age (<27 years [n=14], 27–36 years [n=33], >36 years [n=20]). There was no correlation of the parameters with age (disulfide/native thiol, P=.15; disulfide/total thiol, P=.14).

There was a positive correlation between mMASI score and disulfide, native thiol, and total thiol levels and disulfide/native thiol and disulfide/total thiol ratios, as well as a negative correlation between mMASI score and native thiol/total thiol ratio. The correlations between mMASI scores and disulfide/native thiol and disulfide/total thiol ratios are shown in Figure 2 and eTable 3.

Comment

Melasma is a common condition that may cause psychosocial problems in affected patients and negatively affect quality of life.¹ It occurs in all races but is more common in individuals with darker skin types (eg, Fitzpatrick skin types III and IV). Although melasma is more common in women during reproductive years (50%–70%), it also has been observed in 10% to 30% of men.⁵

Treatment options include topical bleaching agents, chemical peels, and laser therapy, as well as discontinuation of medications that may potentially trigger melasma; use of broad-spectrum sunscreens also is recommended.⁴ Vitamins A, C, and E, as well as niacinamide, are used in the treatment of melasma, especially for their antioxidant properties. The key role of antioxidants in the treatment of melasma supports the importance of oxidative stress in the pathogenesis.⁷ Melasma often is challenging to treat, particularly the mixed or dermal types, due to their stubborn nature. This condition poses a considerable therapeutic challenge for dermatologists.⁴

Oxidative stress and oxidant-antioxidant imbalance previously have been studied in various diseases, but research investigating the presence of oxidative stress in melasma are limited.^7-10 Exposure of the skin to polluted air and intense UVR, as well as some food by-products, cosmetics, and drugs (eg, oral contraceptives), can directly or indirectly cause ROS production in the skin. Reactive oxygen species are thought to be involved in the pathophysiology of melasma by affecting apoptotic pathways and causing cell proliferation. The intermediate heme pathway has pro-oxidant effects and produces ROS and metabolites such as redox-active quinines. Exposure to UVR leads to the generation of ROS, highlighting the role of oxidative stress in the onset of melasma. ⁵

In any cutaneous disease in which oxidative stress plays a role, oxidant and antioxidant levels may be expected to vary both locally and systemically; however, measurement of oxidative stress markers in serum instead of skin is technically and economically more advantageous.⁸ Firstly, serum collection is less invasive and technically simpler than skin biopsies. Drawing blood is a routine procedure that requires minimal specialized equipment and training compared to the extraction and processing of skin samples. Secondly, analyzing serum samples generally is less expensive than processing skin tissue.⁸

In our study, we evaluated dynamic thiol/disulfide homeostasis in serum to investigate the presence of oxidative stress in the setting of melasma. Functional sulfhydryl (-SH) groups in thiols act as substrates for antioxidant enzymes and as free-radical scavengers. They constitute one of the most powerful defense systems against the unwanted effects of ROS. Thiols, which become the main target of ROS under oxidative stress, oxidize with oxidant molecules and form disulfide bridges.¹⁵

Thiol/disulfide homeostasis has been studied many times in dermatologic diseases,^16-19 and the results obtained from these studies are heterogenous depending on the extent of oxidative damage. It has been shown that thiol/disulfide homeostasis plays a role in oxidative stress in conditions such as psoriasis,¹⁷ seborrheic dermatitis,¹¹ atopic dermatitits,¹⁸ and rosacea.¹⁹ In our study, disulfide/native thiol and disulfide/total thiol levels were significantly higher (both P=.025) in the melasma group compared with the control group, which indicates that the thiol/disulfide balance in patients with melasma is shifted to disulfide formation and thiols are oxidized to disulfide bonds in the presence of oxidative stress.

Seçkin et al⁷ evaluated the role of oxidative stress in the pathogenesis of melasma and found that the serum levels of the antioxidants superoxide dismutase and glutathione peroxidase were significantly higher in the patient group compared with the control group (both P<.001). They also found that the levels of nitric oxide (another antioxidant) were increased in the patient group and the levels of protein carbonyl (an oxidative metabolite) were significantly lower (both P<.001). These findings indicated that free-radical damage may be involved in the pathogenesis of melasma.⁷

In a study of 75 patients with melasma, serum levels of the antioxidants melatonin and catalase were significantly (P<.001 and P=.001, respectively) lower in the melasma group compared with the control group, while serum levels of the oxidants protein carbonyl and nitric oxide were significantly higher (P=.002 and P=.001, respectively). No significant correlation was found between oxidative stress parameters and melasma severity.⁸

Choubey et al⁹ found that serum malondialdehyde (an end product of lipid peroxidation), superoxide dismutase, and glutathione peroxidase levels were significantly higher in the melasma group (n=50) compared with the control group (n=50)(all P<.001). In addition, a significant positive correlation (correlation coefficient, +0.307; P<.05) was found between serum malondialdehyde levels and melasma severity. The mean age (SD) of the patients was 32.22 (6.377) years, and the female (n=41) to male (n=9) ratio was 4.55:1. The most common melasma pattern was centrofacial, followed by malar.⁹

In a study with 50 melasma patients and 50 controls, Rahimi et al¹⁰ examined bilirubin and uric acid levels, which are major extracellular antioxidants. The mean age (SD) at disease onset was 32.6 (6.7) years, and the mean MASI score (SD) was 18.1 (9). Serum bilirubin levels were found to be higher in the melasma group than in the control group and were correlated with disease severity. No significant difference in uric acid levels was found between the groups, and no correlation was found between MASI score and bilirubin and uric acid levels.¹⁰

In our study, the melasma group was similar to those in other reportsin the literature regarding gender distribution, mean age, and melasma pattern.^7-10 Additionally, the correlation of mMASI score with disulfide/native thiol and disulfide/total thiol values in the melasma group suggested that oxidative stress also is correlated with melasma severity.

Thiol-based treatments such as n-acetyl cysteine, which contains a thiol compound, may be helpful in melasma.²⁰ In a double-blind, placebo-controlled study, topical n-acetyl cysteine combined with hydroquinone 2% was used in 10 female patients with melasma. Mild to strong bleaching of the skin was observed in 90% (9/10) of the patients.²¹ Systemic use of n-acetyl cysteine in melasma also may be a potential research topic.

Major limitations of our study were the small sample size and lack of measurement of oxidative stress parameters in the skin concurrently with serum.

Conclusion

In our study, the presence of oxidative stress in melasma was demonstrated by evaluating thiol/disulfide homeostasis—one of the strongest markers of oxidative stress. Oxidative stress also correlated with melasma disease severity in our analysis. The data obtained in this study may contribute to understanding the etiopathogenesis of melasma and may open new horizons in treatment; however, more comprehensive studies should be conducted to support our findings.

Practice Gap

The Wood lamp commonly is used as a diagnostic tool for pigmentary skin conditions (eg, vitiligo) or skin conditions that exhibit fluorescence (eg, erythrasma).¹ Recently, its diagnostic efficacy has extended to scabies, in which it unveils a distinctive wavy, bluish-white, linear fluorescence upon illumination.²

Functionally, the Wood lamp operates by subjecting phosphors to UV light within the wavelength range of 320 to 400 nm, inducing fluorescence in substances such as collagen and elastin. In the context of vitiligo, this process manifests as a preferential chalk white fluorescence in areas lacking melanin.¹

Despite its demonstrated effectiveness, the Wood lamp is not without limitations. It comes with a notable financial investment ranging from $70 to $500, requires periodic maintenance such as light bulb replacements, and can be unwieldy.³ Furthermore, its reliance on a power source poses a challenge in settings where immediate access to convenient power outlets is limited, such as inpatient and rural dermatology clinics. These limitations underscore the need for alternative solutions and innovations to address challenges and ensure accessibility in diverse health care environments.

The Tools

Free smartphone applications (apps), such as Ultraviolet Light-UV Lamp by AppBrain or Blacklight UV Light Simulator by That Smile, can simulate UV light and functionally serve as a Wood lamp.

The Technique

UV light apps use LED or organic LED screen pixels to emit a blue light equivalent at 467 nm.⁴ Although these apps are not designed specifically for dermatologic uses, they are mostly free, widely available for Android and iPhone users, and portable. Importantly, they can demonstrate good performance in visualizing vitiligo, as shown in Figure 1—albeit perhaps not reaching the same level as the Wood lamp (Figure 2).

Because these UV light apps are not regulated and their efficacy for medical use has not been firmly established, the Wood lamp remains the gold standard. Therefore, we propose the use of UV light apps in situations when a Wood lamp is not available or convenient, such as in rural, inpatient, or international health care settings.

Practice Implications

Exploring and adopting these free alternatives can contribute to improved accessibility and diagnostic capabilities in diverse health care environments, particularly for communities facing financial constraints. Continued research and validation of these apps in clinical settings will be essential to establish their reliability and effectiveness in enhancing diagnostic practices.

Practice Gap

The Wood lamp commonly is used as a diagnostic tool for pigmentary skin conditions (eg, vitiligo) or skin conditions that exhibit fluorescence (eg, erythrasma).¹ Recently, its diagnostic efficacy has extended to scabies, in which it unveils a distinctive wavy, bluish-white, linear fluorescence upon illumination.²

Functionally, the Wood lamp operates by subjecting phosphors to UV light within the wavelength range of 320 to 400 nm, inducing fluorescence in substances such as collagen and elastin. In the context of vitiligo, this process manifests as a preferential chalk white fluorescence in areas lacking melanin.¹

Despite its demonstrated effectiveness, the Wood lamp is not without limitations. It comes with a notable financial investment ranging from $70 to $500, requires periodic maintenance such as light bulb replacements, and can be unwieldy.³ Furthermore, its reliance on a power source poses a challenge in settings where immediate access to convenient power outlets is limited, such as inpatient and rural dermatology clinics. These limitations underscore the need for alternative solutions and innovations to address challenges and ensure accessibility in diverse health care environments.

The Tools

Free smartphone applications (apps), such as Ultraviolet Light-UV Lamp by AppBrain or Blacklight UV Light Simulator by That Smile, can simulate UV light and functionally serve as a Wood lamp.

The Technique

UV light apps use LED or organic LED screen pixels to emit a blue light equivalent at 467 nm.⁴ Although these apps are not designed specifically for dermatologic uses, they are mostly free, widely available for Android and iPhone users, and portable. Importantly, they can demonstrate good performance in visualizing vitiligo, as shown in Figure 1—albeit perhaps not reaching the same level as the Wood lamp (Figure 2).

Because these UV light apps are not regulated and their efficacy for medical use has not been firmly established, the Wood lamp remains the gold standard. Therefore, we propose the use of UV light apps in situations when a Wood lamp is not available or convenient, such as in rural, inpatient, or international health care settings.

Practice Implications

Exploring and adopting these free alternatives can contribute to improved accessibility and diagnostic capabilities in diverse health care environments, particularly for communities facing financial constraints. Continued research and validation of these apps in clinical settings will be essential to establish their reliability and effectiveness in enhancing diagnostic practices.

Practice Gap

The Wood lamp commonly is used as a diagnostic tool for pigmentary skin conditions (eg, vitiligo) or skin conditions that exhibit fluorescence (eg, erythrasma).¹ Recently, its diagnostic efficacy has extended to scabies, in which it unveils a distinctive wavy, bluish-white, linear fluorescence upon illumination.²

Functionally, the Wood lamp operates by subjecting phosphors to UV light within the wavelength range of 320 to 400 nm, inducing fluorescence in substances such as collagen and elastin. In the context of vitiligo, this process manifests as a preferential chalk white fluorescence in areas lacking melanin.¹

Despite its demonstrated effectiveness, the Wood lamp is not without limitations. It comes with a notable financial investment ranging from $70 to $500, requires periodic maintenance such as light bulb replacements, and can be unwieldy.³ Furthermore, its reliance on a power source poses a challenge in settings where immediate access to convenient power outlets is limited, such as inpatient and rural dermatology clinics. These limitations underscore the need for alternative solutions and innovations to address challenges and ensure accessibility in diverse health care environments.

The Tools

Free smartphone applications (apps), such as Ultraviolet Light-UV Lamp by AppBrain or Blacklight UV Light Simulator by That Smile, can simulate UV light and functionally serve as a Wood lamp.

The Technique

UV light apps use LED or organic LED screen pixels to emit a blue light equivalent at 467 nm.⁴ Although these apps are not designed specifically for dermatologic uses, they are mostly free, widely available for Android and iPhone users, and portable. Importantly, they can demonstrate good performance in visualizing vitiligo, as shown in Figure 1—albeit perhaps not reaching the same level as the Wood lamp (Figure 2).

Because these UV light apps are not regulated and their efficacy for medical use has not been firmly established, the Wood lamp remains the gold standard. Therefore, we propose the use of UV light apps in situations when a Wood lamp is not available or convenient, such as in rural, inpatient, or international health care settings.

Practice Implications

Exploring and adopting these free alternatives can contribute to improved accessibility and diagnostic capabilities in diverse health care environments, particularly for communities facing financial constraints. Continued research and validation of these apps in clinical settings will be essential to establish their reliability and effectiveness in enhancing diagnostic practices.

Celiac disease is a chronic, immune-mediated, systemic disorder caused by intolerance to gluten — a protein present in rye, barley, and wheat grains — that affects genetically predisposed individuals.

Due to its wide spectrum of clinical manifestations, celiac disease resembles a multisystemic disorder. Its most common gastrointestinal (GI) symptoms include chronic diarrhea, weight loss, and abdominal distention. However, celiac disease can also manifest in myriad extraintestinal symptoms, ranging from headache and fatigue to delayed puberty and psychiatric disorders, with differing presentations in children and adults.

To date, the only treatment is adopting a gluten-free diet (GFD). Although key to preventing persistent villous atrophy, the main cause of complications in celiac disease, lifelong adherence to GFD is challenging and may not resolve all clinical issues. These shortcomings have driven recent efforts to develop novel therapeutic options for patients with this disease.

Here are five things to know about celiac disease.
 

1. Rising Prevalence of Celiac Disease and Other Autoimmune Disorders Suggests Environmental Factors May Be at Play

Gluten was first identified as the cause of celiac disease in the 1950s. At that time, the condition was thought to be a relatively rare GI disease of childhood that primarily affected people of European descent, but it is now known to be a common disease affecting those of various ages, races, and ethnicities.

A 2018 meta-analysis found the pooled global prevalence of celiac disease was 1.4%. Incidence has increased by as much as 7.5% annually over the past several decades.

Increased awareness among clinicians and improved detection likely play a role in the trend. However, the growth in celiac disease is consistent with that seen for other autoimmune disorders, according to a 2024 update of evidence surrounding celiac disease. Shared environmental factors have been proposed as triggers for celiac disease and other autoimmune diseases and appear to be influencing their rise, the authors noted. These factors include migration and population growth, changing dietary patterns and food processing practices, and altered wheat consumption.
 

2. No-Biopsy Diagnosis Is Accepted for Children and Shows Promise for Adults

It is estimated that almost 60 million people worldwide have celiac disease, but most remain undiagnosed or misdiagnosed, or they experience significant diagnostic delays.

Prospective data indicate that children with first-degree relatives with celiac disease are at a significantly higher risk of developing the condition, which should prompt screening efforts in this population.

The 2023 updated guidelines from the American College of Gastroenterology (ACG) state that serology testing plays a central role in screening. This commonly involves serological testing for positive serological markers of the disease, including immunoglobulin A (IgA), anti-tissue transglutaminase IgA (tTG-IgA), anti-deamidated gliadin peptide, or endomysial antibodies.

To confirm diagnosis, clinicians have relied on intestinal biopsy since the late 1950s. The ACG still recommends esophagogastroduodenoscopy with multiple duodenal biopsies for confirmation of diagnosis in both children and adults with suspicion of celiac disease. However, recent years have seen a shift toward a no-biopsy approach.

For more than a decade in Europe, a no-biopsy approach has been established practice in pediatric patients, for whom the burden of obtaining a histological confirmation is understandably greater. Most guidelines now permit children to be diagnosed with celiac disease in the absence of a biopsy under specific circumstances (eg, characteristic symptoms of celiac disease and tTG-IgA levels > 10 times the upper limit of normal). The ACG guidelines state that “this approach is a reasonable alternative to the standard approach to a [celiac disease] diagnosis in selected children.”

The ACG does not recommend a no-biopsy approach in adults, noting that, in comparison with children, there is a relative lack of data indicating that serology is predictive in this population. However, it does recognize that physicians may encounter patients for whom a biopsy diagnosis may not be safe or practical. In such cases, an “after-the-fact” diagnosis of likely celiac disease can be given to symptomatic adult patients with a ≥ 10-fold elevation of tTG-IgA and a positive endomysial antibody in a second blood sample.

A 2024 meta-analysis of 18 studies involving over 12,103 adult patients from 15 countries concluded that a no-biopsy approach using tTG-IgA antibody levels ≥ 10 times the upper limit of normal was highly specific and predictive of celiac disease.
 

3. Celiac Disease Is Associated With Several Life-Threatening Conditions

Emerging data indicate that gastroenterologists should be vigilant in screening patients with celiac disease for several other GI conditions.

Inflammatory bowel disease and celiac disease have a strong bidirectional association, suggesting a possible genetic link between the conditions and indicating that physicians should consider the alternate diagnosis when symptoms persist after treatment.

Given the hypervigilance around food and diet inherent to celiac disease, patients are at an increased risk of developing avoidant/restrictive food intake disorder, according to a 2022 retrospective study.

In 2023, Italian investigators showed that children with celiac disease have an elevated prevalence of functional GI disorders even after adopting a GFD for a year, regardless of whether they consumed processed or natural foods. It was unclear whether this was due to a chronic inflammatory process or to nutritional factors.

Complications resulting from celiac disease are not limited to GI disorders. For a variety of underlying pathophysiological reasons, including intestinal permeability, hyposplenism, and malabsorption of nutrients, patients with celiac disease may be at a higher risk for non-GI conditions, such as osteopenia, women’s health disorders (eg, ovarian failure, endometriosis, or pregnancy loss), juvenile idiopathic arthritis in children and rheumatoid arthritis in adults, certain forms of cancer, infectious diseases, and cardiomyopathy.
 

4. GFD Is the Only Treatment, but It’s Imperfect and Frustrating for Patients

GFD is the only treatment for celiac disease and must be adhered to without deviation throughout a patient’s life.

Maintaining unwavering adherence reaps considerable benefits: Improved clinical symptoms, robust mucosal healing, and normalization of serological markers. Yet it also takes a considerable toll on patients. Patients with celiac disease struggle with a host of negative physical, psychological, and social impacts. They also report a higher treatment burden than those with gastroesophageal reflux disease or hypertension, and comparable with end-stage renal disease.

GFD also poses financial challenges. Although the price of gluten-free products has decreased in recent years, they still cost significantly more than items with gluten.

Adherence to GFD does not always equate to complete mucosal recovery. While mucosal recovery is achieved in 95% of children within 2 years of the diet’s adoption, only 34% and 66% of adults obtain it within 2 and 5 years, respectively.

GFD may lead to nutrient imbalances because gluten-free foods are typically low in alimentary fiber, micronutrients (eg, vitamin D, vitamin B12, or folate), and minerals (eg, iron, zinc, magnesium, or calcium). With higher sugar and fat content, GFD may leave patients susceptible to unwanted weight gain.

The pervasiveness of gluten in the food production system makes the risk for cross-contamination high. Gluten is often found in both naturally gluten-free foods and products labeled as such. Gluten-sensing technologies, some of which can be used via smartphone apps, have been developed to help patients identify possible cross-contamination. However, the ACG guidelines recommend against the use of these technologies until there is sufficient evidence supporting their ability to improve adherence and clinical outcomes.
 

5. Novel Therapies for Celiac Disease Are in the Pipeline

The limitations of GFD as the standard treatment for celiac disease have led to an increased focus on developing novel therapeutic interventions. They can be sorted into five key categories: Modulation of the immunostimulatory effects of toxic gluten peptides, elimination of toxic gluten peptides before they reach the intestine, induction of gluten tolerance, modulation of intestinal permeability, and restoration of gut microbiota balance.

Three therapies designed to block antigen presentation by HLA-DQ2/8, the gene alleles that predispose people to celiac disease, show promise: TPM502, an agent that contains three gluten-specific antigenic peptides with overlapping T-cell epitopes for the HLA-DQ2.5 gene; KAN-101, designed to induce gluten tolerance by targeting receptors on the liver; and DONQ52, a multi-specific antibody that targets HLA-DQ2. The KAN-101 therapy received Fast Track designation by the US Food and Drug Administration in 2022.

These and several other agents in clinical and preclinical development are discussed in detail in a 2024 review article. Although no therapies have reached phase 3 testing, when they do, it will undoubtedly be welcomed by those with celiac disease.

A version of this article first appeared on Medscape.com.

Celiac disease is a chronic, immune-mediated, systemic disorder caused by intolerance to gluten — a protein present in rye, barley, and wheat grains — that affects genetically predisposed individuals.

Due to its wide spectrum of clinical manifestations, celiac disease resembles a multisystemic disorder. Its most common gastrointestinal (GI) symptoms include chronic diarrhea, weight loss, and abdominal distention. However, celiac disease can also manifest in myriad extraintestinal symptoms, ranging from headache and fatigue to delayed puberty and psychiatric disorders, with differing presentations in children and adults.

To date, the only treatment is adopting a gluten-free diet (GFD). Although key to preventing persistent villous atrophy, the main cause of complications in celiac disease, lifelong adherence to GFD is challenging and may not resolve all clinical issues. These shortcomings have driven recent efforts to develop novel therapeutic options for patients with this disease.

Here are five things to know about celiac disease.
 

1. Rising Prevalence of Celiac Disease and Other Autoimmune Disorders Suggests Environmental Factors May Be at Play

Gluten was first identified as the cause of celiac disease in the 1950s. At that time, the condition was thought to be a relatively rare GI disease of childhood that primarily affected people of European descent, but it is now known to be a common disease affecting those of various ages, races, and ethnicities.

A 2018 meta-analysis found the pooled global prevalence of celiac disease was 1.4%. Incidence has increased by as much as 7.5% annually over the past several decades.

Increased awareness among clinicians and improved detection likely play a role in the trend. However, the growth in celiac disease is consistent with that seen for other autoimmune disorders, according to a 2024 update of evidence surrounding celiac disease. Shared environmental factors have been proposed as triggers for celiac disease and other autoimmune diseases and appear to be influencing their rise, the authors noted. These factors include migration and population growth, changing dietary patterns and food processing practices, and altered wheat consumption.
 

2. No-Biopsy Diagnosis Is Accepted for Children and Shows Promise for Adults

It is estimated that almost 60 million people worldwide have celiac disease, but most remain undiagnosed or misdiagnosed, or they experience significant diagnostic delays.

Prospective data indicate that children with first-degree relatives with celiac disease are at a significantly higher risk of developing the condition, which should prompt screening efforts in this population.

The 2023 updated guidelines from the American College of Gastroenterology (ACG) state that serology testing plays a central role in screening. This commonly involves serological testing for positive serological markers of the disease, including immunoglobulin A (IgA), anti-tissue transglutaminase IgA (tTG-IgA), anti-deamidated gliadin peptide, or endomysial antibodies.

To confirm diagnosis, clinicians have relied on intestinal biopsy since the late 1950s. The ACG still recommends esophagogastroduodenoscopy with multiple duodenal biopsies for confirmation of diagnosis in both children and adults with suspicion of celiac disease. However, recent years have seen a shift toward a no-biopsy approach.

For more than a decade in Europe, a no-biopsy approach has been established practice in pediatric patients, for whom the burden of obtaining a histological confirmation is understandably greater. Most guidelines now permit children to be diagnosed with celiac disease in the absence of a biopsy under specific circumstances (eg, characteristic symptoms of celiac disease and tTG-IgA levels > 10 times the upper limit of normal). The ACG guidelines state that “this approach is a reasonable alternative to the standard approach to a [celiac disease] diagnosis in selected children.”

The ACG does not recommend a no-biopsy approach in adults, noting that, in comparison with children, there is a relative lack of data indicating that serology is predictive in this population. However, it does recognize that physicians may encounter patients for whom a biopsy diagnosis may not be safe or practical. In such cases, an “after-the-fact” diagnosis of likely celiac disease can be given to symptomatic adult patients with a ≥ 10-fold elevation of tTG-IgA and a positive endomysial antibody in a second blood sample.

A 2024 meta-analysis of 18 studies involving over 12,103 adult patients from 15 countries concluded that a no-biopsy approach using tTG-IgA antibody levels ≥ 10 times the upper limit of normal was highly specific and predictive of celiac disease.
 

3. Celiac Disease Is Associated With Several Life-Threatening Conditions

Emerging data indicate that gastroenterologists should be vigilant in screening patients with celiac disease for several other GI conditions.

Inflammatory bowel disease and celiac disease have a strong bidirectional association, suggesting a possible genetic link between the conditions and indicating that physicians should consider the alternate diagnosis when symptoms persist after treatment.

Given the hypervigilance around food and diet inherent to celiac disease, patients are at an increased risk of developing avoidant/restrictive food intake disorder, according to a 2022 retrospective study.

In 2023, Italian investigators showed that children with celiac disease have an elevated prevalence of functional GI disorders even after adopting a GFD for a year, regardless of whether they consumed processed or natural foods. It was unclear whether this was due to a chronic inflammatory process or to nutritional factors.

Complications resulting from celiac disease are not limited to GI disorders. For a variety of underlying pathophysiological reasons, including intestinal permeability, hyposplenism, and malabsorption of nutrients, patients with celiac disease may be at a higher risk for non-GI conditions, such as osteopenia, women’s health disorders (eg, ovarian failure, endometriosis, or pregnancy loss), juvenile idiopathic arthritis in children and rheumatoid arthritis in adults, certain forms of cancer, infectious diseases, and cardiomyopathy.
 

4. GFD Is the Only Treatment, but It’s Imperfect and Frustrating for Patients

GFD is the only treatment for celiac disease and must be adhered to without deviation throughout a patient’s life.

Maintaining unwavering adherence reaps considerable benefits: Improved clinical symptoms, robust mucosal healing, and normalization of serological markers. Yet it also takes a considerable toll on patients. Patients with celiac disease struggle with a host of negative physical, psychological, and social impacts. They also report a higher treatment burden than those with gastroesophageal reflux disease or hypertension, and comparable with end-stage renal disease.

GFD also poses financial challenges. Although the price of gluten-free products has decreased in recent years, they still cost significantly more than items with gluten.

Adherence to GFD does not always equate to complete mucosal recovery. While mucosal recovery is achieved in 95% of children within 2 years of the diet’s adoption, only 34% and 66% of adults obtain it within 2 and 5 years, respectively.

GFD may lead to nutrient imbalances because gluten-free foods are typically low in alimentary fiber, micronutrients (eg, vitamin D, vitamin B12, or folate), and minerals (eg, iron, zinc, magnesium, or calcium). With higher sugar and fat content, GFD may leave patients susceptible to unwanted weight gain.

The pervasiveness of gluten in the food production system makes the risk for cross-contamination high. Gluten is often found in both naturally gluten-free foods and products labeled as such. Gluten-sensing technologies, some of which can be used via smartphone apps, have been developed to help patients identify possible cross-contamination. However, the ACG guidelines recommend against the use of these technologies until there is sufficient evidence supporting their ability to improve adherence and clinical outcomes.
 

5. Novel Therapies for Celiac Disease Are in the Pipeline

The limitations of GFD as the standard treatment for celiac disease have led to an increased focus on developing novel therapeutic interventions. They can be sorted into five key categories: Modulation of the immunostimulatory effects of toxic gluten peptides, elimination of toxic gluten peptides before they reach the intestine, induction of gluten tolerance, modulation of intestinal permeability, and restoration of gut microbiota balance.

Three therapies designed to block antigen presentation by HLA-DQ2/8, the gene alleles that predispose people to celiac disease, show promise: TPM502, an agent that contains three gluten-specific antigenic peptides with overlapping T-cell epitopes for the HLA-DQ2.5 gene; KAN-101, designed to induce gluten tolerance by targeting receptors on the liver; and DONQ52, a multi-specific antibody that targets HLA-DQ2. The KAN-101 therapy received Fast Track designation by the US Food and Drug Administration in 2022.

These and several other agents in clinical and preclinical development are discussed in detail in a 2024 review article. Although no therapies have reached phase 3 testing, when they do, it will undoubtedly be welcomed by those with celiac disease.

A version of this article first appeared on Medscape.com.

Celiac disease is a chronic, immune-mediated, systemic disorder caused by intolerance to gluten — a protein present in rye, barley, and wheat grains — that affects genetically predisposed individuals.

Due to its wide spectrum of clinical manifestations, celiac disease resembles a multisystemic disorder. Its most common gastrointestinal (GI) symptoms include chronic diarrhea, weight loss, and abdominal distention. However, celiac disease can also manifest in myriad extraintestinal symptoms, ranging from headache and fatigue to delayed puberty and psychiatric disorders, with differing presentations in children and adults.

To date, the only treatment is adopting a gluten-free diet (GFD). Although key to preventing persistent villous atrophy, the main cause of complications in celiac disease, lifelong adherence to GFD is challenging and may not resolve all clinical issues. These shortcomings have driven recent efforts to develop novel therapeutic options for patients with this disease.

Here are five things to know about celiac disease.
 

1. Rising Prevalence of Celiac Disease and Other Autoimmune Disorders Suggests Environmental Factors May Be at Play

Gluten was first identified as the cause of celiac disease in the 1950s. At that time, the condition was thought to be a relatively rare GI disease of childhood that primarily affected people of European descent, but it is now known to be a common disease affecting those of various ages, races, and ethnicities.

A 2018 meta-analysis found the pooled global prevalence of celiac disease was 1.4%. Incidence has increased by as much as 7.5% annually over the past several decades.

Increased awareness among clinicians and improved detection likely play a role in the trend. However, the growth in celiac disease is consistent with that seen for other autoimmune disorders, according to a 2024 update of evidence surrounding celiac disease. Shared environmental factors have been proposed as triggers for celiac disease and other autoimmune diseases and appear to be influencing their rise, the authors noted. These factors include migration and population growth, changing dietary patterns and food processing practices, and altered wheat consumption.
 

2. No-Biopsy Diagnosis Is Accepted for Children and Shows Promise for Adults

It is estimated that almost 60 million people worldwide have celiac disease, but most remain undiagnosed or misdiagnosed, or they experience significant diagnostic delays.

Prospective data indicate that children with first-degree relatives with celiac disease are at a significantly higher risk of developing the condition, which should prompt screening efforts in this population.

The 2023 updated guidelines from the American College of Gastroenterology (ACG) state that serology testing plays a central role in screening. This commonly involves serological testing for positive serological markers of the disease, including immunoglobulin A (IgA), anti-tissue transglutaminase IgA (tTG-IgA), anti-deamidated gliadin peptide, or endomysial antibodies.

To confirm diagnosis, clinicians have relied on intestinal biopsy since the late 1950s. The ACG still recommends esophagogastroduodenoscopy with multiple duodenal biopsies for confirmation of diagnosis in both children and adults with suspicion of celiac disease. However, recent years have seen a shift toward a no-biopsy approach.

For more than a decade in Europe, a no-biopsy approach has been established practice in pediatric patients, for whom the burden of obtaining a histological confirmation is understandably greater. Most guidelines now permit children to be diagnosed with celiac disease in the absence of a biopsy under specific circumstances (eg, characteristic symptoms of celiac disease and tTG-IgA levels > 10 times the upper limit of normal). The ACG guidelines state that “this approach is a reasonable alternative to the standard approach to a [celiac disease] diagnosis in selected children.”

The ACG does not recommend a no-biopsy approach in adults, noting that, in comparison with children, there is a relative lack of data indicating that serology is predictive in this population. However, it does recognize that physicians may encounter patients for whom a biopsy diagnosis may not be safe or practical. In such cases, an “after-the-fact” diagnosis of likely celiac disease can be given to symptomatic adult patients with a ≥ 10-fold elevation of tTG-IgA and a positive endomysial antibody in a second blood sample.

A 2024 meta-analysis of 18 studies involving over 12,103 adult patients from 15 countries concluded that a no-biopsy approach using tTG-IgA antibody levels ≥ 10 times the upper limit of normal was highly specific and predictive of celiac disease.
 

3. Celiac Disease Is Associated With Several Life-Threatening Conditions

Emerging data indicate that gastroenterologists should be vigilant in screening patients with celiac disease for several other GI conditions.

Inflammatory bowel disease and celiac disease have a strong bidirectional association, suggesting a possible genetic link between the conditions and indicating that physicians should consider the alternate diagnosis when symptoms persist after treatment.

Given the hypervigilance around food and diet inherent to celiac disease, patients are at an increased risk of developing avoidant/restrictive food intake disorder, according to a 2022 retrospective study.

In 2023, Italian investigators showed that children with celiac disease have an elevated prevalence of functional GI disorders even after adopting a GFD for a year, regardless of whether they consumed processed or natural foods. It was unclear whether this was due to a chronic inflammatory process or to nutritional factors.

Complications resulting from celiac disease are not limited to GI disorders. For a variety of underlying pathophysiological reasons, including intestinal permeability, hyposplenism, and malabsorption of nutrients, patients with celiac disease may be at a higher risk for non-GI conditions, such as osteopenia, women’s health disorders (eg, ovarian failure, endometriosis, or pregnancy loss), juvenile idiopathic arthritis in children and rheumatoid arthritis in adults, certain forms of cancer, infectious diseases, and cardiomyopathy.
 

4. GFD Is the Only Treatment, but It’s Imperfect and Frustrating for Patients

GFD is the only treatment for celiac disease and must be adhered to without deviation throughout a patient’s life.

Maintaining unwavering adherence reaps considerable benefits: Improved clinical symptoms, robust mucosal healing, and normalization of serological markers. Yet it also takes a considerable toll on patients. Patients with celiac disease struggle with a host of negative physical, psychological, and social impacts. They also report a higher treatment burden than those with gastroesophageal reflux disease or hypertension, and comparable with end-stage renal disease.

GFD also poses financial challenges. Although the price of gluten-free products has decreased in recent years, they still cost significantly more than items with gluten.

Adherence to GFD does not always equate to complete mucosal recovery. While mucosal recovery is achieved in 95% of children within 2 years of the diet’s adoption, only 34% and 66% of adults obtain it within 2 and 5 years, respectively.

GFD may lead to nutrient imbalances because gluten-free foods are typically low in alimentary fiber, micronutrients (eg, vitamin D, vitamin B12, or folate), and minerals (eg, iron, zinc, magnesium, or calcium). With higher sugar and fat content, GFD may leave patients susceptible to unwanted weight gain.

The pervasiveness of gluten in the food production system makes the risk for cross-contamination high. Gluten is often found in both naturally gluten-free foods and products labeled as such. Gluten-sensing technologies, some of which can be used via smartphone apps, have been developed to help patients identify possible cross-contamination. However, the ACG guidelines recommend against the use of these technologies until there is sufficient evidence supporting their ability to improve adherence and clinical outcomes.
 

5. Novel Therapies for Celiac Disease Are in the Pipeline

The limitations of GFD as the standard treatment for celiac disease have led to an increased focus on developing novel therapeutic interventions. They can be sorted into five key categories: Modulation of the immunostimulatory effects of toxic gluten peptides, elimination of toxic gluten peptides before they reach the intestine, induction of gluten tolerance, modulation of intestinal permeability, and restoration of gut microbiota balance.

Three therapies designed to block antigen presentation by HLA-DQ2/8, the gene alleles that predispose people to celiac disease, show promise: TPM502, an agent that contains three gluten-specific antigenic peptides with overlapping T-cell epitopes for the HLA-DQ2.5 gene; KAN-101, designed to induce gluten tolerance by targeting receptors on the liver; and DONQ52, a multi-specific antibody that targets HLA-DQ2. The KAN-101 therapy received Fast Track designation by the US Food and Drug Administration in 2022.

These and several other agents in clinical and preclinical development are discussed in detail in a 2024 review article. Although no therapies have reached phase 3 testing, when they do, it will undoubtedly be welcomed by those with celiac disease.

A version of this article first appeared on Medscape.com.

Despite the influx of adalimumab biosimilars entering the market in 2023, Humira remains on top.

As of January 2024, both high and low concentrations of Humira, the originator adalimumab product, are nearly universally covered by Medicare Part D plans, while only half of these plans covered adalimumab biosimilars, according to a new research letter published online on June 6, 2024, in JAMA.

Of the plans that covered both, only 1.5% had lower-tier placement for biosimilars.

“This study of formulary coverage helps explain limited uptake of adalimumab biosimilars,” wrote the authors, led by Matthew J. Klebanoff, MD, of the University of Pennsylvania, Philadelphia. “Subpar biosimilar adoption will not only undermine their potential to reduce spending but also may deter investments in biosimilar development.”

The analysis included the formulary and enrollment files for 5609 Medicare Part D plans, representing 44.4 million beneficiaries. Drug list prices and whole acquisition costs (WAC) were pulled from the Red Book database, which provides prices for prescription and over-the-counter drugs as well as medical devices and supplies. 

Nearly all (98.9%) of Part D plans covered the high-concentration (100 mg/mL) version of adalimumab with a WAC of $6923. This higher concentration is the most popular formulation of the drug, making up an estimated 85% of prescriptions. By comparison, 26.8% of plans covered the high-concentration version of adalimumab-adaz (Hyrimoz), with a WAC 5% less than the reference product.

The unbranded version of adalimumab-adaz, sold at an 81% discount from the reference product, was covered by 13% of plans. Only 4.6% of plans covered high-concentration adalimumab-bwwd (Hadlima), manufactured by Samsung Bioepis.

In January 2024, no high-concentration adalimumab biosimilar had been granted interchangeability status by the US Food and Drug Administration (FDA). Adalimumab-ryvk (Simlandi) was the first biosimilar to receive this designation and was launched in late May 2024.

Coverage for the lower concentration of adalimumab was nearly universal (98.7% of plans). About half of the plans (50.7%) covered adalimumab-adbm (Cyltezo) at a 5% discount. Adalimumab-adbm (Boehringer Ingelheim) was the first interchangeable Humira biosimilar approved by the FDA, but it is only interchangeable with the less popular, lower concentration formulation of adalimumab.

All other biosimilars were covered by less than 5% of Medicare Part D plans, even with some having a WAC 86% below Humira.

A version of this article appeared on Medscape.com .

Despite the influx of adalimumab biosimilars entering the market in 2023, Humira remains on top.

As of January 2024, both high and low concentrations of Humira, the originator adalimumab product, are nearly universally covered by Medicare Part D plans, while only half of these plans covered adalimumab biosimilars, according to a new research letter published online on June 6, 2024, in JAMA.

Of the plans that covered both, only 1.5% had lower-tier placement for biosimilars.

“This study of formulary coverage helps explain limited uptake of adalimumab biosimilars,” wrote the authors, led by Matthew J. Klebanoff, MD, of the University of Pennsylvania, Philadelphia. “Subpar biosimilar adoption will not only undermine their potential to reduce spending but also may deter investments in biosimilar development.”

The analysis included the formulary and enrollment files for 5609 Medicare Part D plans, representing 44.4 million beneficiaries. Drug list prices and whole acquisition costs (WAC) were pulled from the Red Book database, which provides prices for prescription and over-the-counter drugs as well as medical devices and supplies. 

Nearly all (98.9%) of Part D plans covered the high-concentration (100 mg/mL) version of adalimumab with a WAC of $6923. This higher concentration is the most popular formulation of the drug, making up an estimated 85% of prescriptions. By comparison, 26.8% of plans covered the high-concentration version of adalimumab-adaz (Hyrimoz), with a WAC 5% less than the reference product.

The unbranded version of adalimumab-adaz, sold at an 81% discount from the reference product, was covered by 13% of plans. Only 4.6% of plans covered high-concentration adalimumab-bwwd (Hadlima), manufactured by Samsung Bioepis.

In January 2024, no high-concentration adalimumab biosimilar had been granted interchangeability status by the US Food and Drug Administration (FDA). Adalimumab-ryvk (Simlandi) was the first biosimilar to receive this designation and was launched in late May 2024.

Coverage for the lower concentration of adalimumab was nearly universal (98.7% of plans). About half of the plans (50.7%) covered adalimumab-adbm (Cyltezo) at a 5% discount. Adalimumab-adbm (Boehringer Ingelheim) was the first interchangeable Humira biosimilar approved by the FDA, but it is only interchangeable with the less popular, lower concentration formulation of adalimumab.

All other biosimilars were covered by less than 5% of Medicare Part D plans, even with some having a WAC 86% below Humira.

A version of this article appeared on Medscape.com .

Despite the influx of adalimumab biosimilars entering the market in 2023, Humira remains on top.

As of January 2024, both high and low concentrations of Humira, the originator adalimumab product, are nearly universally covered by Medicare Part D plans, while only half of these plans covered adalimumab biosimilars, according to a new research letter published online on June 6, 2024, in JAMA.

Of the plans that covered both, only 1.5% had lower-tier placement for biosimilars.

“This study of formulary coverage helps explain limited uptake of adalimumab biosimilars,” wrote the authors, led by Matthew J. Klebanoff, MD, of the University of Pennsylvania, Philadelphia. “Subpar biosimilar adoption will not only undermine their potential to reduce spending but also may deter investments in biosimilar development.”

The analysis included the formulary and enrollment files for 5609 Medicare Part D plans, representing 44.4 million beneficiaries. Drug list prices and whole acquisition costs (WAC) were pulled from the Red Book database, which provides prices for prescription and over-the-counter drugs as well as medical devices and supplies. 

Nearly all (98.9%) of Part D plans covered the high-concentration (100 mg/mL) version of adalimumab with a WAC of $6923. This higher concentration is the most popular formulation of the drug, making up an estimated 85% of prescriptions. By comparison, 26.8% of plans covered the high-concentration version of adalimumab-adaz (Hyrimoz), with a WAC 5% less than the reference product.

The unbranded version of adalimumab-adaz, sold at an 81% discount from the reference product, was covered by 13% of plans. Only 4.6% of plans covered high-concentration adalimumab-bwwd (Hadlima), manufactured by Samsung Bioepis.

In January 2024, no high-concentration adalimumab biosimilar had been granted interchangeability status by the US Food and Drug Administration (FDA). Adalimumab-ryvk (Simlandi) was the first biosimilar to receive this designation and was launched in late May 2024.

Coverage for the lower concentration of adalimumab was nearly universal (98.7% of plans). About half of the plans (50.7%) covered adalimumab-adbm (Cyltezo) at a 5% discount. Adalimumab-adbm (Boehringer Ingelheim) was the first interchangeable Humira biosimilar approved by the FDA, but it is only interchangeable with the less popular, lower concentration formulation of adalimumab.

All other biosimilars were covered by less than 5% of Medicare Part D plans, even with some having a WAC 86% below Humira.

A version of this article appeared on Medscape.com .

Upadacitinib (Rinvoq) is now indicated for patients aged 2 years or older with active polyarticular juvenile idiopathic arthritis (pJIA) and psoriatic arthritis (PsA) who cannot tolerate or achieve adequate disease response with one or more tumor necrosis factor (TNF) blockers, according to a press release from manufacturer AbbVie. 

For the youngest patients, upadacitinib is also available as a weight-based oral solution (Rinvoq LQ) in addition to the previously available tablets, according to the company. JIA, which includes pJIA and juvenile PsA, affects nearly 300,000 children and adolescents in the United States, and alternatives to TNF inhibitor (TNFi) therapy are limited, according to the company. 

“Pediatric patients with pJIA and PsA can be severely limited in their ability to complete daily physical tasks and participate in everyday activities. Understanding their needs today and knowing the likelihood of disease in adulthood underscores the need for additional treatment options,” Aarat Patel, MD, a pediatric rheumatologist at Bon Secours Rheumatology Center, Richmond, Virginia, said in the press release. “Having a treatment option available for patients who do not respond well to a TNFi addresses a need for the healthcare community, patients, and their families,” he said.

Upadacitinib, a Janus kinase (JAK) inhibitor, is being studied for multiple immune-mediated inflammatory diseases. The new indication was supported by data from adults with rheumatoid arthritis (RA) and PsA, 51 pediatric patients with pJIA and active polyarthritis, and safety data from 83 pediatric patients aged 2 years to younger than 18 years with pJIA and active polyarthritis. 

In the studies, the drug’s safety in pediatric patients was similar to the known safety profile in adults, which includes increased risk for serious infections such as tuberculosis, cancer, immune system problems, blood clots, and serious allergic reactions to components of the drug, according to the press release. However, the safety and effectiveness of upadacitinib for pJIA and PsA in patients younger than 2 years are unknown.

“Upadacitinib plasma exposures in pediatric patients with pJIA and PsA at the recommended dosage are predicted to be comparable to those observed in adults with RA and PsA based on population pharmacokinetic modeling and simulation,” according to the press release.

Currently, upadacitinib’s only other pediatric indication is for moderate to severe atopic dermatitis in children aged 12 years or older. Upadacitinib also is indicated for treatment of adults with moderate to severe RA, active PsA, active ankylosing spondylitis, active nonradiographic axial spondyloarthritis, and moderate to severe ulcerative colitis and Crohn’s disease, but safety and efficacy for its use in treatment of these conditions in children and adolescents is unknown.

Upadacitinib also is being studied in phase 3 trials for treatment of conditions including alopecia areata, ankylosing spondylitis, atopic dermatitis, axial spondyloarthritis, Crohn’s disease, giant cell arteritis, hidradenitis suppurativa, psoriatic arthritis, RA, systemic lupus erythematosus, Takayasu arteritis, ulcerative colitis, and vitiligo, according to the press release. 

Full prescribing information and safety data for upadacitinib are available here. 

A version of this article appeared on Medscape.com.

Upadacitinib (Rinvoq) is now indicated for patients aged 2 years or older with active polyarticular juvenile idiopathic arthritis (pJIA) and psoriatic arthritis (PsA) who cannot tolerate or achieve adequate disease response with one or more tumor necrosis factor (TNF) blockers, according to a press release from manufacturer AbbVie. 

For the youngest patients, upadacitinib is also available as a weight-based oral solution (Rinvoq LQ) in addition to the previously available tablets, according to the company. JIA, which includes pJIA and juvenile PsA, affects nearly 300,000 children and adolescents in the United States, and alternatives to TNF inhibitor (TNFi) therapy are limited, according to the company. 

“Pediatric patients with pJIA and PsA can be severely limited in their ability to complete daily physical tasks and participate in everyday activities. Understanding their needs today and knowing the likelihood of disease in adulthood underscores the need for additional treatment options,” Aarat Patel, MD, a pediatric rheumatologist at Bon Secours Rheumatology Center, Richmond, Virginia, said in the press release. “Having a treatment option available for patients who do not respond well to a TNFi addresses a need for the healthcare community, patients, and their families,” he said.

Upadacitinib, a Janus kinase (JAK) inhibitor, is being studied for multiple immune-mediated inflammatory diseases. The new indication was supported by data from adults with rheumatoid arthritis (RA) and PsA, 51 pediatric patients with pJIA and active polyarthritis, and safety data from 83 pediatric patients aged 2 years to younger than 18 years with pJIA and active polyarthritis. 

In the studies, the drug’s safety in pediatric patients was similar to the known safety profile in adults, which includes increased risk for serious infections such as tuberculosis, cancer, immune system problems, blood clots, and serious allergic reactions to components of the drug, according to the press release. However, the safety and effectiveness of upadacitinib for pJIA and PsA in patients younger than 2 years are unknown.

“Upadacitinib plasma exposures in pediatric patients with pJIA and PsA at the recommended dosage are predicted to be comparable to those observed in adults with RA and PsA based on population pharmacokinetic modeling and simulation,” according to the press release.

Currently, upadacitinib’s only other pediatric indication is for moderate to severe atopic dermatitis in children aged 12 years or older. Upadacitinib also is indicated for treatment of adults with moderate to severe RA, active PsA, active ankylosing spondylitis, active nonradiographic axial spondyloarthritis, and moderate to severe ulcerative colitis and Crohn’s disease, but safety and efficacy for its use in treatment of these conditions in children and adolescents is unknown.

Upadacitinib also is being studied in phase 3 trials for treatment of conditions including alopecia areata, ankylosing spondylitis, atopic dermatitis, axial spondyloarthritis, Crohn’s disease, giant cell arteritis, hidradenitis suppurativa, psoriatic arthritis, RA, systemic lupus erythematosus, Takayasu arteritis, ulcerative colitis, and vitiligo, according to the press release. 

Full prescribing information and safety data for upadacitinib are available here. 

A version of this article appeared on Medscape.com.

Upadacitinib (Rinvoq) is now indicated for patients aged 2 years or older with active polyarticular juvenile idiopathic arthritis (pJIA) and psoriatic arthritis (PsA) who cannot tolerate or achieve adequate disease response with one or more tumor necrosis factor (TNF) blockers, according to a press release from manufacturer AbbVie. 

For the youngest patients, upadacitinib is also available as a weight-based oral solution (Rinvoq LQ) in addition to the previously available tablets, according to the company. JIA, which includes pJIA and juvenile PsA, affects nearly 300,000 children and adolescents in the United States, and alternatives to TNF inhibitor (TNFi) therapy are limited, according to the company. 

“Pediatric patients with pJIA and PsA can be severely limited in their ability to complete daily physical tasks and participate in everyday activities. Understanding their needs today and knowing the likelihood of disease in adulthood underscores the need for additional treatment options,” Aarat Patel, MD, a pediatric rheumatologist at Bon Secours Rheumatology Center, Richmond, Virginia, said in the press release. “Having a treatment option available for patients who do not respond well to a TNFi addresses a need for the healthcare community, patients, and their families,” he said.

Upadacitinib, a Janus kinase (JAK) inhibitor, is being studied for multiple immune-mediated inflammatory diseases. The new indication was supported by data from adults with rheumatoid arthritis (RA) and PsA, 51 pediatric patients with pJIA and active polyarthritis, and safety data from 83 pediatric patients aged 2 years to younger than 18 years with pJIA and active polyarthritis. 

In the studies, the drug’s safety in pediatric patients was similar to the known safety profile in adults, which includes increased risk for serious infections such as tuberculosis, cancer, immune system problems, blood clots, and serious allergic reactions to components of the drug, according to the press release. However, the safety and effectiveness of upadacitinib for pJIA and PsA in patients younger than 2 years are unknown.

“Upadacitinib plasma exposures in pediatric patients with pJIA and PsA at the recommended dosage are predicted to be comparable to those observed in adults with RA and PsA based on population pharmacokinetic modeling and simulation,” according to the press release.

Currently, upadacitinib’s only other pediatric indication is for moderate to severe atopic dermatitis in children aged 12 years or older. Upadacitinib also is indicated for treatment of adults with moderate to severe RA, active PsA, active ankylosing spondylitis, active nonradiographic axial spondyloarthritis, and moderate to severe ulcerative colitis and Crohn’s disease, but safety and efficacy for its use in treatment of these conditions in children and adolescents is unknown.

Upadacitinib also is being studied in phase 3 trials for treatment of conditions including alopecia areata, ankylosing spondylitis, atopic dermatitis, axial spondyloarthritis, Crohn’s disease, giant cell arteritis, hidradenitis suppurativa, psoriatic arthritis, RA, systemic lupus erythematosus, Takayasu arteritis, ulcerative colitis, and vitiligo, according to the press release. 

Full prescribing information and safety data for upadacitinib are available here. 

A version of this article appeared on Medscape.com.

In a study of adults, an increase of 1 g in estimated 24-hour urinary sodium excretion was associated with 11% higher odds of an atopic dermatitis (AD) diagnosis, 16% higher odds of having active AD, and 11% higher odds of increased severity of AD.

Those are key findings from a cross-sectional analysis of data from the United Kingdom.

“Excessive dietary sodium, common in fast food, may be associated with AD,” corresponding author Katrina Abuabara, MD, MA, MSCE, and colleagues wrote in the study, which was published online in JAMA Dermatology. They referred to recent research using sodium MRI, which showed that “the majority of the body’s exchangeable sodium is stored in the skin and that skin sodium is associated with autoimmune and chronic inflammatory conditions, including AD.” And in another study published in 2019, lesional skin sodium was 30-fold greater in patients with AD than in healthy controls.

To investigate whether there is an association between higher levels of sodium consumption and AD prevalence, activity, and severity at the population level, Dr. Abuabara, of the program for clinical research in the Department of Dermatology at the University of California, San Francisco, and coauthors drew from the UK Biobank, a population-based cohort of more than 500,000 individuals aged 37-73 years at the time of recruitment by the National Health Service. The primary exposure was 24-hour urinary sodium excretion, which was calculated by using the INTERSALT equation, a sex-specific estimation that incorporates body mass index; age; and urine concentrations of potassium, sodium, and creatinine. The primary study outcome was AD or active AD based on diagnostic and prescription codes from linked electronic medical records. The researchers used multivariable logistic regression models adjusted for age, sex, race and ethnicity, Townsend deprivation index, and education to measure the association.

Of the 215,832 Biobank participants included in the analysis, 54% were female, their mean age was 57 years, 95% were White, their mean estimated 24-hour urine sodium excretion was 3.01 g/day, and 10,839 (5%) had a diagnosis of AD. The researchers observed that on multivariable logistic regression, a 1-g increase in estimated 24-hour urine sodium excretion was associated with increased odds of AD (adjusted odds ratio [AOR], 1.11; 95% CI, 1.07-1.14), increased odds of active AD (AOR, 1.16; 95% CI, 1.05-1.28), and increased odds of increasing severity of AD (AOR, 1.11; 95% CI, 1.07-1.15).
 

Validating Results With US Data

To validate the findings, the researchers evaluated a cohort of 13,014 participants from the US-based National Health and Nutrition Examination Survey (NHANES), using pooled data from the 1999-2000, 2001-2002, and 2003-2004 samples. Of the 13,014 participants, 796 reported current AD, and 1493 reported AD in the past year. The mean dietary sodium intake of overall NHANES participants estimated with 24-hour dietary recall questionnaires was 3.45 g, with a mean of 3.47 g for those with current AD and a mean of 3.44 g for those without AD.

The researchers observed that a 1-g/day higher dietary sodium intake was associated with a higher risk for current AD (AOR, 1.22; 95%CI, 1.01-1.47) and a somewhat higher risk for AD in the past year (AOR, 1.14; 95% CI, 0.97-1.35).

“Future work should examine whether variation of sodium intake over time might trigger AD flares and whether it helps to explain heterogeneity in response to new immunomodulatory treatments for AD,” the authors wrote. “Reduced sodium intake was recommended as a treatment for AD more than a century ago, but there have yet to be studies examining the association of dietary sodium reduction with skin sodium concentration or AD severity,” they added. Noting that sodium reduction “has been shown to be a cost-effective intervention for hypertension and other cardiovascular disease outcomes,” they said that their data “support experimental studies of this approach in AD.”

They acknowledged certain limitations of the study, including the fact that a single spot urine sample was used in the UK Biobank cohort, “which only captures dietary intake of the last 24 hours and is not the best measure of usual or long-term intake of sodium.” They also noted that the findings may not be generalizable to other populations and that AD was based on self-report in the NHANES validation cohort.

Adam Friedman, MD, professor and chair of dermatology at George Washington University, Washington, who was asked to comment on the results, said the study by Dr. Abuabara and colleagues “gives us another reason to avoid salt, showing that 1 g/day of higher salt intake increases the risk of AD in an adult population and more severe AD.”

He added that, “Now, can you say that reducing salt intake will have a therapeutic effect or clinically relevant impact? No. [That is] certainly worth exploring but at a minimum, gives some more credibility to keeping it bland.”

The study was supported by a grant from the Medical Student in Aging Research Program, the National Institute on Aging, and the National Eczema Association. Dr. Abuabara reported receiving research funding for her institution from Pfizer and Cosmetique Internacional/La Roche-Posay and consulting fees from Target RWE, Sanofi, Nektar, and Amgen. No other disclosures were reported. Dr. Friedman had no relevant disclosures.

A version of this article appeared on Medscape.com.

In a study of adults, an increase of 1 g in estimated 24-hour urinary sodium excretion was associated with 11% higher odds of an atopic dermatitis (AD) diagnosis, 16% higher odds of having active AD, and 11% higher odds of increased severity of AD.

Those are key findings from a cross-sectional analysis of data from the United Kingdom.

“Excessive dietary sodium, common in fast food, may be associated with AD,” corresponding author Katrina Abuabara, MD, MA, MSCE, and colleagues wrote in the study, which was published online in JAMA Dermatology. They referred to recent research using sodium MRI, which showed that “the majority of the body’s exchangeable sodium is stored in the skin and that skin sodium is associated with autoimmune and chronic inflammatory conditions, including AD.” And in another study published in 2019, lesional skin sodium was 30-fold greater in patients with AD than in healthy controls.

To investigate whether there is an association between higher levels of sodium consumption and AD prevalence, activity, and severity at the population level, Dr. Abuabara, of the program for clinical research in the Department of Dermatology at the University of California, San Francisco, and coauthors drew from the UK Biobank, a population-based cohort of more than 500,000 individuals aged 37-73 years at the time of recruitment by the National Health Service. The primary exposure was 24-hour urinary sodium excretion, which was calculated by using the INTERSALT equation, a sex-specific estimation that incorporates body mass index; age; and urine concentrations of potassium, sodium, and creatinine. The primary study outcome was AD or active AD based on diagnostic and prescription codes from linked electronic medical records. The researchers used multivariable logistic regression models adjusted for age, sex, race and ethnicity, Townsend deprivation index, and education to measure the association.

Of the 215,832 Biobank participants included in the analysis, 54% were female, their mean age was 57 years, 95% were White, their mean estimated 24-hour urine sodium excretion was 3.01 g/day, and 10,839 (5%) had a diagnosis of AD. The researchers observed that on multivariable logistic regression, a 1-g increase in estimated 24-hour urine sodium excretion was associated with increased odds of AD (adjusted odds ratio [AOR], 1.11; 95% CI, 1.07-1.14), increased odds of active AD (AOR, 1.16; 95% CI, 1.05-1.28), and increased odds of increasing severity of AD (AOR, 1.11; 95% CI, 1.07-1.15).
 

Validating Results With US Data

To validate the findings, the researchers evaluated a cohort of 13,014 participants from the US-based National Health and Nutrition Examination Survey (NHANES), using pooled data from the 1999-2000, 2001-2002, and 2003-2004 samples. Of the 13,014 participants, 796 reported current AD, and 1493 reported AD in the past year. The mean dietary sodium intake of overall NHANES participants estimated with 24-hour dietary recall questionnaires was 3.45 g, with a mean of 3.47 g for those with current AD and a mean of 3.44 g for those without AD.

The researchers observed that a 1-g/day higher dietary sodium intake was associated with a higher risk for current AD (AOR, 1.22; 95%CI, 1.01-1.47) and a somewhat higher risk for AD in the past year (AOR, 1.14; 95% CI, 0.97-1.35).

“Future work should examine whether variation of sodium intake over time might trigger AD flares and whether it helps to explain heterogeneity in response to new immunomodulatory treatments for AD,” the authors wrote. “Reduced sodium intake was recommended as a treatment for AD more than a century ago, but there have yet to be studies examining the association of dietary sodium reduction with skin sodium concentration or AD severity,” they added. Noting that sodium reduction “has been shown to be a cost-effective intervention for hypertension and other cardiovascular disease outcomes,” they said that their data “support experimental studies of this approach in AD.”

They acknowledged certain limitations of the study, including the fact that a single spot urine sample was used in the UK Biobank cohort, “which only captures dietary intake of the last 24 hours and is not the best measure of usual or long-term intake of sodium.” They also noted that the findings may not be generalizable to other populations and that AD was based on self-report in the NHANES validation cohort.

Adam Friedman, MD, professor and chair of dermatology at George Washington University, Washington, who was asked to comment on the results, said the study by Dr. Abuabara and colleagues “gives us another reason to avoid salt, showing that 1 g/day of higher salt intake increases the risk of AD in an adult population and more severe AD.”

He added that, “Now, can you say that reducing salt intake will have a therapeutic effect or clinically relevant impact? No. [That is] certainly worth exploring but at a minimum, gives some more credibility to keeping it bland.”

The study was supported by a grant from the Medical Student in Aging Research Program, the National Institute on Aging, and the National Eczema Association. Dr. Abuabara reported receiving research funding for her institution from Pfizer and Cosmetique Internacional/La Roche-Posay and consulting fees from Target RWE, Sanofi, Nektar, and Amgen. No other disclosures were reported. Dr. Friedman had no relevant disclosures.

A version of this article appeared on Medscape.com.

In a study of adults, an increase of 1 g in estimated 24-hour urinary sodium excretion was associated with 11% higher odds of an atopic dermatitis (AD) diagnosis, 16% higher odds of having active AD, and 11% higher odds of increased severity of AD.

Those are key findings from a cross-sectional analysis of data from the United Kingdom.

“Excessive dietary sodium, common in fast food, may be associated with AD,” corresponding author Katrina Abuabara, MD, MA, MSCE, and colleagues wrote in the study, which was published online in JAMA Dermatology. They referred to recent research using sodium MRI, which showed that “the majority of the body’s exchangeable sodium is stored in the skin and that skin sodium is associated with autoimmune and chronic inflammatory conditions, including AD.” And in another study published in 2019, lesional skin sodium was 30-fold greater in patients with AD than in healthy controls.

To investigate whether there is an association between higher levels of sodium consumption and AD prevalence, activity, and severity at the population level, Dr. Abuabara, of the program for clinical research in the Department of Dermatology at the University of California, San Francisco, and coauthors drew from the UK Biobank, a population-based cohort of more than 500,000 individuals aged 37-73 years at the time of recruitment by the National Health Service. The primary exposure was 24-hour urinary sodium excretion, which was calculated by using the INTERSALT equation, a sex-specific estimation that incorporates body mass index; age; and urine concentrations of potassium, sodium, and creatinine. The primary study outcome was AD or active AD based on diagnostic and prescription codes from linked electronic medical records. The researchers used multivariable logistic regression models adjusted for age, sex, race and ethnicity, Townsend deprivation index, and education to measure the association.

Of the 215,832 Biobank participants included in the analysis, 54% were female, their mean age was 57 years, 95% were White, their mean estimated 24-hour urine sodium excretion was 3.01 g/day, and 10,839 (5%) had a diagnosis of AD. The researchers observed that on multivariable logistic regression, a 1-g increase in estimated 24-hour urine sodium excretion was associated with increased odds of AD (adjusted odds ratio [AOR], 1.11; 95% CI, 1.07-1.14), increased odds of active AD (AOR, 1.16; 95% CI, 1.05-1.28), and increased odds of increasing severity of AD (AOR, 1.11; 95% CI, 1.07-1.15).
 

Validating Results With US Data

To validate the findings, the researchers evaluated a cohort of 13,014 participants from the US-based National Health and Nutrition Examination Survey (NHANES), using pooled data from the 1999-2000, 2001-2002, and 2003-2004 samples. Of the 13,014 participants, 796 reported current AD, and 1493 reported AD in the past year. The mean dietary sodium intake of overall NHANES participants estimated with 24-hour dietary recall questionnaires was 3.45 g, with a mean of 3.47 g for those with current AD and a mean of 3.44 g for those without AD.

The researchers observed that a 1-g/day higher dietary sodium intake was associated with a higher risk for current AD (AOR, 1.22; 95%CI, 1.01-1.47) and a somewhat higher risk for AD in the past year (AOR, 1.14; 95% CI, 0.97-1.35).

“Future work should examine whether variation of sodium intake over time might trigger AD flares and whether it helps to explain heterogeneity in response to new immunomodulatory treatments for AD,” the authors wrote. “Reduced sodium intake was recommended as a treatment for AD more than a century ago, but there have yet to be studies examining the association of dietary sodium reduction with skin sodium concentration or AD severity,” they added. Noting that sodium reduction “has been shown to be a cost-effective intervention for hypertension and other cardiovascular disease outcomes,” they said that their data “support experimental studies of this approach in AD.”

They acknowledged certain limitations of the study, including the fact that a single spot urine sample was used in the UK Biobank cohort, “which only captures dietary intake of the last 24 hours and is not the best measure of usual or long-term intake of sodium.” They also noted that the findings may not be generalizable to other populations and that AD was based on self-report in the NHANES validation cohort.

Adam Friedman, MD, professor and chair of dermatology at George Washington University, Washington, who was asked to comment on the results, said the study by Dr. Abuabara and colleagues “gives us another reason to avoid salt, showing that 1 g/day of higher salt intake increases the risk of AD in an adult population and more severe AD.”

He added that, “Now, can you say that reducing salt intake will have a therapeutic effect or clinically relevant impact? No. [That is] certainly worth exploring but at a minimum, gives some more credibility to keeping it bland.”

The study was supported by a grant from the Medical Student in Aging Research Program, the National Institute on Aging, and the National Eczema Association. Dr. Abuabara reported receiving research funding for her institution from Pfizer and Cosmetique Internacional/La Roche-Posay and consulting fees from Target RWE, Sanofi, Nektar, and Amgen. No other disclosures were reported. Dr. Friedman had no relevant disclosures.

A version of this article appeared on Medscape.com.

Olive oil is obtained by mechanical extraction from the fruit of the Olea europaea tree, which is believed to have originated from ancient Iran and Turkestan, later spreading to Anatolia, Syria, Palestine, and Israel. Mechanical extraction of the oil from the olive fruit involves pressure processing, centrifugation, and adhesion filtering.¹ Refining of olive oil is done via alkali refining or physical refining, with physical refining being useful in removing oxidation by-products and pro-oxidant metals. Olive oil is composed mainly of triacylglycerols, which are glycerol esters attached to various fatty acids, with the most common fatty acid being the monounsaturated oleic acid. Additional fatty acids include palmitic acid, linoleic acid, stearic acid, and palmitoleic acid.² Olive oil contains phenolic compounds, the main ones being oleuropein, hydroxytyrosol, and tyrosol. These phenolic compounds are proposed to be strong antioxidants and radical scavengers.³

Mediterranean countries are responsible for approximately 97% of the world’s olive cultivation.⁴ Olive oil historically was used as lamp fuel, lubricant, body ointment, and later as a source of edible oil.¹ Recently, its potential uses in medicine have called for further exploration into other uses for olive oil.

The skin is the largest organ of the body and serves as a protective barrier against pathogens and harmful substances. Skin damage results in 3 main phases to aid in wound healing: inflammation, proliferation, and maturation. In proper skin healing, inflammation will stop once the harmful microbes are removed. However, an excess and prolongation of inflammation can result in delayed healing. Thus, interventions that can limit the amount of inflammation can help promote wound healing. Olive oil contains several anti-inflammatory molecules (compounds or chemicals), including phenolic compounds and omega-3 fatty acids.⁵ Studies also have shown that olive oil can promote re-epithelialization in tissues.⁶ Thus, use of olive oil in wound therapy has been of great interest.

This article will review studies that have investigated the use of olive oil for wound healing of diabetic foot ulcers, pressure ulcers, perineal ulcers, and chronic ulcers. To conduct a comprehensive scoping review of the literature on the effects of olive oil in wound healing, we utilized the resources of the Galter Health Sciences Library & Learning Center (Chicago, Illinois). Our search strategy was structured to encompass a range of relevant databases accessible through the library, including PubMed, Embase, and Web of Science. We formulated our search terms to be broad yet specific to our topic, combining keywords such as olive oil, wound healing, skin repair, and dermal therapy. The inclusion criteria were set to filter studies conducted from January 2000 to December 2019, focusing on clinical trials, observational studies, and review articles. We limited our search to articles published in English, which yielded a preliminary set of articles that were then screened based on their titles and abstracts. Full-text versions of potentially relevant studies were retrieved and assessed for eligibility. We included studies that specifically evaluated the effects of olive oil in wound healing, excluding those that did not directly relate to our research question or had insufficient data. The data extraction from these studies was conducted using a standardized form, capturing study design, population, intervention details, outcomes, and key findings. The synthesis of these data provided a comprehensive overview of the current evidence on the topic, aiding in the identification of gaps in knowledge and directions for future research.

Diabetic Foot Ulcers

Foot ulcers are common in patients with diabetes mellitus and are associated with notable morbidity and mortality. Foot ulcers can clinically manifest in various forms but are classically described as lesions with a deep sinus in the feet. Patients with diabetic foot ulcers are at risk for infection, and severe forms of the ulcers require amputation.^7,8 Routine care of foot ulcers involves irrigation of the ulcer and surrounding area with normal saline solution daily, followed by a dressing with sterile gauze. Studies investigating the effect of olive oil on foot ulcers suggest that olive oil use for care and healing of foot ulcers is an area of interest.

A double-blind, randomized clinical trial investigated the effects of topical olive oil on diabetic foot ulcers.⁹ A total of 34 patients with foot ulcers of Wagner grades 1 (superficial ulcers that involved the skin but not underlying tissue) or 2 (deeper ulcers penetrating to the ligaments and muscles but not the bone) that had remained open and did not improve for more than 3 months were recruited. The patients were randomly assigned to receive topical olive oil and routine care (intervention group) or to receive routine care (control group). Patients who received olive oil had oil poured on their ulcers with gauze wrapped around the ulcer that was soaked with olive oil. The clinical characteristics of the diabetic ulcer (eg, site, grade, size, status of healing) were assessed. The study revealed that after 4 weeks, olive oil significantly decreased ulcer area (P=.01) and ulcer depth (P=.02) compared with the control. Furthermore, there was a significant difference (P=.003) in complete ulcer healing between the olive oil and control groups: 73.3% (11/15) of patients in the olive oil group had complete ulcer healing, whereas 13.3% (2/15) of patients in the control group had complete ulcer healing.⁹ The positive effect of olive oil on the healing of diabetic foot ulcers encourages further investigation as a possible therapy for foot ulcers.

Another randomized controlled trial of 45 patients with diabetic foot ulcers of Wagner grades 1 or 2 investigated the effect of olive oil.¹⁰ Patients were randomly assigned to 1 of 3 groups for 1 month: the olive oil group, the honey group, or the control group. Patients in the olive oil group had their wounds dressed using gauze with olive oil daily, the patients in the honey group had their wounds dressed using gauze with honey daily, and the control group had routine care consisting of irrigation with saline solution and dressing with a sterile gauze. This study calculated a wound healing score based on a predefined checklist for diabetic foot ulcers through 4 variables: wound grading, color, surrounding tissue status, and drainage. Each variable had a maximum score of 100, contributing to a total possible score of 400, which indicated complete healing. A score of 50 signified ­deterioration. Wound healing was categorized as follows: (1) complete healing is indicated by a total score of 400; (2) partial healing was indicated by an increase of at least 30 points from the initial score; (3) lack of healing occurred when there was no change or less than a 30-point increase from the initial score; and (4) aggravation was noted when the score decreased by at least 10 points from the initial assessment. The study revealed that olive oil and honey treatments resulted in an increase in mean score, which indicated better wound healing. Patients in the olive oil group had a mean score of 253.0 before the intervention and 330.5 after the intervention (P<.0001); patients in the honey group had a mean score of 267.5 before the intervention and 371.5 after the intervention (P<.0001).¹⁰

There also have been case reports on combined olive oil and honey in diabetic foot ulcer management. Haghighian et al¹¹ presented a case of a diabetic foot wound that healed completely within 2 weeks after the combined use of olive oil and honey wax. Zahmatkesh and Rashidi¹² observed the healing of a diabetic foot wound over a month with daily dressings of a mixture of heated honey and olive oil, resulting in granulation tissue formation within 5 days. Microvascular changes, such as capillary basement membrane thickening, pericyte degeneration, and impairment of vasodilation and constriction, may contribute to inflammation in blood vessels, which can delay the healing of diabetic foot ulcers.⁷ Because olive oil and honey contain compounds that have antioxidative, antimicrobial, and anti-inflammatory properties, both may play a role in notably reducing inflammation and promoting the healing of foot ulcers.¹³

Pressure Ulcers

A pressure ulcer is a superficial skin injury that is caused by a prolonged period of pressure on the skin, in which the skin becomes red but there is no rupture. Prolonged periods of immobility resulting in a reduction or pause of blood supply are common causes of pressure ulcers.¹⁴ Studies have suggested that topical olive oil may be effective in prevention of pressure ulcers and should be incorporated as part of standard-of-care measures.

In a randomized, single-blind trial, 72 patients with the first stage of bedsore—which is a pressure ulcer—in the sacral, shoulder, heel, or other areas were randomly assigned to either the intervention or control group.¹⁴ Patients in the intervention group had 15 mL of olive oil rubbed on the wound for 20 minutes daily and then washed with tepid water. The Pressure Ulcer Scale for Healing tool was utilized to assess the healing status of the pressure ulcer. This tool considers wound surface size, exudate rate, and tissue type to provide a score of 0 to 17 (0=healed ulcer; 17=progression of ulcer). The mean score (SD) was lower in the olive oil group at days 4 and 7 compared with the control group (day 4: 7.50 [2.823] vs 9.50 [1.732]; day 7: 5.44 [3.806] vs 8.83 [2.864])(P<.001). Furthermore, between days 1 and 7, there was significant improvement in the olive oil group (mean difference, 3.56; P<.001) but no significant change in the control group (mean difference, 0.75; P=.052).¹⁴ The results indicate that patients in the olive oil group had a better ulcer healing status compared with patients in the control group.

In a noninferiority, randomized, double-blind clinical trial, olive oil was compared to a recommended skin care measure of hyperoxygenated fatty acids (HOFAs) for the prevention of pressure ulcers.¹⁵ The study consisted of 571 residents from several nursing homes who were at risk for pressure ulcers. Either olive oil or HOFA was applied to areas at risk for pressure ulcers, with 2 sprays of 0.2 mL per spray to each area every 12 hours. The participants were followed up for 30 days or until a pressure ulcer developed. Researchers performed skin assessments; the Braden Scale was used to assess the risk for pressure ulcers. The incidence difference of pressure ulcers in the olive oil group and HOFA group did not exceed in the noninferiority margin of 7%. Furthermore, Kaplan-Meier survival curves for the time until pressure ulcer onset showed a nonsignificant difference between the 2 groups.¹⁵ These findings suggest that olive oil is as effective as HOFA for the prevention of pressure ulcers. Although the mechanism of olive oil on prevention of pressure ulcers has not yet been determined, it has been suggested that anti-inflammatory compounds in olive oil, such as polyphenol and oleocanthal compounds, play an anti-inflammatory role.

Perineal Ulcers

Episiotomy is a surgical incision that is made to open the vagina during birth to aid in delivery of the baby. In contrast to spontaneous vaginal tears, an episiotomy allows for easier repair and healing of the laceration.¹⁶ Studies were conducted to investigate the effect of olive oil on women with lacerations after an episiotomy.

A total of 90 primigravid women who had undergone episiotomy were recruited and randomly assigned to 1 of 2 interventions: cold compression with gel packs for 20 minutes within 12 hours after delivery for up to 10 days, if necessary, or topical olive oil twice daily within 12 hours after delivery for up to 10 days.¹⁷ Although there was no significant difference in the structural features of the wound, there was a significant difference in the redness severity. After 10 days, the mean REEDA (redness, edema, ecchymosis, discharge, and apposition) score (SD), which assesses tissue healing, was 0.47 (0.96) in patients who received cold compression with gel packs and 0.20 (0.50) in patients who received topical olive oil (P=.04).¹⁷ This study suggests that there is the potential for olive oil to be used for wound healing after episiotomy.

A double-blind trial consisted of 60 women who had mediolateral episiotomy or perineal tear grades 1 and 2 who were randomly assigned to 1 of 2 groups for 10 days: olive oil sitz bath or distilled water sitz bath (control group). The results showed a significant difference in pain severity after 5 and 10 days (P<.05), wound redness after 5 days (P<.0001), and redness (P<.000) and edema (P<.05) 10 days after delivery.¹⁸ This study encourages further investigation of the benefits of olive oil for care after an episiotomy.

Chronic Ulcers

Chronic ulcers are other persistent wounds that do not respond to standard treatments and pose a notable health burden. Their development is influenced by factors such as oxidative stress, microbial infections, and the body’s immune response. A case series was conducted to investigate the wound healing effects of olive oil on chronic ulcers.¹⁹ Fourteen patients who were diagnosed with 1 or more chronic skin ulcers that had not healed with conventional treatment, such as cleansing, debridement, or infection control, were recruited. The mean (SD) of the patients’ Bates-Jensen Wound Assessment Tool score was 39.05 (4.23), indicating that these ulcers had been challenging to treat. In addition, the wounds in this study were found to be infected with bacteria. An ointment consisting of Ceratothoa oestroides olive oil extract was applied to the wounds after they were cleansed. The results showed that Bates-Jensen Wound Assessment Tool scores decreased by 14.7% to 67.5% (mean, 36%; median, 38%) after 3 months of treatment. Furthermore, 5 patients had a completely healed wound, indicating that C oestroides olive oil extract can regenerate chronic ulcers that do not respond to antibacterial agents.¹⁹ These results encourage further investigation of the role of C oestroides olive oil extract on healing properties and microbial control.

Final Thoughts

This review illuminated several key aspects of research on the role of olive oil in wound healing. Although the studies included in this review offer valuable insights, it is essential to acknowledge the variability in the quality of data presented. Several studies demonstrated robust methodology with clear definitions of outcomes and controlled conditions, providing high-quality evidence. However, other studies exhibited limitations, including small sample sizes and potential biases, which may affect the generalizability of the findings. Despite these limitations, the collective evidence suggests potential for olive oil in wound healing, warranting further investigation. Future research should aim for more standardized methodologies and larger, more diverse patient cohorts to validate these findings and explore the mechanisms underlying the therapeutic effects of olive oil.

Olive oil is obtained by mechanical extraction from the fruit of the Olea europaea tree, which is believed to have originated from ancient Iran and Turkestan, later spreading to Anatolia, Syria, Palestine, and Israel. Mechanical extraction of the oil from the olive fruit involves pressure processing, centrifugation, and adhesion filtering.¹ Refining of olive oil is done via alkali refining or physical refining, with physical refining being useful in removing oxidation by-products and pro-oxidant metals. Olive oil is composed mainly of triacylglycerols, which are glycerol esters attached to various fatty acids, with the most common fatty acid being the monounsaturated oleic acid. Additional fatty acids include palmitic acid, linoleic acid, stearic acid, and palmitoleic acid.² Olive oil contains phenolic compounds, the main ones being oleuropein, hydroxytyrosol, and tyrosol. These phenolic compounds are proposed to be strong antioxidants and radical scavengers.³

Mediterranean countries are responsible for approximately 97% of the world’s olive cultivation.⁴ Olive oil historically was used as lamp fuel, lubricant, body ointment, and later as a source of edible oil.¹ Recently, its potential uses in medicine have called for further exploration into other uses for olive oil.

The skin is the largest organ of the body and serves as a protective barrier against pathogens and harmful substances. Skin damage results in 3 main phases to aid in wound healing: inflammation, proliferation, and maturation. In proper skin healing, inflammation will stop once the harmful microbes are removed. However, an excess and prolongation of inflammation can result in delayed healing. Thus, interventions that can limit the amount of inflammation can help promote wound healing. Olive oil contains several anti-inflammatory molecules (compounds or chemicals), including phenolic compounds and omega-3 fatty acids.⁵ Studies also have shown that olive oil can promote re-epithelialization in tissues.⁶ Thus, use of olive oil in wound therapy has been of great interest.

This article will review studies that have investigated the use of olive oil for wound healing of diabetic foot ulcers, pressure ulcers, perineal ulcers, and chronic ulcers. To conduct a comprehensive scoping review of the literature on the effects of olive oil in wound healing, we utilized the resources of the Galter Health Sciences Library & Learning Center (Chicago, Illinois). Our search strategy was structured to encompass a range of relevant databases accessible through the library, including PubMed, Embase, and Web of Science. We formulated our search terms to be broad yet specific to our topic, combining keywords such as olive oil, wound healing, skin repair, and dermal therapy. The inclusion criteria were set to filter studies conducted from January 2000 to December 2019, focusing on clinical trials, observational studies, and review articles. We limited our search to articles published in English, which yielded a preliminary set of articles that were then screened based on their titles and abstracts. Full-text versions of potentially relevant studies were retrieved and assessed for eligibility. We included studies that specifically evaluated the effects of olive oil in wound healing, excluding those that did not directly relate to our research question or had insufficient data. The data extraction from these studies was conducted using a standardized form, capturing study design, population, intervention details, outcomes, and key findings. The synthesis of these data provided a comprehensive overview of the current evidence on the topic, aiding in the identification of gaps in knowledge and directions for future research.

Diabetic Foot Ulcers

Foot ulcers are common in patients with diabetes mellitus and are associated with notable morbidity and mortality. Foot ulcers can clinically manifest in various forms but are classically described as lesions with a deep sinus in the feet. Patients with diabetic foot ulcers are at risk for infection, and severe forms of the ulcers require amputation.^7,8 Routine care of foot ulcers involves irrigation of the ulcer and surrounding area with normal saline solution daily, followed by a dressing with sterile gauze. Studies investigating the effect of olive oil on foot ulcers suggest that olive oil use for care and healing of foot ulcers is an area of interest.

A double-blind, randomized clinical trial investigated the effects of topical olive oil on diabetic foot ulcers.⁹ A total of 34 patients with foot ulcers of Wagner grades 1 (superficial ulcers that involved the skin but not underlying tissue) or 2 (deeper ulcers penetrating to the ligaments and muscles but not the bone) that had remained open and did not improve for more than 3 months were recruited. The patients were randomly assigned to receive topical olive oil and routine care (intervention group) or to receive routine care (control group). Patients who received olive oil had oil poured on their ulcers with gauze wrapped around the ulcer that was soaked with olive oil. The clinical characteristics of the diabetic ulcer (eg, site, grade, size, status of healing) were assessed. The study revealed that after 4 weeks, olive oil significantly decreased ulcer area (P=.01) and ulcer depth (P=.02) compared with the control. Furthermore, there was a significant difference (P=.003) in complete ulcer healing between the olive oil and control groups: 73.3% (11/15) of patients in the olive oil group had complete ulcer healing, whereas 13.3% (2/15) of patients in the control group had complete ulcer healing.⁹ The positive effect of olive oil on the healing of diabetic foot ulcers encourages further investigation as a possible therapy for foot ulcers.

Another randomized controlled trial of 45 patients with diabetic foot ulcers of Wagner grades 1 or 2 investigated the effect of olive oil.¹⁰ Patients were randomly assigned to 1 of 3 groups for 1 month: the olive oil group, the honey group, or the control group. Patients in the olive oil group had their wounds dressed using gauze with olive oil daily, the patients in the honey group had their wounds dressed using gauze with honey daily, and the control group had routine care consisting of irrigation with saline solution and dressing with a sterile gauze. This study calculated a wound healing score based on a predefined checklist for diabetic foot ulcers through 4 variables: wound grading, color, surrounding tissue status, and drainage. Each variable had a maximum score of 100, contributing to a total possible score of 400, which indicated complete healing. A score of 50 signified ­deterioration. Wound healing was categorized as follows: (1) complete healing is indicated by a total score of 400; (2) partial healing was indicated by an increase of at least 30 points from the initial score; (3) lack of healing occurred when there was no change or less than a 30-point increase from the initial score; and (4) aggravation was noted when the score decreased by at least 10 points from the initial assessment. The study revealed that olive oil and honey treatments resulted in an increase in mean score, which indicated better wound healing. Patients in the olive oil group had a mean score of 253.0 before the intervention and 330.5 after the intervention (P<.0001); patients in the honey group had a mean score of 267.5 before the intervention and 371.5 after the intervention (P<.0001).¹⁰

There also have been case reports on combined olive oil and honey in diabetic foot ulcer management. Haghighian et al¹¹ presented a case of a diabetic foot wound that healed completely within 2 weeks after the combined use of olive oil and honey wax. Zahmatkesh and Rashidi¹² observed the healing of a diabetic foot wound over a month with daily dressings of a mixture of heated honey and olive oil, resulting in granulation tissue formation within 5 days. Microvascular changes, such as capillary basement membrane thickening, pericyte degeneration, and impairment of vasodilation and constriction, may contribute to inflammation in blood vessels, which can delay the healing of diabetic foot ulcers.⁷ Because olive oil and honey contain compounds that have antioxidative, antimicrobial, and anti-inflammatory properties, both may play a role in notably reducing inflammation and promoting the healing of foot ulcers.¹³

Pressure Ulcers

A pressure ulcer is a superficial skin injury that is caused by a prolonged period of pressure on the skin, in which the skin becomes red but there is no rupture. Prolonged periods of immobility resulting in a reduction or pause of blood supply are common causes of pressure ulcers.¹⁴ Studies have suggested that topical olive oil may be effective in prevention of pressure ulcers and should be incorporated as part of standard-of-care measures.

In a randomized, single-blind trial, 72 patients with the first stage of bedsore—which is a pressure ulcer—in the sacral, shoulder, heel, or other areas were randomly assigned to either the intervention or control group.¹⁴ Patients in the intervention group had 15 mL of olive oil rubbed on the wound for 20 minutes daily and then washed with tepid water. The Pressure Ulcer Scale for Healing tool was utilized to assess the healing status of the pressure ulcer. This tool considers wound surface size, exudate rate, and tissue type to provide a score of 0 to 17 (0=healed ulcer; 17=progression of ulcer). The mean score (SD) was lower in the olive oil group at days 4 and 7 compared with the control group (day 4: 7.50 [2.823] vs 9.50 [1.732]; day 7: 5.44 [3.806] vs 8.83 [2.864])(P<.001). Furthermore, between days 1 and 7, there was significant improvement in the olive oil group (mean difference, 3.56; P<.001) but no significant change in the control group (mean difference, 0.75; P=.052).¹⁴ The results indicate that patients in the olive oil group had a better ulcer healing status compared with patients in the control group.

In a noninferiority, randomized, double-blind clinical trial, olive oil was compared to a recommended skin care measure of hyperoxygenated fatty acids (HOFAs) for the prevention of pressure ulcers.¹⁵ The study consisted of 571 residents from several nursing homes who were at risk for pressure ulcers. Either olive oil or HOFA was applied to areas at risk for pressure ulcers, with 2 sprays of 0.2 mL per spray to each area every 12 hours. The participants were followed up for 30 days or until a pressure ulcer developed. Researchers performed skin assessments; the Braden Scale was used to assess the risk for pressure ulcers. The incidence difference of pressure ulcers in the olive oil group and HOFA group did not exceed in the noninferiority margin of 7%. Furthermore, Kaplan-Meier survival curves for the time until pressure ulcer onset showed a nonsignificant difference between the 2 groups.¹⁵ These findings suggest that olive oil is as effective as HOFA for the prevention of pressure ulcers. Although the mechanism of olive oil on prevention of pressure ulcers has not yet been determined, it has been suggested that anti-inflammatory compounds in olive oil, such as polyphenol and oleocanthal compounds, play an anti-inflammatory role.

Perineal Ulcers

Episiotomy is a surgical incision that is made to open the vagina during birth to aid in delivery of the baby. In contrast to spontaneous vaginal tears, an episiotomy allows for easier repair and healing of the laceration.¹⁶ Studies were conducted to investigate the effect of olive oil on women with lacerations after an episiotomy.

A total of 90 primigravid women who had undergone episiotomy were recruited and randomly assigned to 1 of 2 interventions: cold compression with gel packs for 20 minutes within 12 hours after delivery for up to 10 days, if necessary, or topical olive oil twice daily within 12 hours after delivery for up to 10 days.¹⁷ Although there was no significant difference in the structural features of the wound, there was a significant difference in the redness severity. After 10 days, the mean REEDA (redness, edema, ecchymosis, discharge, and apposition) score (SD), which assesses tissue healing, was 0.47 (0.96) in patients who received cold compression with gel packs and 0.20 (0.50) in patients who received topical olive oil (P=.04).¹⁷ This study suggests that there is the potential for olive oil to be used for wound healing after episiotomy.

A double-blind trial consisted of 60 women who had mediolateral episiotomy or perineal tear grades 1 and 2 who were randomly assigned to 1 of 2 groups for 10 days: olive oil sitz bath or distilled water sitz bath (control group). The results showed a significant difference in pain severity after 5 and 10 days (P<.05), wound redness after 5 days (P<.0001), and redness (P<.000) and edema (P<.05) 10 days after delivery.¹⁸ This study encourages further investigation of the benefits of olive oil for care after an episiotomy.

Chronic Ulcers

Chronic ulcers are other persistent wounds that do not respond to standard treatments and pose a notable health burden. Their development is influenced by factors such as oxidative stress, microbial infections, and the body’s immune response. A case series was conducted to investigate the wound healing effects of olive oil on chronic ulcers.¹⁹ Fourteen patients who were diagnosed with 1 or more chronic skin ulcers that had not healed with conventional treatment, such as cleansing, debridement, or infection control, were recruited. The mean (SD) of the patients’ Bates-Jensen Wound Assessment Tool score was 39.05 (4.23), indicating that these ulcers had been challenging to treat. In addition, the wounds in this study were found to be infected with bacteria. An ointment consisting of Ceratothoa oestroides olive oil extract was applied to the wounds after they were cleansed. The results showed that Bates-Jensen Wound Assessment Tool scores decreased by 14.7% to 67.5% (mean, 36%; median, 38%) after 3 months of treatment. Furthermore, 5 patients had a completely healed wound, indicating that C oestroides olive oil extract can regenerate chronic ulcers that do not respond to antibacterial agents.¹⁹ These results encourage further investigation of the role of C oestroides olive oil extract on healing properties and microbial control.

Final Thoughts

This review illuminated several key aspects of research on the role of olive oil in wound healing. Although the studies included in this review offer valuable insights, it is essential to acknowledge the variability in the quality of data presented. Several studies demonstrated robust methodology with clear definitions of outcomes and controlled conditions, providing high-quality evidence. However, other studies exhibited limitations, including small sample sizes and potential biases, which may affect the generalizability of the findings. Despite these limitations, the collective evidence suggests potential for olive oil in wound healing, warranting further investigation. Future research should aim for more standardized methodologies and larger, more diverse patient cohorts to validate these findings and explore the mechanisms underlying the therapeutic effects of olive oil.

Olive oil is obtained by mechanical extraction from the fruit of the Olea europaea tree, which is believed to have originated from ancient Iran and Turkestan, later spreading to Anatolia, Syria, Palestine, and Israel. Mechanical extraction of the oil from the olive fruit involves pressure processing, centrifugation, and adhesion filtering.¹ Refining of olive oil is done via alkali refining or physical refining, with physical refining being useful in removing oxidation by-products and pro-oxidant metals. Olive oil is composed mainly of triacylglycerols, which are glycerol esters attached to various fatty acids, with the most common fatty acid being the monounsaturated oleic acid. Additional fatty acids include palmitic acid, linoleic acid, stearic acid, and palmitoleic acid.² Olive oil contains phenolic compounds, the main ones being oleuropein, hydroxytyrosol, and tyrosol. These phenolic compounds are proposed to be strong antioxidants and radical scavengers.³

Mediterranean countries are responsible for approximately 97% of the world’s olive cultivation.⁴ Olive oil historically was used as lamp fuel, lubricant, body ointment, and later as a source of edible oil.¹ Recently, its potential uses in medicine have called for further exploration into other uses for olive oil.

The skin is the largest organ of the body and serves as a protective barrier against pathogens and harmful substances. Skin damage results in 3 main phases to aid in wound healing: inflammation, proliferation, and maturation. In proper skin healing, inflammation will stop once the harmful microbes are removed. However, an excess and prolongation of inflammation can result in delayed healing. Thus, interventions that can limit the amount of inflammation can help promote wound healing. Olive oil contains several anti-inflammatory molecules (compounds or chemicals), including phenolic compounds and omega-3 fatty acids.⁵ Studies also have shown that olive oil can promote re-epithelialization in tissues.⁶ Thus, use of olive oil in wound therapy has been of great interest.

This article will review studies that have investigated the use of olive oil for wound healing of diabetic foot ulcers, pressure ulcers, perineal ulcers, and chronic ulcers. To conduct a comprehensive scoping review of the literature on the effects of olive oil in wound healing, we utilized the resources of the Galter Health Sciences Library & Learning Center (Chicago, Illinois). Our search strategy was structured to encompass a range of relevant databases accessible through the library, including PubMed, Embase, and Web of Science. We formulated our search terms to be broad yet specific to our topic, combining keywords such as olive oil, wound healing, skin repair, and dermal therapy. The inclusion criteria were set to filter studies conducted from January 2000 to December 2019, focusing on clinical trials, observational studies, and review articles. We limited our search to articles published in English, which yielded a preliminary set of articles that were then screened based on their titles and abstracts. Full-text versions of potentially relevant studies were retrieved and assessed for eligibility. We included studies that specifically evaluated the effects of olive oil in wound healing, excluding those that did not directly relate to our research question or had insufficient data. The data extraction from these studies was conducted using a standardized form, capturing study design, population, intervention details, outcomes, and key findings. The synthesis of these data provided a comprehensive overview of the current evidence on the topic, aiding in the identification of gaps in knowledge and directions for future research.

Diabetic Foot Ulcers

Foot ulcers are common in patients with diabetes mellitus and are associated with notable morbidity and mortality. Foot ulcers can clinically manifest in various forms but are classically described as lesions with a deep sinus in the feet. Patients with diabetic foot ulcers are at risk for infection, and severe forms of the ulcers require amputation.^7,8 Routine care of foot ulcers involves irrigation of the ulcer and surrounding area with normal saline solution daily, followed by a dressing with sterile gauze. Studies investigating the effect of olive oil on foot ulcers suggest that olive oil use for care and healing of foot ulcers is an area of interest.

A double-blind, randomized clinical trial investigated the effects of topical olive oil on diabetic foot ulcers.⁹ A total of 34 patients with foot ulcers of Wagner grades 1 (superficial ulcers that involved the skin but not underlying tissue) or 2 (deeper ulcers penetrating to the ligaments and muscles but not the bone) that had remained open and did not improve for more than 3 months were recruited. The patients were randomly assigned to receive topical olive oil and routine care (intervention group) or to receive routine care (control group). Patients who received olive oil had oil poured on their ulcers with gauze wrapped around the ulcer that was soaked with olive oil. The clinical characteristics of the diabetic ulcer (eg, site, grade, size, status of healing) were assessed. The study revealed that after 4 weeks, olive oil significantly decreased ulcer area (P=.01) and ulcer depth (P=.02) compared with the control. Furthermore, there was a significant difference (P=.003) in complete ulcer healing between the olive oil and control groups: 73.3% (11/15) of patients in the olive oil group had complete ulcer healing, whereas 13.3% (2/15) of patients in the control group had complete ulcer healing.⁹ The positive effect of olive oil on the healing of diabetic foot ulcers encourages further investigation as a possible therapy for foot ulcers.

Another randomized controlled trial of 45 patients with diabetic foot ulcers of Wagner grades 1 or 2 investigated the effect of olive oil.¹⁰ Patients were randomly assigned to 1 of 3 groups for 1 month: the olive oil group, the honey group, or the control group. Patients in the olive oil group had their wounds dressed using gauze with olive oil daily, the patients in the honey group had their wounds dressed using gauze with honey daily, and the control group had routine care consisting of irrigation with saline solution and dressing with a sterile gauze. This study calculated a wound healing score based on a predefined checklist for diabetic foot ulcers through 4 variables: wound grading, color, surrounding tissue status, and drainage. Each variable had a maximum score of 100, contributing to a total possible score of 400, which indicated complete healing. A score of 50 signified ­deterioration. Wound healing was categorized as follows: (1) complete healing is indicated by a total score of 400; (2) partial healing was indicated by an increase of at least 30 points from the initial score; (3) lack of healing occurred when there was no change or less than a 30-point increase from the initial score; and (4) aggravation was noted when the score decreased by at least 10 points from the initial assessment. The study revealed that olive oil and honey treatments resulted in an increase in mean score, which indicated better wound healing. Patients in the olive oil group had a mean score of 253.0 before the intervention and 330.5 after the intervention (P<.0001); patients in the honey group had a mean score of 267.5 before the intervention and 371.5 after the intervention (P<.0001).¹⁰

There also have been case reports on combined olive oil and honey in diabetic foot ulcer management. Haghighian et al¹¹ presented a case of a diabetic foot wound that healed completely within 2 weeks after the combined use of olive oil and honey wax. Zahmatkesh and Rashidi¹² observed the healing of a diabetic foot wound over a month with daily dressings of a mixture of heated honey and olive oil, resulting in granulation tissue formation within 5 days. Microvascular changes, such as capillary basement membrane thickening, pericyte degeneration, and impairment of vasodilation and constriction, may contribute to inflammation in blood vessels, which can delay the healing of diabetic foot ulcers.⁷ Because olive oil and honey contain compounds that have antioxidative, antimicrobial, and anti-inflammatory properties, both may play a role in notably reducing inflammation and promoting the healing of foot ulcers.¹³

Pressure Ulcers

A pressure ulcer is a superficial skin injury that is caused by a prolonged period of pressure on the skin, in which the skin becomes red but there is no rupture. Prolonged periods of immobility resulting in a reduction or pause of blood supply are common causes of pressure ulcers.¹⁴ Studies have suggested that topical olive oil may be effective in prevention of pressure ulcers and should be incorporated as part of standard-of-care measures.

In a randomized, single-blind trial, 72 patients with the first stage of bedsore—which is a pressure ulcer—in the sacral, shoulder, heel, or other areas were randomly assigned to either the intervention or control group.¹⁴ Patients in the intervention group had 15 mL of olive oil rubbed on the wound for 20 minutes daily and then washed with tepid water. The Pressure Ulcer Scale for Healing tool was utilized to assess the healing status of the pressure ulcer. This tool considers wound surface size, exudate rate, and tissue type to provide a score of 0 to 17 (0=healed ulcer; 17=progression of ulcer). The mean score (SD) was lower in the olive oil group at days 4 and 7 compared with the control group (day 4: 7.50 [2.823] vs 9.50 [1.732]; day 7: 5.44 [3.806] vs 8.83 [2.864])(P<.001). Furthermore, between days 1 and 7, there was significant improvement in the olive oil group (mean difference, 3.56; P<.001) but no significant change in the control group (mean difference, 0.75; P=.052).¹⁴ The results indicate that patients in the olive oil group had a better ulcer healing status compared with patients in the control group.

In a noninferiority, randomized, double-blind clinical trial, olive oil was compared to a recommended skin care measure of hyperoxygenated fatty acids (HOFAs) for the prevention of pressure ulcers.¹⁵ The study consisted of 571 residents from several nursing homes who were at risk for pressure ulcers. Either olive oil or HOFA was applied to areas at risk for pressure ulcers, with 2 sprays of 0.2 mL per spray to each area every 12 hours. The participants were followed up for 30 days or until a pressure ulcer developed. Researchers performed skin assessments; the Braden Scale was used to assess the risk for pressure ulcers. The incidence difference of pressure ulcers in the olive oil group and HOFA group did not exceed in the noninferiority margin of 7%. Furthermore, Kaplan-Meier survival curves for the time until pressure ulcer onset showed a nonsignificant difference between the 2 groups.¹⁵ These findings suggest that olive oil is as effective as HOFA for the prevention of pressure ulcers. Although the mechanism of olive oil on prevention of pressure ulcers has not yet been determined, it has been suggested that anti-inflammatory compounds in olive oil, such as polyphenol and oleocanthal compounds, play an anti-inflammatory role.

Perineal Ulcers

Episiotomy is a surgical incision that is made to open the vagina during birth to aid in delivery of the baby. In contrast to spontaneous vaginal tears, an episiotomy allows for easier repair and healing of the laceration.¹⁶ Studies were conducted to investigate the effect of olive oil on women with lacerations after an episiotomy.

A total of 90 primigravid women who had undergone episiotomy were recruited and randomly assigned to 1 of 2 interventions: cold compression with gel packs for 20 minutes within 12 hours after delivery for up to 10 days, if necessary, or topical olive oil twice daily within 12 hours after delivery for up to 10 days.¹⁷ Although there was no significant difference in the structural features of the wound, there was a significant difference in the redness severity. After 10 days, the mean REEDA (redness, edema, ecchymosis, discharge, and apposition) score (SD), which assesses tissue healing, was 0.47 (0.96) in patients who received cold compression with gel packs and 0.20 (0.50) in patients who received topical olive oil (P=.04).¹⁷ This study suggests that there is the potential for olive oil to be used for wound healing after episiotomy.

A double-blind trial consisted of 60 women who had mediolateral episiotomy or perineal tear grades 1 and 2 who were randomly assigned to 1 of 2 groups for 10 days: olive oil sitz bath or distilled water sitz bath (control group). The results showed a significant difference in pain severity after 5 and 10 days (P<.05), wound redness after 5 days (P<.0001), and redness (P<.000) and edema (P<.05) 10 days after delivery.¹⁸ This study encourages further investigation of the benefits of olive oil for care after an episiotomy.

Chronic Ulcers

Chronic ulcers are other persistent wounds that do not respond to standard treatments and pose a notable health burden. Their development is influenced by factors such as oxidative stress, microbial infections, and the body’s immune response. A case series was conducted to investigate the wound healing effects of olive oil on chronic ulcers.¹⁹ Fourteen patients who were diagnosed with 1 or more chronic skin ulcers that had not healed with conventional treatment, such as cleansing, debridement, or infection control, were recruited. The mean (SD) of the patients’ Bates-Jensen Wound Assessment Tool score was 39.05 (4.23), indicating that these ulcers had been challenging to treat. In addition, the wounds in this study were found to be infected with bacteria. An ointment consisting of Ceratothoa oestroides olive oil extract was applied to the wounds after they were cleansed. The results showed that Bates-Jensen Wound Assessment Tool scores decreased by 14.7% to 67.5% (mean, 36%; median, 38%) after 3 months of treatment. Furthermore, 5 patients had a completely healed wound, indicating that C oestroides olive oil extract can regenerate chronic ulcers that do not respond to antibacterial agents.¹⁹ These results encourage further investigation of the role of C oestroides olive oil extract on healing properties and microbial control.

Final Thoughts

This review illuminated several key aspects of research on the role of olive oil in wound healing. Although the studies included in this review offer valuable insights, it is essential to acknowledge the variability in the quality of data presented. Several studies demonstrated robust methodology with clear definitions of outcomes and controlled conditions, providing high-quality evidence. However, other studies exhibited limitations, including small sample sizes and potential biases, which may affect the generalizability of the findings. Despite these limitations, the collective evidence suggests potential for olive oil in wound healing, warranting further investigation. Future research should aim for more standardized methodologies and larger, more diverse patient cohorts to validate these findings and explore the mechanisms underlying the therapeutic effects of olive oil.

The Diagnosis: Subungual Exostosis

Subungual exostosis should be considered as a possible cause of an exophytic subungual nodule in a young active female. In our patient, the involvement of the great toe was a clue, as the hallux is the most common location of subungual exostosis. The patient’s age and sex also were supportive, as subungual exostosis is most common in female children and adolescents— particularly those who are active, as trauma is thought to play a possible role in development of this benign tumor.^1-3 Radiography is the preferred modality for diagnosis; in our case, it showed a trabecular bony overgrowth (Figure 1), which confirmed the diagnosis. Subungual exostosis is a rare, benign, osteocartilaginous tumor of trabecular bone. The etiology is unknown but is hypothesized to be related to trauma, infection, or activation of a cartilaginous cyst.^1,3 The subungual nodule may be asymptomatic or painful. Disruption and elevation of the nail plate is common.⁴ The differential diagnosis includes amelanotic melanoma, fibroma, fibrokeratoma, osteochondroma, pyogenic granuloma, squamous cell carcinoma, glomus tumor, and verruca vulgaris, among others.⁵

Physical examination demonstrates a firm, fixed, subungual nodule, often with an accompanying nail deformity. Further workup is required to confirm the benign nature of the lesion and exclude nail tumors such as melanoma or squamous cell carcinoma. Radiography is the gold standard for diagnosis, demonstrating a trabecular bony overgrowth.⁶ Performing a radiograph as the initial diagnostic test spares the patient from unnecessary procedures such as biopsy or expensive imaging techniques such as magnetic resonance imaging. Early lesions may not demonstrate sufficient bone formation shown on radiography. In these situations, a combination of dermoscopy and histopathologic examination may aid in diagnosis (Figure 2).⁴ Vascular ectasia, hyperkeratosis, onycholysis, and ulceration are the most common findings on dermoscopy (in ascending order).⁷ Histopathology typically demonstrates a base or stalk of normal-appearing trabecular bone with a fibrocartilage cap.⁸ However, initial clinical workup via radiography allows for the least-invasive and highest-yield intervention. Clinical suspicion for this condition is important, as it can be diagnosed with noninvasive inexpensive imaging rather than biopsy or more specialized imaging modalities. Appropriate recognition can save young patients from unnecessary and expensive procedures. Treatment typically involves surgical excision; to prevent regrowth, removal of the lesion at the base of the bone is recommended.²

Although amelanotic melanoma also can manifest as a subungual nail tumor, it would be unusual in a young child and would not be expected to show characteristic changes on radiography. A glomus tumor would be painful, is more common on the fingers than on the toes, and typically has a bluish hue.⁹ Verruca vulgaris can occur subungually but is more common around the nailfold and often has the characteristic dermoscopic finding of thrombosed capillaries. It also would not be expected to show characteristic radiographic findings. Osteochondroma can occur in young patients and can appear clinically similar to subungual exostosis; however, it typically is painful.¹⁰

The Diagnosis: Subungual Exostosis

Subungual exostosis should be considered as a possible cause of an exophytic subungual nodule in a young active female. In our patient, the involvement of the great toe was a clue, as the hallux is the most common location of subungual exostosis. The patient’s age and sex also were supportive, as subungual exostosis is most common in female children and adolescents— particularly those who are active, as trauma is thought to play a possible role in development of this benign tumor.^1-3 Radiography is the preferred modality for diagnosis; in our case, it showed a trabecular bony overgrowth (Figure 1), which confirmed the diagnosis. Subungual exostosis is a rare, benign, osteocartilaginous tumor of trabecular bone. The etiology is unknown but is hypothesized to be related to trauma, infection, or activation of a cartilaginous cyst.^1,3 The subungual nodule may be asymptomatic or painful. Disruption and elevation of the nail plate is common.⁴ The differential diagnosis includes amelanotic melanoma, fibroma, fibrokeratoma, osteochondroma, pyogenic granuloma, squamous cell carcinoma, glomus tumor, and verruca vulgaris, among others.⁵

Physical examination demonstrates a firm, fixed, subungual nodule, often with an accompanying nail deformity. Further workup is required to confirm the benign nature of the lesion and exclude nail tumors such as melanoma or squamous cell carcinoma. Radiography is the gold standard for diagnosis, demonstrating a trabecular bony overgrowth.⁶ Performing a radiograph as the initial diagnostic test spares the patient from unnecessary procedures such as biopsy or expensive imaging techniques such as magnetic resonance imaging. Early lesions may not demonstrate sufficient bone formation shown on radiography. In these situations, a combination of dermoscopy and histopathologic examination may aid in diagnosis (Figure 2).⁴ Vascular ectasia, hyperkeratosis, onycholysis, and ulceration are the most common findings on dermoscopy (in ascending order).⁷ Histopathology typically demonstrates a base or stalk of normal-appearing trabecular bone with a fibrocartilage cap.⁸ However, initial clinical workup via radiography allows for the least-invasive and highest-yield intervention. Clinical suspicion for this condition is important, as it can be diagnosed with noninvasive inexpensive imaging rather than biopsy or more specialized imaging modalities. Appropriate recognition can save young patients from unnecessary and expensive procedures. Treatment typically involves surgical excision; to prevent regrowth, removal of the lesion at the base of the bone is recommended.²

Although amelanotic melanoma also can manifest as a subungual nail tumor, it would be unusual in a young child and would not be expected to show characteristic changes on radiography. A glomus tumor would be painful, is more common on the fingers than on the toes, and typically has a bluish hue.⁹ Verruca vulgaris can occur subungually but is more common around the nailfold and often has the characteristic dermoscopic finding of thrombosed capillaries. It also would not be expected to show characteristic radiographic findings. Osteochondroma can occur in young patients and can appear clinically similar to subungual exostosis; however, it typically is painful.¹⁰

The Diagnosis: Subungual Exostosis

Subungual exostosis should be considered as a possible cause of an exophytic subungual nodule in a young active female. In our patient, the involvement of the great toe was a clue, as the hallux is the most common location of subungual exostosis. The patient’s age and sex also were supportive, as subungual exostosis is most common in female children and adolescents— particularly those who are active, as trauma is thought to play a possible role in development of this benign tumor.^1-3 Radiography is the preferred modality for diagnosis; in our case, it showed a trabecular bony overgrowth (Figure 1), which confirmed the diagnosis. Subungual exostosis is a rare, benign, osteocartilaginous tumor of trabecular bone. The etiology is unknown but is hypothesized to be related to trauma, infection, or activation of a cartilaginous cyst.^1,3 The subungual nodule may be asymptomatic or painful. Disruption and elevation of the nail plate is common.⁴ The differential diagnosis includes amelanotic melanoma, fibroma, fibrokeratoma, osteochondroma, pyogenic granuloma, squamous cell carcinoma, glomus tumor, and verruca vulgaris, among others.⁵

Physical examination demonstrates a firm, fixed, subungual nodule, often with an accompanying nail deformity. Further workup is required to confirm the benign nature of the lesion and exclude nail tumors such as melanoma or squamous cell carcinoma. Radiography is the gold standard for diagnosis, demonstrating a trabecular bony overgrowth.⁶ Performing a radiograph as the initial diagnostic test spares the patient from unnecessary procedures such as biopsy or expensive imaging techniques such as magnetic resonance imaging. Early lesions may not demonstrate sufficient bone formation shown on radiography. In these situations, a combination of dermoscopy and histopathologic examination may aid in diagnosis (Figure 2).⁴ Vascular ectasia, hyperkeratosis, onycholysis, and ulceration are the most common findings on dermoscopy (in ascending order).⁷ Histopathology typically demonstrates a base or stalk of normal-appearing trabecular bone with a fibrocartilage cap.⁸ However, initial clinical workup via radiography allows for the least-invasive and highest-yield intervention. Clinical suspicion for this condition is important, as it can be diagnosed with noninvasive inexpensive imaging rather than biopsy or more specialized imaging modalities. Appropriate recognition can save young patients from unnecessary and expensive procedures. Treatment typically involves surgical excision; to prevent regrowth, removal of the lesion at the base of the bone is recommended.²

Although amelanotic melanoma also can manifest as a subungual nail tumor, it would be unusual in a young child and would not be expected to show characteristic changes on radiography. A glomus tumor would be painful, is more common on the fingers than on the toes, and typically has a bluish hue.⁹ Verruca vulgaris can occur subungually but is more common around the nailfold and often has the characteristic dermoscopic finding of thrombosed capillaries. It also would not be expected to show characteristic radiographic findings. Osteochondroma can occur in young patients and can appear clinically similar to subungual exostosis; however, it typically is painful.¹⁰

Over a period of 5 years, the likelihood of major adverse cardiovascular events (MACE) in patients with psoriasis and dyslipidemia who were on statin therapy was 40% greater than that in non-psoriasis patients with dyslipidemia on statin therapy, even after adjusting for covariates, results from a large retrospective study showed.

“It is well-established that psoriasis is an independent risk factor for the development of MACE, with cardiometabolic risk factors being more prevalent and incident among patients with psoriasis,” the study’s first author Ana Ormaza Vera, MD, a dermatology research fellow at Eastern Virginia Medical School, Norfolk, said in an interview after the annual meeting of the Society for Investigational Dermatology, where the study was presented during a late-breaking abstract session.

Dr. Ormaza Vera

Current guidelines from the joint American Academy of Dermatology/National Psoriasis Foundation and the American Academy of Cardiology/American Heart Association Task Force recommend statins, a lipid-lowering and anti-inflammatory therapy, “for patients with psoriasis who have additional risk-enhancing factors, similar to recommendations made for the general population without psoriasis,” she noted. But how the incidence of MACE differs between patients with and without psoriasis while on statin therapy “has not been explored in real-world settings,” she added.

To address this question, the researchers used real-world data from the TriNetX health research network to identify individuals aged 18-90 years with a diagnosis of both psoriasis and lipid disorders who were undergoing treatment with statins. Those with a prior history of MACE were excluded from the analysis. Patients with lipid disorders on statin therapy, but without psoriatic disease, were matched 1:1 by age, sex, race, ethnicity, common risk factors for MACE, and medications shown to reduce MACE risk. The researchers then assessed the cohorts 5 years following their first statin prescription and used the TriNetX analytics tool to calculate the odds ratio (OR) with 95% CI to evaluate the likelihood of MACE in the presence of statin therapy.

Dr. Ormaza Vera and colleagues identified 20,660 patients with psoriasis and 2,768,429 patients without psoriasis who met the criteria for analysis. After propensity score matching, each cohort included 20,660 patients with a mean age of 60 years. During the 5-year observation period, 2725 patients in the psoriasis cohort experienced MACE compared with 2203 patients in the non-psoriasis cohort (OR, 1.40; 95% CI, 1.317-1.488).

“This was an unexpected outcome that challenges the current understanding and highlights the need for further research into tailored treatments for cardiovascular risk in psoriasis patients,” Dr. Ormaza Vera told this news organization.

She acknowledged certain limitations of the study, including its retrospective design, the inherent limitations of an observational study, and the use of electronic medical record data.

Lawrence J. Green, MD, clinical professor of dermatology, George Washington University, Washington, who was asked to comment on the study results, said that the findings imply that there is more than statin use alone to protect someone with psoriasis from having an increased risk for MACE. “This is not really surprising because statin use alone is only part of a prevention strategy in someone with psoriasis who usually has multiple comorbidities,” Dr. Green said. “On the other hand, the study only went out for 5 years and cardiovascular disease is a long accumulating process, so it could also be too early to demonstrate MACE prevention.”

The study was funded by a grant from the American Skin Association. Dr. Ormaza Vera and her coauthors reported having no relevant disclosures. Dr. Green disclosed that he is a speaker, consultant, or investigator for many pharmaceutical companies.

A version of this article appeared on Medscape.com .

Over a period of 5 years, the likelihood of major adverse cardiovascular events (MACE) in patients with psoriasis and dyslipidemia who were on statin therapy was 40% greater than that in non-psoriasis patients with dyslipidemia on statin therapy, even after adjusting for covariates, results from a large retrospective study showed.

“It is well-established that psoriasis is an independent risk factor for the development of MACE, with cardiometabolic risk factors being more prevalent and incident among patients with psoriasis,” the study’s first author Ana Ormaza Vera, MD, a dermatology research fellow at Eastern Virginia Medical School, Norfolk, said in an interview after the annual meeting of the Society for Investigational Dermatology, where the study was presented during a late-breaking abstract session.

Dr. Ormaza Vera

Current guidelines from the joint American Academy of Dermatology/National Psoriasis Foundation and the American Academy of Cardiology/American Heart Association Task Force recommend statins, a lipid-lowering and anti-inflammatory therapy, “for patients with psoriasis who have additional risk-enhancing factors, similar to recommendations made for the general population without psoriasis,” she noted. But how the incidence of MACE differs between patients with and without psoriasis while on statin therapy “has not been explored in real-world settings,” she added.

To address this question, the researchers used real-world data from the TriNetX health research network to identify individuals aged 18-90 years with a diagnosis of both psoriasis and lipid disorders who were undergoing treatment with statins. Those with a prior history of MACE were excluded from the analysis. Patients with lipid disorders on statin therapy, but without psoriatic disease, were matched 1:1 by age, sex, race, ethnicity, common risk factors for MACE, and medications shown to reduce MACE risk. The researchers then assessed the cohorts 5 years following their first statin prescription and used the TriNetX analytics tool to calculate the odds ratio (OR) with 95% CI to evaluate the likelihood of MACE in the presence of statin therapy.

Dr. Ormaza Vera and colleagues identified 20,660 patients with psoriasis and 2,768,429 patients without psoriasis who met the criteria for analysis. After propensity score matching, each cohort included 20,660 patients with a mean age of 60 years. During the 5-year observation period, 2725 patients in the psoriasis cohort experienced MACE compared with 2203 patients in the non-psoriasis cohort (OR, 1.40; 95% CI, 1.317-1.488).

“This was an unexpected outcome that challenges the current understanding and highlights the need for further research into tailored treatments for cardiovascular risk in psoriasis patients,” Dr. Ormaza Vera told this news organization.

She acknowledged certain limitations of the study, including its retrospective design, the inherent limitations of an observational study, and the use of electronic medical record data.

Lawrence J. Green, MD, clinical professor of dermatology, George Washington University, Washington, who was asked to comment on the study results, said that the findings imply that there is more than statin use alone to protect someone with psoriasis from having an increased risk for MACE. “This is not really surprising because statin use alone is only part of a prevention strategy in someone with psoriasis who usually has multiple comorbidities,” Dr. Green said. “On the other hand, the study only went out for 5 years and cardiovascular disease is a long accumulating process, so it could also be too early to demonstrate MACE prevention.”

The study was funded by a grant from the American Skin Association. Dr. Ormaza Vera and her coauthors reported having no relevant disclosures. Dr. Green disclosed that he is a speaker, consultant, or investigator for many pharmaceutical companies.

A version of this article appeared on Medscape.com .

Over a period of 5 years, the likelihood of major adverse cardiovascular events (MACE) in patients with psoriasis and dyslipidemia who were on statin therapy was 40% greater than that in non-psoriasis patients with dyslipidemia on statin therapy, even after adjusting for covariates, results from a large retrospective study showed.

“It is well-established that psoriasis is an independent risk factor for the development of MACE, with cardiometabolic risk factors being more prevalent and incident among patients with psoriasis,” the study’s first author Ana Ormaza Vera, MD, a dermatology research fellow at Eastern Virginia Medical School, Norfolk, said in an interview after the annual meeting of the Society for Investigational Dermatology, where the study was presented during a late-breaking abstract session.

Dr. Ormaza Vera

Current guidelines from the joint American Academy of Dermatology/National Psoriasis Foundation and the American Academy of Cardiology/American Heart Association Task Force recommend statins, a lipid-lowering and anti-inflammatory therapy, “for patients with psoriasis who have additional risk-enhancing factors, similar to recommendations made for the general population without psoriasis,” she noted. But how the incidence of MACE differs between patients with and without psoriasis while on statin therapy “has not been explored in real-world settings,” she added.

To address this question, the researchers used real-world data from the TriNetX health research network to identify individuals aged 18-90 years with a diagnosis of both psoriasis and lipid disorders who were undergoing treatment with statins. Those with a prior history of MACE were excluded from the analysis. Patients with lipid disorders on statin therapy, but without psoriatic disease, were matched 1:1 by age, sex, race, ethnicity, common risk factors for MACE, and medications shown to reduce MACE risk. The researchers then assessed the cohorts 5 years following their first statin prescription and used the TriNetX analytics tool to calculate the odds ratio (OR) with 95% CI to evaluate the likelihood of MACE in the presence of statin therapy.

Dr. Ormaza Vera and colleagues identified 20,660 patients with psoriasis and 2,768,429 patients without psoriasis who met the criteria for analysis. After propensity score matching, each cohort included 20,660 patients with a mean age of 60 years. During the 5-year observation period, 2725 patients in the psoriasis cohort experienced MACE compared with 2203 patients in the non-psoriasis cohort (OR, 1.40; 95% CI, 1.317-1.488).

“This was an unexpected outcome that challenges the current understanding and highlights the need for further research into tailored treatments for cardiovascular risk in psoriasis patients,” Dr. Ormaza Vera told this news organization.

She acknowledged certain limitations of the study, including its retrospective design, the inherent limitations of an observational study, and the use of electronic medical record data.

Lawrence J. Green, MD, clinical professor of dermatology, George Washington University, Washington, who was asked to comment on the study results, said that the findings imply that there is more than statin use alone to protect someone with psoriasis from having an increased risk for MACE. “This is not really surprising because statin use alone is only part of a prevention strategy in someone with psoriasis who usually has multiple comorbidities,” Dr. Green said. “On the other hand, the study only went out for 5 years and cardiovascular disease is a long accumulating process, so it could also be too early to demonstrate MACE prevention.”

The study was funded by a grant from the American Skin Association. Dr. Ormaza Vera and her coauthors reported having no relevant disclosures. Dr. Green disclosed that he is a speaker, consultant, or investigator for many pharmaceutical companies.

A version of this article appeared on Medscape.com .