Clinical Review

Melasma (also known as chloasma faciei) is a common chronic skin disorder that results in well-demarcated, hyperpigmented, tan to dark patches that mostly appear in sun-exposed areas such as the face and neck and sometimes the arms. The exact prevalence or incidence is not known but is estimated to be 1% to 50% overall depending on the ethnic population and geographic location.^1,2 Melasma predominantly affects women, but research has shown that approximately 10% to 20% of men are affected by this condition.^3,4 Although melasma can affect patients of all skin types, it primarily affects those with darker skin tones.⁵ The groups most often affected are women of Black, Hispanic, Middle Eastern, and Southeast Asian ethnicity. Although the pathogenesis is complex and not fully understood, multiple pathways and etiologies have been theorized to cause melasma. Potential causes include exposure to UV radiation, oral contraceptives, hormonal changes, medications, thyroid dysfunction, genetics, and pregnancy.^6,7 Cytokines and growth factors, including adipokine and angiopoietin, synthesized by sebaceous glands play a role in the pathogenic mechanism of melasma. Cytokines and growth factors are hypothesized to modulate the function of melanocytes.⁸ Both melanocytes and sebocytes are controlled by α–melanocyte-stimulating hormone. Therefore, overexpression of α–melanocyte-stimulating hormone will result in overproduction of these 2 cell types, resulting in melasma. Melasma can be classified into 4 subtypes using Wood lamp examination: epidermal, dermal, mixed, or indeterminate.³ Furthermore, melasma is divided into subgroups based on the location: malar region, mandibular region, and centrofacial patch pattern.^9,10 The involvement of sebaceous glands in the pathogenesis of melasma may explain the predilection for the centrofacial region, which is the most common pattern.

The severity of melasma can be assessed using the melasma area and severity index (MASI), which is calculated by subjective assessment of 3 main factors: (1) facial area of involvement; (2) darkness of affected region; and (3) homogeneity, with the extent of melasma indicated by a score ranging from 0 to 48.¹¹ The modified MASI (mMASI) subsequently was introduced to assist with assessing the severity of melasma and creating distinct ranges for mild, moderate, and severe cases, ranging from 0 (mild) to 24 (severe).¹² Both indices are used in research to assess the improvement of melasma with treatment.

Patients with melasma report a decrease in quality of life, increased emotional stress, and lower self-esteem due to cosmesis.¹³ Treatment of melasma can be highly challenging and often is complicated by relapsing. Historically, the treatment of melasma has included the use of chemical lightening agents. Additional treatment options include the use of lasers and complex chemical peels,^9,10 but these interventions may result in adverse outcomes for individuals with darker skin tones. The current gold-standard treatment is topical hydroquinone and broad-spectrum sunscreen. Although hydroquinone is effective in the treatment of melasma, relapse is common. The goal of melasma management is not only to treat acute hyperpigmentation but also to prevent relapse. Other therapies that currently are being explored for the clinically sustained treatment of melasma include tranexamic acid (TXA)(trans-4-[aminomethyl]cyclohexanecarboxylic acid),^9,10 an antifibrinolytic agent routinely used to prevent blood loss during surgery and in the management of menorrhagia. It is a synthetic derivative of lysine and serves as a potent plasmin inhibitor by blocking the lysine-binding sites of plasminogen molecules, thus preventing the conversion of plasminogen to plasmin. It also prevents fibrinolysis and blood loss.

In addition to its hemostatic properties, TXA has been found to have hypopigmentation properties.^14,15 Plasminogen also can be found in human epidermal basal cells and human keratinocytes, and it is postulated that TXA’s interaction with these cells explains its hypopigmentation properties. Both UV radiation and hormones activate plasminogen into plasmin, resulting in the activation of tyrosinase and melanogenesis.^14,15 Tranexamic acid is postulated to inhibit the keratinocyte-plasminogen pathway, thus leading to the inhibition of UV-induced and hormone-induced pigmentation. Also, TXA serves as a competitive inhibitor for tyrosinase due to its structural similarity to tyrosine.¹⁵ The combination of these 2 mechanisms contributes to the skin-lightening effects of TXA, making it a potential treatment for melasma.

Furthermore, the use of microneedling is being explored as a treatment option for melasma. Microneedling creates microscopic punctures in the skin using tiny needles, resulting in a wound-healing response and skin resurfacing. The microneedling technique is utilized to create small holes in the skin, with needle depths that can be adjusted from 0.5 to 3.5 mm to target different layers of the dermis and allow for discreet application of TXA.¹⁶ We sought to look at the current literature on the use and effectiveness of microneedling in combination with TXA to treat melasma and prevent relapse.

Methods

A systematic review was performed of PubMed articles indexed for MEDLINE and Embase in November 2021 to compile available articles that studied TXA and microneedling as a treatment for melasma. The PubMed search terms were (melasma) AND (microneedling* OR ‘tranexamic acid’ OR TXA or TA). The Embase search terms were (cholasma OR melasma) AND (tranexamic acid OR TXA) AND (microneedling)(Figure). The search was then limited to ”randomized controlled trial” and ”clinical trial” in English-language journals. Duplicates were excluded. After thorough evaluation, articles that discussed the use of TXA in combination with treatment options other than microneedling also were excluded.

Results

The literature search yielded a total of 12 articles that assessed the effectiveness of TXA and microneedling for the treatment of melasma (Table).^17-28 Several articles concluded that TXA was equally effective at reducing melasma lesions when compared with the standard treatment of hydroquinone. Some of the reviewed articles also demonstrated the effectiveness of microneedling in improving melasma lesions as a stand-alone treatment. These studies highlighted the enhanced efficacy of the combined treatment of TXA and microneedling compared with their individual uses.^17-28

Comment

Melasma is a common chronic hyperpigmentation disorder, making its treatment clinically challenging. Many patients experience symptom relapses, and limited effective treatment options make achieving complete clearance difficult, underscoring the need for improved therapeutic approaches. Recently, researchers have explored alternative treatments to address the challenges of melasma management. Tranexamic acid is an antifibrinolytic used to prevent blood loss and has emerged as a potential treatment for melasma. Similarly, microneedling—a technique in which multiple punctures are made in the skin to activate and stimulate wound healing and skin rejuvenation—shows promise for melasma.

Oral TXA for Melasma—Oral TXA has been shown to reduce melasma lesions. Del Rosario et al¹⁷ recruited 44 women (39 of whom completed the study) with moderate to severe melasma and randomized them into 2 groups: oral TXA and placebo. This study demonstrated a 49% reduction in the mMASI score in all participants taking oral TXA (250 mg twice daily [BID]) compared with an 18% reduction in the control group (placebo capsule BID) after 3 months of treatment. In patients with moderate and severe melasma, 45% and 51% mMASI score reductions were reported in the treatment group, respectively, vs 16% and 19% score reductions in placebo group, respectively. These researchers concluded that oral TXA may be effective at treating moderate to severe melasma. Although patients with severe melasma had a better response to treatment, their improvement was not sustained compared with patients with moderate melasma after a 3-month posttreatment follow-up.¹⁷

Microneedling Plus TXA for Melasma—Microneedling alone has been shown to be effective for melasma. El Attar et al¹⁸ conducted a split-face study of microneedling (1.5-mm depth) plus topical TXA (0.5 mL)(right side of the face[treatment arm]) compared with microneedling (1.5-mm depth) plus topical vitamin C (0.5 mL)(left side of the face [control group]) in 20 women with melasma. The sessions were repeated every 2 weeks for a total of 6 sessions. Although researchers found no statistically significant differences between the 2 treatment sides, microneedling plus TXA showed a slight advantage over microneedling plus vitamin C in dermoscopic examination. Both sides showed improvement in pigmented lesions, but vitamin C–treated lesions did not show an improvement in vascularity vs TXA.¹⁸

Saleh et al¹⁹ further showed that combination treatment with microneedling and TXA may improve clinical outcomes better than microneedling alone. Their study demonstrated a reduction in MASI score that was significantly higher in the combination treatment group compared with the microneedling alone group (P=.001). There was a significant reduction in melanoma antigen recognized by T cells 1 (MART-1)–positive cells in the combination treatment group compared with the microneedling alone group (P=.001). Lastly, combined therapy improved melasma patches better than microneedling alone.¹⁹

Xu et al²⁰ conducted a split-face study (N=28) exploring the effectiveness of transdermal application of topical TXA using a microarray pen with microneedles (vibration at 3000×/min) plus topical TXA on one side of the face, while the other side received only topical TXA as a control. After 12 weeks of treatment, combination therapy with microneedling and TXA decreased brown spot scores, lowered melanin index (MI) values, improved blinded physician assessment, and improved patient satisfaction vs TXA therapy alone.²⁰

Kaur et al²¹ conducted a split-face, randomized, controlled trial of microneedling (1-mm depth) with TXA solution 10% vs microneedling (1-mm depth) with distilled water alone for 8 weeks (N=40). They graded participant responses to treatment using reductions in mMASI scores¹² at every 2 weeks of follow-up (no response, minimal or poor response=0%–25%; partial or fair response=26%–50%; good response=51%–75%; and excellent response=>75%). They reported an overall reduction in mMASI scores for both the treatment side and the control side in all participants, showing a 65.92% improvement in mean mMASI scores on the treatment side vs 20.75% improvement on the control side at week 8. Both sides showed statistically significant reductions in mean mMASI scores (P<.05). Clinically, 40% (16/40) of participants showed an excellent response to combined treatment compared with 0% (0/40) to microneedling alone. Overall, patient satisfaction was similar across both groups. This study demonstrated that microneedling alone improves melasma, but a combination of microneedling plus TXA showed a better clinical reduction in melasma. However, the researchers did not follow up with participants posttreatment, so it remains unclear if the improved clinical outcomes were sustained long-term.²¹

Ebrahim et al²² reported that the combination of 0.5 mL TXA (4 mg/mL) and microneedling (0.25- to 1-mm depth) was effective for melasma. Although there was improvement within microneedling and TXA, the study also showed that intradermal injection of TXA was significant in reducing mean mMASI scores and improving melasma (P<.001). The reduction in mMASI scores for the group receiving intradermal injections of TXA (left side; 74.8% reduction in mean mMASI score) vs the group receiving microneedling application of TXA (right side; 73.6% reduction in mean mMASI score) was not statistically significant. These findings suggest that the mode of TXA application may not be critical in determining clinical responses to TXA treatment. Although there was no reported statistically significant difference in clinical outcomes between the 2 treatments, patient satisfaction was higher on the microneedling side. Only 8 of 50 participants (16%) experienced recurrence 3 months posttreatment.²²

Saki et al²³ compared the efficacy of topical hydroquinone (2%) to intradermal TXA injections in treating melasma. They found intradermal TXA injections to be a clinically effective mode of treatment.²³

Sharma et al²⁴ explored the efficacy and safety of oral TXA by randomly assigning 100 Indian patients (20 of whom withdrew before study completion) with melasma into 2 groups: group A received TXA 250 mg twice daily, and group B received intradermal microinjections of TXA (4 mg/mL) every 4 weeks. The MASI scores were assessed at 4-week intervals for a total of 12 weeks. There was a decrease in MASI scores in both groups, and there was no statistically significant difference in mean percentage reduction in MASI scores between the 2 routes of drug administration, further suggesting the effectiveness of TXA independent of administration route. Two patients in group A relapsed at 24 weeks, and there were no relapses in group B, which may suggest a minimal superiority of TXA plus microneedling at providing more sustainable results compared with oral TXA alone. A notable limitation of this study was a high dropout rate as well as lack of long-term follow-up with participants, limiting the generalizability of the conclusions.²⁴

Cassiano et al²⁵ assigned 64 women with melasma to 1 of 3 treatment groups or a control group to compare the effectiveness of microneedling (M group: 1.5 mm; 2 sessions), oral TXA (T group: 250 mg/d twice daily for 60 days), and a combination of microneedling (2 sessions) and oral TXA (MT group: 250 mg/d twice daily for 60 days)with placebo for clinically reducing melasma lesions. The intervention period was 60 days followed by a 60-day maintenance phase for a total study period of 120 days. The researchers evaluated mMASI scores, quality of life, and difference in colorimetric luminosity. All treatment groups showed a reduction in mMASI scores at both 30 days and 60 days, indicating improved melasma severity. The MT and T groups had more significant improvement at 30 days compared with the control group (P<.03), suggesting that microneedling plus TXA and TXA alone promote faster improvement in melasma lesions. By 60 days, the M, T, and MT groups outperformed the control group, with no significant differences between the M, T, and MT groups. However, at the 120-day maintenance follow-up, the T group did not maintain its improvement compared with the control group. The M and MT groups showed no significance difference in effectiveness at 120 days, suggesting that microneedling may promote less frequent relapse and sustained remission compared to TXA alone.²⁵

Hydroquinone for Melasma—Additional studies on the use of TXA treatments show that TXA may be an equally effective alternative to the standard use of hydroquinone treatment. Shamsi Meymandi et al²⁶ did not find a statistically significant difference in treatment with TXA plus microneedling vs the standard regimen of hydroquinone. More importantly, patient and physician satisfaction assessments were similar between the 2 groups. Compared to hydroquinone, nightly treatment is not necessary with microneedling and TXA.²⁶

Xing et al²⁷ supported these conclusions with their study. They compared 3 study arms for a duration of 12 weeks: group A received topical 1.8% liposomal TXA BID, group B received stamp-mode electric microneedling with 5% TXA weekly, and group C applied 2% ­hydroquinone cream nightly. The study concluded that all 3 groups showed a significant reduction in mean MI by the end of the study, but a better MI improvement was observed in groups B and C (both P<.001) compared with group A (P<.01).²⁷

Zaky et al²⁸ showed that both hydroquinone and combination treatment of TXA plus microneedling are effective at improving melasma lesions. Further studies are needed to definitively conclude if combination treatment is more efficacious than hydroquinone; if the combination is more effective, it provides a treatment option for patients with melasma who may not be good candidates for hydroquinone treatment.

Study Limitations—One limitation in all the studies evaluated is the sample size. Because they all had small sample sizes, it is difficult to definitively conclude that the combination TXA and microneedling is an effective and appropriate treatment for patients with melasma. Furthermore, the quality of these studies was mostly dependent on subjectivity of the mMASI scores. Future large randomized controlled trials with a diverse participant population are needed to assess the effectiveness of TXA and microneedling in melasma treatment.

Another limitation is that many of the studies did not follow the patients longitudinally, which did not allow for an evaluation of whether patients had a relapse of melasma. Due to the chronic nature of melasma and frequent disease recurrence, future longitudinal studies are needed to monitor for disease recurrence.

Conclusion

Tranexamic acid and microneedling are potential treatment options for patients with melasma, and combination therapy appears more effective than either TXA or microneedling alone at providing sustained improvement of melasma lesions. Combination therapy appears safe and well tolerated, but its effect on reducing long-term disease recurrence is yet to be established.

Melasma (also known as chloasma faciei) is a common chronic skin disorder that results in well-demarcated, hyperpigmented, tan to dark patches that mostly appear in sun-exposed areas such as the face and neck and sometimes the arms. The exact prevalence or incidence is not known but is estimated to be 1% to 50% overall depending on the ethnic population and geographic location.^1,2 Melasma predominantly affects women, but research has shown that approximately 10% to 20% of men are affected by this condition.^3,4 Although melasma can affect patients of all skin types, it primarily affects those with darker skin tones.⁵ The groups most often affected are women of Black, Hispanic, Middle Eastern, and Southeast Asian ethnicity. Although the pathogenesis is complex and not fully understood, multiple pathways and etiologies have been theorized to cause melasma. Potential causes include exposure to UV radiation, oral contraceptives, hormonal changes, medications, thyroid dysfunction, genetics, and pregnancy.^6,7 Cytokines and growth factors, including adipokine and angiopoietin, synthesized by sebaceous glands play a role in the pathogenic mechanism of melasma. Cytokines and growth factors are hypothesized to modulate the function of melanocytes.⁸ Both melanocytes and sebocytes are controlled by α–melanocyte-stimulating hormone. Therefore, overexpression of α–melanocyte-stimulating hormone will result in overproduction of these 2 cell types, resulting in melasma. Melasma can be classified into 4 subtypes using Wood lamp examination: epidermal, dermal, mixed, or indeterminate.³ Furthermore, melasma is divided into subgroups based on the location: malar region, mandibular region, and centrofacial patch pattern.^9,10 The involvement of sebaceous glands in the pathogenesis of melasma may explain the predilection for the centrofacial region, which is the most common pattern.

The severity of melasma can be assessed using the melasma area and severity index (MASI), which is calculated by subjective assessment of 3 main factors: (1) facial area of involvement; (2) darkness of affected region; and (3) homogeneity, with the extent of melasma indicated by a score ranging from 0 to 48.¹¹ The modified MASI (mMASI) subsequently was introduced to assist with assessing the severity of melasma and creating distinct ranges for mild, moderate, and severe cases, ranging from 0 (mild) to 24 (severe).¹² Both indices are used in research to assess the improvement of melasma with treatment.

Patients with melasma report a decrease in quality of life, increased emotional stress, and lower self-esteem due to cosmesis.¹³ Treatment of melasma can be highly challenging and often is complicated by relapsing. Historically, the treatment of melasma has included the use of chemical lightening agents. Additional treatment options include the use of lasers and complex chemical peels,^9,10 but these interventions may result in adverse outcomes for individuals with darker skin tones. The current gold-standard treatment is topical hydroquinone and broad-spectrum sunscreen. Although hydroquinone is effective in the treatment of melasma, relapse is common. The goal of melasma management is not only to treat acute hyperpigmentation but also to prevent relapse. Other therapies that currently are being explored for the clinically sustained treatment of melasma include tranexamic acid (TXA)(trans-4-[aminomethyl]cyclohexanecarboxylic acid),^9,10 an antifibrinolytic agent routinely used to prevent blood loss during surgery and in the management of menorrhagia. It is a synthetic derivative of lysine and serves as a potent plasmin inhibitor by blocking the lysine-binding sites of plasminogen molecules, thus preventing the conversion of plasminogen to plasmin. It also prevents fibrinolysis and blood loss.

In addition to its hemostatic properties, TXA has been found to have hypopigmentation properties.^14,15 Plasminogen also can be found in human epidermal basal cells and human keratinocytes, and it is postulated that TXA’s interaction with these cells explains its hypopigmentation properties. Both UV radiation and hormones activate plasminogen into plasmin, resulting in the activation of tyrosinase and melanogenesis.^14,15 Tranexamic acid is postulated to inhibit the keratinocyte-plasminogen pathway, thus leading to the inhibition of UV-induced and hormone-induced pigmentation. Also, TXA serves as a competitive inhibitor for tyrosinase due to its structural similarity to tyrosine.¹⁵ The combination of these 2 mechanisms contributes to the skin-lightening effects of TXA, making it a potential treatment for melasma.

Furthermore, the use of microneedling is being explored as a treatment option for melasma. Microneedling creates microscopic punctures in the skin using tiny needles, resulting in a wound-healing response and skin resurfacing. The microneedling technique is utilized to create small holes in the skin, with needle depths that can be adjusted from 0.5 to 3.5 mm to target different layers of the dermis and allow for discreet application of TXA.¹⁶ We sought to look at the current literature on the use and effectiveness of microneedling in combination with TXA to treat melasma and prevent relapse.

Methods

A systematic review was performed of PubMed articles indexed for MEDLINE and Embase in November 2021 to compile available articles that studied TXA and microneedling as a treatment for melasma. The PubMed search terms were (melasma) AND (microneedling* OR ‘tranexamic acid’ OR TXA or TA). The Embase search terms were (cholasma OR melasma) AND (tranexamic acid OR TXA) AND (microneedling)(Figure). The search was then limited to ”randomized controlled trial” and ”clinical trial” in English-language journals. Duplicates were excluded. After thorough evaluation, articles that discussed the use of TXA in combination with treatment options other than microneedling also were excluded.

Results

The literature search yielded a total of 12 articles that assessed the effectiveness of TXA and microneedling for the treatment of melasma (Table).^17-28 Several articles concluded that TXA was equally effective at reducing melasma lesions when compared with the standard treatment of hydroquinone. Some of the reviewed articles also demonstrated the effectiveness of microneedling in improving melasma lesions as a stand-alone treatment. These studies highlighted the enhanced efficacy of the combined treatment of TXA and microneedling compared with their individual uses.^17-28

Comment

Melasma is a common chronic hyperpigmentation disorder, making its treatment clinically challenging. Many patients experience symptom relapses, and limited effective treatment options make achieving complete clearance difficult, underscoring the need for improved therapeutic approaches. Recently, researchers have explored alternative treatments to address the challenges of melasma management. Tranexamic acid is an antifibrinolytic used to prevent blood loss and has emerged as a potential treatment for melasma. Similarly, microneedling—a technique in which multiple punctures are made in the skin to activate and stimulate wound healing and skin rejuvenation—shows promise for melasma.

Oral TXA for Melasma—Oral TXA has been shown to reduce melasma lesions. Del Rosario et al¹⁷ recruited 44 women (39 of whom completed the study) with moderate to severe melasma and randomized them into 2 groups: oral TXA and placebo. This study demonstrated a 49% reduction in the mMASI score in all participants taking oral TXA (250 mg twice daily [BID]) compared with an 18% reduction in the control group (placebo capsule BID) after 3 months of treatment. In patients with moderate and severe melasma, 45% and 51% mMASI score reductions were reported in the treatment group, respectively, vs 16% and 19% score reductions in placebo group, respectively. These researchers concluded that oral TXA may be effective at treating moderate to severe melasma. Although patients with severe melasma had a better response to treatment, their improvement was not sustained compared with patients with moderate melasma after a 3-month posttreatment follow-up.¹⁷

Microneedling Plus TXA for Melasma—Microneedling alone has been shown to be effective for melasma. El Attar et al¹⁸ conducted a split-face study of microneedling (1.5-mm depth) plus topical TXA (0.5 mL)(right side of the face[treatment arm]) compared with microneedling (1.5-mm depth) plus topical vitamin C (0.5 mL)(left side of the face [control group]) in 20 women with melasma. The sessions were repeated every 2 weeks for a total of 6 sessions. Although researchers found no statistically significant differences between the 2 treatment sides, microneedling plus TXA showed a slight advantage over microneedling plus vitamin C in dermoscopic examination. Both sides showed improvement in pigmented lesions, but vitamin C–treated lesions did not show an improvement in vascularity vs TXA.¹⁸

Saleh et al¹⁹ further showed that combination treatment with microneedling and TXA may improve clinical outcomes better than microneedling alone. Their study demonstrated a reduction in MASI score that was significantly higher in the combination treatment group compared with the microneedling alone group (P=.001). There was a significant reduction in melanoma antigen recognized by T cells 1 (MART-1)–positive cells in the combination treatment group compared with the microneedling alone group (P=.001). Lastly, combined therapy improved melasma patches better than microneedling alone.¹⁹

Xu et al²⁰ conducted a split-face study (N=28) exploring the effectiveness of transdermal application of topical TXA using a microarray pen with microneedles (vibration at 3000×/min) plus topical TXA on one side of the face, while the other side received only topical TXA as a control. After 12 weeks of treatment, combination therapy with microneedling and TXA decreased brown spot scores, lowered melanin index (MI) values, improved blinded physician assessment, and improved patient satisfaction vs TXA therapy alone.²⁰

Kaur et al²¹ conducted a split-face, randomized, controlled trial of microneedling (1-mm depth) with TXA solution 10% vs microneedling (1-mm depth) with distilled water alone for 8 weeks (N=40). They graded participant responses to treatment using reductions in mMASI scores¹² at every 2 weeks of follow-up (no response, minimal or poor response=0%–25%; partial or fair response=26%–50%; good response=51%–75%; and excellent response=>75%). They reported an overall reduction in mMASI scores for both the treatment side and the control side in all participants, showing a 65.92% improvement in mean mMASI scores on the treatment side vs 20.75% improvement on the control side at week 8. Both sides showed statistically significant reductions in mean mMASI scores (P<.05). Clinically, 40% (16/40) of participants showed an excellent response to combined treatment compared with 0% (0/40) to microneedling alone. Overall, patient satisfaction was similar across both groups. This study demonstrated that microneedling alone improves melasma, but a combination of microneedling plus TXA showed a better clinical reduction in melasma. However, the researchers did not follow up with participants posttreatment, so it remains unclear if the improved clinical outcomes were sustained long-term.²¹

Ebrahim et al²² reported that the combination of 0.5 mL TXA (4 mg/mL) and microneedling (0.25- to 1-mm depth) was effective for melasma. Although there was improvement within microneedling and TXA, the study also showed that intradermal injection of TXA was significant in reducing mean mMASI scores and improving melasma (P<.001). The reduction in mMASI scores for the group receiving intradermal injections of TXA (left side; 74.8% reduction in mean mMASI score) vs the group receiving microneedling application of TXA (right side; 73.6% reduction in mean mMASI score) was not statistically significant. These findings suggest that the mode of TXA application may not be critical in determining clinical responses to TXA treatment. Although there was no reported statistically significant difference in clinical outcomes between the 2 treatments, patient satisfaction was higher on the microneedling side. Only 8 of 50 participants (16%) experienced recurrence 3 months posttreatment.²²

Saki et al²³ compared the efficacy of topical hydroquinone (2%) to intradermal TXA injections in treating melasma. They found intradermal TXA injections to be a clinically effective mode of treatment.²³

Sharma et al²⁴ explored the efficacy and safety of oral TXA by randomly assigning 100 Indian patients (20 of whom withdrew before study completion) with melasma into 2 groups: group A received TXA 250 mg twice daily, and group B received intradermal microinjections of TXA (4 mg/mL) every 4 weeks. The MASI scores were assessed at 4-week intervals for a total of 12 weeks. There was a decrease in MASI scores in both groups, and there was no statistically significant difference in mean percentage reduction in MASI scores between the 2 routes of drug administration, further suggesting the effectiveness of TXA independent of administration route. Two patients in group A relapsed at 24 weeks, and there were no relapses in group B, which may suggest a minimal superiority of TXA plus microneedling at providing more sustainable results compared with oral TXA alone. A notable limitation of this study was a high dropout rate as well as lack of long-term follow-up with participants, limiting the generalizability of the conclusions.²⁴

Cassiano et al²⁵ assigned 64 women with melasma to 1 of 3 treatment groups or a control group to compare the effectiveness of microneedling (M group: 1.5 mm; 2 sessions), oral TXA (T group: 250 mg/d twice daily for 60 days), and a combination of microneedling (2 sessions) and oral TXA (MT group: 250 mg/d twice daily for 60 days)with placebo for clinically reducing melasma lesions. The intervention period was 60 days followed by a 60-day maintenance phase for a total study period of 120 days. The researchers evaluated mMASI scores, quality of life, and difference in colorimetric luminosity. All treatment groups showed a reduction in mMASI scores at both 30 days and 60 days, indicating improved melasma severity. The MT and T groups had more significant improvement at 30 days compared with the control group (P<.03), suggesting that microneedling plus TXA and TXA alone promote faster improvement in melasma lesions. By 60 days, the M, T, and MT groups outperformed the control group, with no significant differences between the M, T, and MT groups. However, at the 120-day maintenance follow-up, the T group did not maintain its improvement compared with the control group. The M and MT groups showed no significance difference in effectiveness at 120 days, suggesting that microneedling may promote less frequent relapse and sustained remission compared to TXA alone.²⁵

Hydroquinone for Melasma—Additional studies on the use of TXA treatments show that TXA may be an equally effective alternative to the standard use of hydroquinone treatment. Shamsi Meymandi et al²⁶ did not find a statistically significant difference in treatment with TXA plus microneedling vs the standard regimen of hydroquinone. More importantly, patient and physician satisfaction assessments were similar between the 2 groups. Compared to hydroquinone, nightly treatment is not necessary with microneedling and TXA.²⁶

Xing et al²⁷ supported these conclusions with their study. They compared 3 study arms for a duration of 12 weeks: group A received topical 1.8% liposomal TXA BID, group B received stamp-mode electric microneedling with 5% TXA weekly, and group C applied 2% ­hydroquinone cream nightly. The study concluded that all 3 groups showed a significant reduction in mean MI by the end of the study, but a better MI improvement was observed in groups B and C (both P<.001) compared with group A (P<.01).²⁷

Zaky et al²⁸ showed that both hydroquinone and combination treatment of TXA plus microneedling are effective at improving melasma lesions. Further studies are needed to definitively conclude if combination treatment is more efficacious than hydroquinone; if the combination is more effective, it provides a treatment option for patients with melasma who may not be good candidates for hydroquinone treatment.

Study Limitations—One limitation in all the studies evaluated is the sample size. Because they all had small sample sizes, it is difficult to definitively conclude that the combination TXA and microneedling is an effective and appropriate treatment for patients with melasma. Furthermore, the quality of these studies was mostly dependent on subjectivity of the mMASI scores. Future large randomized controlled trials with a diverse participant population are needed to assess the effectiveness of TXA and microneedling in melasma treatment.

Another limitation is that many of the studies did not follow the patients longitudinally, which did not allow for an evaluation of whether patients had a relapse of melasma. Due to the chronic nature of melasma and frequent disease recurrence, future longitudinal studies are needed to monitor for disease recurrence.

Conclusion

Tranexamic acid and microneedling are potential treatment options for patients with melasma, and combination therapy appears more effective than either TXA or microneedling alone at providing sustained improvement of melasma lesions. Combination therapy appears safe and well tolerated, but its effect on reducing long-term disease recurrence is yet to be established.

Melasma (also known as chloasma faciei) is a common chronic skin disorder that results in well-demarcated, hyperpigmented, tan to dark patches that mostly appear in sun-exposed areas such as the face and neck and sometimes the arms. The exact prevalence or incidence is not known but is estimated to be 1% to 50% overall depending on the ethnic population and geographic location.^1,2 Melasma predominantly affects women, but research has shown that approximately 10% to 20% of men are affected by this condition.^3,4 Although melasma can affect patients of all skin types, it primarily affects those with darker skin tones.⁵ The groups most often affected are women of Black, Hispanic, Middle Eastern, and Southeast Asian ethnicity. Although the pathogenesis is complex and not fully understood, multiple pathways and etiologies have been theorized to cause melasma. Potential causes include exposure to UV radiation, oral contraceptives, hormonal changes, medications, thyroid dysfunction, genetics, and pregnancy.^6,7 Cytokines and growth factors, including adipokine and angiopoietin, synthesized by sebaceous glands play a role in the pathogenic mechanism of melasma. Cytokines and growth factors are hypothesized to modulate the function of melanocytes.⁸ Both melanocytes and sebocytes are controlled by α–melanocyte-stimulating hormone. Therefore, overexpression of α–melanocyte-stimulating hormone will result in overproduction of these 2 cell types, resulting in melasma. Melasma can be classified into 4 subtypes using Wood lamp examination: epidermal, dermal, mixed, or indeterminate.³ Furthermore, melasma is divided into subgroups based on the location: malar region, mandibular region, and centrofacial patch pattern.^9,10 The involvement of sebaceous glands in the pathogenesis of melasma may explain the predilection for the centrofacial region, which is the most common pattern.

The severity of melasma can be assessed using the melasma area and severity index (MASI), which is calculated by subjective assessment of 3 main factors: (1) facial area of involvement; (2) darkness of affected region; and (3) homogeneity, with the extent of melasma indicated by a score ranging from 0 to 48.¹¹ The modified MASI (mMASI) subsequently was introduced to assist with assessing the severity of melasma and creating distinct ranges for mild, moderate, and severe cases, ranging from 0 (mild) to 24 (severe).¹² Both indices are used in research to assess the improvement of melasma with treatment.

Patients with melasma report a decrease in quality of life, increased emotional stress, and lower self-esteem due to cosmesis.¹³ Treatment of melasma can be highly challenging and often is complicated by relapsing. Historically, the treatment of melasma has included the use of chemical lightening agents. Additional treatment options include the use of lasers and complex chemical peels,^9,10 but these interventions may result in adverse outcomes for individuals with darker skin tones. The current gold-standard treatment is topical hydroquinone and broad-spectrum sunscreen. Although hydroquinone is effective in the treatment of melasma, relapse is common. The goal of melasma management is not only to treat acute hyperpigmentation but also to prevent relapse. Other therapies that currently are being explored for the clinically sustained treatment of melasma include tranexamic acid (TXA)(trans-4-[aminomethyl]cyclohexanecarboxylic acid),^9,10 an antifibrinolytic agent routinely used to prevent blood loss during surgery and in the management of menorrhagia. It is a synthetic derivative of lysine and serves as a potent plasmin inhibitor by blocking the lysine-binding sites of plasminogen molecules, thus preventing the conversion of plasminogen to plasmin. It also prevents fibrinolysis and blood loss.

In addition to its hemostatic properties, TXA has been found to have hypopigmentation properties.^14,15 Plasminogen also can be found in human epidermal basal cells and human keratinocytes, and it is postulated that TXA’s interaction with these cells explains its hypopigmentation properties. Both UV radiation and hormones activate plasminogen into plasmin, resulting in the activation of tyrosinase and melanogenesis.^14,15 Tranexamic acid is postulated to inhibit the keratinocyte-plasminogen pathway, thus leading to the inhibition of UV-induced and hormone-induced pigmentation. Also, TXA serves as a competitive inhibitor for tyrosinase due to its structural similarity to tyrosine.¹⁵ The combination of these 2 mechanisms contributes to the skin-lightening effects of TXA, making it a potential treatment for melasma.

Furthermore, the use of microneedling is being explored as a treatment option for melasma. Microneedling creates microscopic punctures in the skin using tiny needles, resulting in a wound-healing response and skin resurfacing. The microneedling technique is utilized to create small holes in the skin, with needle depths that can be adjusted from 0.5 to 3.5 mm to target different layers of the dermis and allow for discreet application of TXA.¹⁶ We sought to look at the current literature on the use and effectiveness of microneedling in combination with TXA to treat melasma and prevent relapse.

Methods

A systematic review was performed of PubMed articles indexed for MEDLINE and Embase in November 2021 to compile available articles that studied TXA and microneedling as a treatment for melasma. The PubMed search terms were (melasma) AND (microneedling* OR ‘tranexamic acid’ OR TXA or TA). The Embase search terms were (cholasma OR melasma) AND (tranexamic acid OR TXA) AND (microneedling)(Figure). The search was then limited to ”randomized controlled trial” and ”clinical trial” in English-language journals. Duplicates were excluded. After thorough evaluation, articles that discussed the use of TXA in combination with treatment options other than microneedling also were excluded.

Results

The literature search yielded a total of 12 articles that assessed the effectiveness of TXA and microneedling for the treatment of melasma (Table).^17-28 Several articles concluded that TXA was equally effective at reducing melasma lesions when compared with the standard treatment of hydroquinone. Some of the reviewed articles also demonstrated the effectiveness of microneedling in improving melasma lesions as a stand-alone treatment. These studies highlighted the enhanced efficacy of the combined treatment of TXA and microneedling compared with their individual uses.^17-28

Comment

Melasma is a common chronic hyperpigmentation disorder, making its treatment clinically challenging. Many patients experience symptom relapses, and limited effective treatment options make achieving complete clearance difficult, underscoring the need for improved therapeutic approaches. Recently, researchers have explored alternative treatments to address the challenges of melasma management. Tranexamic acid is an antifibrinolytic used to prevent blood loss and has emerged as a potential treatment for melasma. Similarly, microneedling—a technique in which multiple punctures are made in the skin to activate and stimulate wound healing and skin rejuvenation—shows promise for melasma.

Oral TXA for Melasma—Oral TXA has been shown to reduce melasma lesions. Del Rosario et al¹⁷ recruited 44 women (39 of whom completed the study) with moderate to severe melasma and randomized them into 2 groups: oral TXA and placebo. This study demonstrated a 49% reduction in the mMASI score in all participants taking oral TXA (250 mg twice daily [BID]) compared with an 18% reduction in the control group (placebo capsule BID) after 3 months of treatment. In patients with moderate and severe melasma, 45% and 51% mMASI score reductions were reported in the treatment group, respectively, vs 16% and 19% score reductions in placebo group, respectively. These researchers concluded that oral TXA may be effective at treating moderate to severe melasma. Although patients with severe melasma had a better response to treatment, their improvement was not sustained compared with patients with moderate melasma after a 3-month posttreatment follow-up.¹⁷

Microneedling Plus TXA for Melasma—Microneedling alone has been shown to be effective for melasma. El Attar et al¹⁸ conducted a split-face study of microneedling (1.5-mm depth) plus topical TXA (0.5 mL)(right side of the face[treatment arm]) compared with microneedling (1.5-mm depth) plus topical vitamin C (0.5 mL)(left side of the face [control group]) in 20 women with melasma. The sessions were repeated every 2 weeks for a total of 6 sessions. Although researchers found no statistically significant differences between the 2 treatment sides, microneedling plus TXA showed a slight advantage over microneedling plus vitamin C in dermoscopic examination. Both sides showed improvement in pigmented lesions, but vitamin C–treated lesions did not show an improvement in vascularity vs TXA.¹⁸

Saleh et al¹⁹ further showed that combination treatment with microneedling and TXA may improve clinical outcomes better than microneedling alone. Their study demonstrated a reduction in MASI score that was significantly higher in the combination treatment group compared with the microneedling alone group (P=.001). There was a significant reduction in melanoma antigen recognized by T cells 1 (MART-1)–positive cells in the combination treatment group compared with the microneedling alone group (P=.001). Lastly, combined therapy improved melasma patches better than microneedling alone.¹⁹

Xu et al²⁰ conducted a split-face study (N=28) exploring the effectiveness of transdermal application of topical TXA using a microarray pen with microneedles (vibration at 3000×/min) plus topical TXA on one side of the face, while the other side received only topical TXA as a control. After 12 weeks of treatment, combination therapy with microneedling and TXA decreased brown spot scores, lowered melanin index (MI) values, improved blinded physician assessment, and improved patient satisfaction vs TXA therapy alone.²⁰

Kaur et al²¹ conducted a split-face, randomized, controlled trial of microneedling (1-mm depth) with TXA solution 10% vs microneedling (1-mm depth) with distilled water alone for 8 weeks (N=40). They graded participant responses to treatment using reductions in mMASI scores¹² at every 2 weeks of follow-up (no response, minimal or poor response=0%–25%; partial or fair response=26%–50%; good response=51%–75%; and excellent response=>75%). They reported an overall reduction in mMASI scores for both the treatment side and the control side in all participants, showing a 65.92% improvement in mean mMASI scores on the treatment side vs 20.75% improvement on the control side at week 8. Both sides showed statistically significant reductions in mean mMASI scores (P<.05). Clinically, 40% (16/40) of participants showed an excellent response to combined treatment compared with 0% (0/40) to microneedling alone. Overall, patient satisfaction was similar across both groups. This study demonstrated that microneedling alone improves melasma, but a combination of microneedling plus TXA showed a better clinical reduction in melasma. However, the researchers did not follow up with participants posttreatment, so it remains unclear if the improved clinical outcomes were sustained long-term.²¹

Ebrahim et al²² reported that the combination of 0.5 mL TXA (4 mg/mL) and microneedling (0.25- to 1-mm depth) was effective for melasma. Although there was improvement within microneedling and TXA, the study also showed that intradermal injection of TXA was significant in reducing mean mMASI scores and improving melasma (P<.001). The reduction in mMASI scores for the group receiving intradermal injections of TXA (left side; 74.8% reduction in mean mMASI score) vs the group receiving microneedling application of TXA (right side; 73.6% reduction in mean mMASI score) was not statistically significant. These findings suggest that the mode of TXA application may not be critical in determining clinical responses to TXA treatment. Although there was no reported statistically significant difference in clinical outcomes between the 2 treatments, patient satisfaction was higher on the microneedling side. Only 8 of 50 participants (16%) experienced recurrence 3 months posttreatment.²²

Saki et al²³ compared the efficacy of topical hydroquinone (2%) to intradermal TXA injections in treating melasma. They found intradermal TXA injections to be a clinically effective mode of treatment.²³

Sharma et al²⁴ explored the efficacy and safety of oral TXA by randomly assigning 100 Indian patients (20 of whom withdrew before study completion) with melasma into 2 groups: group A received TXA 250 mg twice daily, and group B received intradermal microinjections of TXA (4 mg/mL) every 4 weeks. The MASI scores were assessed at 4-week intervals for a total of 12 weeks. There was a decrease in MASI scores in both groups, and there was no statistically significant difference in mean percentage reduction in MASI scores between the 2 routes of drug administration, further suggesting the effectiveness of TXA independent of administration route. Two patients in group A relapsed at 24 weeks, and there were no relapses in group B, which may suggest a minimal superiority of TXA plus microneedling at providing more sustainable results compared with oral TXA alone. A notable limitation of this study was a high dropout rate as well as lack of long-term follow-up with participants, limiting the generalizability of the conclusions.²⁴

Cassiano et al²⁵ assigned 64 women with melasma to 1 of 3 treatment groups or a control group to compare the effectiveness of microneedling (M group: 1.5 mm; 2 sessions), oral TXA (T group: 250 mg/d twice daily for 60 days), and a combination of microneedling (2 sessions) and oral TXA (MT group: 250 mg/d twice daily for 60 days)with placebo for clinically reducing melasma lesions. The intervention period was 60 days followed by a 60-day maintenance phase for a total study period of 120 days. The researchers evaluated mMASI scores, quality of life, and difference in colorimetric luminosity. All treatment groups showed a reduction in mMASI scores at both 30 days and 60 days, indicating improved melasma severity. The MT and T groups had more significant improvement at 30 days compared with the control group (P<.03), suggesting that microneedling plus TXA and TXA alone promote faster improvement in melasma lesions. By 60 days, the M, T, and MT groups outperformed the control group, with no significant differences between the M, T, and MT groups. However, at the 120-day maintenance follow-up, the T group did not maintain its improvement compared with the control group. The M and MT groups showed no significance difference in effectiveness at 120 days, suggesting that microneedling may promote less frequent relapse and sustained remission compared to TXA alone.²⁵

Hydroquinone for Melasma—Additional studies on the use of TXA treatments show that TXA may be an equally effective alternative to the standard use of hydroquinone treatment. Shamsi Meymandi et al²⁶ did not find a statistically significant difference in treatment with TXA plus microneedling vs the standard regimen of hydroquinone. More importantly, patient and physician satisfaction assessments were similar between the 2 groups. Compared to hydroquinone, nightly treatment is not necessary with microneedling and TXA.²⁶

Xing et al²⁷ supported these conclusions with their study. They compared 3 study arms for a duration of 12 weeks: group A received topical 1.8% liposomal TXA BID, group B received stamp-mode electric microneedling with 5% TXA weekly, and group C applied 2% ­hydroquinone cream nightly. The study concluded that all 3 groups showed a significant reduction in mean MI by the end of the study, but a better MI improvement was observed in groups B and C (both P<.001) compared with group A (P<.01).²⁷

Zaky et al²⁸ showed that both hydroquinone and combination treatment of TXA plus microneedling are effective at improving melasma lesions. Further studies are needed to definitively conclude if combination treatment is more efficacious than hydroquinone; if the combination is more effective, it provides a treatment option for patients with melasma who may not be good candidates for hydroquinone treatment.

Study Limitations—One limitation in all the studies evaluated is the sample size. Because they all had small sample sizes, it is difficult to definitively conclude that the combination TXA and microneedling is an effective and appropriate treatment for patients with melasma. Furthermore, the quality of these studies was mostly dependent on subjectivity of the mMASI scores. Future large randomized controlled trials with a diverse participant population are needed to assess the effectiveness of TXA and microneedling in melasma treatment.

Another limitation is that many of the studies did not follow the patients longitudinally, which did not allow for an evaluation of whether patients had a relapse of melasma. Due to the chronic nature of melasma and frequent disease recurrence, future longitudinal studies are needed to monitor for disease recurrence.

Conclusion

Tranexamic acid and microneedling are potential treatment options for patients with melasma, and combination therapy appears more effective than either TXA or microneedling alone at providing sustained improvement of melasma lesions. Combination therapy appears safe and well tolerated, but its effect on reducing long-term disease recurrence is yet to be established.

Skin grafting is a surgical technique used to cover skin defects resulting from the removal of skin tumors, ulcers, or burn injuries.^1-3 Complications can occur at both donor and recipient sites and may include bleeding, hematoma/seroma formation, postoperative pain, infection, scarring, paresthesia, skin pigmentation, graft contracture, and graft failure.^1,2,4,5 The development of epidermal tumors is not commonly reported among the complications of skin grafting; however, cases of epidermal tumor development on skin graft donor sites during the postoperative period have been reported.^6-12

We performed a systematic review of the literature for cases of epidermal tumor development on skin graft donor sites in patients undergoing autologous skin graft surgery. We present the clinical characteristics of these cases and discuss the nature of these tumors.

Methods

Search Strategy and Study Selection—A literature search was conducted by 2 independent researchers (Z.P. and V.P.) for articles published before December 2022 in the following databases: MEDLINE/PubMed, Web of Science, Scopus, Cochrane Library, OpenGrey, Google Scholar, and WorldCat. Search terms included all possible combinations of the following: keratoacanthoma, molluscum sebaceum, basal cell carcinoma, squamous cell carcinoma, acanthoma, wart, Merkel cell carcinoma, verruca, Bowen disease, keratosis, skin cancer, cutaneous cancer, skin neoplasia, cutaneous neoplasia, and skin tumor. The literature search terms were selected based on the World Health Organization classification of skin tumors.¹³ Manual bibliography checks were performed on all eligible search results for possible relevant studies. Discrepancies were resolved through discussion and, if needed, mediation by a third researcher (N.C.). To be included, a study had to report a case(s) of epidermal tumor(s) that was confirmed by histopathology and arose on a graft donor site in a patient receiving autologous skin grafts for any reason. No language, geographic, or report date restrictions were set.

Data Extraction, Quality Assessment, and Statistical Analysis—We adhered to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines.¹⁴ Two independent researchers (Z.P. and V.P.) retrieved the data from the included studies. We have used the terms case and patient interchangeably, and 1 month was measured as 4 weeks for simplicity. Disagreements were resolved by discussion and mediation by a third researcher (N.C.). The quality of the included studies was assessed by 2 researchers (M.P. and V.P.) using the tool proposed by Murad et al.¹⁵

We used descriptive statistical analysis to analyze clinical characteristics of the included cases. We performed separate descriptive analyses based on the most frequently reported types of epidermal tumors and compared the differences between different groups using the Mann-Whitney U test, χ2 test, and Fisher exact test. The level of significance was set at P<.05. All statistical analyses were conducted using SPSS (version 29).

Results

Literature Search and Characteristics of Included Studies—The initial literature search identified 1378 studies, which were screened based on title and abstract. After removing duplicate and irrelevant studies and evaluating the full text of eligible studies, 31 studies (4 case series and 27 case reports) were included in the systematic review (Figure).^6-12,16-39 Quality assessment of the included studies is presented in Table 1.

Clinical Characteristics of Included Patients—Our systematic review included 36 patients with a mean age of 63 years and a male to female ratio of 2:1. The 2 most common causes for skin grafting were burn wounds and surgical excision of skin tumors. Most grafts were harvested from the thighs. The development of a solitary lesion on the donor area was reported in two-thirds of the patients, while more than 1 lesion developed in the remaining one-third of patients. The median time to tumor development was 6.5 weeks. In most cases, a split-thickness skin graft was used.

Cutaneous squamous cell carcinomas (CSCCs) were found in 23 patients, with well-differentiated CSCCs in 19 of these cases. Additionally, keratoacanthomas (KAs) were found in 10 patients. The majority of patients underwent surgical excision of the tumor. The median follow-up time was 12 months, during which recurrences were noted in a small percentage of cases. Clinical characteristics of included patients are presented in Table 2.

Comment

Reasons for Tumor Development on Skin Graft Donor Sites—The etiology behind epidermal tumor development on graft donor sites is unclear. According to one theory, iatrogenic contamination of the donor site during the removal of a primary epidermal tumor could be responsible. However, contemporary surgical procedures dictate the use of different sets of instruments for separate surgical sites. Moreover, this theory cannot explain the occurrence of epidermal tumors on donor sites in patients who have undergone skin grafting for the repair of burn wounds.³⁷

Another theory suggests that hematogenous and/or lymphatic spread can occur from the site of the primary epidermal tumor to the donor site, which has increased vascularization.^16,37 However, this theory also fails to provide an explanation for the development of epidermal tumors in patients who receive skin grafts for burn wounds.

A third theory states that the microenvironment of the donor site is key to tumor development. The donor site undergoes acute inflammation due to the trauma from harvesting the skin graft. According to this theory, acute inflammation could promote neoplastic growth and thus explain the development of epidermal tumors on the donor site.^8,26 However, the relationship between acute inflammation and carcinogenesis remains unclear. What is known to date is that the development of CSCC has been documented primarily in chronically inflamed tissues, whereas the development of KA—a variant of CSCC with distinctive and more benign clinical characteristics—can be expected in the setting of acute trauma-related inflammation.^13,40,41

Based on our systematic review, we propose that well-differentiated CSCC on graft donor sites might actually be misdiagnosed KA, given that the histopathologic differential diagnosis between CSCC and KA is extremely challenging.⁴² This hypothesis could explain the development of well-differentiated CSCC and KA on graft donor sites.

Conclusion

Development of CSCC and KA on graft donor sites can be listed among the postoperative complications of autologous skin grafting. Patients and physicians should be aware of this potential complication, and donor sites should be monitored for the occurrence of epidermal tumors.

Skin grafting is a surgical technique used to cover skin defects resulting from the removal of skin tumors, ulcers, or burn injuries.^1-3 Complications can occur at both donor and recipient sites and may include bleeding, hematoma/seroma formation, postoperative pain, infection, scarring, paresthesia, skin pigmentation, graft contracture, and graft failure.^1,2,4,5 The development of epidermal tumors is not commonly reported among the complications of skin grafting; however, cases of epidermal tumor development on skin graft donor sites during the postoperative period have been reported.^6-12

We performed a systematic review of the literature for cases of epidermal tumor development on skin graft donor sites in patients undergoing autologous skin graft surgery. We present the clinical characteristics of these cases and discuss the nature of these tumors.

Methods

Search Strategy and Study Selection—A literature search was conducted by 2 independent researchers (Z.P. and V.P.) for articles published before December 2022 in the following databases: MEDLINE/PubMed, Web of Science, Scopus, Cochrane Library, OpenGrey, Google Scholar, and WorldCat. Search terms included all possible combinations of the following: keratoacanthoma, molluscum sebaceum, basal cell carcinoma, squamous cell carcinoma, acanthoma, wart, Merkel cell carcinoma, verruca, Bowen disease, keratosis, skin cancer, cutaneous cancer, skin neoplasia, cutaneous neoplasia, and skin tumor. The literature search terms were selected based on the World Health Organization classification of skin tumors.¹³ Manual bibliography checks were performed on all eligible search results for possible relevant studies. Discrepancies were resolved through discussion and, if needed, mediation by a third researcher (N.C.). To be included, a study had to report a case(s) of epidermal tumor(s) that was confirmed by histopathology and arose on a graft donor site in a patient receiving autologous skin grafts for any reason. No language, geographic, or report date restrictions were set.

Data Extraction, Quality Assessment, and Statistical Analysis—We adhered to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines.¹⁴ Two independent researchers (Z.P. and V.P.) retrieved the data from the included studies. We have used the terms case and patient interchangeably, and 1 month was measured as 4 weeks for simplicity. Disagreements were resolved by discussion and mediation by a third researcher (N.C.). The quality of the included studies was assessed by 2 researchers (M.P. and V.P.) using the tool proposed by Murad et al.¹⁵

We used descriptive statistical analysis to analyze clinical characteristics of the included cases. We performed separate descriptive analyses based on the most frequently reported types of epidermal tumors and compared the differences between different groups using the Mann-Whitney U test, χ2 test, and Fisher exact test. The level of significance was set at P<.05. All statistical analyses were conducted using SPSS (version 29).

Results

Literature Search and Characteristics of Included Studies—The initial literature search identified 1378 studies, which were screened based on title and abstract. After removing duplicate and irrelevant studies and evaluating the full text of eligible studies, 31 studies (4 case series and 27 case reports) were included in the systematic review (Figure).^6-12,16-39 Quality assessment of the included studies is presented in Table 1.

Clinical Characteristics of Included Patients—Our systematic review included 36 patients with a mean age of 63 years and a male to female ratio of 2:1. The 2 most common causes for skin grafting were burn wounds and surgical excision of skin tumors. Most grafts were harvested from the thighs. The development of a solitary lesion on the donor area was reported in two-thirds of the patients, while more than 1 lesion developed in the remaining one-third of patients. The median time to tumor development was 6.5 weeks. In most cases, a split-thickness skin graft was used.

Cutaneous squamous cell carcinomas (CSCCs) were found in 23 patients, with well-differentiated CSCCs in 19 of these cases. Additionally, keratoacanthomas (KAs) were found in 10 patients. The majority of patients underwent surgical excision of the tumor. The median follow-up time was 12 months, during which recurrences were noted in a small percentage of cases. Clinical characteristics of included patients are presented in Table 2.

Comment

Reasons for Tumor Development on Skin Graft Donor Sites—The etiology behind epidermal tumor development on graft donor sites is unclear. According to one theory, iatrogenic contamination of the donor site during the removal of a primary epidermal tumor could be responsible. However, contemporary surgical procedures dictate the use of different sets of instruments for separate surgical sites. Moreover, this theory cannot explain the occurrence of epidermal tumors on donor sites in patients who have undergone skin grafting for the repair of burn wounds.³⁷

Another theory suggests that hematogenous and/or lymphatic spread can occur from the site of the primary epidermal tumor to the donor site, which has increased vascularization.^16,37 However, this theory also fails to provide an explanation for the development of epidermal tumors in patients who receive skin grafts for burn wounds.

A third theory states that the microenvironment of the donor site is key to tumor development. The donor site undergoes acute inflammation due to the trauma from harvesting the skin graft. According to this theory, acute inflammation could promote neoplastic growth and thus explain the development of epidermal tumors on the donor site.^8,26 However, the relationship between acute inflammation and carcinogenesis remains unclear. What is known to date is that the development of CSCC has been documented primarily in chronically inflamed tissues, whereas the development of KA—a variant of CSCC with distinctive and more benign clinical characteristics—can be expected in the setting of acute trauma-related inflammation.^13,40,41

Based on our systematic review, we propose that well-differentiated CSCC on graft donor sites might actually be misdiagnosed KA, given that the histopathologic differential diagnosis between CSCC and KA is extremely challenging.⁴² This hypothesis could explain the development of well-differentiated CSCC and KA on graft donor sites.

Conclusion

Development of CSCC and KA on graft donor sites can be listed among the postoperative complications of autologous skin grafting. Patients and physicians should be aware of this potential complication, and donor sites should be monitored for the occurrence of epidermal tumors.

Skin grafting is a surgical technique used to cover skin defects resulting from the removal of skin tumors, ulcers, or burn injuries.^1-3 Complications can occur at both donor and recipient sites and may include bleeding, hematoma/seroma formation, postoperative pain, infection, scarring, paresthesia, skin pigmentation, graft contracture, and graft failure.^1,2,4,5 The development of epidermal tumors is not commonly reported among the complications of skin grafting; however, cases of epidermal tumor development on skin graft donor sites during the postoperative period have been reported.^6-12

We performed a systematic review of the literature for cases of epidermal tumor development on skin graft donor sites in patients undergoing autologous skin graft surgery. We present the clinical characteristics of these cases and discuss the nature of these tumors.

Methods

Search Strategy and Study Selection—A literature search was conducted by 2 independent researchers (Z.P. and V.P.) for articles published before December 2022 in the following databases: MEDLINE/PubMed, Web of Science, Scopus, Cochrane Library, OpenGrey, Google Scholar, and WorldCat. Search terms included all possible combinations of the following: keratoacanthoma, molluscum sebaceum, basal cell carcinoma, squamous cell carcinoma, acanthoma, wart, Merkel cell carcinoma, verruca, Bowen disease, keratosis, skin cancer, cutaneous cancer, skin neoplasia, cutaneous neoplasia, and skin tumor. The literature search terms were selected based on the World Health Organization classification of skin tumors.¹³ Manual bibliography checks were performed on all eligible search results for possible relevant studies. Discrepancies were resolved through discussion and, if needed, mediation by a third researcher (N.C.). To be included, a study had to report a case(s) of epidermal tumor(s) that was confirmed by histopathology and arose on a graft donor site in a patient receiving autologous skin grafts for any reason. No language, geographic, or report date restrictions were set.

Data Extraction, Quality Assessment, and Statistical Analysis—We adhered to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines.¹⁴ Two independent researchers (Z.P. and V.P.) retrieved the data from the included studies. We have used the terms case and patient interchangeably, and 1 month was measured as 4 weeks for simplicity. Disagreements were resolved by discussion and mediation by a third researcher (N.C.). The quality of the included studies was assessed by 2 researchers (M.P. and V.P.) using the tool proposed by Murad et al.¹⁵

We used descriptive statistical analysis to analyze clinical characteristics of the included cases. We performed separate descriptive analyses based on the most frequently reported types of epidermal tumors and compared the differences between different groups using the Mann-Whitney U test, χ2 test, and Fisher exact test. The level of significance was set at P<.05. All statistical analyses were conducted using SPSS (version 29).

Results

Literature Search and Characteristics of Included Studies—The initial literature search identified 1378 studies, which were screened based on title and abstract. After removing duplicate and irrelevant studies and evaluating the full text of eligible studies, 31 studies (4 case series and 27 case reports) were included in the systematic review (Figure).^6-12,16-39 Quality assessment of the included studies is presented in Table 1.

Clinical Characteristics of Included Patients—Our systematic review included 36 patients with a mean age of 63 years and a male to female ratio of 2:1. The 2 most common causes for skin grafting were burn wounds and surgical excision of skin tumors. Most grafts were harvested from the thighs. The development of a solitary lesion on the donor area was reported in two-thirds of the patients, while more than 1 lesion developed in the remaining one-third of patients. The median time to tumor development was 6.5 weeks. In most cases, a split-thickness skin graft was used.

Cutaneous squamous cell carcinomas (CSCCs) were found in 23 patients, with well-differentiated CSCCs in 19 of these cases. Additionally, keratoacanthomas (KAs) were found in 10 patients. The majority of patients underwent surgical excision of the tumor. The median follow-up time was 12 months, during which recurrences were noted in a small percentage of cases. Clinical characteristics of included patients are presented in Table 2.

Comment

Reasons for Tumor Development on Skin Graft Donor Sites—The etiology behind epidermal tumor development on graft donor sites is unclear. According to one theory, iatrogenic contamination of the donor site during the removal of a primary epidermal tumor could be responsible. However, contemporary surgical procedures dictate the use of different sets of instruments for separate surgical sites. Moreover, this theory cannot explain the occurrence of epidermal tumors on donor sites in patients who have undergone skin grafting for the repair of burn wounds.³⁷

Another theory suggests that hematogenous and/or lymphatic spread can occur from the site of the primary epidermal tumor to the donor site, which has increased vascularization.^16,37 However, this theory also fails to provide an explanation for the development of epidermal tumors in patients who receive skin grafts for burn wounds.

A third theory states that the microenvironment of the donor site is key to tumor development. The donor site undergoes acute inflammation due to the trauma from harvesting the skin graft. According to this theory, acute inflammation could promote neoplastic growth and thus explain the development of epidermal tumors on the donor site.^8,26 However, the relationship between acute inflammation and carcinogenesis remains unclear. What is known to date is that the development of CSCC has been documented primarily in chronically inflamed tissues, whereas the development of KA—a variant of CSCC with distinctive and more benign clinical characteristics—can be expected in the setting of acute trauma-related inflammation.^13,40,41

Based on our systematic review, we propose that well-differentiated CSCC on graft donor sites might actually be misdiagnosed KA, given that the histopathologic differential diagnosis between CSCC and KA is extremely challenging.⁴² This hypothesis could explain the development of well-differentiated CSCC and KA on graft donor sites.

Conclusion

Development of CSCC and KA on graft donor sites can be listed among the postoperative complications of autologous skin grafting. Patients and physicians should be aware of this potential complication, and donor sites should be monitored for the occurrence of epidermal tumors.

Illicit use of the veterinary tranquilizer xylazine continues to spread across the United States. The drug, which is increasingly mixed with fentanyl, often fails to respond to the opioid overdose reversal medication naloxone and can cause severe necrotic lesions.

A report released by Millennium Health, a specialty lab that provides medication monitoring for pain management, drug treatment, and behavioral and substance use disorder treatment centers across the country, showed the number of urine specimens collected and tested at the US drug treatment centers were positive for xylazine in the most recent 6 months.

As previously reported by this news organization, in late 2022, the US Food and Drug Administration (FDA) issued a communication alerting clinicians about the special management required for opioid overdoses tainted with xylazine, which is also known as “tranq” or “tranq dope.”

Subsequently, in early 2023, The White House Office of National Drug Control Policy designated xylazine combined with fentanyl as an emerging threat to the United States.

Both the FDA and the Drug Enforcement Administration have taken steps to try to stop trafficking of the combination. However, despite these efforts, xylazine use has continued to spread.

The Millennium Health Signals report showed that the greatest increase in xylazine use was largely in the western United States. In the first 6 months of 2023, 3% of urine drug tests (UDTs) in Washington, Oregon, California, Hawaii, and Alaska were positive for xylazine. From November 2023 to April 2024, this rose to 8%, a 147% increase. In the Mountain West, xylazine-positive UDTs increased from 2% in 2023 to 4% in 2024, an increase of 94%. In addition to growth in the West, the report showed that xylazine use increased by more than 100% in New England — from 14% in 2023 to 28% in 2024.

Nationally, 16% of all urine specimens were positive for xylazine from late 2023 to April 2024, up slightly from 14% from April to October 2023.

Xylazine use was highest in the East and in the mid-Atlantic United States. Still, positivity rates in the mid-Atlantic dropped from 44% to 33%. The states included in that group were New York, Pennsylvania, Delaware, and New Jersey. East North Central states (Ohio, Michigan, Wisconsin, Indiana, and Illinois) also experienced a decline in positive tests from 32% to 30%.

The South Atlantic states, which include Maryland, Virginia, West Virginia, North and South Carolina, Georgia, and Florida, had a 17% increase in positivity — from 22% to 26%.

From April 2023 to April 2024 state-level UDT positivity rates were 40% in Pennsylvania, 37% in New York, and 35% in Ohio. But rates vary by locality. In Clermont and Hamilton counties in Ohio — both in the Cincinnati area — about 70% of specimens were positive for xylazine.

About one third of specimens in Maryland and South Carolina contained xylazine.

“Because xylazine exposure remains a significant challenge in the East and is a growing concern in the West, clinicians across the US need to be prepared to recognize and address the consequences of xylazine use — like diminished responses to naloxone and severe skin wounds that may lead to amputation — among people who use fentanyl,” Millennium Health Chief Clinical Officer Angela Huskey, PharmD, said in a press release.

The Health Signals Alert analyzed more than 50,000 fentanyl-positive UDT specimens collected between April 12, 2023, and April 11, 2024. Millennium Health researchers analyzed xylazine positivity rates in fentanyl-positive UDT specimens by the US Census Division and state.

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

Illicit use of the veterinary tranquilizer xylazine continues to spread across the United States. The drug, which is increasingly mixed with fentanyl, often fails to respond to the opioid overdose reversal medication naloxone and can cause severe necrotic lesions.

A report released by Millennium Health, a specialty lab that provides medication monitoring for pain management, drug treatment, and behavioral and substance use disorder treatment centers across the country, showed the number of urine specimens collected and tested at the US drug treatment centers were positive for xylazine in the most recent 6 months.

As previously reported by this news organization, in late 2022, the US Food and Drug Administration (FDA) issued a communication alerting clinicians about the special management required for opioid overdoses tainted with xylazine, which is also known as “tranq” or “tranq dope.”

Subsequently, in early 2023, The White House Office of National Drug Control Policy designated xylazine combined with fentanyl as an emerging threat to the United States.

Both the FDA and the Drug Enforcement Administration have taken steps to try to stop trafficking of the combination. However, despite these efforts, xylazine use has continued to spread.

The Millennium Health Signals report showed that the greatest increase in xylazine use was largely in the western United States. In the first 6 months of 2023, 3% of urine drug tests (UDTs) in Washington, Oregon, California, Hawaii, and Alaska were positive for xylazine. From November 2023 to April 2024, this rose to 8%, a 147% increase. In the Mountain West, xylazine-positive UDTs increased from 2% in 2023 to 4% in 2024, an increase of 94%. In addition to growth in the West, the report showed that xylazine use increased by more than 100% in New England — from 14% in 2023 to 28% in 2024.

Nationally, 16% of all urine specimens were positive for xylazine from late 2023 to April 2024, up slightly from 14% from April to October 2023.

Xylazine use was highest in the East and in the mid-Atlantic United States. Still, positivity rates in the mid-Atlantic dropped from 44% to 33%. The states included in that group were New York, Pennsylvania, Delaware, and New Jersey. East North Central states (Ohio, Michigan, Wisconsin, Indiana, and Illinois) also experienced a decline in positive tests from 32% to 30%.

The South Atlantic states, which include Maryland, Virginia, West Virginia, North and South Carolina, Georgia, and Florida, had a 17% increase in positivity — from 22% to 26%.

From April 2023 to April 2024 state-level UDT positivity rates were 40% in Pennsylvania, 37% in New York, and 35% in Ohio. But rates vary by locality. In Clermont and Hamilton counties in Ohio — both in the Cincinnati area — about 70% of specimens were positive for xylazine.

About one third of specimens in Maryland and South Carolina contained xylazine.

“Because xylazine exposure remains a significant challenge in the East and is a growing concern in the West, clinicians across the US need to be prepared to recognize and address the consequences of xylazine use — like diminished responses to naloxone and severe skin wounds that may lead to amputation — among people who use fentanyl,” Millennium Health Chief Clinical Officer Angela Huskey, PharmD, said in a press release.

The Health Signals Alert analyzed more than 50,000 fentanyl-positive UDT specimens collected between April 12, 2023, and April 11, 2024. Millennium Health researchers analyzed xylazine positivity rates in fentanyl-positive UDT specimens by the US Census Division and state.

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

Illicit use of the veterinary tranquilizer xylazine continues to spread across the United States. The drug, which is increasingly mixed with fentanyl, often fails to respond to the opioid overdose reversal medication naloxone and can cause severe necrotic lesions.

A report released by Millennium Health, a specialty lab that provides medication monitoring for pain management, drug treatment, and behavioral and substance use disorder treatment centers across the country, showed the number of urine specimens collected and tested at the US drug treatment centers were positive for xylazine in the most recent 6 months.

As previously reported by this news organization, in late 2022, the US Food and Drug Administration (FDA) issued a communication alerting clinicians about the special management required for opioid overdoses tainted with xylazine, which is also known as “tranq” or “tranq dope.”

Subsequently, in early 2023, The White House Office of National Drug Control Policy designated xylazine combined with fentanyl as an emerging threat to the United States.

Both the FDA and the Drug Enforcement Administration have taken steps to try to stop trafficking of the combination. However, despite these efforts, xylazine use has continued to spread.

The Millennium Health Signals report showed that the greatest increase in xylazine use was largely in the western United States. In the first 6 months of 2023, 3% of urine drug tests (UDTs) in Washington, Oregon, California, Hawaii, and Alaska were positive for xylazine. From November 2023 to April 2024, this rose to 8%, a 147% increase. In the Mountain West, xylazine-positive UDTs increased from 2% in 2023 to 4% in 2024, an increase of 94%. In addition to growth in the West, the report showed that xylazine use increased by more than 100% in New England — from 14% in 2023 to 28% in 2024.

Nationally, 16% of all urine specimens were positive for xylazine from late 2023 to April 2024, up slightly from 14% from April to October 2023.

Xylazine use was highest in the East and in the mid-Atlantic United States. Still, positivity rates in the mid-Atlantic dropped from 44% to 33%. The states included in that group were New York, Pennsylvania, Delaware, and New Jersey. East North Central states (Ohio, Michigan, Wisconsin, Indiana, and Illinois) also experienced a decline in positive tests from 32% to 30%.

The South Atlantic states, which include Maryland, Virginia, West Virginia, North and South Carolina, Georgia, and Florida, had a 17% increase in positivity — from 22% to 26%.

From April 2023 to April 2024 state-level UDT positivity rates were 40% in Pennsylvania, 37% in New York, and 35% in Ohio. But rates vary by locality. In Clermont and Hamilton counties in Ohio — both in the Cincinnati area — about 70% of specimens were positive for xylazine.

About one third of specimens in Maryland and South Carolina contained xylazine.

“Because xylazine exposure remains a significant challenge in the East and is a growing concern in the West, clinicians across the US need to be prepared to recognize and address the consequences of xylazine use — like diminished responses to naloxone and severe skin wounds that may lead to amputation — among people who use fentanyl,” Millennium Health Chief Clinical Officer Angela Huskey, PharmD, said in a press release.

The Health Signals Alert analyzed more than 50,000 fentanyl-positive UDT specimens collected between April 12, 2023, and April 11, 2024. Millennium Health researchers analyzed xylazine positivity rates in fentanyl-positive UDT specimens by the US Census Division and state.

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

Nail disorders are common among pediatric patients but often are underdiagnosed or misdiagnosed because of their unique disease manifestations. These conditions may severely impact quality of life. There are few nail disease clinical trials that include children. Consequently, most treatment recommendations are based on case series and expert consensus recommendations. We review inflammatory and infectious nail disorders in pediatric patients. By describing characteristics, clinical manifestations, and management approaches for these conditions, we aim to provide guidance to dermatologists in their diagnosis and treatment.

INFLAMMATORY NAIL DISORDERS

Nail Psoriasis

Nail involvement in children with psoriasis is common, with prevalence estimates ranging from 17% to 39.2%.¹ Nail matrix psoriasis may manifest with pitting (large irregular pits) and leukonychia as well as chromonychia and nail plate crumbling. Onycholysis, oil drop spots (salmon patches), and subungual hyperkeratosis can be seen in nail bed psoriasis. Nail pitting is the most frequently observed clinical finding (Figure 1).^2,3 In a cross-sectional multicenter study of 313 children with cutaneous psoriasis in France, nail findings were present in 101 patients (32.3%). There were associations between nail findings and presence of psoriatic arthritis (P=.03), palmoplantar psoriasis (P<.001), and severity of psoriatic disease, defined as use of systemic treatment with phototherapy (psoralen plus UVA, UVB), traditional systemic treatment (acitretin, methotrexate, cyclosporine), or a biologic (P=.003).⁴

Topical steroids and vitamin D analogues may be used with or without occlusion and may be efficacious.⁵ Several case reports describe systemic treatments for psoriasis in children, including methotrexate, acitretin, and apremilast (approved for children 6 years and older for plaque psoriasis by the US Food and Drug Administration [FDA]).² There are 5 biologic drugs currently approved for the treatment of pediatric psoriasis—adalimumab, etanercept, ustekinumab, secukinumab, ixekizumab—and 6 drugs currently undergoing phase 3 studies—brodalumab, guselkumab, risankizumab, tildrakizumab, certolizumab pegol, and deucravacitinib (Table 1).^6-15 Adalimumab is specifically approved for moderate to severe nail psoriasis in adults 18 years and older.

Intralesional steroid injections are sometimes useful in the management of nail matrix psoriasis; however, appropriate patient selection is critical due to the pain associated with the procedure. In a prospective study of 16 children (age range, 9–17 years) with nail psoriasis treated with intralesional triamcinolone (ILTAC) 2.5 to 5 mg/mL every 4 to 8 weeks for a minimum of 3 to 6 months, 9 patients achieved resolution and 6 had improvement of clinical findings.¹⁶ Local adverse events were mild, including injection-site pain (66%), subungual hematoma (n=1), Beau lines (n=1), proximal nail fold hypopigmentation (n=2), and proximal nail fold atrophy (n=2). Because the proximal nail fold in children is thinner than in adults, there may be an increased risk for nail fold hypopigmentation and atrophy in children. Therefore, a maximum ILTAC concentration of 2.5 mg/mL with 0.2 mL maximum volume per nail per session is recommended for children younger than 15 years.¹⁶

Nail Lichen Planus

Nail lichen planus (NLP) is uncommon in children, with few biopsy-proven cases documented in the literature.¹⁷ Common clinical findings are onychorrhexis, nail plate thinning, fissuring, splitting, and atrophy with koilonychia.⁵ Although pterygium development (irreversible nail matrix scarring) is uncommon in pediatric patients, NLP can be progressive and may cause irreversible destruction of the nail matrix and subsequent nail loss, warranting therapeutic intervention.¹⁸

Treatment of NLP may be difficult, as there are no options that work in all patients. Current literature supports the use of systemic corticosteroids or ILTAC for the treatment of NLP; however, recurrence rates can be high. According to an expert consensus paper on NLP treatment, ILTAC may be injected in a concentration of 2.5, 5, or 10 mg/mL according to disease severity.¹⁹ In severe or resistant cases, intramuscular (IM) triamcinolone may be considered, especially if more than 3 nails are affected. A dosage of 0.5 to 1 mg/kg/mo for at least 3 to 6 months is recommended for both children and adults, with 1 mg/kg/mo recommended in the active treatment phase (first 2–3 months).¹⁹ In a retrospective review of 5 pediatric patients with NLP treated with IM triamcinolone 0.5 mg/kg/mo, 3 patients had resolution and 2 improved with treatment.²⁰ In a prospective study of 10 children with NLP, IM triamcinolone at a dosage of 0.5 to 1 mg/kg every 30 days for 3 to 6 months resulted in resolution of nail findings in 9 patients.¹⁷ In a prospective study of 14 pediatric patients with NLP treated with 2.5 to 5 mg/mL of ILTAC, 10 achieved resolution and 3 improved.¹⁶

Intralesional triamcinolone injections may be better suited for teenagers compared to younger children who may be more apprehensive of needles. To minimize pain, it is recommended to inject ILTAC slowly at room temperature, with use of “talkesthesia” and vibration devices, 1% lidocaine, or ethyl chloride spray.¹⁸

Trachyonychia

Trachyonychia is characterized by the presence of sandpaperlike nails. It manifests with brittle thin nails with longitudinal ridging, onychoschizia, and thickened hyperkeratotic cuticles. Trachyonychia typically involves multiple nails, with a peak age of onset between 3 and 12 years.^21,22 There are 2 variants: the opaque type with rough longitudinal ridging, and the shiny variant with opalescent nails and pits that reflect light. The opaque variant is more common and is associated with psoriasis, whereas the shiny variant is less common and is associated with alopecia areata.²³ Although most cases are idiopathic, some are associated with psoriasis and alopecia areata, as previously noted, as well as atopic dermatitis (AD) and lichen planus.^22,24

Fortunately, trachyonychia does not lead to permanent nail damage or pterygium, making treatment primarily focused on addressing functional and cosmetic concerns.²⁴ Spontaneous resolution occurs in approximately 50% of patients. In a prospective study of 11 patients with idiopathic trachyonychia, there was partial improvement in 5 of 9 patients treated with topical steroids, 1 with only petrolatum, and 1 with vitamin supplements. Complete resolution was reported in 1 patient treated with topical steroids.²⁵ Because trachyonychia often is self-resolving, no treatment is required and a conservative approach is strongly recommended.²⁶ Treatment options include topical corticosteroids, tazarotene, and 5-fluorouracil. Intralesional triamcinolone, systemic cyclosporine, retinoids, systemic corticosteroids, and tofacitinib have been described in case reports, though none of these have been shown to be 100% efficacious.²⁴

Nail Lichen Striatus

Lichen striatus involving the nail is uncommon and is characterized by onycholysis, longitudinal ridging, ­splitting, and fraying, as well as what appears to be a subungual tumor. It can encompass the entire nail or may be isolated to a portion of the nail (Figure 2). Usually, a Blaschko-linear array of flesh-colored papules on the more proximal digit directly adjacent to the nail dystrophy will be seen, though nail findings can occur in ­isolation.^27-29 The underlying pathophysiology is not clear; however, one hypothesis is that a triggering event, such as trauma, induces the expression of antigens that elicit a self-limiting immune-mediated response by CD8 T lymphocytes.³⁰

Generally, nail lichen striatus spontaneously resolves in 1 to 2 years without treatment. In a prospective study of 5 patients with nail lichen striatus, the median time to resolution was 22.6 months (range, 10–30 months).³¹ Topical steroids may be used for pruritus. In one case report, a 3-year-old boy with nail lichen striatus of 4 months’ duration was treated with tacrolimus ointment 0.03% daily for 3 months.²⁸

Nail AD

Nail changes with AD may be more common in adults than children or are underreported. In a study of 777 adults with AD, nail dystrophy was present in 124 patients (16%), whereas in a study of 250 pediatric patients with AD (aged 0-2 years), nail dystrophy was present in only 4 patients.^32,33

Periungual inflammation from AD causes the nail changes.³⁴ In a cross-sectional study of 24 pediatric patients with nail dystrophy due to AD, transverse grooves (Beau lines) were present in 25% (6/24), nail pitting in 16.7% (4/24), koilonychia in 16.7% (4/24), trachyonychia in 12.5% (3/24), leukonychia in 12.5% (3/24), brachyonychia in 8.3% (2/24), melanonychia in 8.3% (2/24), onychomadesis in 8.3% (2/24), onychoschizia in 8.3% (2/24), and onycholysis in 8.3% (2/24). There was an association between disease severity and presence of toenail dystrophy (P=.03).³⁵

Topical steroids with or without occlusion can be used to treat nail changes. Although there is limited literature describing the treatment of nail AD in children, a 61-year-old man with nail changes associated with AD achieved resolution with 3 months of treatment with dupilumab.³⁶ Anecdotally, most patients will improve with usual cutaneous AD management.

INFECTIOUS NAIL DISORDERS

Viral Infections

Hand, Foot, and Mouth Disease—Hand, foot, and mouth disease (HFMD) is a common childhood viral infection caused by various enteroviruses, most commonly coxsackievirus A16, with the A6 variant causing more severe disease. Fever and painful vesicles involving the oral mucosa as well as palms and soles give the disease its name. Nail changes are common. In a prospective study involving 130 patients with laboratory-confirmed coxsackievirus CA6 serotype infection, 37% developed onychomadesis vs only 5% of 145 cases with non-CA6 enterovirus infection who developed nail findings. There was an association between CA6 infection and presence of nail changes (P<.001).³⁷

Findings ranging from transverse grooves (Beau lines) to complete nail shedding (onychomadesis)(Figure 3) may be seen.^38,39 Nail findings in HFMD are due to transient inhibition of nail growth and present approximately 3 to 6 weeks after infection.⁴⁰ Onychomadesis is seen in 30% to 68% of patients with HFMD.^37,41,42 Nail findings in HFMD spontaneously resolve with nail growth (2–3 mm per month for fingernails and 1 mm per month for toenails) and do not require specific treatment. Although the appearance of nail changes associated with HFMD can be disturbing, dermatologists can reassure children and their parents that the nails will resolve with the next cycle of growth.

Kawasaki Disease—Kawasaki disease (KD) is a vasculitis primarily affecting children and infants. Although the specific pathogen and pathophysiology is not entirely clear, clinical observations have suggested an infectious cause, most likely a virus.⁴³ In Japan, more than 15,000 cases of KD are documented annually, while approximately 4200 cases are seen in the United States.⁴⁴ In a prospective study from 1984 to 1990, 4 of 26 (15.4%) patients with KD presented with nail manifestations during the late acute phase or early convalescent phase of disease. There were no significant associations between nail dystrophy and severity of KD, such as coronary artery aneurysm.⁴⁵

Nail changes reported in children with KD include onychomadesis, onycholysis, orange-brown chromonychia, splinter hemorrhages, Beau lines, and pincer nails. In a review of nail changes associated with KD from 1980 to 2021, orange-brown transverse chromonychia, which may evolve into transverse leukonychia, was the most common nail finding reported, occurring in 17 of 31 (54.8%) patients.⁴⁴ It has been hypothesized that nail changes may result from blood flow disturbance due to the underlying vasculitis.⁴⁶ Nail changes appear several weeks after the onset of fever and are self-limited. Resolution occurs with nail growth, with no treatment required.

FUNGAL INFECTIONS

Onychomycosis

Onychomycosis is a fungal infection of the nails that occurs in 0.2% to 5.5% of pediatric patients, and its prevalence may be increasing, which may be due to environmental factors or increased rates of diabetes mellitus and obesity in the pediatric population.⁴⁷ Onychomycosis represents 15.5% of nail dystrophies in pediatric patients.⁴⁸ Some dermatologists treat presumptive onychomycosis without confirmation; however, we do not recommend that approach. Because the differential is broad and the duration of treatment is long, mycologic examination (potassium hydroxide preparation, fungal culture, polymerase chain reaction, and/or histopathology) should be obtained to confirm onychomycosis prior to initiation of antifungal management. Family members of affected individuals should be evaluated and treated, if indicated, for onychomycosis and tinea pedis, as household transmission is common.

Currently, there are 2 topical FDA-approved treatments for pediatric onychomycosis in children 6 years and older (Table 2).^49,50 There is a discussion of the need for confirmatory testing for onychomycosis in children, particularly when systemic treatment is prescribed. In a retrospective review of 269 pediatric patients with onychomycosis prescribed terbinafine, 53.5% (n=144) underwent laboratory monitoring of liver function and complete blood cell counts, and 12.5% had grade 1 laboratory abnormalities either prior to (12/144 [8.3%]) or during (6/144 [4.2%]) therapy.⁵¹ Baseline transaminase monitoring is recommended, though subsequent routine laboratory monitoring in healthy children may have limited utility with associated increased costs, incidental findings, and patient discomfort and likely is not needed.⁵¹

Pediatric onychomycosis responds better to topical therapy than adult disease, and pediatric patients do not always require systemic treatment.⁵² Ciclopirox is not FDA approved for the treatment of pediatric onychomycosis, but in a 32-week clinical trial of ciclopirox lacquer 8% use in 40 patients, 77% (27/35) of treated patients achieved mycologic cure. Overall, 71% of treated patients (25/35) vs 22% (2/9) of controls achieved efficacy (defined as investigator global assessment score of 2 or lower).⁵² In an open-label, single-arm clinical trial assessing tavaborole solution 5% applied once daily for 48 weeks for the treatment of toenail onychomycosis in pediatric patients (aged 6–17 years), 36.2% (20/55) of patients achieved mycologic cure, and 8.5% (5/55) achieved complete cure at week 52 with mild or minimal adverse effects.⁵³ In an open-label, phase 4 study of the safety and efficacy of efinaconazole solution 10% applied once daily for 48 weeks in pediatric patients (aged 6 to 16 years) (n=60), 65% (35/60) achieved mycologic cure, 42% (25/60) achieved clinical cure, and 40% (24/60) achieved complete cure at 52 weeks. The most common adverse effects of efina­conazole were local and included ingrown toenail (1/60), application-site dermatitis (1/60), application-site vesicles (1/60), and application-site pain (1/60).⁵⁴

In a systematic review of systemic antifungals for onychomycosis in 151 pediatric patients, itraconazole, fluconazole, griseofulvin, and terbinafine resulted in complete cure rates similar to those of the adult population, with excellent safety profiles.⁵⁵ Depending on the situation, initiation of treatment with topical medications followed by addition of systemic antifungal agents only if needed may be an appropriate course of action.

BACTERIAL INFECTIONS

Acute Paronychia

Acute paronychia is a nail-fold infection that develops after the protective nail barrier has been compromised.⁵⁶ In children, thumb-sucking, nail-biting, frequent oral manipulation of the digits, and poor skin hygiene are risk factors. Acute paronychia also may develop in association with congenital malalignment of the great toenails.⁵⁷

Clinical manifestations include localized pain, erythema, and nail fold edema (Figure 4). Purulent material and abscess formation may ensue. Staphylococcus aureus as well as methicillin-resistant S aureus and Streptococcus pyogenes are classically the most common causes of acute paronychia. Treatment of paronychia is based on severity. In mild cases, warm soaks with topical antibiotics are indicated. Oral antibiotics should be prescribed for more severe presentations. If there is no improvement after 48 hours, surgical drainage is required to facilitate healing.⁵⁶

FINAL THOUGHTS

Inflammatory and infectious nail disorders in children are relatively common and may impact the physical and emotional well-being of young patients. By understanding the distinctive features of these nail disorders in pediatric patients, dermatologists can provide anticipatory guidance and informed treatment options to children and their parents. Further research is needed to expand our understanding of pediatric nail disorders and create targeted therapeutic interventions, particularly for NLP and psoriasis.

Nail disorders are common among pediatric patients but often are underdiagnosed or misdiagnosed because of their unique disease manifestations. These conditions may severely impact quality of life. There are few nail disease clinical trials that include children. Consequently, most treatment recommendations are based on case series and expert consensus recommendations. We review inflammatory and infectious nail disorders in pediatric patients. By describing characteristics, clinical manifestations, and management approaches for these conditions, we aim to provide guidance to dermatologists in their diagnosis and treatment.

INFLAMMATORY NAIL DISORDERS

Nail Psoriasis

Nail involvement in children with psoriasis is common, with prevalence estimates ranging from 17% to 39.2%.¹ Nail matrix psoriasis may manifest with pitting (large irregular pits) and leukonychia as well as chromonychia and nail plate crumbling. Onycholysis, oil drop spots (salmon patches), and subungual hyperkeratosis can be seen in nail bed psoriasis. Nail pitting is the most frequently observed clinical finding (Figure 1).^2,3 In a cross-sectional multicenter study of 313 children with cutaneous psoriasis in France, nail findings were present in 101 patients (32.3%). There were associations between nail findings and presence of psoriatic arthritis (P=.03), palmoplantar psoriasis (P<.001), and severity of psoriatic disease, defined as use of systemic treatment with phototherapy (psoralen plus UVA, UVB), traditional systemic treatment (acitretin, methotrexate, cyclosporine), or a biologic (P=.003).⁴

Topical steroids and vitamin D analogues may be used with or without occlusion and may be efficacious.⁵ Several case reports describe systemic treatments for psoriasis in children, including methotrexate, acitretin, and apremilast (approved for children 6 years and older for plaque psoriasis by the US Food and Drug Administration [FDA]).² There are 5 biologic drugs currently approved for the treatment of pediatric psoriasis—adalimumab, etanercept, ustekinumab, secukinumab, ixekizumab—and 6 drugs currently undergoing phase 3 studies—brodalumab, guselkumab, risankizumab, tildrakizumab, certolizumab pegol, and deucravacitinib (Table 1).^6-15 Adalimumab is specifically approved for moderate to severe nail psoriasis in adults 18 years and older.

Intralesional steroid injections are sometimes useful in the management of nail matrix psoriasis; however, appropriate patient selection is critical due to the pain associated with the procedure. In a prospective study of 16 children (age range, 9–17 years) with nail psoriasis treated with intralesional triamcinolone (ILTAC) 2.5 to 5 mg/mL every 4 to 8 weeks for a minimum of 3 to 6 months, 9 patients achieved resolution and 6 had improvement of clinical findings.¹⁶ Local adverse events were mild, including injection-site pain (66%), subungual hematoma (n=1), Beau lines (n=1), proximal nail fold hypopigmentation (n=2), and proximal nail fold atrophy (n=2). Because the proximal nail fold in children is thinner than in adults, there may be an increased risk for nail fold hypopigmentation and atrophy in children. Therefore, a maximum ILTAC concentration of 2.5 mg/mL with 0.2 mL maximum volume per nail per session is recommended for children younger than 15 years.¹⁶

Nail Lichen Planus

Nail lichen planus (NLP) is uncommon in children, with few biopsy-proven cases documented in the literature.¹⁷ Common clinical findings are onychorrhexis, nail plate thinning, fissuring, splitting, and atrophy with koilonychia.⁵ Although pterygium development (irreversible nail matrix scarring) is uncommon in pediatric patients, NLP can be progressive and may cause irreversible destruction of the nail matrix and subsequent nail loss, warranting therapeutic intervention.¹⁸

Treatment of NLP may be difficult, as there are no options that work in all patients. Current literature supports the use of systemic corticosteroids or ILTAC for the treatment of NLP; however, recurrence rates can be high. According to an expert consensus paper on NLP treatment, ILTAC may be injected in a concentration of 2.5, 5, or 10 mg/mL according to disease severity.¹⁹ In severe or resistant cases, intramuscular (IM) triamcinolone may be considered, especially if more than 3 nails are affected. A dosage of 0.5 to 1 mg/kg/mo for at least 3 to 6 months is recommended for both children and adults, with 1 mg/kg/mo recommended in the active treatment phase (first 2–3 months).¹⁹ In a retrospective review of 5 pediatric patients with NLP treated with IM triamcinolone 0.5 mg/kg/mo, 3 patients had resolution and 2 improved with treatment.²⁰ In a prospective study of 10 children with NLP, IM triamcinolone at a dosage of 0.5 to 1 mg/kg every 30 days for 3 to 6 months resulted in resolution of nail findings in 9 patients.¹⁷ In a prospective study of 14 pediatric patients with NLP treated with 2.5 to 5 mg/mL of ILTAC, 10 achieved resolution and 3 improved.¹⁶

Intralesional triamcinolone injections may be better suited for teenagers compared to younger children who may be more apprehensive of needles. To minimize pain, it is recommended to inject ILTAC slowly at room temperature, with use of “talkesthesia” and vibration devices, 1% lidocaine, or ethyl chloride spray.¹⁸

Trachyonychia

Trachyonychia is characterized by the presence of sandpaperlike nails. It manifests with brittle thin nails with longitudinal ridging, onychoschizia, and thickened hyperkeratotic cuticles. Trachyonychia typically involves multiple nails, with a peak age of onset between 3 and 12 years.^21,22 There are 2 variants: the opaque type with rough longitudinal ridging, and the shiny variant with opalescent nails and pits that reflect light. The opaque variant is more common and is associated with psoriasis, whereas the shiny variant is less common and is associated with alopecia areata.²³ Although most cases are idiopathic, some are associated with psoriasis and alopecia areata, as previously noted, as well as atopic dermatitis (AD) and lichen planus.^22,24

Fortunately, trachyonychia does not lead to permanent nail damage or pterygium, making treatment primarily focused on addressing functional and cosmetic concerns.²⁴ Spontaneous resolution occurs in approximately 50% of patients. In a prospective study of 11 patients with idiopathic trachyonychia, there was partial improvement in 5 of 9 patients treated with topical steroids, 1 with only petrolatum, and 1 with vitamin supplements. Complete resolution was reported in 1 patient treated with topical steroids.²⁵ Because trachyonychia often is self-resolving, no treatment is required and a conservative approach is strongly recommended.²⁶ Treatment options include topical corticosteroids, tazarotene, and 5-fluorouracil. Intralesional triamcinolone, systemic cyclosporine, retinoids, systemic corticosteroids, and tofacitinib have been described in case reports, though none of these have been shown to be 100% efficacious.²⁴

Nail Lichen Striatus

Lichen striatus involving the nail is uncommon and is characterized by onycholysis, longitudinal ridging, ­splitting, and fraying, as well as what appears to be a subungual tumor. It can encompass the entire nail or may be isolated to a portion of the nail (Figure 2). Usually, a Blaschko-linear array of flesh-colored papules on the more proximal digit directly adjacent to the nail dystrophy will be seen, though nail findings can occur in ­isolation.^27-29 The underlying pathophysiology is not clear; however, one hypothesis is that a triggering event, such as trauma, induces the expression of antigens that elicit a self-limiting immune-mediated response by CD8 T lymphocytes.³⁰

Generally, nail lichen striatus spontaneously resolves in 1 to 2 years without treatment. In a prospective study of 5 patients with nail lichen striatus, the median time to resolution was 22.6 months (range, 10–30 months).³¹ Topical steroids may be used for pruritus. In one case report, a 3-year-old boy with nail lichen striatus of 4 months’ duration was treated with tacrolimus ointment 0.03% daily for 3 months.²⁸

Nail AD

Nail changes with AD may be more common in adults than children or are underreported. In a study of 777 adults with AD, nail dystrophy was present in 124 patients (16%), whereas in a study of 250 pediatric patients with AD (aged 0-2 years), nail dystrophy was present in only 4 patients.^32,33

Periungual inflammation from AD causes the nail changes.³⁴ In a cross-sectional study of 24 pediatric patients with nail dystrophy due to AD, transverse grooves (Beau lines) were present in 25% (6/24), nail pitting in 16.7% (4/24), koilonychia in 16.7% (4/24), trachyonychia in 12.5% (3/24), leukonychia in 12.5% (3/24), brachyonychia in 8.3% (2/24), melanonychia in 8.3% (2/24), onychomadesis in 8.3% (2/24), onychoschizia in 8.3% (2/24), and onycholysis in 8.3% (2/24). There was an association between disease severity and presence of toenail dystrophy (P=.03).³⁵

Topical steroids with or without occlusion can be used to treat nail changes. Although there is limited literature describing the treatment of nail AD in children, a 61-year-old man with nail changes associated with AD achieved resolution with 3 months of treatment with dupilumab.³⁶ Anecdotally, most patients will improve with usual cutaneous AD management.

INFECTIOUS NAIL DISORDERS

Viral Infections

Hand, Foot, and Mouth Disease—Hand, foot, and mouth disease (HFMD) is a common childhood viral infection caused by various enteroviruses, most commonly coxsackievirus A16, with the A6 variant causing more severe disease. Fever and painful vesicles involving the oral mucosa as well as palms and soles give the disease its name. Nail changes are common. In a prospective study involving 130 patients with laboratory-confirmed coxsackievirus CA6 serotype infection, 37% developed onychomadesis vs only 5% of 145 cases with non-CA6 enterovirus infection who developed nail findings. There was an association between CA6 infection and presence of nail changes (P<.001).³⁷

Findings ranging from transverse grooves (Beau lines) to complete nail shedding (onychomadesis)(Figure 3) may be seen.^38,39 Nail findings in HFMD are due to transient inhibition of nail growth and present approximately 3 to 6 weeks after infection.⁴⁰ Onychomadesis is seen in 30% to 68% of patients with HFMD.^37,41,42 Nail findings in HFMD spontaneously resolve with nail growth (2–3 mm per month for fingernails and 1 mm per month for toenails) and do not require specific treatment. Although the appearance of nail changes associated with HFMD can be disturbing, dermatologists can reassure children and their parents that the nails will resolve with the next cycle of growth.

Kawasaki Disease—Kawasaki disease (KD) is a vasculitis primarily affecting children and infants. Although the specific pathogen and pathophysiology is not entirely clear, clinical observations have suggested an infectious cause, most likely a virus.⁴³ In Japan, more than 15,000 cases of KD are documented annually, while approximately 4200 cases are seen in the United States.⁴⁴ In a prospective study from 1984 to 1990, 4 of 26 (15.4%) patients with KD presented with nail manifestations during the late acute phase or early convalescent phase of disease. There were no significant associations between nail dystrophy and severity of KD, such as coronary artery aneurysm.⁴⁵

Nail changes reported in children with KD include onychomadesis, onycholysis, orange-brown chromonychia, splinter hemorrhages, Beau lines, and pincer nails. In a review of nail changes associated with KD from 1980 to 2021, orange-brown transverse chromonychia, which may evolve into transverse leukonychia, was the most common nail finding reported, occurring in 17 of 31 (54.8%) patients.⁴⁴ It has been hypothesized that nail changes may result from blood flow disturbance due to the underlying vasculitis.⁴⁶ Nail changes appear several weeks after the onset of fever and are self-limited. Resolution occurs with nail growth, with no treatment required.

FUNGAL INFECTIONS

Onychomycosis

Onychomycosis is a fungal infection of the nails that occurs in 0.2% to 5.5% of pediatric patients, and its prevalence may be increasing, which may be due to environmental factors or increased rates of diabetes mellitus and obesity in the pediatric population.⁴⁷ Onychomycosis represents 15.5% of nail dystrophies in pediatric patients.⁴⁸ Some dermatologists treat presumptive onychomycosis without confirmation; however, we do not recommend that approach. Because the differential is broad and the duration of treatment is long, mycologic examination (potassium hydroxide preparation, fungal culture, polymerase chain reaction, and/or histopathology) should be obtained to confirm onychomycosis prior to initiation of antifungal management. Family members of affected individuals should be evaluated and treated, if indicated, for onychomycosis and tinea pedis, as household transmission is common.

Currently, there are 2 topical FDA-approved treatments for pediatric onychomycosis in children 6 years and older (Table 2).^49,50 There is a discussion of the need for confirmatory testing for onychomycosis in children, particularly when systemic treatment is prescribed. In a retrospective review of 269 pediatric patients with onychomycosis prescribed terbinafine, 53.5% (n=144) underwent laboratory monitoring of liver function and complete blood cell counts, and 12.5% had grade 1 laboratory abnormalities either prior to (12/144 [8.3%]) or during (6/144 [4.2%]) therapy.⁵¹ Baseline transaminase monitoring is recommended, though subsequent routine laboratory monitoring in healthy children may have limited utility with associated increased costs, incidental findings, and patient discomfort and likely is not needed.⁵¹

Pediatric onychomycosis responds better to topical therapy than adult disease, and pediatric patients do not always require systemic treatment.⁵² Ciclopirox is not FDA approved for the treatment of pediatric onychomycosis, but in a 32-week clinical trial of ciclopirox lacquer 8% use in 40 patients, 77% (27/35) of treated patients achieved mycologic cure. Overall, 71% of treated patients (25/35) vs 22% (2/9) of controls achieved efficacy (defined as investigator global assessment score of 2 or lower).⁵² In an open-label, single-arm clinical trial assessing tavaborole solution 5% applied once daily for 48 weeks for the treatment of toenail onychomycosis in pediatric patients (aged 6–17 years), 36.2% (20/55) of patients achieved mycologic cure, and 8.5% (5/55) achieved complete cure at week 52 with mild or minimal adverse effects.⁵³ In an open-label, phase 4 study of the safety and efficacy of efinaconazole solution 10% applied once daily for 48 weeks in pediatric patients (aged 6 to 16 years) (n=60), 65% (35/60) achieved mycologic cure, 42% (25/60) achieved clinical cure, and 40% (24/60) achieved complete cure at 52 weeks. The most common adverse effects of efina­conazole were local and included ingrown toenail (1/60), application-site dermatitis (1/60), application-site vesicles (1/60), and application-site pain (1/60).⁵⁴

In a systematic review of systemic antifungals for onychomycosis in 151 pediatric patients, itraconazole, fluconazole, griseofulvin, and terbinafine resulted in complete cure rates similar to those of the adult population, with excellent safety profiles.⁵⁵ Depending on the situation, initiation of treatment with topical medications followed by addition of systemic antifungal agents only if needed may be an appropriate course of action.

BACTERIAL INFECTIONS

Acute Paronychia

Acute paronychia is a nail-fold infection that develops after the protective nail barrier has been compromised.⁵⁶ In children, thumb-sucking, nail-biting, frequent oral manipulation of the digits, and poor skin hygiene are risk factors. Acute paronychia also may develop in association with congenital malalignment of the great toenails.⁵⁷

Clinical manifestations include localized pain, erythema, and nail fold edema (Figure 4). Purulent material and abscess formation may ensue. Staphylococcus aureus as well as methicillin-resistant S aureus and Streptococcus pyogenes are classically the most common causes of acute paronychia. Treatment of paronychia is based on severity. In mild cases, warm soaks with topical antibiotics are indicated. Oral antibiotics should be prescribed for more severe presentations. If there is no improvement after 48 hours, surgical drainage is required to facilitate healing.⁵⁶

FINAL THOUGHTS

Inflammatory and infectious nail disorders in children are relatively common and may impact the physical and emotional well-being of young patients. By understanding the distinctive features of these nail disorders in pediatric patients, dermatologists can provide anticipatory guidance and informed treatment options to children and their parents. Further research is needed to expand our understanding of pediatric nail disorders and create targeted therapeutic interventions, particularly for NLP and psoriasis.

Nail disorders are common among pediatric patients but often are underdiagnosed or misdiagnosed because of their unique disease manifestations. These conditions may severely impact quality of life. There are few nail disease clinical trials that include children. Consequently, most treatment recommendations are based on case series and expert consensus recommendations. We review inflammatory and infectious nail disorders in pediatric patients. By describing characteristics, clinical manifestations, and management approaches for these conditions, we aim to provide guidance to dermatologists in their diagnosis and treatment.

INFLAMMATORY NAIL DISORDERS

Nail Psoriasis

Nail involvement in children with psoriasis is common, with prevalence estimates ranging from 17% to 39.2%.¹ Nail matrix psoriasis may manifest with pitting (large irregular pits) and leukonychia as well as chromonychia and nail plate crumbling. Onycholysis, oil drop spots (salmon patches), and subungual hyperkeratosis can be seen in nail bed psoriasis. Nail pitting is the most frequently observed clinical finding (Figure 1).^2,3 In a cross-sectional multicenter study of 313 children with cutaneous psoriasis in France, nail findings were present in 101 patients (32.3%). There were associations between nail findings and presence of psoriatic arthritis (P=.03), palmoplantar psoriasis (P<.001), and severity of psoriatic disease, defined as use of systemic treatment with phototherapy (psoralen plus UVA, UVB), traditional systemic treatment (acitretin, methotrexate, cyclosporine), or a biologic (P=.003).⁴

Topical steroids and vitamin D analogues may be used with or without occlusion and may be efficacious.⁵ Several case reports describe systemic treatments for psoriasis in children, including methotrexate, acitretin, and apremilast (approved for children 6 years and older for plaque psoriasis by the US Food and Drug Administration [FDA]).² There are 5 biologic drugs currently approved for the treatment of pediatric psoriasis—adalimumab, etanercept, ustekinumab, secukinumab, ixekizumab—and 6 drugs currently undergoing phase 3 studies—brodalumab, guselkumab, risankizumab, tildrakizumab, certolizumab pegol, and deucravacitinib (Table 1).^6-15 Adalimumab is specifically approved for moderate to severe nail psoriasis in adults 18 years and older.

Intralesional steroid injections are sometimes useful in the management of nail matrix psoriasis; however, appropriate patient selection is critical due to the pain associated with the procedure. In a prospective study of 16 children (age range, 9–17 years) with nail psoriasis treated with intralesional triamcinolone (ILTAC) 2.5 to 5 mg/mL every 4 to 8 weeks for a minimum of 3 to 6 months, 9 patients achieved resolution and 6 had improvement of clinical findings.¹⁶ Local adverse events were mild, including injection-site pain (66%), subungual hematoma (n=1), Beau lines (n=1), proximal nail fold hypopigmentation (n=2), and proximal nail fold atrophy (n=2). Because the proximal nail fold in children is thinner than in adults, there may be an increased risk for nail fold hypopigmentation and atrophy in children. Therefore, a maximum ILTAC concentration of 2.5 mg/mL with 0.2 mL maximum volume per nail per session is recommended for children younger than 15 years.¹⁶

Nail Lichen Planus

Nail lichen planus (NLP) is uncommon in children, with few biopsy-proven cases documented in the literature.¹⁷ Common clinical findings are onychorrhexis, nail plate thinning, fissuring, splitting, and atrophy with koilonychia.⁵ Although pterygium development (irreversible nail matrix scarring) is uncommon in pediatric patients, NLP can be progressive and may cause irreversible destruction of the nail matrix and subsequent nail loss, warranting therapeutic intervention.¹⁸

Treatment of NLP may be difficult, as there are no options that work in all patients. Current literature supports the use of systemic corticosteroids or ILTAC for the treatment of NLP; however, recurrence rates can be high. According to an expert consensus paper on NLP treatment, ILTAC may be injected in a concentration of 2.5, 5, or 10 mg/mL according to disease severity.¹⁹ In severe or resistant cases, intramuscular (IM) triamcinolone may be considered, especially if more than 3 nails are affected. A dosage of 0.5 to 1 mg/kg/mo for at least 3 to 6 months is recommended for both children and adults, with 1 mg/kg/mo recommended in the active treatment phase (first 2–3 months).¹⁹ In a retrospective review of 5 pediatric patients with NLP treated with IM triamcinolone 0.5 mg/kg/mo, 3 patients had resolution and 2 improved with treatment.²⁰ In a prospective study of 10 children with NLP, IM triamcinolone at a dosage of 0.5 to 1 mg/kg every 30 days for 3 to 6 months resulted in resolution of nail findings in 9 patients.¹⁷ In a prospective study of 14 pediatric patients with NLP treated with 2.5 to 5 mg/mL of ILTAC, 10 achieved resolution and 3 improved.¹⁶

Intralesional triamcinolone injections may be better suited for teenagers compared to younger children who may be more apprehensive of needles. To minimize pain, it is recommended to inject ILTAC slowly at room temperature, with use of “talkesthesia” and vibration devices, 1% lidocaine, or ethyl chloride spray.¹⁸

Trachyonychia

Trachyonychia is characterized by the presence of sandpaperlike nails. It manifests with brittle thin nails with longitudinal ridging, onychoschizia, and thickened hyperkeratotic cuticles. Trachyonychia typically involves multiple nails, with a peak age of onset between 3 and 12 years.^21,22 There are 2 variants: the opaque type with rough longitudinal ridging, and the shiny variant with opalescent nails and pits that reflect light. The opaque variant is more common and is associated with psoriasis, whereas the shiny variant is less common and is associated with alopecia areata.²³ Although most cases are idiopathic, some are associated with psoriasis and alopecia areata, as previously noted, as well as atopic dermatitis (AD) and lichen planus.^22,24

Fortunately, trachyonychia does not lead to permanent nail damage or pterygium, making treatment primarily focused on addressing functional and cosmetic concerns.²⁴ Spontaneous resolution occurs in approximately 50% of patients. In a prospective study of 11 patients with idiopathic trachyonychia, there was partial improvement in 5 of 9 patients treated with topical steroids, 1 with only petrolatum, and 1 with vitamin supplements. Complete resolution was reported in 1 patient treated with topical steroids.²⁵ Because trachyonychia often is self-resolving, no treatment is required and a conservative approach is strongly recommended.²⁶ Treatment options include topical corticosteroids, tazarotene, and 5-fluorouracil. Intralesional triamcinolone, systemic cyclosporine, retinoids, systemic corticosteroids, and tofacitinib have been described in case reports, though none of these have been shown to be 100% efficacious.²⁴

Nail Lichen Striatus

Lichen striatus involving the nail is uncommon and is characterized by onycholysis, longitudinal ridging, ­splitting, and fraying, as well as what appears to be a subungual tumor. It can encompass the entire nail or may be isolated to a portion of the nail (Figure 2). Usually, a Blaschko-linear array of flesh-colored papules on the more proximal digit directly adjacent to the nail dystrophy will be seen, though nail findings can occur in ­isolation.^27-29 The underlying pathophysiology is not clear; however, one hypothesis is that a triggering event, such as trauma, induces the expression of antigens that elicit a self-limiting immune-mediated response by CD8 T lymphocytes.³⁰

Generally, nail lichen striatus spontaneously resolves in 1 to 2 years without treatment. In a prospective study of 5 patients with nail lichen striatus, the median time to resolution was 22.6 months (range, 10–30 months).³¹ Topical steroids may be used for pruritus. In one case report, a 3-year-old boy with nail lichen striatus of 4 months’ duration was treated with tacrolimus ointment 0.03% daily for 3 months.²⁸

Nail AD

Nail changes with AD may be more common in adults than children or are underreported. In a study of 777 adults with AD, nail dystrophy was present in 124 patients (16%), whereas in a study of 250 pediatric patients with AD (aged 0-2 years), nail dystrophy was present in only 4 patients.^32,33

Periungual inflammation from AD causes the nail changes.³⁴ In a cross-sectional study of 24 pediatric patients with nail dystrophy due to AD, transverse grooves (Beau lines) were present in 25% (6/24), nail pitting in 16.7% (4/24), koilonychia in 16.7% (4/24), trachyonychia in 12.5% (3/24), leukonychia in 12.5% (3/24), brachyonychia in 8.3% (2/24), melanonychia in 8.3% (2/24), onychomadesis in 8.3% (2/24), onychoschizia in 8.3% (2/24), and onycholysis in 8.3% (2/24). There was an association between disease severity and presence of toenail dystrophy (P=.03).³⁵

Topical steroids with or without occlusion can be used to treat nail changes. Although there is limited literature describing the treatment of nail AD in children, a 61-year-old man with nail changes associated with AD achieved resolution with 3 months of treatment with dupilumab.³⁶ Anecdotally, most patients will improve with usual cutaneous AD management.

INFECTIOUS NAIL DISORDERS

Viral Infections

Hand, Foot, and Mouth Disease—Hand, foot, and mouth disease (HFMD) is a common childhood viral infection caused by various enteroviruses, most commonly coxsackievirus A16, with the A6 variant causing more severe disease. Fever and painful vesicles involving the oral mucosa as well as palms and soles give the disease its name. Nail changes are common. In a prospective study involving 130 patients with laboratory-confirmed coxsackievirus CA6 serotype infection, 37% developed onychomadesis vs only 5% of 145 cases with non-CA6 enterovirus infection who developed nail findings. There was an association between CA6 infection and presence of nail changes (P<.001).³⁷

Findings ranging from transverse grooves (Beau lines) to complete nail shedding (onychomadesis)(Figure 3) may be seen.^38,39 Nail findings in HFMD are due to transient inhibition of nail growth and present approximately 3 to 6 weeks after infection.⁴⁰ Onychomadesis is seen in 30% to 68% of patients with HFMD.^37,41,42 Nail findings in HFMD spontaneously resolve with nail growth (2–3 mm per month for fingernails and 1 mm per month for toenails) and do not require specific treatment. Although the appearance of nail changes associated with HFMD can be disturbing, dermatologists can reassure children and their parents that the nails will resolve with the next cycle of growth.

Kawasaki Disease—Kawasaki disease (KD) is a vasculitis primarily affecting children and infants. Although the specific pathogen and pathophysiology is not entirely clear, clinical observations have suggested an infectious cause, most likely a virus.⁴³ In Japan, more than 15,000 cases of KD are documented annually, while approximately 4200 cases are seen in the United States.⁴⁴ In a prospective study from 1984 to 1990, 4 of 26 (15.4%) patients with KD presented with nail manifestations during the late acute phase or early convalescent phase of disease. There were no significant associations between nail dystrophy and severity of KD, such as coronary artery aneurysm.⁴⁵

Nail changes reported in children with KD include onychomadesis, onycholysis, orange-brown chromonychia, splinter hemorrhages, Beau lines, and pincer nails. In a review of nail changes associated with KD from 1980 to 2021, orange-brown transverse chromonychia, which may evolve into transverse leukonychia, was the most common nail finding reported, occurring in 17 of 31 (54.8%) patients.⁴⁴ It has been hypothesized that nail changes may result from blood flow disturbance due to the underlying vasculitis.⁴⁶ Nail changes appear several weeks after the onset of fever and are self-limited. Resolution occurs with nail growth, with no treatment required.

FUNGAL INFECTIONS

Onychomycosis

Onychomycosis is a fungal infection of the nails that occurs in 0.2% to 5.5% of pediatric patients, and its prevalence may be increasing, which may be due to environmental factors or increased rates of diabetes mellitus and obesity in the pediatric population.⁴⁷ Onychomycosis represents 15.5% of nail dystrophies in pediatric patients.⁴⁸ Some dermatologists treat presumptive onychomycosis without confirmation; however, we do not recommend that approach. Because the differential is broad and the duration of treatment is long, mycologic examination (potassium hydroxide preparation, fungal culture, polymerase chain reaction, and/or histopathology) should be obtained to confirm onychomycosis prior to initiation of antifungal management. Family members of affected individuals should be evaluated and treated, if indicated, for onychomycosis and tinea pedis, as household transmission is common.

Currently, there are 2 topical FDA-approved treatments for pediatric onychomycosis in children 6 years and older (Table 2).^49,50 There is a discussion of the need for confirmatory testing for onychomycosis in children, particularly when systemic treatment is prescribed. In a retrospective review of 269 pediatric patients with onychomycosis prescribed terbinafine, 53.5% (n=144) underwent laboratory monitoring of liver function and complete blood cell counts, and 12.5% had grade 1 laboratory abnormalities either prior to (12/144 [8.3%]) or during (6/144 [4.2%]) therapy.⁵¹ Baseline transaminase monitoring is recommended, though subsequent routine laboratory monitoring in healthy children may have limited utility with associated increased costs, incidental findings, and patient discomfort and likely is not needed.⁵¹

Pediatric onychomycosis responds better to topical therapy than adult disease, and pediatric patients do not always require systemic treatment.⁵² Ciclopirox is not FDA approved for the treatment of pediatric onychomycosis, but in a 32-week clinical trial of ciclopirox lacquer 8% use in 40 patients, 77% (27/35) of treated patients achieved mycologic cure. Overall, 71% of treated patients (25/35) vs 22% (2/9) of controls achieved efficacy (defined as investigator global assessment score of 2 or lower).⁵² In an open-label, single-arm clinical trial assessing tavaborole solution 5% applied once daily for 48 weeks for the treatment of toenail onychomycosis in pediatric patients (aged 6–17 years), 36.2% (20/55) of patients achieved mycologic cure, and 8.5% (5/55) achieved complete cure at week 52 with mild or minimal adverse effects.⁵³ In an open-label, phase 4 study of the safety and efficacy of efinaconazole solution 10% applied once daily for 48 weeks in pediatric patients (aged 6 to 16 years) (n=60), 65% (35/60) achieved mycologic cure, 42% (25/60) achieved clinical cure, and 40% (24/60) achieved complete cure at 52 weeks. The most common adverse effects of efina­conazole were local and included ingrown toenail (1/60), application-site dermatitis (1/60), application-site vesicles (1/60), and application-site pain (1/60).⁵⁴

In a systematic review of systemic antifungals for onychomycosis in 151 pediatric patients, itraconazole, fluconazole, griseofulvin, and terbinafine resulted in complete cure rates similar to those of the adult population, with excellent safety profiles.⁵⁵ Depending on the situation, initiation of treatment with topical medications followed by addition of systemic antifungal agents only if needed may be an appropriate course of action.

BACTERIAL INFECTIONS

Acute Paronychia

Acute paronychia is a nail-fold infection that develops after the protective nail barrier has been compromised.⁵⁶ In children, thumb-sucking, nail-biting, frequent oral manipulation of the digits, and poor skin hygiene are risk factors. Acute paronychia also may develop in association with congenital malalignment of the great toenails.⁵⁷

Clinical manifestations include localized pain, erythema, and nail fold edema (Figure 4). Purulent material and abscess formation may ensue. Staphylococcus aureus as well as methicillin-resistant S aureus and Streptococcus pyogenes are classically the most common causes of acute paronychia. Treatment of paronychia is based on severity. In mild cases, warm soaks with topical antibiotics are indicated. Oral antibiotics should be prescribed for more severe presentations. If there is no improvement after 48 hours, surgical drainage is required to facilitate healing.⁵⁶

FINAL THOUGHTS

Inflammatory and infectious nail disorders in children are relatively common and may impact the physical and emotional well-being of young patients. By understanding the distinctive features of these nail disorders in pediatric patients, dermatologists can provide anticipatory guidance and informed treatment options to children and their parents. Further research is needed to expand our understanding of pediatric nail disorders and create targeted therapeutic interventions, particularly for NLP and psoriasis.

Bacterial and nonbacterial components of the gut microbiome and their function can accurately differentiate children with autism spectrum disorder (ASD) from neurotypical children, new research shows. 

The findings could form the basis for development of a noninvasive diagnostic test for ASD and also provide novel therapeutic targets, wrote investigators, led by Siew C. Ng, MBBS, PhD, with the Microbiota I-Center (MagIC), the Chinese University of Hong Kong.

Their study was published online in Nature Microbiology. 
 

Beyond Bacteria

The gut microbiome has been shown to play a central role in modulating the gut-brain axis, potentially influencing the development of ASD. 

However, most studies in ASD have focused on the bacterial component of the microbiome. Whether nonbacterial microorganisms (such as gut archaea, fungi, and viruses) or function of the gut microbiome are altered in ASD remains unclear. 

To investigate, the researchers performed metagenomic sequencing on fecal samples from 1627 boys and girls aged 1-13 years with and without ASD from five cohorts in China. 

After controlling for diet, medication, and comorbidity, they identified 14 archaea, 51 bacteria, 7 fungi, 18 viruses, 27 microbial genes, and 12 metabolic pathways that were altered in children with ASD. 

Machine-learning models using single-kingdom panels (archaea, bacteria, fungi, viruses) achieved area under the curve (AUC) values ranging from 0.68 to 0.87 in differentiating children with ASD from neurotypical control children. 

A model based on a panel of 31 multikingdom and functional markers achieved “high predictive value” for ASD, achieving an AUC of 0.91, with comparable performance among boys and girls. 

“The reproducible performance of the models across ages, sexes, and cohorts highlights their potential as promising diagnostic tools for ASD,” the investigators wrote. 

They also noted that the accuracy of the model was largely driven by the biosynthesis pathways of ubiquinol-7 and thiamine diphosphate, which were less abundant in children with ASD, and may serve as therapeutic targets. 
 

‘Exciting’ Possibilities 

“This study broadens our understanding by including fungi, archaea, and viruses, where previous studies have largely focused on the role of gut bacteria in autism,” Bhismadev Chakrabarti, PhD, research director of the Centre for Autism at the University of Reading, United Kingdom, said in a statement from the nonprofit UK Science Media Centre. 

“The results are broadly in line with previous studies that show reduced microbial diversity in autistic individuals. It also examines one of the largest samples seen in a study like this, which further strengthens the results,” Dr. Chakrabarti added. 

He said this research may provide “new ways of detecting autism, if microbial markers turn out to strengthen the ability of genetic and behavioral tests to detect autism. A future platform that can combine genetic, microbial, and simple behavioral assessments could help address the detection gap.

“One limitation of this data is that it cannot assess any causal role for the microbiota in the development of autism,” Dr. Chakrabarti noted. 

This study was supported by InnoHK, the Government of Hong Kong, Special Administrative Region of the People’s Republic of China, The D. H. Chen Foundation, and the New Cornerstone Science Foundation through the New Cornerstone Investigator Program. Dr. Ng has served as an advisory board member for Pfizer, Ferring, Janssen, and AbbVie; has received honoraria as a speaker for Ferring, Tillotts, Menarini, Janssen, AbbVie, and Takeda; is a scientific cofounder and shareholder of GenieBiome; receives patent royalties through her affiliated institutions; and is named as a co-inventor of patent applications that cover the therapeutic and diagnostic use of microbiome. Dr. Chakrabarti has no relevant conflicts of interest.
 

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

Bacterial and nonbacterial components of the gut microbiome and their function can accurately differentiate children with autism spectrum disorder (ASD) from neurotypical children, new research shows. 

The findings could form the basis for development of a noninvasive diagnostic test for ASD and also provide novel therapeutic targets, wrote investigators, led by Siew C. Ng, MBBS, PhD, with the Microbiota I-Center (MagIC), the Chinese University of Hong Kong.

Their study was published online in Nature Microbiology. 
 

Beyond Bacteria

The gut microbiome has been shown to play a central role in modulating the gut-brain axis, potentially influencing the development of ASD. 

However, most studies in ASD have focused on the bacterial component of the microbiome. Whether nonbacterial microorganisms (such as gut archaea, fungi, and viruses) or function of the gut microbiome are altered in ASD remains unclear. 

To investigate, the researchers performed metagenomic sequencing on fecal samples from 1627 boys and girls aged 1-13 years with and without ASD from five cohorts in China. 

After controlling for diet, medication, and comorbidity, they identified 14 archaea, 51 bacteria, 7 fungi, 18 viruses, 27 microbial genes, and 12 metabolic pathways that were altered in children with ASD. 

Machine-learning models using single-kingdom panels (archaea, bacteria, fungi, viruses) achieved area under the curve (AUC) values ranging from 0.68 to 0.87 in differentiating children with ASD from neurotypical control children. 

A model based on a panel of 31 multikingdom and functional markers achieved “high predictive value” for ASD, achieving an AUC of 0.91, with comparable performance among boys and girls. 

“The reproducible performance of the models across ages, sexes, and cohorts highlights their potential as promising diagnostic tools for ASD,” the investigators wrote. 

They also noted that the accuracy of the model was largely driven by the biosynthesis pathways of ubiquinol-7 and thiamine diphosphate, which were less abundant in children with ASD, and may serve as therapeutic targets. 
 

‘Exciting’ Possibilities 

“This study broadens our understanding by including fungi, archaea, and viruses, where previous studies have largely focused on the role of gut bacteria in autism,” Bhismadev Chakrabarti, PhD, research director of the Centre for Autism at the University of Reading, United Kingdom, said in a statement from the nonprofit UK Science Media Centre. 

“The results are broadly in line with previous studies that show reduced microbial diversity in autistic individuals. It also examines one of the largest samples seen in a study like this, which further strengthens the results,” Dr. Chakrabarti added. 

He said this research may provide “new ways of detecting autism, if microbial markers turn out to strengthen the ability of genetic and behavioral tests to detect autism. A future platform that can combine genetic, microbial, and simple behavioral assessments could help address the detection gap.

“One limitation of this data is that it cannot assess any causal role for the microbiota in the development of autism,” Dr. Chakrabarti noted. 

This study was supported by InnoHK, the Government of Hong Kong, Special Administrative Region of the People’s Republic of China, The D. H. Chen Foundation, and the New Cornerstone Science Foundation through the New Cornerstone Investigator Program. Dr. Ng has served as an advisory board member for Pfizer, Ferring, Janssen, and AbbVie; has received honoraria as a speaker for Ferring, Tillotts, Menarini, Janssen, AbbVie, and Takeda; is a scientific cofounder and shareholder of GenieBiome; receives patent royalties through her affiliated institutions; and is named as a co-inventor of patent applications that cover the therapeutic and diagnostic use of microbiome. Dr. Chakrabarti has no relevant conflicts of interest.
 

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

Bacterial and nonbacterial components of the gut microbiome and their function can accurately differentiate children with autism spectrum disorder (ASD) from neurotypical children, new research shows. 

The findings could form the basis for development of a noninvasive diagnostic test for ASD and also provide novel therapeutic targets, wrote investigators, led by Siew C. Ng, MBBS, PhD, with the Microbiota I-Center (MagIC), the Chinese University of Hong Kong.

Their study was published online in Nature Microbiology. 
 

Beyond Bacteria

The gut microbiome has been shown to play a central role in modulating the gut-brain axis, potentially influencing the development of ASD. 

However, most studies in ASD have focused on the bacterial component of the microbiome. Whether nonbacterial microorganisms (such as gut archaea, fungi, and viruses) or function of the gut microbiome are altered in ASD remains unclear. 

To investigate, the researchers performed metagenomic sequencing on fecal samples from 1627 boys and girls aged 1-13 years with and without ASD from five cohorts in China. 

After controlling for diet, medication, and comorbidity, they identified 14 archaea, 51 bacteria, 7 fungi, 18 viruses, 27 microbial genes, and 12 metabolic pathways that were altered in children with ASD. 

Machine-learning models using single-kingdom panels (archaea, bacteria, fungi, viruses) achieved area under the curve (AUC) values ranging from 0.68 to 0.87 in differentiating children with ASD from neurotypical control children. 

A model based on a panel of 31 multikingdom and functional markers achieved “high predictive value” for ASD, achieving an AUC of 0.91, with comparable performance among boys and girls. 

“The reproducible performance of the models across ages, sexes, and cohorts highlights their potential as promising diagnostic tools for ASD,” the investigators wrote. 

They also noted that the accuracy of the model was largely driven by the biosynthesis pathways of ubiquinol-7 and thiamine diphosphate, which were less abundant in children with ASD, and may serve as therapeutic targets. 
 

‘Exciting’ Possibilities 

“This study broadens our understanding by including fungi, archaea, and viruses, where previous studies have largely focused on the role of gut bacteria in autism,” Bhismadev Chakrabarti, PhD, research director of the Centre for Autism at the University of Reading, United Kingdom, said in a statement from the nonprofit UK Science Media Centre. 

“The results are broadly in line with previous studies that show reduced microbial diversity in autistic individuals. It also examines one of the largest samples seen in a study like this, which further strengthens the results,” Dr. Chakrabarti added. 

He said this research may provide “new ways of detecting autism, if microbial markers turn out to strengthen the ability of genetic and behavioral tests to detect autism. A future platform that can combine genetic, microbial, and simple behavioral assessments could help address the detection gap.

“One limitation of this data is that it cannot assess any causal role for the microbiota in the development of autism,” Dr. Chakrabarti noted. 

This study was supported by InnoHK, the Government of Hong Kong, Special Administrative Region of the People’s Republic of China, The D. H. Chen Foundation, and the New Cornerstone Science Foundation through the New Cornerstone Investigator Program. Dr. Ng has served as an advisory board member for Pfizer, Ferring, Janssen, and AbbVie; has received honoraria as a speaker for Ferring, Tillotts, Menarini, Janssen, AbbVie, and Takeda; is a scientific cofounder and shareholder of GenieBiome; receives patent royalties through her affiliated institutions; and is named as a co-inventor of patent applications that cover the therapeutic and diagnostic use of microbiome. Dr. Chakrabarti has no relevant conflicts of interest.
 

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

TOPLINE:

Combat exposure is strongly associated with chronic pain in active-duty servicewomen and female civilian dependents of military personnel on active duty; a lower socioeconomic status and mental health conditions further increased the likelihood of chronic pain.

METHODOLOGY:

• Researchers analyzed claims data from the Military Health System to identify chronic pain diagnoses among active-duty servicewomen and civilian dependents of individuals on active duty.
• A total of 3,473,401 individuals (median age, 29 years) were included in the study, with 644,478 active-duty servicewomen and 2,828,923 civilian dependents.
• The study compared the incidence of chronic pain during 2006-2013, a period of heightened deployment intensity, with 2014-2020, a period of reduced deployment intensity.
• The primary outcome was the diagnosis of chronic pain.

TAKEAWAY:

• Active-duty servicewomen in the years 2006-2013 had a 53% increase in the odds of reporting chronic pain compared with those in the period between 2014 and 2020 (odds ratio [OR], 1.53; 95% CI, 1.48-1.58).
• Civilian dependents in the years 2006-2013 had a 96% increase in the odds of chronic pain compared with those in the later interval (OR, 1.96; 95% CI, 1.93-1.99).
• In 2006-2013, junior enlisted active-duty servicewomen had nearly a twofold increase in the odds of chronic pain (OR, 1.95; 95% CI, 1.83-2.09), while junior enlisted dependents had more than a threefold increase in the odds of chronic pain (OR, 3.05; 95% CI, 2.87-3.25) compared with senior officers.
• Comorbid mental conditions also were associated with an increased odds of reporting chronic pain (OR, 1.67; 95% CI, 1.65-1.69).

IN PRACTICE:

“The potential for higher rates of chronic pain in women veterans has been theorized to result from differences in support structures, family conflict, coping strategies, stress regulation, and exposure to military sexual trauma,” the authors wrote. “Our results suggest that these contributing factors may carry over to the women dependents of combat veterans in addition, indicating a line of research that requires urgent further exploration.”

SOURCE:

The study was led by Andrew J. Schoenfeld, MD, MSc, of the Center for Surgery and Public Health, Department of Orthopaedic Surgery at Brigham and Women’s Hospital and Harvard Medical School, in Boston. It was published online on July 5, 2024, in JAMA Network Open.

LIMITATIONS:

This study relied on claims-based data, which may have issues with coding accuracy and limited clinical granularity. The population size reduced over time owing to military downsizing, which could impact the findings. The prevalence of chronic pain in the population was likely underestimated because individuals who did not report symptoms or were diagnosed after separation from service were not identified.

DISCLOSURES:

This study was funded by the US Department of Defense. The lead author reported receiving grants and personal fees, serving as the editor-in-chief for Spine, acting as a consultant, and having other ties with various sources outside the submitted work.
 

This article was created 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.

TOPLINE:

Combat exposure is strongly associated with chronic pain in active-duty servicewomen and female civilian dependents of military personnel on active duty; a lower socioeconomic status and mental health conditions further increased the likelihood of chronic pain.

METHODOLOGY:

• Researchers analyzed claims data from the Military Health System to identify chronic pain diagnoses among active-duty servicewomen and civilian dependents of individuals on active duty.
• A total of 3,473,401 individuals (median age, 29 years) were included in the study, with 644,478 active-duty servicewomen and 2,828,923 civilian dependents.
• The study compared the incidence of chronic pain during 2006-2013, a period of heightened deployment intensity, with 2014-2020, a period of reduced deployment intensity.
• The primary outcome was the diagnosis of chronic pain.

TAKEAWAY:

• Active-duty servicewomen in the years 2006-2013 had a 53% increase in the odds of reporting chronic pain compared with those in the period between 2014 and 2020 (odds ratio [OR], 1.53; 95% CI, 1.48-1.58).
• Civilian dependents in the years 2006-2013 had a 96% increase in the odds of chronic pain compared with those in the later interval (OR, 1.96; 95% CI, 1.93-1.99).
• In 2006-2013, junior enlisted active-duty servicewomen had nearly a twofold increase in the odds of chronic pain (OR, 1.95; 95% CI, 1.83-2.09), while junior enlisted dependents had more than a threefold increase in the odds of chronic pain (OR, 3.05; 95% CI, 2.87-3.25) compared with senior officers.
• Comorbid mental conditions also were associated with an increased odds of reporting chronic pain (OR, 1.67; 95% CI, 1.65-1.69).

IN PRACTICE:

“The potential for higher rates of chronic pain in women veterans has been theorized to result from differences in support structures, family conflict, coping strategies, stress regulation, and exposure to military sexual trauma,” the authors wrote. “Our results suggest that these contributing factors may carry over to the women dependents of combat veterans in addition, indicating a line of research that requires urgent further exploration.”

SOURCE:

The study was led by Andrew J. Schoenfeld, MD, MSc, of the Center for Surgery and Public Health, Department of Orthopaedic Surgery at Brigham and Women’s Hospital and Harvard Medical School, in Boston. It was published online on July 5, 2024, in JAMA Network Open.

LIMITATIONS:

This study relied on claims-based data, which may have issues with coding accuracy and limited clinical granularity. The population size reduced over time owing to military downsizing, which could impact the findings. The prevalence of chronic pain in the population was likely underestimated because individuals who did not report symptoms or were diagnosed after separation from service were not identified.

DISCLOSURES:

This study was funded by the US Department of Defense. The lead author reported receiving grants and personal fees, serving as the editor-in-chief for Spine, acting as a consultant, and having other ties with various sources outside the submitted work.
 

This article was created 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.

TOPLINE:

Combat exposure is strongly associated with chronic pain in active-duty servicewomen and female civilian dependents of military personnel on active duty; a lower socioeconomic status and mental health conditions further increased the likelihood of chronic pain.

METHODOLOGY:

• Researchers analyzed claims data from the Military Health System to identify chronic pain diagnoses among active-duty servicewomen and civilian dependents of individuals on active duty.
• A total of 3,473,401 individuals (median age, 29 years) were included in the study, with 644,478 active-duty servicewomen and 2,828,923 civilian dependents.
• The study compared the incidence of chronic pain during 2006-2013, a period of heightened deployment intensity, with 2014-2020, a period of reduced deployment intensity.
• The primary outcome was the diagnosis of chronic pain.

TAKEAWAY:

• Active-duty servicewomen in the years 2006-2013 had a 53% increase in the odds of reporting chronic pain compared with those in the period between 2014 and 2020 (odds ratio [OR], 1.53; 95% CI, 1.48-1.58).
• Civilian dependents in the years 2006-2013 had a 96% increase in the odds of chronic pain compared with those in the later interval (OR, 1.96; 95% CI, 1.93-1.99).
• In 2006-2013, junior enlisted active-duty servicewomen had nearly a twofold increase in the odds of chronic pain (OR, 1.95; 95% CI, 1.83-2.09), while junior enlisted dependents had more than a threefold increase in the odds of chronic pain (OR, 3.05; 95% CI, 2.87-3.25) compared with senior officers.
• Comorbid mental conditions also were associated with an increased odds of reporting chronic pain (OR, 1.67; 95% CI, 1.65-1.69).

IN PRACTICE:

“The potential for higher rates of chronic pain in women veterans has been theorized to result from differences in support structures, family conflict, coping strategies, stress regulation, and exposure to military sexual trauma,” the authors wrote. “Our results suggest that these contributing factors may carry over to the women dependents of combat veterans in addition, indicating a line of research that requires urgent further exploration.”

SOURCE:

The study was led by Andrew J. Schoenfeld, MD, MSc, of the Center for Surgery and Public Health, Department of Orthopaedic Surgery at Brigham and Women’s Hospital and Harvard Medical School, in Boston. It was published online on July 5, 2024, in JAMA Network Open.

LIMITATIONS:

This study relied on claims-based data, which may have issues with coding accuracy and limited clinical granularity. The population size reduced over time owing to military downsizing, which could impact the findings. The prevalence of chronic pain in the population was likely underestimated because individuals who did not report symptoms or were diagnosed after separation from service were not identified.

DISCLOSURES:

This study was funded by the US Department of Defense. The lead author reported receiving grants and personal fees, serving as the editor-in-chief for Spine, acting as a consultant, and having other ties with various sources outside the submitted work.
 

This article was created 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.

TOPLINE:

A higher intake of ultraprocessed foods increases the risk for systemic lupus erythematosus (SLE) by over 50% in women. The risk doubled in those with anti–double-stranded DNA antibodies.

METHODOLOGY:

• Researchers assessed 204,175 women from two Nurses’ Health Study cohorts from 1984 to 2016.
• Participants completed semiquantitative food frequency questionnaires every 4 years for the assessment of dietary intake.
• Incident SLE cases were self-reported and confirmed using medical records, with 212 cases identified.

TAKEAWAY:

• A higher cumulative average daily intake of ultraprocessed foods was associated with a 56% increased risk for SLE (95% confidence interval [CI], 1.04-2.32).
• The risk for anti–double-stranded DNA antibody-positive SLE was more than doubled (hazard ratio, 2.05; 95% CI, 1.15-3.65).
• Sugar or artificially sweetened beverages were associated with a 45% increased risk for SLE (95% CI, 1.01-2.09).
• No significant interactions with body mass index were observed in the association between ultraprocessed food intake and SLE.

IN PRACTICE:

This study is too preliminary to have practical application.

SOURCE:

The study was led by Sinara Rossato, PhD, Harvard T.H. Chan School of Public Health, Boston. It was published online in Arthritis Care & Research.

LIMITATIONS:

The study’s generalizability is limited due to the predominantly White female population of registered nurses. The relatively high baseline age of participants may not fully capture the peak incidence age range for SLE. The observational nature of the study cannot establish causality between ultraprocessed food intake and SLE risk.

DISCLOSURES:

The study was supported by the National Institutes of Health. The authors did not declare any competing interests.

This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication.

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

TOPLINE:

A higher intake of ultraprocessed foods increases the risk for systemic lupus erythematosus (SLE) by over 50% in women. The risk doubled in those with anti–double-stranded DNA antibodies.

METHODOLOGY:

• Researchers assessed 204,175 women from two Nurses’ Health Study cohorts from 1984 to 2016.
• Participants completed semiquantitative food frequency questionnaires every 4 years for the assessment of dietary intake.
• Incident SLE cases were self-reported and confirmed using medical records, with 212 cases identified.

TAKEAWAY:

• A higher cumulative average daily intake of ultraprocessed foods was associated with a 56% increased risk for SLE (95% confidence interval [CI], 1.04-2.32).
• The risk for anti–double-stranded DNA antibody-positive SLE was more than doubled (hazard ratio, 2.05; 95% CI, 1.15-3.65).
• Sugar or artificially sweetened beverages were associated with a 45% increased risk for SLE (95% CI, 1.01-2.09).
• No significant interactions with body mass index were observed in the association between ultraprocessed food intake and SLE.

IN PRACTICE:

This study is too preliminary to have practical application.

SOURCE:

The study was led by Sinara Rossato, PhD, Harvard T.H. Chan School of Public Health, Boston. It was published online in Arthritis Care & Research.

LIMITATIONS:

The study’s generalizability is limited due to the predominantly White female population of registered nurses. The relatively high baseline age of participants may not fully capture the peak incidence age range for SLE. The observational nature of the study cannot establish causality between ultraprocessed food intake and SLE risk.

DISCLOSURES:

The study was supported by the National Institutes of Health. The authors did not declare any competing interests.

This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication.

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

TOPLINE:

A higher intake of ultraprocessed foods increases the risk for systemic lupus erythematosus (SLE) by over 50% in women. The risk doubled in those with anti–double-stranded DNA antibodies.

METHODOLOGY:

• Researchers assessed 204,175 women from two Nurses’ Health Study cohorts from 1984 to 2016.
• Participants completed semiquantitative food frequency questionnaires every 4 years for the assessment of dietary intake.
• Incident SLE cases were self-reported and confirmed using medical records, with 212 cases identified.

TAKEAWAY:

• A higher cumulative average daily intake of ultraprocessed foods was associated with a 56% increased risk for SLE (95% confidence interval [CI], 1.04-2.32).
• The risk for anti–double-stranded DNA antibody-positive SLE was more than doubled (hazard ratio, 2.05; 95% CI, 1.15-3.65).
• Sugar or artificially sweetened beverages were associated with a 45% increased risk for SLE (95% CI, 1.01-2.09).
• No significant interactions with body mass index were observed in the association between ultraprocessed food intake and SLE.

IN PRACTICE:

This study is too preliminary to have practical application.

SOURCE:

The study was led by Sinara Rossato, PhD, Harvard T.H. Chan School of Public Health, Boston. It was published online in Arthritis Care & Research.

LIMITATIONS:

The study’s generalizability is limited due to the predominantly White female population of registered nurses. The relatively high baseline age of participants may not fully capture the peak incidence age range for SLE. The observational nature of the study cannot establish causality between ultraprocessed food intake and SLE risk.

DISCLOSURES:

The study was supported by the National Institutes of Health. The authors did not declare any competing interests.

This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication.

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

A Seattle plastic surgeon who illegally restricted patients from posting negative reviews about his practice and directed his staff to post fake positive reviews will pay $5 million for violating Washington state’s consumer protection law.

According to a July 1 consent decree, Javad Sajan, MD, and his practice Allure Esthetic must pay $1.5 million in restitution to 21,000 patients and $3.5 million to the state for manipulation of patient ratings.

The settlement resolves a federal lawsuit brought by Washington State Attorney General Bob Ferguson that accused the doctor of illegally suppressing patients’ negative reviews by “forcing” them to sign nondisclosure agreements (NDAs) before they received care. In an April decision, US District Judge Ricardo S. Martinez sided with the state, ruling that Allure Esthetic’s actions violated the federal Consumer Review Fairness Act (CRFA).

“Writing a truthful review about a business should not subject you to threats or intimidation,” Mr. Ferguson said in a July 2 statement. “Consumers rely on reviews when determining who to trust, especially services that affect their health and safety. This resolution holds Allure accountable for brazenly violating that trust — and the law — and ensures the clinic stops its harmful conduct.”

In court documents, Dr. Sajan’s attorneys had argued that the agreements did not violate CRFA because patients had the opportunity to modify the language or decline signing them.

The surgeon’s practice is “pleased to have resolved its case with the Attorney General’s Office,” according to a statement provided by Dr. Sajan’s attorney. “The cooperative settlement, while not admitting fault and resolving claims asserted by both sides, allows Allure Esthetic to continue to focus on its core mission of providing compassionate care to patients and serving the community. The decision to settle was not an easy one, but it was necessary to allocate time and resources where they matter most — the patients.” 

The dispute stemmed from NDAs that Dr. Sajan’s practice required patients to sign starting in 2017, according to Mr. Ferguson’s complaint. The terms instructed patients to contact the business directly if they had concerns rather than post a negative review.

If patients posted negative reviews, the clinic, in some cases, threatened litigation, according to the lawsuit. In other cases, patients were allegedly offered money and free services in exchange for taking the reviews down. Patients who accepted cash or services were required to sign a second agreement forbidding them from posting future negative reviews and imposing a $250,000 penalty for failure to comply, according to court documents.

In addition, Mr. Ferguson accused Dr. Sajan of creating fake positive accounts of patient experiences and buying fake followers on social media. State investigators found Dr. Sajan directed Allure Esthetic’s employees to create fake Gmail accounts to post the false reviews, many of which are still online today, according to the state’s complaint.

Mr. Ferguson also claimed Dr. Sajan and his practice manipulated social media to appear more popular by purchasing followers through an online vendor. The practice also allegedly used a social media bot tool to buy thousands of fake likes on Instagram, YouTube, and other social media.

After filing the lawsuit, Mr. Ferguson’s office uncovered further evidence of Dr. Sajan’s efforts to influence his professional reputation through fabrication, according to the July 2 release. Allure Esthetic “rigged” “best doctor” competitions hosted by local media outlets by paying staff and contractors to vote for Dr. Sajan as “best plastic surgeon” in the region, according to the release. The staff cast as many votes as websites allowed, despite not being patients of Allure Esthetic.

The practice also allegedly edited before-and-after photos of patients to make their results appear better and kept tens of thousands of dollars in rebates intended for its patients.

In addition to paying $5 million, the consent decree requires Dr. Sajan and his practice also:

• Stop posting or influencing consumer reviews; perform a full audit of all public reviews on Google, Yelp, and other third-party review platforms; and request removal of every review Allure Esthetic was involved in creating, posting, or shaping in any manner.
• Remove all misleading “before-and-after” photographs of plastic surgery procedures from its website and social media and stop altering photographs of future procedures.
• Cease use of and attempts to enforce all illegal NDAs and notify patients who previously signed them that they are released from the terms of those NDAs.
• Pay a third-party forensic accounting firm to perform a full, independent audit of Allure Esthetic’s consumer rebate program to identify consumers who are owed rebates that were unlawfully claimed by Allure Esthetic.

Additionally, the attorney general’s office will continue to monitor Allure Esthetic, and upon request, the practice must provide information that demonstrates its compliance with the consent decree for the next 10 years.

The practice must also develop internal policies and implement a training program to educate staff about nondeceptive advertising and compliance with consumer protection laws.

Dr. Sajan and his practice agreed to the terms of the consent decree, and the settlement is not considered an admission of liability.

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

A Seattle plastic surgeon who illegally restricted patients from posting negative reviews about his practice and directed his staff to post fake positive reviews will pay $5 million for violating Washington state’s consumer protection law.

According to a July 1 consent decree, Javad Sajan, MD, and his practice Allure Esthetic must pay $1.5 million in restitution to 21,000 patients and $3.5 million to the state for manipulation of patient ratings.

The settlement resolves a federal lawsuit brought by Washington State Attorney General Bob Ferguson that accused the doctor of illegally suppressing patients’ negative reviews by “forcing” them to sign nondisclosure agreements (NDAs) before they received care. In an April decision, US District Judge Ricardo S. Martinez sided with the state, ruling that Allure Esthetic’s actions violated the federal Consumer Review Fairness Act (CRFA).

“Writing a truthful review about a business should not subject you to threats or intimidation,” Mr. Ferguson said in a July 2 statement. “Consumers rely on reviews when determining who to trust, especially services that affect their health and safety. This resolution holds Allure accountable for brazenly violating that trust — and the law — and ensures the clinic stops its harmful conduct.”

In court documents, Dr. Sajan’s attorneys had argued that the agreements did not violate CRFA because patients had the opportunity to modify the language or decline signing them.

The surgeon’s practice is “pleased to have resolved its case with the Attorney General’s Office,” according to a statement provided by Dr. Sajan’s attorney. “The cooperative settlement, while not admitting fault and resolving claims asserted by both sides, allows Allure Esthetic to continue to focus on its core mission of providing compassionate care to patients and serving the community. The decision to settle was not an easy one, but it was necessary to allocate time and resources where they matter most — the patients.” 

The dispute stemmed from NDAs that Dr. Sajan’s practice required patients to sign starting in 2017, according to Mr. Ferguson’s complaint. The terms instructed patients to contact the business directly if they had concerns rather than post a negative review.

If patients posted negative reviews, the clinic, in some cases, threatened litigation, according to the lawsuit. In other cases, patients were allegedly offered money and free services in exchange for taking the reviews down. Patients who accepted cash or services were required to sign a second agreement forbidding them from posting future negative reviews and imposing a $250,000 penalty for failure to comply, according to court documents.

In addition, Mr. Ferguson accused Dr. Sajan of creating fake positive accounts of patient experiences and buying fake followers on social media. State investigators found Dr. Sajan directed Allure Esthetic’s employees to create fake Gmail accounts to post the false reviews, many of which are still online today, according to the state’s complaint.

Mr. Ferguson also claimed Dr. Sajan and his practice manipulated social media to appear more popular by purchasing followers through an online vendor. The practice also allegedly used a social media bot tool to buy thousands of fake likes on Instagram, YouTube, and other social media.

After filing the lawsuit, Mr. Ferguson’s office uncovered further evidence of Dr. Sajan’s efforts to influence his professional reputation through fabrication, according to the July 2 release. Allure Esthetic “rigged” “best doctor” competitions hosted by local media outlets by paying staff and contractors to vote for Dr. Sajan as “best plastic surgeon” in the region, according to the release. The staff cast as many votes as websites allowed, despite not being patients of Allure Esthetic.

The practice also allegedly edited before-and-after photos of patients to make their results appear better and kept tens of thousands of dollars in rebates intended for its patients.

In addition to paying $5 million, the consent decree requires Dr. Sajan and his practice also:

• Stop posting or influencing consumer reviews; perform a full audit of all public reviews on Google, Yelp, and other third-party review platforms; and request removal of every review Allure Esthetic was involved in creating, posting, or shaping in any manner.
• Remove all misleading “before-and-after” photographs of plastic surgery procedures from its website and social media and stop altering photographs of future procedures.
• Cease use of and attempts to enforce all illegal NDAs and notify patients who previously signed them that they are released from the terms of those NDAs.
• Pay a third-party forensic accounting firm to perform a full, independent audit of Allure Esthetic’s consumer rebate program to identify consumers who are owed rebates that were unlawfully claimed by Allure Esthetic.

Additionally, the attorney general’s office will continue to monitor Allure Esthetic, and upon request, the practice must provide information that demonstrates its compliance with the consent decree for the next 10 years.

The practice must also develop internal policies and implement a training program to educate staff about nondeceptive advertising and compliance with consumer protection laws.

Dr. Sajan and his practice agreed to the terms of the consent decree, and the settlement is not considered an admission of liability.

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

A Seattle plastic surgeon who illegally restricted patients from posting negative reviews about his practice and directed his staff to post fake positive reviews will pay $5 million for violating Washington state’s consumer protection law.

According to a July 1 consent decree, Javad Sajan, MD, and his practice Allure Esthetic must pay $1.5 million in restitution to 21,000 patients and $3.5 million to the state for manipulation of patient ratings.

The settlement resolves a federal lawsuit brought by Washington State Attorney General Bob Ferguson that accused the doctor of illegally suppressing patients’ negative reviews by “forcing” them to sign nondisclosure agreements (NDAs) before they received care. In an April decision, US District Judge Ricardo S. Martinez sided with the state, ruling that Allure Esthetic’s actions violated the federal Consumer Review Fairness Act (CRFA).

“Writing a truthful review about a business should not subject you to threats or intimidation,” Mr. Ferguson said in a July 2 statement. “Consumers rely on reviews when determining who to trust, especially services that affect their health and safety. This resolution holds Allure accountable for brazenly violating that trust — and the law — and ensures the clinic stops its harmful conduct.”

In court documents, Dr. Sajan’s attorneys had argued that the agreements did not violate CRFA because patients had the opportunity to modify the language or decline signing them.

The surgeon’s practice is “pleased to have resolved its case with the Attorney General’s Office,” according to a statement provided by Dr. Sajan’s attorney. “The cooperative settlement, while not admitting fault and resolving claims asserted by both sides, allows Allure Esthetic to continue to focus on its core mission of providing compassionate care to patients and serving the community. The decision to settle was not an easy one, but it was necessary to allocate time and resources where they matter most — the patients.” 

The dispute stemmed from NDAs that Dr. Sajan’s practice required patients to sign starting in 2017, according to Mr. Ferguson’s complaint. The terms instructed patients to contact the business directly if they had concerns rather than post a negative review.

If patients posted negative reviews, the clinic, in some cases, threatened litigation, according to the lawsuit. In other cases, patients were allegedly offered money and free services in exchange for taking the reviews down. Patients who accepted cash or services were required to sign a second agreement forbidding them from posting future negative reviews and imposing a $250,000 penalty for failure to comply, according to court documents.

In addition, Mr. Ferguson accused Dr. Sajan of creating fake positive accounts of patient experiences and buying fake followers on social media. State investigators found Dr. Sajan directed Allure Esthetic’s employees to create fake Gmail accounts to post the false reviews, many of which are still online today, according to the state’s complaint.

Mr. Ferguson also claimed Dr. Sajan and his practice manipulated social media to appear more popular by purchasing followers through an online vendor. The practice also allegedly used a social media bot tool to buy thousands of fake likes on Instagram, YouTube, and other social media.

After filing the lawsuit, Mr. Ferguson’s office uncovered further evidence of Dr. Sajan’s efforts to influence his professional reputation through fabrication, according to the July 2 release. Allure Esthetic “rigged” “best doctor” competitions hosted by local media outlets by paying staff and contractors to vote for Dr. Sajan as “best plastic surgeon” in the region, according to the release. The staff cast as many votes as websites allowed, despite not being patients of Allure Esthetic.

The practice also allegedly edited before-and-after photos of patients to make their results appear better and kept tens of thousands of dollars in rebates intended for its patients.

In addition to paying $5 million, the consent decree requires Dr. Sajan and his practice also:

• Stop posting or influencing consumer reviews; perform a full audit of all public reviews on Google, Yelp, and other third-party review platforms; and request removal of every review Allure Esthetic was involved in creating, posting, or shaping in any manner.
• Remove all misleading “before-and-after” photographs of plastic surgery procedures from its website and social media and stop altering photographs of future procedures.
• Cease use of and attempts to enforce all illegal NDAs and notify patients who previously signed them that they are released from the terms of those NDAs.
• Pay a third-party forensic accounting firm to perform a full, independent audit of Allure Esthetic’s consumer rebate program to identify consumers who are owed rebates that were unlawfully claimed by Allure Esthetic.

Additionally, the attorney general’s office will continue to monitor Allure Esthetic, and upon request, the practice must provide information that demonstrates its compliance with the consent decree for the next 10 years.

The practice must also develop internal policies and implement a training program to educate staff about nondeceptive advertising and compliance with consumer protection laws.

Dr. Sajan and his practice agreed to the terms of the consent decree, and the settlement is not considered an admission of liability.

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

TOPLINE:

Patients taking a glucagon-like peptide 1 receptor agonist (GLP-1 RA) experience only a modest delay in gastric emptying of solid foods and no significant delay for liquids, compared with those receiving placebo, indicating that patients may not need to discontinue these medications before surgery.

METHODOLOGY:

• GLP-1 RAs, while effective in managing diabetes and obesity, are linked to delayed gastric emptying, which may pose risks during procedures requiring anesthesia or sedation due to potential aspiration of gastric contents.
• Researchers conducted a meta-analysis to quantify the duration of delay in gastric emptying caused by GLP-1 RAs in patients with diabetes and/or excessive body weight, which could guide periprocedural management decisions in the future.
• The primary outcome was halftime, the time required for 50% of solid gastric contents to empty, measured using scintigraphy. This analysis included data from five studies involving 247 patients who received either a GLP-1 RA or placebo.
• The secondary outcome was gastric emptying of liquids measured using the acetaminophen absorption test. Ten studies including 411 patients who received either a GLP-1 RA or placebo were included in this analysis.

TAKEAWAY:

• The mean gastric emptying halftime for solid foods was 138.4 minutes with a GLP-1 RA and 95.0 minutes with placebo, resulting in a pooled mean difference of 36.0 minutes (P < .01).
• No significant difference was found in the gastric emptying time for liquids between the GLP-1 RA and placebo groups. Furthermore, the amount of gastric emptying noted at 4 or 5 hours on the acetaminophen absorption test was comparable between these groups.
• The gastric emptying time for both solids and liquids did not differ between GLP-1 RA formulations or between short-acting or long-acting GLP-1 RAs.

IN PRACTICE:

“Based on current evidence, a conservative approach with a liquid diet on the day before procedures while continuing GLP-1 RA therapy would represent the most sensible approach until more conclusive data on a solid diet are available,” the authors wrote.

SOURCE:

The study, led by Brent Hiramoto, MD, MPH, of the Center for Gastrointestinal Motility at Brigham and Women’s Hospital and Harvard Medical School, Boston, was published online in The American Journal of Gastroenterology.

LIMITATIONS:

The small number of studies utilizing some diagnostic modalities, such as breath testing, precluded a formal meta-analysis of these subgroups. The results could not be stratified by indication for GLP-1 RA (diabetes or obesity) because of insufficient studies in each category.

DISCLOSURES:

The lead author was supported by the National Institute of Diabetes and Digestive and Kidney Diseases. One author declared serving on the advisory boards of three pharmaceutical companies.

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

TOPLINE:

Patients taking a glucagon-like peptide 1 receptor agonist (GLP-1 RA) experience only a modest delay in gastric emptying of solid foods and no significant delay for liquids, compared with those receiving placebo, indicating that patients may not need to discontinue these medications before surgery.

METHODOLOGY:

• GLP-1 RAs, while effective in managing diabetes and obesity, are linked to delayed gastric emptying, which may pose risks during procedures requiring anesthesia or sedation due to potential aspiration of gastric contents.
• Researchers conducted a meta-analysis to quantify the duration of delay in gastric emptying caused by GLP-1 RAs in patients with diabetes and/or excessive body weight, which could guide periprocedural management decisions in the future.
• The primary outcome was halftime, the time required for 50% of solid gastric contents to empty, measured using scintigraphy. This analysis included data from five studies involving 247 patients who received either a GLP-1 RA or placebo.
• The secondary outcome was gastric emptying of liquids measured using the acetaminophen absorption test. Ten studies including 411 patients who received either a GLP-1 RA or placebo were included in this analysis.

TAKEAWAY:

• The mean gastric emptying halftime for solid foods was 138.4 minutes with a GLP-1 RA and 95.0 minutes with placebo, resulting in a pooled mean difference of 36.0 minutes (P < .01).
• No significant difference was found in the gastric emptying time for liquids between the GLP-1 RA and placebo groups. Furthermore, the amount of gastric emptying noted at 4 or 5 hours on the acetaminophen absorption test was comparable between these groups.
• The gastric emptying time for both solids and liquids did not differ between GLP-1 RA formulations or between short-acting or long-acting GLP-1 RAs.

IN PRACTICE:

“Based on current evidence, a conservative approach with a liquid diet on the day before procedures while continuing GLP-1 RA therapy would represent the most sensible approach until more conclusive data on a solid diet are available,” the authors wrote.

SOURCE:

The study, led by Brent Hiramoto, MD, MPH, of the Center for Gastrointestinal Motility at Brigham and Women’s Hospital and Harvard Medical School, Boston, was published online in The American Journal of Gastroenterology.

LIMITATIONS:

The small number of studies utilizing some diagnostic modalities, such as breath testing, precluded a formal meta-analysis of these subgroups. The results could not be stratified by indication for GLP-1 RA (diabetes or obesity) because of insufficient studies in each category.

DISCLOSURES:

The lead author was supported by the National Institute of Diabetes and Digestive and Kidney Diseases. One author declared serving on the advisory boards of three pharmaceutical companies.

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

TOPLINE:

Patients taking a glucagon-like peptide 1 receptor agonist (GLP-1 RA) experience only a modest delay in gastric emptying of solid foods and no significant delay for liquids, compared with those receiving placebo, indicating that patients may not need to discontinue these medications before surgery.

METHODOLOGY:

• GLP-1 RAs, while effective in managing diabetes and obesity, are linked to delayed gastric emptying, which may pose risks during procedures requiring anesthesia or sedation due to potential aspiration of gastric contents.
• Researchers conducted a meta-analysis to quantify the duration of delay in gastric emptying caused by GLP-1 RAs in patients with diabetes and/or excessive body weight, which could guide periprocedural management decisions in the future.
• The primary outcome was halftime, the time required for 50% of solid gastric contents to empty, measured using scintigraphy. This analysis included data from five studies involving 247 patients who received either a GLP-1 RA or placebo.
• The secondary outcome was gastric emptying of liquids measured using the acetaminophen absorption test. Ten studies including 411 patients who received either a GLP-1 RA or placebo were included in this analysis.

TAKEAWAY:

• The mean gastric emptying halftime for solid foods was 138.4 minutes with a GLP-1 RA and 95.0 minutes with placebo, resulting in a pooled mean difference of 36.0 minutes (P < .01).
• No significant difference was found in the gastric emptying time for liquids between the GLP-1 RA and placebo groups. Furthermore, the amount of gastric emptying noted at 4 or 5 hours on the acetaminophen absorption test was comparable between these groups.
• The gastric emptying time for both solids and liquids did not differ between GLP-1 RA formulations or between short-acting or long-acting GLP-1 RAs.

IN PRACTICE:

“Based on current evidence, a conservative approach with a liquid diet on the day before procedures while continuing GLP-1 RA therapy would represent the most sensible approach until more conclusive data on a solid diet are available,” the authors wrote.

SOURCE:

The study, led by Brent Hiramoto, MD, MPH, of the Center for Gastrointestinal Motility at Brigham and Women’s Hospital and Harvard Medical School, Boston, was published online in The American Journal of Gastroenterology.

LIMITATIONS:

The small number of studies utilizing some diagnostic modalities, such as breath testing, precluded a formal meta-analysis of these subgroups. The results could not be stratified by indication for GLP-1 RA (diabetes or obesity) because of insufficient studies in each category.

DISCLOSURES:

The lead author was supported by the National Institute of Diabetes and Digestive and Kidney Diseases. One author declared serving on the advisory boards of three pharmaceutical companies.

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

Should 5 mg of tamoxifen — known as “baby TAM” — or the usual 20 mg dose be standard of care for breast cancer prevention in high-risk women?

Research to date clearly shows that tamoxifen can reduce the risk for breast cancer in high-risk individuals by 30%-50%. Recent evidence also indicates that this chemoprevention approach can reduce the risk of dying from breast cancer by as much as 57%.

In 2019, the US Preventive Services Task Force issued updated recommendations that clinicians offer risk-reducing medications, such as tamoxifen, raloxifene, or aromatase inhibitors, to women at an increased risk for breast cancer and a low risk for adverse medication effects.

However, this prophylactic strategy remains underused.

A major roadblock: The drugs’ side effects, which include venous thromboembolic events and endometrial cancer as well as symptoms of menopause, such as hot flashes and sexual issues, have made uptake and adherence a challenge.

Offering women a lower dose of tamoxifen could allay fears about toxicities and improve uptake as well as reduce side effects and boost long-term adherence among those receiving baby TAM.

However, experts remain uncertain about whether patients need the standard dose to experience the full prevention benefit.
 

The Debate

Years ago, Andrea De Censi, MD, a breast cancer researcher at the Galliera Hospital in Genova, Italy, and his colleagues reasoned that, because tamoxifen is a competitive estrogen receptor inhibitor, it may indeed have a minimal effective dose below 20 mg/d.

The fruits of that line of thought were presented to the world in the TAM-01 trial, first published in 2019, which pitted tamoxifen 5 mg/d for 3 years against placebo in 500 women with high-risk lesions, including lobular and ductal carcinoma in situ.

Dr. De Censi and colleagues found that baby TAM reduced the risk for invasive breast cancer by 52% and the risk for contralateral breast cancer by 75%.

Treatment adherence was slightly higher in the baby TAM group at 65% vs 61% in the placebo group.

A recent 10-year follow-up showed ongoing benefits associated with baby TAM vs placebo — a 42% reduction in breast cancer and a 64% drop in contralateral lesions.

The baby TAM group vs placebo experienced a slight increase in hot flashes but no significant increase in other common side effects.

Regarding serious adverse events, the baby TAM arm had one case of stage 1 endometrial cancer (0.4% of patients) and 20 cases of endometrial polyps (5%) vs 13 cases of endometrial polyps in the placebo arm. But there were no significant differences in thrombosis, cataracts, bone fractures, and other serious events.

Dr. De Censi said he’s surprised the baby TAM vs tamoxifen topic is still being debated. “Baby TAM, in my opinion, is a new standard of care for endocrine prevention of breast cancer in high-risk [women],” and baby TAM over 3 years is enough, said Dr. De Censi during a debate on the topic at the 2024 European Society for Medical Oncology Breast Cancer Congress in Berlin.

Gareth Evans, MD, a cancer genetics and prevention specialist at the University of Manchester, Manchester, England, however, isn’t convinced.

During the debate, Dr. Evans explained that  his main concern was that the baby TAM trial was limited to women with high-risk lesions, not other common reasons for tamoxifen prophylaxis, such as a positive family history or BRCA mutations.

“In Manchester, we have put over a thousand women on tamoxifen who have a family history or other risk factors, not high-risk lesions,” and there simply isn’t definitive evidence for baby TAM in these women, Dr. Evans said.

The vast weight of evidence for tamoxifen prophylaxis, he added, is in trials involving tens of thousands of women, followed in some cases for 20 years, who received the 20 mg dose for 5 years.

As a result, women in Manchester are started on 20 mg and dropped down to 5 mg only for side effects. That way, Evans explained, we are not taking away the benefit among women who can tolerate 20 mg.

Meanwhile, there’s no evidence that baby TAM improves medication adherence, he noted. Trials have reported similar adherence rates to baby TAM and standard dose tamoxifen as well as no definitive evidence that the risk for cancer and thrombosis is less with baby TAM, he said.

In fact, Dr. Evans noted, “many women take tamoxifen 20 mg for 5 years with no side effects.”

Overall, “I don’t think we’ve got the evidence yet to drop” dosages, particularly in women without high-risk lesions, Dr. Evans said. A real concern, he added, is poor metabolizers for whom 5 mg won’t be enough to have a preventive effect.

Dr. De Censi noted, however, that there will likely never be a definitive answer to the question of baby TAM vs standard dosing because industry has no financial incentive to do a head-to-head trial; tamoxifen went off patent over 30 years ago.

Still, a poll of the audience favored Evans’ approach — 80% said they would start high-risk women on 20 mg for breast cancer prophylaxis and reduce for side effects as needed.

Dr. De Censi didn’t have any disclosures. Dr. Evans is a consultant/advisor for AstraZeneca, SpringWorks, Recursion, Everything Genetic, and Syantra.

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

Should 5 mg of tamoxifen — known as “baby TAM” — or the usual 20 mg dose be standard of care for breast cancer prevention in high-risk women?

Research to date clearly shows that tamoxifen can reduce the risk for breast cancer in high-risk individuals by 30%-50%. Recent evidence also indicates that this chemoprevention approach can reduce the risk of dying from breast cancer by as much as 57%.

In 2019, the US Preventive Services Task Force issued updated recommendations that clinicians offer risk-reducing medications, such as tamoxifen, raloxifene, or aromatase inhibitors, to women at an increased risk for breast cancer and a low risk for adverse medication effects.

However, this prophylactic strategy remains underused.

A major roadblock: The drugs’ side effects, which include venous thromboembolic events and endometrial cancer as well as symptoms of menopause, such as hot flashes and sexual issues, have made uptake and adherence a challenge.

Offering women a lower dose of tamoxifen could allay fears about toxicities and improve uptake as well as reduce side effects and boost long-term adherence among those receiving baby TAM.

However, experts remain uncertain about whether patients need the standard dose to experience the full prevention benefit.
 

The Debate

Years ago, Andrea De Censi, MD, a breast cancer researcher at the Galliera Hospital in Genova, Italy, and his colleagues reasoned that, because tamoxifen is a competitive estrogen receptor inhibitor, it may indeed have a minimal effective dose below 20 mg/d.

The fruits of that line of thought were presented to the world in the TAM-01 trial, first published in 2019, which pitted tamoxifen 5 mg/d for 3 years against placebo in 500 women with high-risk lesions, including lobular and ductal carcinoma in situ.

Dr. De Censi and colleagues found that baby TAM reduced the risk for invasive breast cancer by 52% and the risk for contralateral breast cancer by 75%.

Treatment adherence was slightly higher in the baby TAM group at 65% vs 61% in the placebo group.

A recent 10-year follow-up showed ongoing benefits associated with baby TAM vs placebo — a 42% reduction in breast cancer and a 64% drop in contralateral lesions.

The baby TAM group vs placebo experienced a slight increase in hot flashes but no significant increase in other common side effects.

Regarding serious adverse events, the baby TAM arm had one case of stage 1 endometrial cancer (0.4% of patients) and 20 cases of endometrial polyps (5%) vs 13 cases of endometrial polyps in the placebo arm. But there were no significant differences in thrombosis, cataracts, bone fractures, and other serious events.

Dr. De Censi said he’s surprised the baby TAM vs tamoxifen topic is still being debated. “Baby TAM, in my opinion, is a new standard of care for endocrine prevention of breast cancer in high-risk [women],” and baby TAM over 3 years is enough, said Dr. De Censi during a debate on the topic at the 2024 European Society for Medical Oncology Breast Cancer Congress in Berlin.

Gareth Evans, MD, a cancer genetics and prevention specialist at the University of Manchester, Manchester, England, however, isn’t convinced.

During the debate, Dr. Evans explained that  his main concern was that the baby TAM trial was limited to women with high-risk lesions, not other common reasons for tamoxifen prophylaxis, such as a positive family history or BRCA mutations.

“In Manchester, we have put over a thousand women on tamoxifen who have a family history or other risk factors, not high-risk lesions,” and there simply isn’t definitive evidence for baby TAM in these women, Dr. Evans said.

The vast weight of evidence for tamoxifen prophylaxis, he added, is in trials involving tens of thousands of women, followed in some cases for 20 years, who received the 20 mg dose for 5 years.

As a result, women in Manchester are started on 20 mg and dropped down to 5 mg only for side effects. That way, Evans explained, we are not taking away the benefit among women who can tolerate 20 mg.

Meanwhile, there’s no evidence that baby TAM improves medication adherence, he noted. Trials have reported similar adherence rates to baby TAM and standard dose tamoxifen as well as no definitive evidence that the risk for cancer and thrombosis is less with baby TAM, he said.

In fact, Dr. Evans noted, “many women take tamoxifen 20 mg for 5 years with no side effects.”

Overall, “I don’t think we’ve got the evidence yet to drop” dosages, particularly in women without high-risk lesions, Dr. Evans said. A real concern, he added, is poor metabolizers for whom 5 mg won’t be enough to have a preventive effect.

Dr. De Censi noted, however, that there will likely never be a definitive answer to the question of baby TAM vs standard dosing because industry has no financial incentive to do a head-to-head trial; tamoxifen went off patent over 30 years ago.

Still, a poll of the audience favored Evans’ approach — 80% said they would start high-risk women on 20 mg for breast cancer prophylaxis and reduce for side effects as needed.

Dr. De Censi didn’t have any disclosures. Dr. Evans is a consultant/advisor for AstraZeneca, SpringWorks, Recursion, Everything Genetic, and Syantra.

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

Should 5 mg of tamoxifen — known as “baby TAM” — or the usual 20 mg dose be standard of care for breast cancer prevention in high-risk women?

Research to date clearly shows that tamoxifen can reduce the risk for breast cancer in high-risk individuals by 30%-50%. Recent evidence also indicates that this chemoprevention approach can reduce the risk of dying from breast cancer by as much as 57%.

In 2019, the US Preventive Services Task Force issued updated recommendations that clinicians offer risk-reducing medications, such as tamoxifen, raloxifene, or aromatase inhibitors, to women at an increased risk for breast cancer and a low risk for adverse medication effects.

However, this prophylactic strategy remains underused.

A major roadblock: The drugs’ side effects, which include venous thromboembolic events and endometrial cancer as well as symptoms of menopause, such as hot flashes and sexual issues, have made uptake and adherence a challenge.

Offering women a lower dose of tamoxifen could allay fears about toxicities and improve uptake as well as reduce side effects and boost long-term adherence among those receiving baby TAM.

However, experts remain uncertain about whether patients need the standard dose to experience the full prevention benefit.
 

The Debate

Years ago, Andrea De Censi, MD, a breast cancer researcher at the Galliera Hospital in Genova, Italy, and his colleagues reasoned that, because tamoxifen is a competitive estrogen receptor inhibitor, it may indeed have a minimal effective dose below 20 mg/d.

The fruits of that line of thought were presented to the world in the TAM-01 trial, first published in 2019, which pitted tamoxifen 5 mg/d for 3 years against placebo in 500 women with high-risk lesions, including lobular and ductal carcinoma in situ.

Dr. De Censi and colleagues found that baby TAM reduced the risk for invasive breast cancer by 52% and the risk for contralateral breast cancer by 75%.

Treatment adherence was slightly higher in the baby TAM group at 65% vs 61% in the placebo group.

A recent 10-year follow-up showed ongoing benefits associated with baby TAM vs placebo — a 42% reduction in breast cancer and a 64% drop in contralateral lesions.

The baby TAM group vs placebo experienced a slight increase in hot flashes but no significant increase in other common side effects.

Regarding serious adverse events, the baby TAM arm had one case of stage 1 endometrial cancer (0.4% of patients) and 20 cases of endometrial polyps (5%) vs 13 cases of endometrial polyps in the placebo arm. But there were no significant differences in thrombosis, cataracts, bone fractures, and other serious events.

Dr. De Censi said he’s surprised the baby TAM vs tamoxifen topic is still being debated. “Baby TAM, in my opinion, is a new standard of care for endocrine prevention of breast cancer in high-risk [women],” and baby TAM over 3 years is enough, said Dr. De Censi during a debate on the topic at the 2024 European Society for Medical Oncology Breast Cancer Congress in Berlin.

Gareth Evans, MD, a cancer genetics and prevention specialist at the University of Manchester, Manchester, England, however, isn’t convinced.

During the debate, Dr. Evans explained that  his main concern was that the baby TAM trial was limited to women with high-risk lesions, not other common reasons for tamoxifen prophylaxis, such as a positive family history or BRCA mutations.

“In Manchester, we have put over a thousand women on tamoxifen who have a family history or other risk factors, not high-risk lesions,” and there simply isn’t definitive evidence for baby TAM in these women, Dr. Evans said.

The vast weight of evidence for tamoxifen prophylaxis, he added, is in trials involving tens of thousands of women, followed in some cases for 20 years, who received the 20 mg dose for 5 years.

As a result, women in Manchester are started on 20 mg and dropped down to 5 mg only for side effects. That way, Evans explained, we are not taking away the benefit among women who can tolerate 20 mg.

Meanwhile, there’s no evidence that baby TAM improves medication adherence, he noted. Trials have reported similar adherence rates to baby TAM and standard dose tamoxifen as well as no definitive evidence that the risk for cancer and thrombosis is less with baby TAM, he said.

In fact, Dr. Evans noted, “many women take tamoxifen 20 mg for 5 years with no side effects.”

Overall, “I don’t think we’ve got the evidence yet to drop” dosages, particularly in women without high-risk lesions, Dr. Evans said. A real concern, he added, is poor metabolizers for whom 5 mg won’t be enough to have a preventive effect.

Dr. De Censi noted, however, that there will likely never be a definitive answer to the question of baby TAM vs standard dosing because industry has no financial incentive to do a head-to-head trial; tamoxifen went off patent over 30 years ago.

Still, a poll of the audience favored Evans’ approach — 80% said they would start high-risk women on 20 mg for breast cancer prophylaxis and reduce for side effects as needed.

Dr. De Censi didn’t have any disclosures. Dr. Evans is a consultant/advisor for AstraZeneca, SpringWorks, Recursion, Everything Genetic, and Syantra.

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