When treating patients for ulcerative colitis (UC), clinicians should consider using vedolizumab, because the drug has been found to be both safe and highly effective in patients who have never received tumor necrosis factor (TNF)–antagonist treatment and those who have but did not benefit from it, according to a study published in the February issue of Clinical Gastroenterology and Hepatology (doi: 10.1016/j.cgh.2016.08.044).

“Approximately 50% of patients with UC do not respond to induction therapy with TNF antagonists or lose response over time such that after 1 year of treatment, clinical remission is observed in only 17%-34% of patients,” explained the authors of the report, led by Brian G. Feagan, MD, of the University of Western Ontario in London. “Furthermore, the risk of serious infection (with immunosuppressants in general, and TNF antagonists specifically) is an important concern [so] alternative approaches to treatment are needed.”

For this study, Dr. Feagan and his colleagues turned to the GEMINI 1 trial, which evaluated vedolizumab in patients with moderate and severe UC via a multicenter, phase III, randomized, placebo-controlled trial. This study produced data on 374 subjects who had been randomized into cohorts receiving either vedolizumab intravenously or a placebo. However, this number was deemed too low, so a further 521 patients were enrolled for an open-label study and randomized in the same 3:2 ratio as the previous study. The former study was called Cohort 1 and the latter called Cohort 2.

“Eligible patients had UC for [at least] 6 months before enrollment, MCS [Mayo Clinic scores for disease activity] from 6 to 12, and endoscopic subscores of [at least] 2 within 7 days before the first dose of study drug, and evidence of disease extending [at least] 15 cm proximal to the rectum,” the authors explained.

Vedolizumab was administered at baseline, with follow-up evaluations at 2, 4, and 6 weeks. Subjects who experienced a clinical response – defined as an MCS reduction of at least 3 points and 30%, along with at least a 1-point reduction in rectal bleeding and an absolute rectal bleeding subscore of either 0 or 1 – were re-randomized into cohorts that received the drug every 4 weeks or every 8 weeks, for a period of up to 46 weeks. The total length of the study was, therefore, 52 weeks; for patients that were re-randomized, follow-up evaluations took place every 4 weeks.

A total of 464 patients who were enrolled and completed the study were naive to TNF antagonists, while 367 had previously been treated with TNF antagonists unsuccessfully. At 6-week follow-up, 53.1% of naive subjects receiving vedolizumab had achieved clinical response, versus 26.3% of naive subjects on placebo (absolute difference, 26.4%; 95% confidence interval, 12.4-40.4). Similarly, those with previous TNF antagonist exposure who were given vedolizumab had a 39.0% clinical response rate, versus 20.6% of those on placebo (AD, 18.1%; 95% CI, 2.8-33.5).

At week 52, naive subjects on vedolizumab continued to have far higher rates of clinical response than did those on placebo, with 46.9% and 19.0%, respectively (AD, 28.0%; 95% CI, 14.9-41.1). For those with previous TNF antagonist exposure, the disparity between vedolizumab and placebo was similarly profound: 36.1% versus 5.3%, respectively (AD, 29.5%; 95% CI, 12.8-46.1).

Adverse event rates between naive and previously exposed patients were not significantly different, according to the findings. In naive patients, 74% of those on vedolizumab experienced an adverse event, and 9% experienced a serious adverse event. For those on placebo, those rates were 75% and 16%, respectively. For patients who had previously been on a TNF antagonist, subjects on vedolizumab had an 88% rate of adverse events and a 17% rate of serious adverse events, compared with 84% and 11%, respectively, for those on placebo.

“It is notable that, in maintenance, the absolute remission rates were substantially lower in the TNF failure population for both vedolizumab-treated and placebo-treated patients,” the investigators noted, positing that “The relatively low placebo response rate in the TNF-failure group could be attributed to the presence of a greater proportion of patients with more refractory disease and poor prognostic factors, such as pancolitis and long disease duration.”

The study was funded by Millennium Pharmaceuticals. Dr. Feagan disclosed serving as a consultant and receiving financial support for research from Millennium and other companies. No other coauthors reported relevant financial disclosures.
 

[email protected]

When treating patients for ulcerative colitis (UC), clinicians should consider using vedolizumab, because the drug has been found to be both safe and highly effective in patients who have never received tumor necrosis factor (TNF)–antagonist treatment and those who have but did not benefit from it, according to a study published in the February issue of Clinical Gastroenterology and Hepatology (doi: 10.1016/j.cgh.2016.08.044).

“Approximately 50% of patients with UC do not respond to induction therapy with TNF antagonists or lose response over time such that after 1 year of treatment, clinical remission is observed in only 17%-34% of patients,” explained the authors of the report, led by Brian G. Feagan, MD, of the University of Western Ontario in London. “Furthermore, the risk of serious infection (with immunosuppressants in general, and TNF antagonists specifically) is an important concern [so] alternative approaches to treatment are needed.”

For this study, Dr. Feagan and his colleagues turned to the GEMINI 1 trial, which evaluated vedolizumab in patients with moderate and severe UC via a multicenter, phase III, randomized, placebo-controlled trial. This study produced data on 374 subjects who had been randomized into cohorts receiving either vedolizumab intravenously or a placebo. However, this number was deemed too low, so a further 521 patients were enrolled for an open-label study and randomized in the same 3:2 ratio as the previous study. The former study was called Cohort 1 and the latter called Cohort 2.

“Eligible patients had UC for [at least] 6 months before enrollment, MCS [Mayo Clinic scores for disease activity] from 6 to 12, and endoscopic subscores of [at least] 2 within 7 days before the first dose of study drug, and evidence of disease extending [at least] 15 cm proximal to the rectum,” the authors explained.

Vedolizumab was administered at baseline, with follow-up evaluations at 2, 4, and 6 weeks. Subjects who experienced a clinical response – defined as an MCS reduction of at least 3 points and 30%, along with at least a 1-point reduction in rectal bleeding and an absolute rectal bleeding subscore of either 0 or 1 – were re-randomized into cohorts that received the drug every 4 weeks or every 8 weeks, for a period of up to 46 weeks. The total length of the study was, therefore, 52 weeks; for patients that were re-randomized, follow-up evaluations took place every 4 weeks.

A total of 464 patients who were enrolled and completed the study were naive to TNF antagonists, while 367 had previously been treated with TNF antagonists unsuccessfully. At 6-week follow-up, 53.1% of naive subjects receiving vedolizumab had achieved clinical response, versus 26.3% of naive subjects on placebo (absolute difference, 26.4%; 95% confidence interval, 12.4-40.4). Similarly, those with previous TNF antagonist exposure who were given vedolizumab had a 39.0% clinical response rate, versus 20.6% of those on placebo (AD, 18.1%; 95% CI, 2.8-33.5).

At week 52, naive subjects on vedolizumab continued to have far higher rates of clinical response than did those on placebo, with 46.9% and 19.0%, respectively (AD, 28.0%; 95% CI, 14.9-41.1). For those with previous TNF antagonist exposure, the disparity between vedolizumab and placebo was similarly profound: 36.1% versus 5.3%, respectively (AD, 29.5%; 95% CI, 12.8-46.1).

Adverse event rates between naive and previously exposed patients were not significantly different, according to the findings. In naive patients, 74% of those on vedolizumab experienced an adverse event, and 9% experienced a serious adverse event. For those on placebo, those rates were 75% and 16%, respectively. For patients who had previously been on a TNF antagonist, subjects on vedolizumab had an 88% rate of adverse events and a 17% rate of serious adverse events, compared with 84% and 11%, respectively, for those on placebo.

“It is notable that, in maintenance, the absolute remission rates were substantially lower in the TNF failure population for both vedolizumab-treated and placebo-treated patients,” the investigators noted, positing that “The relatively low placebo response rate in the TNF-failure group could be attributed to the presence of a greater proportion of patients with more refractory disease and poor prognostic factors, such as pancolitis and long disease duration.”

The study was funded by Millennium Pharmaceuticals. Dr. Feagan disclosed serving as a consultant and receiving financial support for research from Millennium and other companies. No other coauthors reported relevant financial disclosures.
 

[email protected]

When treating patients for ulcerative colitis (UC), clinicians should consider using vedolizumab, because the drug has been found to be both safe and highly effective in patients who have never received tumor necrosis factor (TNF)–antagonist treatment and those who have but did not benefit from it, according to a study published in the February issue of Clinical Gastroenterology and Hepatology (doi: 10.1016/j.cgh.2016.08.044).

“Approximately 50% of patients with UC do not respond to induction therapy with TNF antagonists or lose response over time such that after 1 year of treatment, clinical remission is observed in only 17%-34% of patients,” explained the authors of the report, led by Brian G. Feagan, MD, of the University of Western Ontario in London. “Furthermore, the risk of serious infection (with immunosuppressants in general, and TNF antagonists specifically) is an important concern [so] alternative approaches to treatment are needed.”

For this study, Dr. Feagan and his colleagues turned to the GEMINI 1 trial, which evaluated vedolizumab in patients with moderate and severe UC via a multicenter, phase III, randomized, placebo-controlled trial. This study produced data on 374 subjects who had been randomized into cohorts receiving either vedolizumab intravenously or a placebo. However, this number was deemed too low, so a further 521 patients were enrolled for an open-label study and randomized in the same 3:2 ratio as the previous study. The former study was called Cohort 1 and the latter called Cohort 2.

“Eligible patients had UC for [at least] 6 months before enrollment, MCS [Mayo Clinic scores for disease activity] from 6 to 12, and endoscopic subscores of [at least] 2 within 7 days before the first dose of study drug, and evidence of disease extending [at least] 15 cm proximal to the rectum,” the authors explained.

Vedolizumab was administered at baseline, with follow-up evaluations at 2, 4, and 6 weeks. Subjects who experienced a clinical response – defined as an MCS reduction of at least 3 points and 30%, along with at least a 1-point reduction in rectal bleeding and an absolute rectal bleeding subscore of either 0 or 1 – were re-randomized into cohorts that received the drug every 4 weeks or every 8 weeks, for a period of up to 46 weeks. The total length of the study was, therefore, 52 weeks; for patients that were re-randomized, follow-up evaluations took place every 4 weeks.

A total of 464 patients who were enrolled and completed the study were naive to TNF antagonists, while 367 had previously been treated with TNF antagonists unsuccessfully. At 6-week follow-up, 53.1% of naive subjects receiving vedolizumab had achieved clinical response, versus 26.3% of naive subjects on placebo (absolute difference, 26.4%; 95% confidence interval, 12.4-40.4). Similarly, those with previous TNF antagonist exposure who were given vedolizumab had a 39.0% clinical response rate, versus 20.6% of those on placebo (AD, 18.1%; 95% CI, 2.8-33.5).

At week 52, naive subjects on vedolizumab continued to have far higher rates of clinical response than did those on placebo, with 46.9% and 19.0%, respectively (AD, 28.0%; 95% CI, 14.9-41.1). For those with previous TNF antagonist exposure, the disparity between vedolizumab and placebo was similarly profound: 36.1% versus 5.3%, respectively (AD, 29.5%; 95% CI, 12.8-46.1).

Adverse event rates between naive and previously exposed patients were not significantly different, according to the findings. In naive patients, 74% of those on vedolizumab experienced an adverse event, and 9% experienced a serious adverse event. For those on placebo, those rates were 75% and 16%, respectively. For patients who had previously been on a TNF antagonist, subjects on vedolizumab had an 88% rate of adverse events and a 17% rate of serious adverse events, compared with 84% and 11%, respectively, for those on placebo.

“It is notable that, in maintenance, the absolute remission rates were substantially lower in the TNF failure population for both vedolizumab-treated and placebo-treated patients,” the investigators noted, positing that “The relatively low placebo response rate in the TNF-failure group could be attributed to the presence of a greater proportion of patients with more refractory disease and poor prognostic factors, such as pancolitis and long disease duration.”

The study was funded by Millennium Pharmaceuticals. Dr. Feagan disclosed serving as a consultant and receiving financial support for research from Millennium and other companies. No other coauthors reported relevant financial disclosures.
 

[email protected]

The American Academy of Neurology (AAN) has published evidence-based recommendations for management of restless legs syndrome (RLS) in adults. The practice guideline was published online ahead of print November 16, 2016, in Neurology. The practice guideline addresses the question: What are safe and effective therapies, including both pharmacologic and nonpharmacologic approaches, for the symptoms and clinical consequences (eg, disturbed sleep, periodic limb movements in sleep, depression/anxiety, and decreased quality of life) of RLS in adults.

“When addressing RLS, clinicians and patients must first determine whether symptoms require treatment, the setting in which this practice guideline is relevant,” said John W. Winkelman, MD, PhD, and colleagues. Dr. Winkelman is an Associate Professor of Psychiatry at Harvard Medical School and Medical Director of the Sleep Health Center of Brigham and Women’s Hospital in Boston.

“Treatment should be considered if RLS symptoms interfere with sleep or daytime function to an important degree,” the guideline authors said. “Before determining the best treatment, it is important to first ensure there are no contributing factors to RLS symptoms (eg, iron deficiency or serotonergic antidepressants). The guidelines advise clinicians to consider prescribing a pharmacologic agent to reduce RLS symptoms in patients with moderate to severe primary RLS. There is strong (Level A) evidence for use of pramipexole, rotigotine, cabergoline, and gabapentin enacarbil; moderate evidence (Level B) supports ropinirole, pregabalin, and IV ferric carboxymaltose; and weak evidence (Level C) supports levodopa. When considering efficacy alone, clinicians may prefer cabergoline. It is rarely used in clinical practice for RLS, however, because it is associated with a risk of cardiac valvulopathy. Clinicians are also advised to consider the augmentation risks associated with dopaminergic agents.

For patients with periodic limb movement disorder, there is strong (Level A) evidence supporting ropinirole. Moderate evidence (Level B) supports pramipexole, rotigotine, cabergoline, and pregabalin; and weak evidence (Level C) supporting levodopa. The authors note insufficient evidence (Level U) for gabapentin enacarbil and ferric carboxymaltose. With regard to objective sleep measures (eg, total sleep time, sleep efficiency, sleep latency, wake after sleep onset) there is moderate evidence (Level B) supporting ropinirole, gabapentin, encarbil, and pregabalin. However, there is insufficient evidence (Level U) supporting pamipexole, rotigotine, cabergoline, or levodopa.

For subjective sleep measures, cabergoline and gabapentin enacarbil have Level A evidence; ropinirole, pramipexole, rotigotine, and pregabalin have Level B evidence; and levodopa and prolonged-release oxycodone/naloxone, and vibratory stimulation have Level C evidence. Insufficient evidence (Level U) exists for ferric carboxymaltose and iron sucrose.When patients with RLS fail to respond to other treatments, clinicians are advised to consider prescribing prolonged-release oxycodone/naloxone (Level C) or to consider nonpharmacologic options, including pneumatic compression (Level B), infrared spectroscopy or transcranial magnetic stimulation (Level C), and vibrating pads (Level C).

For iron-deficient patients with RLS (ferritin levels ≤ 75 µg/L), clinicians are advised to prescribe ferrous sulfate with vitamin C. In patients on hemodialysis with secondary RLS, clinicians are advised to prescribe vitamin C and E supplementation (Level B), ropinirole, levodopa, or exercise (Level C).

—Erica Tricarico

Suggested Reading

Winkelman JW, Armstrong MJ, Allen RP, et al. Practice guideline summary: treatment of restless legs syndrome in adults: report of the Guideline Development, Dissemination, and Implementation Subcommittee of the American Academy of Neurology. Neurology. 2016 Nov 16 [Epub ahead of print].

The American Academy of Neurology (AAN) has published evidence-based recommendations for management of restless legs syndrome (RLS) in adults. The practice guideline was published online ahead of print November 16, 2016, in Neurology. The practice guideline addresses the question: What are safe and effective therapies, including both pharmacologic and nonpharmacologic approaches, for the symptoms and clinical consequences (eg, disturbed sleep, periodic limb movements in sleep, depression/anxiety, and decreased quality of life) of RLS in adults.

“When addressing RLS, clinicians and patients must first determine whether symptoms require treatment, the setting in which this practice guideline is relevant,” said John W. Winkelman, MD, PhD, and colleagues. Dr. Winkelman is an Associate Professor of Psychiatry at Harvard Medical School and Medical Director of the Sleep Health Center of Brigham and Women’s Hospital in Boston.

“Treatment should be considered if RLS symptoms interfere with sleep or daytime function to an important degree,” the guideline authors said. “Before determining the best treatment, it is important to first ensure there are no contributing factors to RLS symptoms (eg, iron deficiency or serotonergic antidepressants). The guidelines advise clinicians to consider prescribing a pharmacologic agent to reduce RLS symptoms in patients with moderate to severe primary RLS. There is strong (Level A) evidence for use of pramipexole, rotigotine, cabergoline, and gabapentin enacarbil; moderate evidence (Level B) supports ropinirole, pregabalin, and IV ferric carboxymaltose; and weak evidence (Level C) supports levodopa. When considering efficacy alone, clinicians may prefer cabergoline. It is rarely used in clinical practice for RLS, however, because it is associated with a risk of cardiac valvulopathy. Clinicians are also advised to consider the augmentation risks associated with dopaminergic agents.

For patients with periodic limb movement disorder, there is strong (Level A) evidence supporting ropinirole. Moderate evidence (Level B) supports pramipexole, rotigotine, cabergoline, and pregabalin; and weak evidence (Level C) supporting levodopa. The authors note insufficient evidence (Level U) for gabapentin enacarbil and ferric carboxymaltose. With regard to objective sleep measures (eg, total sleep time, sleep efficiency, sleep latency, wake after sleep onset) there is moderate evidence (Level B) supporting ropinirole, gabapentin, encarbil, and pregabalin. However, there is insufficient evidence (Level U) supporting pamipexole, rotigotine, cabergoline, or levodopa.

For subjective sleep measures, cabergoline and gabapentin enacarbil have Level A evidence; ropinirole, pramipexole, rotigotine, and pregabalin have Level B evidence; and levodopa and prolonged-release oxycodone/naloxone, and vibratory stimulation have Level C evidence. Insufficient evidence (Level U) exists for ferric carboxymaltose and iron sucrose.When patients with RLS fail to respond to other treatments, clinicians are advised to consider prescribing prolonged-release oxycodone/naloxone (Level C) or to consider nonpharmacologic options, including pneumatic compression (Level B), infrared spectroscopy or transcranial magnetic stimulation (Level C), and vibrating pads (Level C).

For iron-deficient patients with RLS (ferritin levels ≤ 75 µg/L), clinicians are advised to prescribe ferrous sulfate with vitamin C. In patients on hemodialysis with secondary RLS, clinicians are advised to prescribe vitamin C and E supplementation (Level B), ropinirole, levodopa, or exercise (Level C).

—Erica Tricarico

Suggested Reading

Winkelman JW, Armstrong MJ, Allen RP, et al. Practice guideline summary: treatment of restless legs syndrome in adults: report of the Guideline Development, Dissemination, and Implementation Subcommittee of the American Academy of Neurology. Neurology. 2016 Nov 16 [Epub ahead of print].

The American Academy of Neurology (AAN) has published evidence-based recommendations for management of restless legs syndrome (RLS) in adults. The practice guideline was published online ahead of print November 16, 2016, in Neurology. The practice guideline addresses the question: What are safe and effective therapies, including both pharmacologic and nonpharmacologic approaches, for the symptoms and clinical consequences (eg, disturbed sleep, periodic limb movements in sleep, depression/anxiety, and decreased quality of life) of RLS in adults.

“When addressing RLS, clinicians and patients must first determine whether symptoms require treatment, the setting in which this practice guideline is relevant,” said John W. Winkelman, MD, PhD, and colleagues. Dr. Winkelman is an Associate Professor of Psychiatry at Harvard Medical School and Medical Director of the Sleep Health Center of Brigham and Women’s Hospital in Boston.

“Treatment should be considered if RLS symptoms interfere with sleep or daytime function to an important degree,” the guideline authors said. “Before determining the best treatment, it is important to first ensure there are no contributing factors to RLS symptoms (eg, iron deficiency or serotonergic antidepressants). The guidelines advise clinicians to consider prescribing a pharmacologic agent to reduce RLS symptoms in patients with moderate to severe primary RLS. There is strong (Level A) evidence for use of pramipexole, rotigotine, cabergoline, and gabapentin enacarbil; moderate evidence (Level B) supports ropinirole, pregabalin, and IV ferric carboxymaltose; and weak evidence (Level C) supports levodopa. When considering efficacy alone, clinicians may prefer cabergoline. It is rarely used in clinical practice for RLS, however, because it is associated with a risk of cardiac valvulopathy. Clinicians are also advised to consider the augmentation risks associated with dopaminergic agents.

For patients with periodic limb movement disorder, there is strong (Level A) evidence supporting ropinirole. Moderate evidence (Level B) supports pramipexole, rotigotine, cabergoline, and pregabalin; and weak evidence (Level C) supporting levodopa. The authors note insufficient evidence (Level U) for gabapentin enacarbil and ferric carboxymaltose. With regard to objective sleep measures (eg, total sleep time, sleep efficiency, sleep latency, wake after sleep onset) there is moderate evidence (Level B) supporting ropinirole, gabapentin, encarbil, and pregabalin. However, there is insufficient evidence (Level U) supporting pamipexole, rotigotine, cabergoline, or levodopa.

For subjective sleep measures, cabergoline and gabapentin enacarbil have Level A evidence; ropinirole, pramipexole, rotigotine, and pregabalin have Level B evidence; and levodopa and prolonged-release oxycodone/naloxone, and vibratory stimulation have Level C evidence. Insufficient evidence (Level U) exists for ferric carboxymaltose and iron sucrose.When patients with RLS fail to respond to other treatments, clinicians are advised to consider prescribing prolonged-release oxycodone/naloxone (Level C) or to consider nonpharmacologic options, including pneumatic compression (Level B), infrared spectroscopy or transcranial magnetic stimulation (Level C), and vibrating pads (Level C).

For iron-deficient patients with RLS (ferritin levels ≤ 75 µg/L), clinicians are advised to prescribe ferrous sulfate with vitamin C. In patients on hemodialysis with secondary RLS, clinicians are advised to prescribe vitamin C and E supplementation (Level B), ropinirole, levodopa, or exercise (Level C).

—Erica Tricarico

Suggested Reading

Winkelman JW, Armstrong MJ, Allen RP, et al. Practice guideline summary: treatment of restless legs syndrome in adults: report of the Guideline Development, Dissemination, and Implementation Subcommittee of the American Academy of Neurology. Neurology. 2016 Nov 16 [Epub ahead of print].

Onychomadesis is an acute, noninflammatory, painless, proximal separation of the nail plate from the nail matrix. It occurs due to an abrupt stoppage of nail production by matrix cells, producing temporary cessation of nail growth with or without subsequent complete shedding of nails.^1-10 Onychomadesis has a wide spectrum of clinical presentations ranging from mild transverse ridges of the nail plate (Beau lines) to complete nail shedding.^4,11 Onychomadesis may be related to systemic and dermatologic diseases, drugs (eg, chemotherapeutic agents, anticonvulsants, lithium, retinoids), nail trauma, fever, or infection,⁵ and a connection between onychomadesis and hand-foot-and-mouth disease (HFMD) was first described by Clementz et al¹² following outbreaks in Europe, Asia, and the United States.

Epidemiology

Onychomadesis has been observed in children of all ages including neonates. Neonatal onychomadesis is thought to be related to perinatal stressors and birth trauma, with possible exacerbation by superimposed candidiasis.¹⁰ Depending on the underlying cause, there may be involvement of a single nail or multiple nails. Nag et al¹ noted that onychomadesis was most commonly observed in nails of the middle finger (73.7%), followed by the thumb (63.2%) and ring finger (52.6%). Fingernails are more commonly involved than toenails.¹

Clementz et al¹² first proposed the association between onychomadesis and HFMD in 2000. Patients with a history of HFMD were found to be 14 times more likely to develop onychomadesis (relative risk, 14; 95% confidence interval, 4.57-42.86).⁴ A common pathogen for HFMD is coxsackievirus A6 (CVA6),^13,14 but the mechanism of onychomadesis in HFMD remains unclear.^5,7,13 Outbreaks of HFMD have been reported in Spain, Finland, Japan, Thailand, the United States, Singapore, and China.¹⁵ During an outbreak of HFMD in Taiwan, the incidence of onychomadesis following CVA6 infection was 37% (48/130) compared to 5% (7/145) in cases with non-CVA6 causative strains.¹⁶ There also have been observed differences in the prevalence of onychomadesis by age: a 55% (18/33) occurrence rate was noted in the youngest age group (range, 9–23 months), 30% (8/27) in the middle age group (range, 24–32 months), and 4% (1/28) in the oldest age group (range, 33–42 months), with an average of 4 nails shed per case.¹⁷ A study in Spain also found a high occurrence of onychomadesis in a nursery setting, with 92% (11/12) of onychomadesis cases preceded by HFMD 2 months prior.¹⁸

Etiology

Local trauma to the nail bed is the most common cause of single-digit onychomadesis.⁴ Multiple-digit involvement suggests a systemic etiology such as fever, erythroderma, and Kawasaki disease; use of drugs (eg, chemotherapeutic agents, anticonvulsants, lithium, retinoids); and viral infections such as HFMD and varicella at the infantile age (Table).^5,9,19 Most drug-related nail changes are the outcome of acute toxicity to the proliferating nail matrix epithelium. If onychomadesis affects all nails at the same level, the patient’s history of medication use and other treatments taken 2 to 3 weeks prior to the appearance of the nail findings should be evaluated. Chemotherapeutic agents produce nail changes in a high proportion of patients, which often are related to drug dosage. These effects also are reproducible with re-administration of the drug.²⁰ Onychomadesis also has been reported as a possible side effect of anticonvulsants such as valproic acid (VPA).²¹ One study evaluating the link between VPA and onychomadesis indicated that nail changes may be due to a disturbance of zinc metabolism.²² However, the pathomechanism of onychomadesis associated with VPA treatment remains unclear.²¹ Onychomadesis also has developed after an allergic drug reaction to oral penicillin V after treatment of a sore throat in a 23-month-old child.²³

Nail involvement has been reported in 10% of cases of inflammatory conditions such as lichen planus²¹; however, it may be more common but underrecognized and underreported. Grover et al⁹ indicated that lichen planus–induced severe inflammation in the matrix of the nail unit leading to a temporary growth arrest was the possible mechanism leading to nail shedding. Prompt systemic and intramatricial steroid treatment of lichen planus is required to avoid potential scarring of the nail matrix and permanent damage.⁹

Onychomadesis also has been reported following varicella infection (chickenpox). Podder et al¹⁹ reported the case of a 7-year-old girl who had recovered from a varicella infection 5 weeks prior and presented with onychomadesis of the right index fingernail with all other fingernails and toenails appearing normal. Kocak and Koçak⁵ reported onychomadesis in 2 sisters with varicella infection. There are few reported cases, so it is still unclear whether varicella infection is an inciting factor.¹⁹

One of the most studied viral infections linked to onychomadesis is HFMD, which is a common viral infection that mostly affects children younger than 10 years.¹ The precise mechanism of onychomadesis for these viral infection events remains unclear.^7,10,13 Several theories have been delineated, including nail matrix arrest from fever occurring during HFMD.⁶ However, this cause is unlikely, as fevers are typically low grade and present only for a few hours.^4,6,13 Direct inflammation spreading from skin lesions of HFMD around the nails or maceration associated with finger blisters could cause onychomadesis.^1,5,7 Haneke²⁴ hypothesized that nail shedding may be the consequence of vesicles localized in the periungual tissue, but studies have shown incidence without prior lesions on the fingers and no relationship between nail matrix arrest and severity of HFMD.^5,6,13 Bettoli et al²⁵ reported that inflammation secondary to viral infection around the nail matrix might be induced directly by viruses or indirectly by virus-specific immunocomplexes and consequent distal embolism. Osterback et al¹⁴ used reverse transcription–polymerase chain reaction to detect CVA6 in fragmented nails from 2 children and 1 parent following an HFMD episode, suggesting that virus replication could damage the nail matrix, resulting in onychomadesis. Cabrerizo et al¹⁸ also suggested that virus replication directly damages the nail matrix based on the presence of CVA6 in shed nails. Because fingernails with onychomadesis are not always of the fingers affected by HFMD, an indirect effect of viral infection on the nail matrix is more plausible.⁸ Additional studies are needed to clarify the virus-associated mechanism of nail matrix arrest.⁶ Finally, frequent washing of hands¹⁵ resulting in maceration, Candida infection, and allergic contact dermatitis² may be possible causes. It is unclear if onychomadesis following HFMD is related to viral replication, inflammation, or intensive hygienic measures, and further investigation is needed.^2,15

Clinical Characteristics

The ventral floor is the site of the germinal matrix and is responsible for 90% of nail production. As a result, more of the nail plate substance is produced proximally, leading to a natural convex curvature from the proximal to distal nail.¹¹ Beau lines are transverse ridging of the nail plates.⁶ Onychomadesis may be viewed as a more severe form of Beau lines, with complete separation and possible shedding of the nail plate (Figure).^3,4 In both cases, an insult to the nail matrix is followed by recovery and production of the nail plate at the nail matrix.⁴ In Beau lines, slowing or disruption of cell growth from the proximal matrix results in a thinner nail plate, leading to transverse depressions. Onychomadesis has a similar pathophysiology but is associated with a complete halt in the nail plate production.³

Diagnosis

The diagnosis of onychomadesis is made clinically.^3,10 Distinct nail changes can be detected by inspection and palpation of the nail plate,^3,11 which allows for differentiation between Beau lines and complete nail shedding. Additionally, any signs of nail trauma need to be noted, as well as pain, swelling, or pruritus, as these symptoms also can guide in determining the etiology of the nail dystrophy. Ultrasonography can confirm the diagnosis, as the defect can be identified beneath the proximal nail fold.^3,26 When it occurs after HFMD or varicella, onychomadesis tends to present in 28 to 40 days following infection.^4,6,10 Physicians should consider underlying associations. A review of viral illnesses within 1 to 2 months prior to development of nail changes often will identify the causative disease.⁴ Each patient should be evaluated for recent nail trauma; medications; viral infection; and autoimmune, systemic, and inflammatory diseases.

Treatment

Onychomadesis typically is mild and self-limited.^4,10 There is no specific treatment,¹⁰ but a conservative approach to management is recommended. Treatment of any underlying medical conditions or discontinuation of an offending medication may help to prevent recurrent onychomadesis.³ Supportive care along with protection of the nail bed by maintaining short nails and using adhesive bandages over the affected nails to avoid snagging the nail or ripping off the partially attached nails is recommended.⁴ In some cases, onychomadesis has been treated with topical application of urea cream 40% under occlusion²⁷ or halcinonide cream 0.1% under occlusion for 5 to 6 days,²⁸ but these treatments have not been universally effective.³ External use of basic fibroblast growth factor to stimulate new regrowth of the nail plate has been advocated.³ It is important to reassure patients that as long as the underlying causes are eliminated and the nail matrix has not been permanently scarred, the nails should grow back within 12 weeks or sooner in children. Thus, typically only reassurance and counseling of parents/guardians is required for onychomadesis in children.^1,2 However, the nails may be dystrophic or fail to regrow if there is poor peripheral circulation or permanent nail matrix damage.

Conclusion

Fortunately, onychomadesis is self-limited. Physicians should look for underlying causes of onychomadesis, including a history of viral infections such as HFMD and varicella as well as systemic diseases and use of medications. As long as any underlying disorder or condition has been resolved, spontaneous regrowth of healthy nails usually but not always occurs within 12 weeks or sooner in children.

Onychomadesis is an acute, noninflammatory, painless, proximal separation of the nail plate from the nail matrix. It occurs due to an abrupt stoppage of nail production by matrix cells, producing temporary cessation of nail growth with or without subsequent complete shedding of nails.^1-10 Onychomadesis has a wide spectrum of clinical presentations ranging from mild transverse ridges of the nail plate (Beau lines) to complete nail shedding.^4,11 Onychomadesis may be related to systemic and dermatologic diseases, drugs (eg, chemotherapeutic agents, anticonvulsants, lithium, retinoids), nail trauma, fever, or infection,⁵ and a connection between onychomadesis and hand-foot-and-mouth disease (HFMD) was first described by Clementz et al¹² following outbreaks in Europe, Asia, and the United States.

Epidemiology

Onychomadesis has been observed in children of all ages including neonates. Neonatal onychomadesis is thought to be related to perinatal stressors and birth trauma, with possible exacerbation by superimposed candidiasis.¹⁰ Depending on the underlying cause, there may be involvement of a single nail or multiple nails. Nag et al¹ noted that onychomadesis was most commonly observed in nails of the middle finger (73.7%), followed by the thumb (63.2%) and ring finger (52.6%). Fingernails are more commonly involved than toenails.¹

Clementz et al¹² first proposed the association between onychomadesis and HFMD in 2000. Patients with a history of HFMD were found to be 14 times more likely to develop onychomadesis (relative risk, 14; 95% confidence interval, 4.57-42.86).⁴ A common pathogen for HFMD is coxsackievirus A6 (CVA6),^13,14 but the mechanism of onychomadesis in HFMD remains unclear.^5,7,13 Outbreaks of HFMD have been reported in Spain, Finland, Japan, Thailand, the United States, Singapore, and China.¹⁵ During an outbreak of HFMD in Taiwan, the incidence of onychomadesis following CVA6 infection was 37% (48/130) compared to 5% (7/145) in cases with non-CVA6 causative strains.¹⁶ There also have been observed differences in the prevalence of onychomadesis by age: a 55% (18/33) occurrence rate was noted in the youngest age group (range, 9–23 months), 30% (8/27) in the middle age group (range, 24–32 months), and 4% (1/28) in the oldest age group (range, 33–42 months), with an average of 4 nails shed per case.¹⁷ A study in Spain also found a high occurrence of onychomadesis in a nursery setting, with 92% (11/12) of onychomadesis cases preceded by HFMD 2 months prior.¹⁸

Etiology

Local trauma to the nail bed is the most common cause of single-digit onychomadesis.⁴ Multiple-digit involvement suggests a systemic etiology such as fever, erythroderma, and Kawasaki disease; use of drugs (eg, chemotherapeutic agents, anticonvulsants, lithium, retinoids); and viral infections such as HFMD and varicella at the infantile age (Table).^5,9,19 Most drug-related nail changes are the outcome of acute toxicity to the proliferating nail matrix epithelium. If onychomadesis affects all nails at the same level, the patient’s history of medication use and other treatments taken 2 to 3 weeks prior to the appearance of the nail findings should be evaluated. Chemotherapeutic agents produce nail changes in a high proportion of patients, which often are related to drug dosage. These effects also are reproducible with re-administration of the drug.²⁰ Onychomadesis also has been reported as a possible side effect of anticonvulsants such as valproic acid (VPA).²¹ One study evaluating the link between VPA and onychomadesis indicated that nail changes may be due to a disturbance of zinc metabolism.²² However, the pathomechanism of onychomadesis associated with VPA treatment remains unclear.²¹ Onychomadesis also has developed after an allergic drug reaction to oral penicillin V after treatment of a sore throat in a 23-month-old child.²³

Nail involvement has been reported in 10% of cases of inflammatory conditions such as lichen planus²¹; however, it may be more common but underrecognized and underreported. Grover et al⁹ indicated that lichen planus–induced severe inflammation in the matrix of the nail unit leading to a temporary growth arrest was the possible mechanism leading to nail shedding. Prompt systemic and intramatricial steroid treatment of lichen planus is required to avoid potential scarring of the nail matrix and permanent damage.⁹

Onychomadesis also has been reported following varicella infection (chickenpox). Podder et al¹⁹ reported the case of a 7-year-old girl who had recovered from a varicella infection 5 weeks prior and presented with onychomadesis of the right index fingernail with all other fingernails and toenails appearing normal. Kocak and Koçak⁵ reported onychomadesis in 2 sisters with varicella infection. There are few reported cases, so it is still unclear whether varicella infection is an inciting factor.¹⁹

One of the most studied viral infections linked to onychomadesis is HFMD, which is a common viral infection that mostly affects children younger than 10 years.¹ The precise mechanism of onychomadesis for these viral infection events remains unclear.^7,10,13 Several theories have been delineated, including nail matrix arrest from fever occurring during HFMD.⁶ However, this cause is unlikely, as fevers are typically low grade and present only for a few hours.^4,6,13 Direct inflammation spreading from skin lesions of HFMD around the nails or maceration associated with finger blisters could cause onychomadesis.^1,5,7 Haneke²⁴ hypothesized that nail shedding may be the consequence of vesicles localized in the periungual tissue, but studies have shown incidence without prior lesions on the fingers and no relationship between nail matrix arrest and severity of HFMD.^5,6,13 Bettoli et al²⁵ reported that inflammation secondary to viral infection around the nail matrix might be induced directly by viruses or indirectly by virus-specific immunocomplexes and consequent distal embolism. Osterback et al¹⁴ used reverse transcription–polymerase chain reaction to detect CVA6 in fragmented nails from 2 children and 1 parent following an HFMD episode, suggesting that virus replication could damage the nail matrix, resulting in onychomadesis. Cabrerizo et al¹⁸ also suggested that virus replication directly damages the nail matrix based on the presence of CVA6 in shed nails. Because fingernails with onychomadesis are not always of the fingers affected by HFMD, an indirect effect of viral infection on the nail matrix is more plausible.⁸ Additional studies are needed to clarify the virus-associated mechanism of nail matrix arrest.⁶ Finally, frequent washing of hands¹⁵ resulting in maceration, Candida infection, and allergic contact dermatitis² may be possible causes. It is unclear if onychomadesis following HFMD is related to viral replication, inflammation, or intensive hygienic measures, and further investigation is needed.^2,15

Clinical Characteristics

The ventral floor is the site of the germinal matrix and is responsible for 90% of nail production. As a result, more of the nail plate substance is produced proximally, leading to a natural convex curvature from the proximal to distal nail.¹¹ Beau lines are transverse ridging of the nail plates.⁶ Onychomadesis may be viewed as a more severe form of Beau lines, with complete separation and possible shedding of the nail plate (Figure).^3,4 In both cases, an insult to the nail matrix is followed by recovery and production of the nail plate at the nail matrix.⁴ In Beau lines, slowing or disruption of cell growth from the proximal matrix results in a thinner nail plate, leading to transverse depressions. Onychomadesis has a similar pathophysiology but is associated with a complete halt in the nail plate production.³

Diagnosis

The diagnosis of onychomadesis is made clinically.^3,10 Distinct nail changes can be detected by inspection and palpation of the nail plate,^3,11 which allows for differentiation between Beau lines and complete nail shedding. Additionally, any signs of nail trauma need to be noted, as well as pain, swelling, or pruritus, as these symptoms also can guide in determining the etiology of the nail dystrophy. Ultrasonography can confirm the diagnosis, as the defect can be identified beneath the proximal nail fold.^3,26 When it occurs after HFMD or varicella, onychomadesis tends to present in 28 to 40 days following infection.^4,6,10 Physicians should consider underlying associations. A review of viral illnesses within 1 to 2 months prior to development of nail changes often will identify the causative disease.⁴ Each patient should be evaluated for recent nail trauma; medications; viral infection; and autoimmune, systemic, and inflammatory diseases.

Treatment

Onychomadesis typically is mild and self-limited.^4,10 There is no specific treatment,¹⁰ but a conservative approach to management is recommended. Treatment of any underlying medical conditions or discontinuation of an offending medication may help to prevent recurrent onychomadesis.³ Supportive care along with protection of the nail bed by maintaining short nails and using adhesive bandages over the affected nails to avoid snagging the nail or ripping off the partially attached nails is recommended.⁴ In some cases, onychomadesis has been treated with topical application of urea cream 40% under occlusion²⁷ or halcinonide cream 0.1% under occlusion for 5 to 6 days,²⁸ but these treatments have not been universally effective.³ External use of basic fibroblast growth factor to stimulate new regrowth of the nail plate has been advocated.³ It is important to reassure patients that as long as the underlying causes are eliminated and the nail matrix has not been permanently scarred, the nails should grow back within 12 weeks or sooner in children. Thus, typically only reassurance and counseling of parents/guardians is required for onychomadesis in children.^1,2 However, the nails may be dystrophic or fail to regrow if there is poor peripheral circulation or permanent nail matrix damage.

Conclusion

Fortunately, onychomadesis is self-limited. Physicians should look for underlying causes of onychomadesis, including a history of viral infections such as HFMD and varicella as well as systemic diseases and use of medications. As long as any underlying disorder or condition has been resolved, spontaneous regrowth of healthy nails usually but not always occurs within 12 weeks or sooner in children.

Onychomadesis is an acute, noninflammatory, painless, proximal separation of the nail plate from the nail matrix. It occurs due to an abrupt stoppage of nail production by matrix cells, producing temporary cessation of nail growth with or without subsequent complete shedding of nails.^1-10 Onychomadesis has a wide spectrum of clinical presentations ranging from mild transverse ridges of the nail plate (Beau lines) to complete nail shedding.^4,11 Onychomadesis may be related to systemic and dermatologic diseases, drugs (eg, chemotherapeutic agents, anticonvulsants, lithium, retinoids), nail trauma, fever, or infection,⁵ and a connection between onychomadesis and hand-foot-and-mouth disease (HFMD) was first described by Clementz et al¹² following outbreaks in Europe, Asia, and the United States.

Epidemiology

Onychomadesis has been observed in children of all ages including neonates. Neonatal onychomadesis is thought to be related to perinatal stressors and birth trauma, with possible exacerbation by superimposed candidiasis.¹⁰ Depending on the underlying cause, there may be involvement of a single nail or multiple nails. Nag et al¹ noted that onychomadesis was most commonly observed in nails of the middle finger (73.7%), followed by the thumb (63.2%) and ring finger (52.6%). Fingernails are more commonly involved than toenails.¹

Clementz et al¹² first proposed the association between onychomadesis and HFMD in 2000. Patients with a history of HFMD were found to be 14 times more likely to develop onychomadesis (relative risk, 14; 95% confidence interval, 4.57-42.86).⁴ A common pathogen for HFMD is coxsackievirus A6 (CVA6),^13,14 but the mechanism of onychomadesis in HFMD remains unclear.^5,7,13 Outbreaks of HFMD have been reported in Spain, Finland, Japan, Thailand, the United States, Singapore, and China.¹⁵ During an outbreak of HFMD in Taiwan, the incidence of onychomadesis following CVA6 infection was 37% (48/130) compared to 5% (7/145) in cases with non-CVA6 causative strains.¹⁶ There also have been observed differences in the prevalence of onychomadesis by age: a 55% (18/33) occurrence rate was noted in the youngest age group (range, 9–23 months), 30% (8/27) in the middle age group (range, 24–32 months), and 4% (1/28) in the oldest age group (range, 33–42 months), with an average of 4 nails shed per case.¹⁷ A study in Spain also found a high occurrence of onychomadesis in a nursery setting, with 92% (11/12) of onychomadesis cases preceded by HFMD 2 months prior.¹⁸

Etiology

Local trauma to the nail bed is the most common cause of single-digit onychomadesis.⁴ Multiple-digit involvement suggests a systemic etiology such as fever, erythroderma, and Kawasaki disease; use of drugs (eg, chemotherapeutic agents, anticonvulsants, lithium, retinoids); and viral infections such as HFMD and varicella at the infantile age (Table).^5,9,19 Most drug-related nail changes are the outcome of acute toxicity to the proliferating nail matrix epithelium. If onychomadesis affects all nails at the same level, the patient’s history of medication use and other treatments taken 2 to 3 weeks prior to the appearance of the nail findings should be evaluated. Chemotherapeutic agents produce nail changes in a high proportion of patients, which often are related to drug dosage. These effects also are reproducible with re-administration of the drug.²⁰ Onychomadesis also has been reported as a possible side effect of anticonvulsants such as valproic acid (VPA).²¹ One study evaluating the link between VPA and onychomadesis indicated that nail changes may be due to a disturbance of zinc metabolism.²² However, the pathomechanism of onychomadesis associated with VPA treatment remains unclear.²¹ Onychomadesis also has developed after an allergic drug reaction to oral penicillin V after treatment of a sore throat in a 23-month-old child.²³

Nail involvement has been reported in 10% of cases of inflammatory conditions such as lichen planus²¹; however, it may be more common but underrecognized and underreported. Grover et al⁹ indicated that lichen planus–induced severe inflammation in the matrix of the nail unit leading to a temporary growth arrest was the possible mechanism leading to nail shedding. Prompt systemic and intramatricial steroid treatment of lichen planus is required to avoid potential scarring of the nail matrix and permanent damage.⁹

Onychomadesis also has been reported following varicella infection (chickenpox). Podder et al¹⁹ reported the case of a 7-year-old girl who had recovered from a varicella infection 5 weeks prior and presented with onychomadesis of the right index fingernail with all other fingernails and toenails appearing normal. Kocak and Koçak⁵ reported onychomadesis in 2 sisters with varicella infection. There are few reported cases, so it is still unclear whether varicella infection is an inciting factor.¹⁹

One of the most studied viral infections linked to onychomadesis is HFMD, which is a common viral infection that mostly affects children younger than 10 years.¹ The precise mechanism of onychomadesis for these viral infection events remains unclear.^7,10,13 Several theories have been delineated, including nail matrix arrest from fever occurring during HFMD.⁶ However, this cause is unlikely, as fevers are typically low grade and present only for a few hours.^4,6,13 Direct inflammation spreading from skin lesions of HFMD around the nails or maceration associated with finger blisters could cause onychomadesis.^1,5,7 Haneke²⁴ hypothesized that nail shedding may be the consequence of vesicles localized in the periungual tissue, but studies have shown incidence without prior lesions on the fingers and no relationship between nail matrix arrest and severity of HFMD.^5,6,13 Bettoli et al²⁵ reported that inflammation secondary to viral infection around the nail matrix might be induced directly by viruses or indirectly by virus-specific immunocomplexes and consequent distal embolism. Osterback et al¹⁴ used reverse transcription–polymerase chain reaction to detect CVA6 in fragmented nails from 2 children and 1 parent following an HFMD episode, suggesting that virus replication could damage the nail matrix, resulting in onychomadesis. Cabrerizo et al¹⁸ also suggested that virus replication directly damages the nail matrix based on the presence of CVA6 in shed nails. Because fingernails with onychomadesis are not always of the fingers affected by HFMD, an indirect effect of viral infection on the nail matrix is more plausible.⁸ Additional studies are needed to clarify the virus-associated mechanism of nail matrix arrest.⁶ Finally, frequent washing of hands¹⁵ resulting in maceration, Candida infection, and allergic contact dermatitis² may be possible causes. It is unclear if onychomadesis following HFMD is related to viral replication, inflammation, or intensive hygienic measures, and further investigation is needed.^2,15

Clinical Characteristics

The ventral floor is the site of the germinal matrix and is responsible for 90% of nail production. As a result, more of the nail plate substance is produced proximally, leading to a natural convex curvature from the proximal to distal nail.¹¹ Beau lines are transverse ridging of the nail plates.⁶ Onychomadesis may be viewed as a more severe form of Beau lines, with complete separation and possible shedding of the nail plate (Figure).^3,4 In both cases, an insult to the nail matrix is followed by recovery and production of the nail plate at the nail matrix.⁴ In Beau lines, slowing or disruption of cell growth from the proximal matrix results in a thinner nail plate, leading to transverse depressions. Onychomadesis has a similar pathophysiology but is associated with a complete halt in the nail plate production.³

Diagnosis

The diagnosis of onychomadesis is made clinically.^3,10 Distinct nail changes can be detected by inspection and palpation of the nail plate,^3,11 which allows for differentiation between Beau lines and complete nail shedding. Additionally, any signs of nail trauma need to be noted, as well as pain, swelling, or pruritus, as these symptoms also can guide in determining the etiology of the nail dystrophy. Ultrasonography can confirm the diagnosis, as the defect can be identified beneath the proximal nail fold.^3,26 When it occurs after HFMD or varicella, onychomadesis tends to present in 28 to 40 days following infection.^4,6,10 Physicians should consider underlying associations. A review of viral illnesses within 1 to 2 months prior to development of nail changes often will identify the causative disease.⁴ Each patient should be evaluated for recent nail trauma; medications; viral infection; and autoimmune, systemic, and inflammatory diseases.

Treatment

Onychomadesis typically is mild and self-limited.^4,10 There is no specific treatment,¹⁰ but a conservative approach to management is recommended. Treatment of any underlying medical conditions or discontinuation of an offending medication may help to prevent recurrent onychomadesis.³ Supportive care along with protection of the nail bed by maintaining short nails and using adhesive bandages over the affected nails to avoid snagging the nail or ripping off the partially attached nails is recommended.⁴ In some cases, onychomadesis has been treated with topical application of urea cream 40% under occlusion²⁷ or halcinonide cream 0.1% under occlusion for 5 to 6 days,²⁸ but these treatments have not been universally effective.³ External use of basic fibroblast growth factor to stimulate new regrowth of the nail plate has been advocated.³ It is important to reassure patients that as long as the underlying causes are eliminated and the nail matrix has not been permanently scarred, the nails should grow back within 12 weeks or sooner in children. Thus, typically only reassurance and counseling of parents/guardians is required for onychomadesis in children.^1,2 However, the nails may be dystrophic or fail to regrow if there is poor peripheral circulation or permanent nail matrix damage.

Conclusion

Fortunately, onychomadesis is self-limited. Physicians should look for underlying causes of onychomadesis, including a history of viral infections such as HFMD and varicella as well as systemic diseases and use of medications. As long as any underlying disorder or condition has been resolved, spontaneous regrowth of healthy nails usually but not always occurs within 12 weeks or sooner in children.

Enbrel

Amgen Inc announces that the US Food and Drug Administration has approved the supplemental Biologics License Application for the expanded use of Enbrel (etanercept) for the treatment of moderate to severe plaque psoriasis in pediatric patients (aged 4–17 years). Enbrel, a tumor necrosis factor blocker, was approved for the treatment of moderate to severe plaque psoriasis in adults in 2004. For more information, visit www.enbrel.com.

Eucrisa

Pfizer Inc announces US Food and Drug Administration approval of Eucrisa (crisaborole) ointment 2% for the treatment of mild to moderate atopic dermatitis in patients 2 years and older. Eucrisa is a nonsteroidal topical phosphodiesterase 4 inhibitor and is applied twice daily. This approval provides patients with atopic dermatitis another treatment alternative, as this community has not had a new prescription treatment for more than 10 years. For more information, visit www.pfizer.com.

Isdinceutics

Isdin based in Spain has launched the Isdinceutics line of physician-dispensed cosmeceuticals to the US market, which focuses on vitamins and hydrators rather than chemicals to rejuvenate the skin. Isdinceutics features a daily antioxidant routine with Flavo-C Ultraglican and Flavo-C Serum to reduce the appearance of microwrinkles and elevate the skin’s natural moisture production. Products to correct pigmentation problems as well as undereye circles and puffiness also are available. For more information, visit www.isdin.com/us.

If you would like your product included in Product News, please email a press release to the Editorial Office at [email protected].

Enbrel

Amgen Inc announces that the US Food and Drug Administration has approved the supplemental Biologics License Application for the expanded use of Enbrel (etanercept) for the treatment of moderate to severe plaque psoriasis in pediatric patients (aged 4–17 years). Enbrel, a tumor necrosis factor blocker, was approved for the treatment of moderate to severe plaque psoriasis in adults in 2004. For more information, visit www.enbrel.com.

Eucrisa

Pfizer Inc announces US Food and Drug Administration approval of Eucrisa (crisaborole) ointment 2% for the treatment of mild to moderate atopic dermatitis in patients 2 years and older. Eucrisa is a nonsteroidal topical phosphodiesterase 4 inhibitor and is applied twice daily. This approval provides patients with atopic dermatitis another treatment alternative, as this community has not had a new prescription treatment for more than 10 years. For more information, visit www.pfizer.com.

Isdinceutics

Isdin based in Spain has launched the Isdinceutics line of physician-dispensed cosmeceuticals to the US market, which focuses on vitamins and hydrators rather than chemicals to rejuvenate the skin. Isdinceutics features a daily antioxidant routine with Flavo-C Ultraglican and Flavo-C Serum to reduce the appearance of microwrinkles and elevate the skin’s natural moisture production. Products to correct pigmentation problems as well as undereye circles and puffiness also are available. For more information, visit www.isdin.com/us.

If you would like your product included in Product News, please email a press release to the Editorial Office at [email protected].

Enbrel

Amgen Inc announces that the US Food and Drug Administration has approved the supplemental Biologics License Application for the expanded use of Enbrel (etanercept) for the treatment of moderate to severe plaque psoriasis in pediatric patients (aged 4–17 years). Enbrel, a tumor necrosis factor blocker, was approved for the treatment of moderate to severe plaque psoriasis in adults in 2004. For more information, visit www.enbrel.com.

Eucrisa

Pfizer Inc announces US Food and Drug Administration approval of Eucrisa (crisaborole) ointment 2% for the treatment of mild to moderate atopic dermatitis in patients 2 years and older. Eucrisa is a nonsteroidal topical phosphodiesterase 4 inhibitor and is applied twice daily. This approval provides patients with atopic dermatitis another treatment alternative, as this community has not had a new prescription treatment for more than 10 years. For more information, visit www.pfizer.com.

Isdinceutics

Isdin based in Spain has launched the Isdinceutics line of physician-dispensed cosmeceuticals to the US market, which focuses on vitamins and hydrators rather than chemicals to rejuvenate the skin. Isdinceutics features a daily antioxidant routine with Flavo-C Ultraglican and Flavo-C Serum to reduce the appearance of microwrinkles and elevate the skin’s natural moisture production. Products to correct pigmentation problems as well as undereye circles and puffiness also are available. For more information, visit www.isdin.com/us.

If you would like your product included in Product News, please email a press release to the Editorial Office at [email protected].

Submental fat (SMF) accumulation within the subcutaneous (preplatysmal) or subplatysmal fat compartment of the cervical anatomy results in an obtuse cervicomental angle and loss of mandibular and cervical contours. It is a common cosmetic concern due to its aesthetic association with weight gain and aging.¹ Minimally invasive or noninvasive submental lipolytic agents and techniques are sought for patients who are not candidates for surgery or prefer more conservative cosmetic treatments. These methods typically are only effective in addressing preplatysmal SMF, as subplatysmal SMF requires more surgical methods due to its less-accessible location. The pathology of SMF should initially be assessed by clinical examination or ultrasonography. In this article, we review the most relevant clinical and safety data on minimally invasive and noninvasive treatments for SMF, including laser-assisted lipolysis (LAL), radiofrequency (RF)–assisted lipolysis, deoxycholic acid (DCA), and cryolipolysis.

MINIMALLY INVASIVE MODALITIES

Traditional, or tumescent, liposuction is still widely considered the most effective method for removal of large masses of adiposity. Laser- and RF-assisted adjuncts have been more recently developed to improve patient side effects and recovery time and reduce the manual effort of surgeons. Of note, these adjuncts, with some exceptions, still require the same invasiveness as traditional liposuction, involving submental stab incisions of up to 2.4 mm.

Laser-Assisted Lipolysis

Laser-assisted lipolysis produces a similar effect as suction-assisted lipoplasty by focusing pulses of laser energy through a 1-mm wide fiber optic cannula and inducing thermally mediated adipolysis. The directed laser results in adipocyte rupturing with added benefits of skin retraction and small vessel coagulation, thus lessening intraoperative blood loss.² This technique typically requires smaller incisions than traditional liposuction. The most common laser lipolysis systems used in cosmetic dermatology are the 920- to 980-nm diode lasers and 1064- to 1440-nm Nd:YAG lasers. The 924-nm diode, 1064-nm Nd:YAG, and 1064/1320-nm Nd:YAG have been best characterized in clinical trials, as reviewed by Fakhouri et al,³ with demonstrated efficacy in reducing SMF density.

The first randomized prospective trial comparing LAL (using 1064-nm Nd:YAG) and traditional liposuction in various anatomical areas on 25 patients showed no difference in cosmetic results, ecchymoses, edema, or retraction, and significantly lower postoperative pain ratings (P<.0001) in LAL.⁴ A more recent prospective randomized comparison of LAL (980-nm diode laser; 6–8 W) and traditional liposuction of the submental area in 40 female patients showed greater reduction in SMF thickness in the LAL group compared to the liposuction group at 2-month follow-up (6.2 vs 8.22 unspecified units; P<.001) with significant improvement from baseline in both groups (P<.001).⁵ However, the cosmetic benefit of LAL over traditional liposuction remains controversial and has not been unequivocally established in the literature.

Common adverse events (AEs) are postoperative swelling, ecchymoses, and pain, and complications of interest are nodularity, skin infections, burns, and nerve damage.⁶ In one retrospective investigation (N=537), these complications occurred at a rate of less than 1% (4 burns and 1 skin infection).⁶ Patients treated with LAL may report fewer AEs, especially pain and bleeding, compared to liposuction-treated patients.³

RF-Assisted Lipolysis

Radiofrequency-assisted lipolysis is one of the newest technologies in lipocontouring. NeckTite (Invasix Aesthetic Solutions) is effective for treatment of preplatysmal adiposity and cervicomental lipocontouring; a 2.4-mm bipolar probe that is inserted into the subdermal space and connected with an external electrode emits RF energy and simultaneously coagulates and aspirates adipose tissue. NeckTite also may be used in conjunction with FaceTite (Invasix Aesthetic Solutions), which promotes fibroseptal network remodeling and dermal contraction.²

In the first published investigation of the efficacy and safety of NeckTite, 47 of 55 patients received treatment of slight to moderate SMF (average body mass index [BMI], 25 kg/m²) with NeckTite and FaceTite or NeckTite alone.⁷ At 6-month follow-up, 87% (48/55) of patients subjectively rated treatment efficacy as satisfactory, and 2 independent physicians rated the improvement between before-and-after frontal and lateral photographs of the submental area as moderate to excellent in 95% (52/55) of all cases. Reported complications in this study were full-thickness burns resulting in minor scarring (2/55 [4%]), neck tissue hardness that resolved with daily massage after 3 months (5/55 [9%]), and transient facial nerve paresis of the mandibular branch that resolved after 2 months (1/55 [2%]).⁷

NONINVASIVE MODALITIES

RF-Assisted Contouring

Another exciting development in RF technology is truSculpt (Cutera), a noninvasive contouring device that is placed over the epidermis and emits RF energy that preferentially heats fat more than other tissue types. In a single-center prospective trial of efficacy and safety in the treatment of SMF, 17 patients received 2 treatments with truSculpt administered 1 month apart.⁸ At 1- and 6-month follow-up, 82.3% (14/17) and 52.9% (9/17) of patients showed improvement on physician assessment. Submental circumference and ultrasonographic fat thickness reductions at 1-month follow-up were 1.4 cm (5.7% of pretreatment circumference [P<.001]) and 5.4 mm (9.7% of pretreatment fat thickness [P=.005]), respectively. At further longer-term follow-up to 6 months, submental circumference was 0.9 cm (3.8% of pretreatment circumference [P<.001]) and ultrasonographic fat reduction was 6.8 mm (10.5% of pretreatment fat thickness [P=.006]). Commonly reported AEs were pain (rate not given), erythema (8/17 [47%]), edema (1/17 [6%]), and vesicle formation (1/17 [6%]); all were self-resolving. Erythema usually subsided within 6 hours posttreatment. No other AEs or complications were reported.⁸

Deoxycholic Acid

Deoxycholic acid (DCA)(formerly ATX-101) is an injectable liquid formulation of synthetic DCA that was approved by the US Food and Drug Administration (FDA) in 2015 for moderate to severe SMF. Deoxycholic acid exists endogenously as a bile salt emulsifier and has been shown to cause dose-dependent adipocyte lysis, necrosis, disruption and dissolution of fat architecture, and inflammatory targeting of adipocytes by immune cells.^9,10 Thus, DCA causes targeted adipocytolysis and is a novel medical agent in the treatment of SMF. Supplied in 2-mL vials, clinicians may inject 10 mL at each treatment for up to 6 treatments administered 1 month apart.¹¹

Efficacy

REFINE-1, a pivotal North American–based phase 3 trial, investigated the efficacy and safety of DCA.¹² A total of 506 participants with scores of 2 (moderate) or 3 (severe) on the Clinician-Reported Submental Fat Rating Scale (CR-SMFRS) and a mean BMI of 29 kg/m² were randomized to receive preplatysmal fat injections of 2 mg/cm² of DCA (n=256) or placebo (n=250). Participants received up to 10 mL of product (mean total of 25 mL of DCA across all visits) at each treatment session for up to 6 sessions depending on individual efficacy, with approximately 28 days between sessions. Sixty-four percent of the treatment group received all 6 treatments. At 12-week follow-up after the last treatment session, 70% of DCA-treated participants versus 18.6% of placebo-treated participants (P<.001) improved by 1 grade or more on the CR-SMFRS and 13.4% versus 0% (P<.001) improved by 2 grades or more. Skin laxity was unchanged or improved in 92.7% of the DCA group and 87.6% of the placebo group.¹²

REFINE-2, the second of the North American phase 3 trials, had parallel inclusionary criteria and study design and established efficacy of 2 mg/cm² DCA over placebo in 516 participants (randomized 1:1).¹³ At 12 weeks posttreatment, 66.5% of DCA-treated participants versus 22.2% of placebo-treated participants improved by 1 grade or more according to the CR-SMFRS (P<.001) and 18.6% versus 3% improved by 2 grades or more in SMF (P<.001). Magnetic resonance imaging analysis of participants in the DCA (n=113) and placebo groups (n=112) showed that 40.2% versus 5.2% (P<.001) exhibited 10% or more reduction in submental volume, with similar comparative rates of SMF thickness reduction via caliper measurements.¹³
 

Safety

Safety data from REFINE-1 showed higher rates of treatment-related AEs in DCA-treated participants compared to placebo, including hematoma (70% vs 67.3%), anesthesia (66.9% vs 4.4%), pain (65.4% vs 23.4%), edema (52.9% vs 21.8%), induration (18.3% vs 1.6%), paresthesia (12.8% vs 3.2%), nodule formation (12.5% vs 0.8%), and pruritus (8.6% vs 3.6%).¹² In this trial, 11 of 258 cases (4.3%) of marginal mandibular nerve paresis and asymmetric smile occurred, all in DCA-treated participants and with a median duration of 31 days. Dysphagia resolving in a median duration of 4 days occurred in 1.6% (4/258) of DCA-treated participants.¹² REFINE-2 exhibited similar rates of common AEs. Complications of note were 14 cases of marginal mandibular nerve paresis (11 in DCA group, 3 in placebo group) attributed to injection technique, 1 case of skin ulceration possibly related to accidental injection into dermis, and 6 cases of dysphagia in DCA participants attributed to higher volume treatment sessions and postinjection swelling. Dysphagia lasted a median of 2.5 days and resolved without sequelae.¹³

Overall, DCA demonstrated high rates of minor injection-site AEs that resolved without sequelae and could be mitigated by comfort therapies (eg, lidocaine, nonsteroidal anti-inflammatory drugs) as well as understanding the anatomy of the submental region. Adverse effects of particular interest included marginal mandibular nerve palsy, skin ulceration, and dysphagia.^12,13

Cryolipolysis

Cryolipolysis is an advancement that utilizes the application of noninvasive cooling temperatures to the skin’s surface to destroy underlying adipocytes based on the concept that lipid-filled cells are more susceptible to cold-induced injury than water-filled cells. Thus, cryolipolysis selectively targets adipose tissue, leading to cell death without harm to surrounding cells and without the need for surgery or injections.¹⁴

Cryolipolysis typically is delivered via a vacuum applicator (CoolMini, Zeltiq Aesthetics Inc), which applies temperatures of –10°C (14°F) to the skin in cycles of 60 minutes each. Initially approved by the FDA for treatment of flank adiposity in 2010, cryolipolysis has since been approved for treatment of the abdomen, thighs, and submental area.¹⁴ An advantage of cryolipolysis is that it does not require frequent treatment sessions for maximal efficacy.

Efficacy

The efficacy of cryolipolysis in the treatment of SMF was established in a multicenter device investigation resulting in its FDA approval for the submental region.¹⁵ Sixty participants with a mean BMI of 31.8 kg/m² received 1 (1/60) or 2 (59/60) treatment sessions of the submental area administered 6 weeks apart. Primary efficacy assessments included analysis by 3 blinded reviewers who viewed photographs of each participant at baseline, immediately posttreatment, 6 weeks posttreatment, and 12 weeks posttreatment; ultrasonographic measurements of SMF thickness; and a 12-point patient satisfaction questionnaire. Blinded reviewers correctly identified baseline images in 91.4% (55/60) of cases. Ultrasonography confirmed a mean reduction in SMF of 2 mm (P<.0001) or 20% of fat thickness at 12 weeks posttreatment. On subjective patient satisfaction surveys, 83% (50/60) of participants were satisfied with the procedure and 77% (46/60) reported a visible reduction in fat and perceived an improvement in appearance.¹⁵

Safety

The most common immediate posttreatment AEs were erythema/purpura (100%), numbness (90%), edema (62%), tingling (30%), blanching (25%), and bruising (3%) at the site of cryolipolysis with resolution within 1 week posttreatment, except for numbness.¹⁵ At 6-week follow-up, all AEs had resolved, except continued numbness in 4 participants that resolved by 12-week follow-up. A further event of note was fullness in the throat in 1 participant that was attributed to swelling and resolved at 40 days posttreatment without incident. No serious AEs were reported in this trial.¹⁵

A particularly concerning but rare complication that is increasing in awareness is paradoxical adipose hyperplasia following cryolipolysis. Patients may develop firm painless areas of soft tissue enlargements in the area of cryolipolysis typically 3 to 6 months posttreatment.¹⁶ The largest published report recorded an incidence rate of 0.46% (n=2, all males) at a single-center institution of 422 cryolipolysis treatments.¹⁶ Other incidence rates reported are 0.0051% and 0.78%.¹⁷ Causes and associations are not known, though male gender is speculated to increase risk.

Conclusion

This article highlights the available information on advances in minimally invasive and noninvasive treatments for SMF accumulation. The efficacy and safety trials varied in quality and in different methods of end point analysis of SMF reduction. Further, few trials have featured head-to-head comparisons of treatments.

Although liposuction and adjuncts remain the gold standard in large-mass lipid removal, these procedures are invasive and exhibit typical risks of surgery. Given its sensitive location, the submental area may require the use of more delicate therapeutic methods, including completely noninvasive devices such as truSculpt and cryolipolysis. Regardless of the chosen treatment, the most important factors in yielding patient satisfaction and SMF improvement are proper patient selection and an understanding of the anatomical source of adiposity to be addressed with the therapeutic modalities.

[polldaddy:9711250]

Submental fat (SMF) accumulation within the subcutaneous (preplatysmal) or subplatysmal fat compartment of the cervical anatomy results in an obtuse cervicomental angle and loss of mandibular and cervical contours. It is a common cosmetic concern due to its aesthetic association with weight gain and aging.¹ Minimally invasive or noninvasive submental lipolytic agents and techniques are sought for patients who are not candidates for surgery or prefer more conservative cosmetic treatments. These methods typically are only effective in addressing preplatysmal SMF, as subplatysmal SMF requires more surgical methods due to its less-accessible location. The pathology of SMF should initially be assessed by clinical examination or ultrasonography. In this article, we review the most relevant clinical and safety data on minimally invasive and noninvasive treatments for SMF, including laser-assisted lipolysis (LAL), radiofrequency (RF)–assisted lipolysis, deoxycholic acid (DCA), and cryolipolysis.

MINIMALLY INVASIVE MODALITIES

Traditional, or tumescent, liposuction is still widely considered the most effective method for removal of large masses of adiposity. Laser- and RF-assisted adjuncts have been more recently developed to improve patient side effects and recovery time and reduce the manual effort of surgeons. Of note, these adjuncts, with some exceptions, still require the same invasiveness as traditional liposuction, involving submental stab incisions of up to 2.4 mm.

Laser-Assisted Lipolysis

Laser-assisted lipolysis produces a similar effect as suction-assisted lipoplasty by focusing pulses of laser energy through a 1-mm wide fiber optic cannula and inducing thermally mediated adipolysis. The directed laser results in adipocyte rupturing with added benefits of skin retraction and small vessel coagulation, thus lessening intraoperative blood loss.² This technique typically requires smaller incisions than traditional liposuction. The most common laser lipolysis systems used in cosmetic dermatology are the 920- to 980-nm diode lasers and 1064- to 1440-nm Nd:YAG lasers. The 924-nm diode, 1064-nm Nd:YAG, and 1064/1320-nm Nd:YAG have been best characterized in clinical trials, as reviewed by Fakhouri et al,³ with demonstrated efficacy in reducing SMF density.

The first randomized prospective trial comparing LAL (using 1064-nm Nd:YAG) and traditional liposuction in various anatomical areas on 25 patients showed no difference in cosmetic results, ecchymoses, edema, or retraction, and significantly lower postoperative pain ratings (P<.0001) in LAL.⁴ A more recent prospective randomized comparison of LAL (980-nm diode laser; 6–8 W) and traditional liposuction of the submental area in 40 female patients showed greater reduction in SMF thickness in the LAL group compared to the liposuction group at 2-month follow-up (6.2 vs 8.22 unspecified units; P<.001) with significant improvement from baseline in both groups (P<.001).⁵ However, the cosmetic benefit of LAL over traditional liposuction remains controversial and has not been unequivocally established in the literature.

Common adverse events (AEs) are postoperative swelling, ecchymoses, and pain, and complications of interest are nodularity, skin infections, burns, and nerve damage.⁶ In one retrospective investigation (N=537), these complications occurred at a rate of less than 1% (4 burns and 1 skin infection).⁶ Patients treated with LAL may report fewer AEs, especially pain and bleeding, compared to liposuction-treated patients.³

RF-Assisted Lipolysis

Radiofrequency-assisted lipolysis is one of the newest technologies in lipocontouring. NeckTite (Invasix Aesthetic Solutions) is effective for treatment of preplatysmal adiposity and cervicomental lipocontouring; a 2.4-mm bipolar probe that is inserted into the subdermal space and connected with an external electrode emits RF energy and simultaneously coagulates and aspirates adipose tissue. NeckTite also may be used in conjunction with FaceTite (Invasix Aesthetic Solutions), which promotes fibroseptal network remodeling and dermal contraction.²

In the first published investigation of the efficacy and safety of NeckTite, 47 of 55 patients received treatment of slight to moderate SMF (average body mass index [BMI], 25 kg/m²) with NeckTite and FaceTite or NeckTite alone.⁷ At 6-month follow-up, 87% (48/55) of patients subjectively rated treatment efficacy as satisfactory, and 2 independent physicians rated the improvement between before-and-after frontal and lateral photographs of the submental area as moderate to excellent in 95% (52/55) of all cases. Reported complications in this study were full-thickness burns resulting in minor scarring (2/55 [4%]), neck tissue hardness that resolved with daily massage after 3 months (5/55 [9%]), and transient facial nerve paresis of the mandibular branch that resolved after 2 months (1/55 [2%]).⁷

NONINVASIVE MODALITIES

RF-Assisted Contouring

Another exciting development in RF technology is truSculpt (Cutera), a noninvasive contouring device that is placed over the epidermis and emits RF energy that preferentially heats fat more than other tissue types. In a single-center prospective trial of efficacy and safety in the treatment of SMF, 17 patients received 2 treatments with truSculpt administered 1 month apart.⁸ At 1- and 6-month follow-up, 82.3% (14/17) and 52.9% (9/17) of patients showed improvement on physician assessment. Submental circumference and ultrasonographic fat thickness reductions at 1-month follow-up were 1.4 cm (5.7% of pretreatment circumference [P<.001]) and 5.4 mm (9.7% of pretreatment fat thickness [P=.005]), respectively. At further longer-term follow-up to 6 months, submental circumference was 0.9 cm (3.8% of pretreatment circumference [P<.001]) and ultrasonographic fat reduction was 6.8 mm (10.5% of pretreatment fat thickness [P=.006]). Commonly reported AEs were pain (rate not given), erythema (8/17 [47%]), edema (1/17 [6%]), and vesicle formation (1/17 [6%]); all were self-resolving. Erythema usually subsided within 6 hours posttreatment. No other AEs or complications were reported.⁸

Deoxycholic Acid

Deoxycholic acid (DCA)(formerly ATX-101) is an injectable liquid formulation of synthetic DCA that was approved by the US Food and Drug Administration (FDA) in 2015 for moderate to severe SMF. Deoxycholic acid exists endogenously as a bile salt emulsifier and has been shown to cause dose-dependent adipocyte lysis, necrosis, disruption and dissolution of fat architecture, and inflammatory targeting of adipocytes by immune cells.^9,10 Thus, DCA causes targeted adipocytolysis and is a novel medical agent in the treatment of SMF. Supplied in 2-mL vials, clinicians may inject 10 mL at each treatment for up to 6 treatments administered 1 month apart.¹¹

Efficacy

REFINE-1, a pivotal North American–based phase 3 trial, investigated the efficacy and safety of DCA.¹² A total of 506 participants with scores of 2 (moderate) or 3 (severe) on the Clinician-Reported Submental Fat Rating Scale (CR-SMFRS) and a mean BMI of 29 kg/m² were randomized to receive preplatysmal fat injections of 2 mg/cm² of DCA (n=256) or placebo (n=250). Participants received up to 10 mL of product (mean total of 25 mL of DCA across all visits) at each treatment session for up to 6 sessions depending on individual efficacy, with approximately 28 days between sessions. Sixty-four percent of the treatment group received all 6 treatments. At 12-week follow-up after the last treatment session, 70% of DCA-treated participants versus 18.6% of placebo-treated participants (P<.001) improved by 1 grade or more on the CR-SMFRS and 13.4% versus 0% (P<.001) improved by 2 grades or more. Skin laxity was unchanged or improved in 92.7% of the DCA group and 87.6% of the placebo group.¹²

REFINE-2, the second of the North American phase 3 trials, had parallel inclusionary criteria and study design and established efficacy of 2 mg/cm² DCA over placebo in 516 participants (randomized 1:1).¹³ At 12 weeks posttreatment, 66.5% of DCA-treated participants versus 22.2% of placebo-treated participants improved by 1 grade or more according to the CR-SMFRS (P<.001) and 18.6% versus 3% improved by 2 grades or more in SMF (P<.001). Magnetic resonance imaging analysis of participants in the DCA (n=113) and placebo groups (n=112) showed that 40.2% versus 5.2% (P<.001) exhibited 10% or more reduction in submental volume, with similar comparative rates of SMF thickness reduction via caliper measurements.¹³
 

Safety

Safety data from REFINE-1 showed higher rates of treatment-related AEs in DCA-treated participants compared to placebo, including hematoma (70% vs 67.3%), anesthesia (66.9% vs 4.4%), pain (65.4% vs 23.4%), edema (52.9% vs 21.8%), induration (18.3% vs 1.6%), paresthesia (12.8% vs 3.2%), nodule formation (12.5% vs 0.8%), and pruritus (8.6% vs 3.6%).¹² In this trial, 11 of 258 cases (4.3%) of marginal mandibular nerve paresis and asymmetric smile occurred, all in DCA-treated participants and with a median duration of 31 days. Dysphagia resolving in a median duration of 4 days occurred in 1.6% (4/258) of DCA-treated participants.¹² REFINE-2 exhibited similar rates of common AEs. Complications of note were 14 cases of marginal mandibular nerve paresis (11 in DCA group, 3 in placebo group) attributed to injection technique, 1 case of skin ulceration possibly related to accidental injection into dermis, and 6 cases of dysphagia in DCA participants attributed to higher volume treatment sessions and postinjection swelling. Dysphagia lasted a median of 2.5 days and resolved without sequelae.¹³

Overall, DCA demonstrated high rates of minor injection-site AEs that resolved without sequelae and could be mitigated by comfort therapies (eg, lidocaine, nonsteroidal anti-inflammatory drugs) as well as understanding the anatomy of the submental region. Adverse effects of particular interest included marginal mandibular nerve palsy, skin ulceration, and dysphagia.^12,13

Cryolipolysis

Cryolipolysis is an advancement that utilizes the application of noninvasive cooling temperatures to the skin’s surface to destroy underlying adipocytes based on the concept that lipid-filled cells are more susceptible to cold-induced injury than water-filled cells. Thus, cryolipolysis selectively targets adipose tissue, leading to cell death without harm to surrounding cells and without the need for surgery or injections.¹⁴

Cryolipolysis typically is delivered via a vacuum applicator (CoolMini, Zeltiq Aesthetics Inc), which applies temperatures of –10°C (14°F) to the skin in cycles of 60 minutes each. Initially approved by the FDA for treatment of flank adiposity in 2010, cryolipolysis has since been approved for treatment of the abdomen, thighs, and submental area.¹⁴ An advantage of cryolipolysis is that it does not require frequent treatment sessions for maximal efficacy.

Efficacy

The efficacy of cryolipolysis in the treatment of SMF was established in a multicenter device investigation resulting in its FDA approval for the submental region.¹⁵ Sixty participants with a mean BMI of 31.8 kg/m² received 1 (1/60) or 2 (59/60) treatment sessions of the submental area administered 6 weeks apart. Primary efficacy assessments included analysis by 3 blinded reviewers who viewed photographs of each participant at baseline, immediately posttreatment, 6 weeks posttreatment, and 12 weeks posttreatment; ultrasonographic measurements of SMF thickness; and a 12-point patient satisfaction questionnaire. Blinded reviewers correctly identified baseline images in 91.4% (55/60) of cases. Ultrasonography confirmed a mean reduction in SMF of 2 mm (P<.0001) or 20% of fat thickness at 12 weeks posttreatment. On subjective patient satisfaction surveys, 83% (50/60) of participants were satisfied with the procedure and 77% (46/60) reported a visible reduction in fat and perceived an improvement in appearance.¹⁵

Safety

The most common immediate posttreatment AEs were erythema/purpura (100%), numbness (90%), edema (62%), tingling (30%), blanching (25%), and bruising (3%) at the site of cryolipolysis with resolution within 1 week posttreatment, except for numbness.¹⁵ At 6-week follow-up, all AEs had resolved, except continued numbness in 4 participants that resolved by 12-week follow-up. A further event of note was fullness in the throat in 1 participant that was attributed to swelling and resolved at 40 days posttreatment without incident. No serious AEs were reported in this trial.¹⁵

A particularly concerning but rare complication that is increasing in awareness is paradoxical adipose hyperplasia following cryolipolysis. Patients may develop firm painless areas of soft tissue enlargements in the area of cryolipolysis typically 3 to 6 months posttreatment.¹⁶ The largest published report recorded an incidence rate of 0.46% (n=2, all males) at a single-center institution of 422 cryolipolysis treatments.¹⁶ Other incidence rates reported are 0.0051% and 0.78%.¹⁷ Causes and associations are not known, though male gender is speculated to increase risk.

Conclusion

This article highlights the available information on advances in minimally invasive and noninvasive treatments for SMF accumulation. The efficacy and safety trials varied in quality and in different methods of end point analysis of SMF reduction. Further, few trials have featured head-to-head comparisons of treatments.

Although liposuction and adjuncts remain the gold standard in large-mass lipid removal, these procedures are invasive and exhibit typical risks of surgery. Given its sensitive location, the submental area may require the use of more delicate therapeutic methods, including completely noninvasive devices such as truSculpt and cryolipolysis. Regardless of the chosen treatment, the most important factors in yielding patient satisfaction and SMF improvement are proper patient selection and an understanding of the anatomical source of adiposity to be addressed with the therapeutic modalities.

[polldaddy:9711250]

Submental fat (SMF) accumulation within the subcutaneous (preplatysmal) or subplatysmal fat compartment of the cervical anatomy results in an obtuse cervicomental angle and loss of mandibular and cervical contours. It is a common cosmetic concern due to its aesthetic association with weight gain and aging.¹ Minimally invasive or noninvasive submental lipolytic agents and techniques are sought for patients who are not candidates for surgery or prefer more conservative cosmetic treatments. These methods typically are only effective in addressing preplatysmal SMF, as subplatysmal SMF requires more surgical methods due to its less-accessible location. The pathology of SMF should initially be assessed by clinical examination or ultrasonography. In this article, we review the most relevant clinical and safety data on minimally invasive and noninvasive treatments for SMF, including laser-assisted lipolysis (LAL), radiofrequency (RF)–assisted lipolysis, deoxycholic acid (DCA), and cryolipolysis.

MINIMALLY INVASIVE MODALITIES

Traditional, or tumescent, liposuction is still widely considered the most effective method for removal of large masses of adiposity. Laser- and RF-assisted adjuncts have been more recently developed to improve patient side effects and recovery time and reduce the manual effort of surgeons. Of note, these adjuncts, with some exceptions, still require the same invasiveness as traditional liposuction, involving submental stab incisions of up to 2.4 mm.

Laser-Assisted Lipolysis

Laser-assisted lipolysis produces a similar effect as suction-assisted lipoplasty by focusing pulses of laser energy through a 1-mm wide fiber optic cannula and inducing thermally mediated adipolysis. The directed laser results in adipocyte rupturing with added benefits of skin retraction and small vessel coagulation, thus lessening intraoperative blood loss.² This technique typically requires smaller incisions than traditional liposuction. The most common laser lipolysis systems used in cosmetic dermatology are the 920- to 980-nm diode lasers and 1064- to 1440-nm Nd:YAG lasers. The 924-nm diode, 1064-nm Nd:YAG, and 1064/1320-nm Nd:YAG have been best characterized in clinical trials, as reviewed by Fakhouri et al,³ with demonstrated efficacy in reducing SMF density.

The first randomized prospective trial comparing LAL (using 1064-nm Nd:YAG) and traditional liposuction in various anatomical areas on 25 patients showed no difference in cosmetic results, ecchymoses, edema, or retraction, and significantly lower postoperative pain ratings (P<.0001) in LAL.⁴ A more recent prospective randomized comparison of LAL (980-nm diode laser; 6–8 W) and traditional liposuction of the submental area in 40 female patients showed greater reduction in SMF thickness in the LAL group compared to the liposuction group at 2-month follow-up (6.2 vs 8.22 unspecified units; P<.001) with significant improvement from baseline in both groups (P<.001).⁵ However, the cosmetic benefit of LAL over traditional liposuction remains controversial and has not been unequivocally established in the literature.

Common adverse events (AEs) are postoperative swelling, ecchymoses, and pain, and complications of interest are nodularity, skin infections, burns, and nerve damage.⁶ In one retrospective investigation (N=537), these complications occurred at a rate of less than 1% (4 burns and 1 skin infection).⁶ Patients treated with LAL may report fewer AEs, especially pain and bleeding, compared to liposuction-treated patients.³

RF-Assisted Lipolysis

Radiofrequency-assisted lipolysis is one of the newest technologies in lipocontouring. NeckTite (Invasix Aesthetic Solutions) is effective for treatment of preplatysmal adiposity and cervicomental lipocontouring; a 2.4-mm bipolar probe that is inserted into the subdermal space and connected with an external electrode emits RF energy and simultaneously coagulates and aspirates adipose tissue. NeckTite also may be used in conjunction with FaceTite (Invasix Aesthetic Solutions), which promotes fibroseptal network remodeling and dermal contraction.²

In the first published investigation of the efficacy and safety of NeckTite, 47 of 55 patients received treatment of slight to moderate SMF (average body mass index [BMI], 25 kg/m²) with NeckTite and FaceTite or NeckTite alone.⁷ At 6-month follow-up, 87% (48/55) of patients subjectively rated treatment efficacy as satisfactory, and 2 independent physicians rated the improvement between before-and-after frontal and lateral photographs of the submental area as moderate to excellent in 95% (52/55) of all cases. Reported complications in this study were full-thickness burns resulting in minor scarring (2/55 [4%]), neck tissue hardness that resolved with daily massage after 3 months (5/55 [9%]), and transient facial nerve paresis of the mandibular branch that resolved after 2 months (1/55 [2%]).⁷

NONINVASIVE MODALITIES

RF-Assisted Contouring

Another exciting development in RF technology is truSculpt (Cutera), a noninvasive contouring device that is placed over the epidermis and emits RF energy that preferentially heats fat more than other tissue types. In a single-center prospective trial of efficacy and safety in the treatment of SMF, 17 patients received 2 treatments with truSculpt administered 1 month apart.⁸ At 1- and 6-month follow-up, 82.3% (14/17) and 52.9% (9/17) of patients showed improvement on physician assessment. Submental circumference and ultrasonographic fat thickness reductions at 1-month follow-up were 1.4 cm (5.7% of pretreatment circumference [P<.001]) and 5.4 mm (9.7% of pretreatment fat thickness [P=.005]), respectively. At further longer-term follow-up to 6 months, submental circumference was 0.9 cm (3.8% of pretreatment circumference [P<.001]) and ultrasonographic fat reduction was 6.8 mm (10.5% of pretreatment fat thickness [P=.006]). Commonly reported AEs were pain (rate not given), erythema (8/17 [47%]), edema (1/17 [6%]), and vesicle formation (1/17 [6%]); all were self-resolving. Erythema usually subsided within 6 hours posttreatment. No other AEs or complications were reported.⁸

Deoxycholic Acid

Deoxycholic acid (DCA)(formerly ATX-101) is an injectable liquid formulation of synthetic DCA that was approved by the US Food and Drug Administration (FDA) in 2015 for moderate to severe SMF. Deoxycholic acid exists endogenously as a bile salt emulsifier and has been shown to cause dose-dependent adipocyte lysis, necrosis, disruption and dissolution of fat architecture, and inflammatory targeting of adipocytes by immune cells.^9,10 Thus, DCA causes targeted adipocytolysis and is a novel medical agent in the treatment of SMF. Supplied in 2-mL vials, clinicians may inject 10 mL at each treatment for up to 6 treatments administered 1 month apart.¹¹

Efficacy

REFINE-1, a pivotal North American–based phase 3 trial, investigated the efficacy and safety of DCA.¹² A total of 506 participants with scores of 2 (moderate) or 3 (severe) on the Clinician-Reported Submental Fat Rating Scale (CR-SMFRS) and a mean BMI of 29 kg/m² were randomized to receive preplatysmal fat injections of 2 mg/cm² of DCA (n=256) or placebo (n=250). Participants received up to 10 mL of product (mean total of 25 mL of DCA across all visits) at each treatment session for up to 6 sessions depending on individual efficacy, with approximately 28 days between sessions. Sixty-four percent of the treatment group received all 6 treatments. At 12-week follow-up after the last treatment session, 70% of DCA-treated participants versus 18.6% of placebo-treated participants (P<.001) improved by 1 grade or more on the CR-SMFRS and 13.4% versus 0% (P<.001) improved by 2 grades or more. Skin laxity was unchanged or improved in 92.7% of the DCA group and 87.6% of the placebo group.¹²

REFINE-2, the second of the North American phase 3 trials, had parallel inclusionary criteria and study design and established efficacy of 2 mg/cm² DCA over placebo in 516 participants (randomized 1:1).¹³ At 12 weeks posttreatment, 66.5% of DCA-treated participants versus 22.2% of placebo-treated participants improved by 1 grade or more according to the CR-SMFRS (P<.001) and 18.6% versus 3% improved by 2 grades or more in SMF (P<.001). Magnetic resonance imaging analysis of participants in the DCA (n=113) and placebo groups (n=112) showed that 40.2% versus 5.2% (P<.001) exhibited 10% or more reduction in submental volume, with similar comparative rates of SMF thickness reduction via caliper measurements.¹³
 

Safety

Safety data from REFINE-1 showed higher rates of treatment-related AEs in DCA-treated participants compared to placebo, including hematoma (70% vs 67.3%), anesthesia (66.9% vs 4.4%), pain (65.4% vs 23.4%), edema (52.9% vs 21.8%), induration (18.3% vs 1.6%), paresthesia (12.8% vs 3.2%), nodule formation (12.5% vs 0.8%), and pruritus (8.6% vs 3.6%).¹² In this trial, 11 of 258 cases (4.3%) of marginal mandibular nerve paresis and asymmetric smile occurred, all in DCA-treated participants and with a median duration of 31 days. Dysphagia resolving in a median duration of 4 days occurred in 1.6% (4/258) of DCA-treated participants.¹² REFINE-2 exhibited similar rates of common AEs. Complications of note were 14 cases of marginal mandibular nerve paresis (11 in DCA group, 3 in placebo group) attributed to injection technique, 1 case of skin ulceration possibly related to accidental injection into dermis, and 6 cases of dysphagia in DCA participants attributed to higher volume treatment sessions and postinjection swelling. Dysphagia lasted a median of 2.5 days and resolved without sequelae.¹³

Overall, DCA demonstrated high rates of minor injection-site AEs that resolved without sequelae and could be mitigated by comfort therapies (eg, lidocaine, nonsteroidal anti-inflammatory drugs) as well as understanding the anatomy of the submental region. Adverse effects of particular interest included marginal mandibular nerve palsy, skin ulceration, and dysphagia.^12,13

Cryolipolysis

Cryolipolysis is an advancement that utilizes the application of noninvasive cooling temperatures to the skin’s surface to destroy underlying adipocytes based on the concept that lipid-filled cells are more susceptible to cold-induced injury than water-filled cells. Thus, cryolipolysis selectively targets adipose tissue, leading to cell death without harm to surrounding cells and without the need for surgery or injections.¹⁴

Cryolipolysis typically is delivered via a vacuum applicator (CoolMini, Zeltiq Aesthetics Inc), which applies temperatures of –10°C (14°F) to the skin in cycles of 60 minutes each. Initially approved by the FDA for treatment of flank adiposity in 2010, cryolipolysis has since been approved for treatment of the abdomen, thighs, and submental area.¹⁴ An advantage of cryolipolysis is that it does not require frequent treatment sessions for maximal efficacy.

Efficacy

The efficacy of cryolipolysis in the treatment of SMF was established in a multicenter device investigation resulting in its FDA approval for the submental region.¹⁵ Sixty participants with a mean BMI of 31.8 kg/m² received 1 (1/60) or 2 (59/60) treatment sessions of the submental area administered 6 weeks apart. Primary efficacy assessments included analysis by 3 blinded reviewers who viewed photographs of each participant at baseline, immediately posttreatment, 6 weeks posttreatment, and 12 weeks posttreatment; ultrasonographic measurements of SMF thickness; and a 12-point patient satisfaction questionnaire. Blinded reviewers correctly identified baseline images in 91.4% (55/60) of cases. Ultrasonography confirmed a mean reduction in SMF of 2 mm (P<.0001) or 20% of fat thickness at 12 weeks posttreatment. On subjective patient satisfaction surveys, 83% (50/60) of participants were satisfied with the procedure and 77% (46/60) reported a visible reduction in fat and perceived an improvement in appearance.¹⁵

Safety

The most common immediate posttreatment AEs were erythema/purpura (100%), numbness (90%), edema (62%), tingling (30%), blanching (25%), and bruising (3%) at the site of cryolipolysis with resolution within 1 week posttreatment, except for numbness.¹⁵ At 6-week follow-up, all AEs had resolved, except continued numbness in 4 participants that resolved by 12-week follow-up. A further event of note was fullness in the throat in 1 participant that was attributed to swelling and resolved at 40 days posttreatment without incident. No serious AEs were reported in this trial.¹⁵

A particularly concerning but rare complication that is increasing in awareness is paradoxical adipose hyperplasia following cryolipolysis. Patients may develop firm painless areas of soft tissue enlargements in the area of cryolipolysis typically 3 to 6 months posttreatment.¹⁶ The largest published report recorded an incidence rate of 0.46% (n=2, all males) at a single-center institution of 422 cryolipolysis treatments.¹⁶ Other incidence rates reported are 0.0051% and 0.78%.¹⁷ Causes and associations are not known, though male gender is speculated to increase risk.

Conclusion

This article highlights the available information on advances in minimally invasive and noninvasive treatments for SMF accumulation. The efficacy and safety trials varied in quality and in different methods of end point analysis of SMF reduction. Further, few trials have featured head-to-head comparisons of treatments.

Although liposuction and adjuncts remain the gold standard in large-mass lipid removal, these procedures are invasive and exhibit typical risks of surgery. Given its sensitive location, the submental area may require the use of more delicate therapeutic methods, including completely noninvasive devices such as truSculpt and cryolipolysis. Regardless of the chosen treatment, the most important factors in yielding patient satisfaction and SMF improvement are proper patient selection and an understanding of the anatomical source of adiposity to be addressed with the therapeutic modalities.

[polldaddy:9711250]

Basal cell carcinoma (BCC) is the most prevalent malignancy in white individuals and its incidence is rapidly increasing. Despite its low mortality rate, BCC can cause severe morbidity and remains a serious health problem with a high economic burden for health care systems. The incidence of BCC is higher in individuals who have red or blonde hair, light eye color, and/or Fitzpatrick skin types I and II. The risk for developing BCC also increases with age, and men are more frequently affected than women.^1,2 Although several factors have been implicated in the etiology of this condition, such as exposure to ionizing radiation, trauma, chemical carcinogenesis, immunosuppression, predisposing syndromes, and host factors (eg, traits that affect susceptibility to disease),^3-5 exposure to UV radiation is considered to be a major risk factor, with most BCCs presenting in sun-exposed areas of the body (eg, face, neck). Prolongate suberythrodermal UV doses, which do not burn the skin but cause erythema in the histological level, can lead to formation of pyrimidine dimers in the dermal and epidermal tissues and cause DNA mutation with potential carcinogenic effects. Due to a large number of outdoor occupations, it is likely that outdoor workers (OWs) with a history of UV exposure may develop BCCs with different features than those seen in indoor workers (IWs). However, there has been debate about the relevance of occupational UV exposure as a risk factor for BCC development.^6,7 The aim of this study was to compare the clinical and histological features of BCCs in OWs versus IWs at a referral hospital in southern Spain.

Methods

Using the electronic pathology records at a referral hospital in southern Spain, we identified medical records between May 1, 2010, and May 1, 2011, of specimens containing the term skin in the specimen box and basal cell carcinoma in the diagnosis box. We excluded patients with a history of or concomitant squamous cell carcinoma. Reexcision of incompletely excised lesions; punch, shave or incisional biopsies; and palliative excisions also were excluded. The specimens were reviewed and classified according to the differentiation pattern of BCC (ie, nodular, superficial, morpheic, micronodular). Basal cell carcinomas with mixed features were classified according to the most predominant subtype.

We also gathered information regarding the patients’ work history (ie, any job held during their lifetime with a minimum duration of 6 months). Patients were asked about the type of work and start/end dates. In patients who performed OW, we evaluated hours per day and months as well as the type of clothing worn (eg, head covering, socks/stockings during work in the summer months).

Each patient was classified as an OW or IW based on his/her stated occupation. The OWs included those who performed all or most of their work (≥6 hours per day for at least 6 months) outdoors in direct sunlight. Most patients in this group included farmers and fishermen. Indoor workers were those who performed most of their work in an indoor environment (eg, shop, factory, office, hospital, library, bank, school, laboratory). Most patients in this group included mechanics and shop assistants. A small group of individuals could not be classified as OWs or IWs and therefore were excluded from the study. Individuals with a history of exposure to ionizing radiation, chemical carcinogenesis, immunosuppression, or predisposing syndromes also were excluded.

We included variables that could be considered independent risk factors for BCC, including age, sex, eye color, natural hair color, Fitzpatrick skin type, history of sunburns, and family history. All data were collected via a personal interview performed by a single dermatologist (H.H-E.) during the follow-up with the patients conducted after obtaining all medical records and contacting eligible patients; none of the patients were lost on follow-up.

The study was approved by the hospital’s ethics committee and written consent was obtained from all recruited patients for analyzing the data acquired and accessing the relevant diagnostic documents (eg, pathology reports).

The cohorts were compared by a χ² test and Student t test, which were performed using the SPSS software version 15. Statistical significance was determined using α=.05, and all tests were 2-sided.

Results

A total of 308 patients were included in the study, comprising 178 (58%) OWs and 130 (42%) IWs. Table 1 summarizes the characteristics of each cohort with the statistical outcomes.

The mean age (SD) of the OWs was significantly higher than the IWs (75.17 [10.74] vs 69.73 [9.98] years; P<.001). The sex distribution among the 2 cohorts was significantly different (P=.002); the OW group featured a slightly higher proportion of men than women (92 [52%] vs 86 [48%]), whereas women were clearly more prevalent in the IW group than men (85 [65%] vs 45 [35%]).

No significant differences regarding eye color (blue/gray vs brown/black) between the 2 cohorts were found (P>.05). In the same way, the 2 cohorts did not show differences in the natural hair color (red/blonde vs brown/black)(P>.05).

Fitzpatrick skin type II was the most common between both cohorts (82 [46%] OWs and 75 [58%] IWs), but no statistical differences regarding the proportions of each skin type were found (P>.05).

History of sunburns (>2 episodes) was significantly different between the 2 cohorts. The incidence of second-degree sunburns in childhood was higher in IWs (P<.00001), while the incidence of second-degree sunburns in adulthood was higher in OWs (P=.002).

Most OWs had a positive family history of BCC (101 [57%]), while the majority of IWs had a negative family history of BCC (90 [69%]). This difference was statistically significant (P=.03).

Table 2 shows the distribution of anatomic sites of BCCs in OWs and IWs. The nose was the most frequently affected area in OWs (35 cases [20%]), while the cheek was the most common location (23 [18%]) in IWs. Comparison of the frequency of BCC incidence for each anatomic location revealed that only the rate for truncal BCC was significantly different; IWs had a higher incidence of truncal BCCs than OWs (P=.0035). Although the differences between groups were not statistically significant, there was a trend toward a higher incidence of BCCs on the forehead in OW (P=.06).

In both cohorts, the most prevalent histologic subtype was nodular BCC (133 [75%] OWs and 88 [68%] IWs), followed by superficial BCC (17 [10%] OWs and 27 [21%] IWs). The incidence rate of nodular BCCs was statistically different between the 2 cohorts, with OWs showing a higher incidence compared to IWs (P=.024). Regarding the superficial subtype, the opposite was observed: IWs had significantly increased risk compared to OWs (P=.05). There was a trend toward a higher incidence of morpheic BCCs in OWs than IWs, but the difference was not statistically significant (P=.07).

Comment

Skin cancer due to occupational UV exposure is more common than is generally recognized,^6,7 but occupational UV exposure as a risk factor for BCC is still an ongoing debate. In this study, we analyzed the different clinical and histological features of BCC in OWs versus IWs.

The geographic area where this study was performed is characterized by a subtropical Mediterranean climate with irregular rainfall; a short, cool to mild winter; and long, dry, hot summers. Summer temperatures usually are hot and regularly exceed 35°C (95°F). UV index (UVI) is a measure of the amount of skin-damaging UV radiation expected to reach the earth’s surface when the sun is highest in the sky (around midday) and ranges from 1 (low risk) to 10 (maximum risk). In southern Spain, the mean UVI is approximately 6 and can reach up to 9 or sometimes 10 in the summer months. Although Fitzpatrick skin types II and III are most common, the elevated UVI indicates that the general population in southern Spain is at a high risk for developing skin cancer.

In our study the mean age of IWs was lower than OWs, which suggests that IWs may develop BCC at a younger age than OWs. This finding is consistent with studies showing that cumulative occupational UV exposure has been associated with development of BCCs in older age groups, while acute intermittent recreational sun exposure, particularly sustained in childhood and adolescence, is linked with BCC in younger patients.⁶

The role of sex as a risk factor for BCC remains unclear. Some reports show that BCC is more common in men than in women.^8-10 In our study, sex distribution was statistically significant (P=.002); there were more women in the IW cohort and more men in the OW cohort. These differences may be explained by cultural and lifestyle patterns, as women who are IWs tend to have office jobs in urban settings and wear modern fashion clothes at work and for recreation. In rural settings, women have agricultural jobs and tend to wear more traditional clothes that offer sun protection.

Positive family history has been suggested to be a constitutional risk factor for BCC development.^8,11,12 In our study, we observed that positive family history was more common in OWs, while most IWs had a negative family history. These differences were significant (P=.03), and OWs had a 2.6-fold increased likelihood of having a positive family history of BCC compared to IWs. Cultural and lifestyle patterns may partially explain this finding. In rural settings, workers tend to have the same job as their parents as a traditional way of life and therefore have similar patterns of UV exposure; in urban settings, individuals may have different jobs than their parents and therefore the pattern of UV exposure may be different. However, a genetic predisposition for developing BCC cannot be excluded. In addition, we have to consider that the information on family history of BCC in the patients was self-reported and not validated, which may limit the results.

The difference in history of second-degree sunburn in childhood was significantly higher in IWs than in OWs (P<.00001). The OW group had a significant rate of sunburns in adulthood (P=.002). The relationship between UV radiation and BCC is complex, and the patterns of sun exposure and their occurrence in different periods of lifetime (ie, childhood vs adulthood) remain controversial.¹³ The overall history of severe sunburns seems to be more important than simply the tendency to burn or tan,^14,15 and a history of sunburns in childhood and adolescence has been associated with early-onset BCC.⁶ Our findings were consistent in that the age of onset of BCCs was lower in IWs who had a history of sunburns in childhood. Basal cell carcinomas developed at older ages in OWs who had a higher incidence of sunburns in adulthood. However, we have to consider that the retrospective nature of the data collection on sunburns in childhood and adulthood was potentially limited, as the information was based on the patients’ memory. Additionally, other non-UV risk factors for BCC, such as ionizing radiation exposure, were not analyzed.

The majority of BCCs developed in sun-exposed areas of the head and neck in both cohorts, and only 35 (20%) and 28 (22%) BCCs were located on the trunk, arms, or legs in OWs and IWs, respectively. In our study, the rate of BCCs on the trunk was significantly lower in OWs than in IWs (P=.0035). Basal cell carcinomas on the trunk have been suggested to be linked to genetic susceptibility^16,17 and reduced DNA repair capacity¹⁸ rather than sun exposure. Our findings support this hypothesis and suggest that occupational sun exposure has no direct relation with truncal BCC. This outcome is consistent with the result of a case-control study conducted by Pelucchi et al¹⁹ (N=1040). The authors concluded that occupational UV exposure was not associated with truncal BCC development but with head/neck BCC, indicating that there may be different etiological mechanisms between truncal and head/neck BCC.¹⁹ In the largest BCC case series published in the literature with 13,457 specimens, the authors stated that tumors on the trunk may represent a particular variant of BCC, in which the theory of chronic versus intermittent UV exposure cannot be simply extrapolated as it is for the rest of BCC sites. Other factors such as genetic predisposition could be involved in the development of truncal BCC.²⁰ Similarly, Ramos et al²¹ suggested that nonmelanoma skin cancers in sun-protected anatomic sites may occur in individuals with impairment in the DNA repair process.

The classification of histological subtypes of BCC helps to predict tumor behavior,²² which can impact the prognosis. In our study, nodular BCC was the most common subtype in both cohorts, followed by superficial BCC. The nodular subtype was increased in OWs compared to IWs, while the superficial subtype was most common in IWs. Bastiaens et al²³ and McCormack et al²⁴ have suggested that the most frequent subtypes of BCC (nodular and superficial) may represent different tumors with distinct causal factors. According to these authors, nodular subtypes are associated with cumulative UV exposure, while superficial subtypes are associated with more intense and intermittent UV exposure. The results of the current study support this hypothesis, as the OW cohort with cumulative UV exposure showed more incidence of nodular BCC than IWs, while the patients with intense and intermittent sun exposure (the IWs) showed more risk of superficial BCC.

The importance of occupational UV exposure in OWs as a risk factor for BCC is still an ongoing discussion. Our data show that occupational UV exposure may be considered an etiological factor for BCC according to histological subtype and anatomic site. Our study is limited by the retrospective nature of the data collection regarding occupation and childhood sunburns, which were based on the patients’ memory and therefore potentially biased. Data regarding family history of BCC also was self-reported and not validated. Another limiting factor was that other non-UV risk factors for BCC, such as ionizing radiation exposure, were not considered. The limited sample size also may have impacted the study results. Among the strengths of the study are the complete response rate, the similar catchment area of OWs and IWs, the common hospital setting of the 2 cohorts, and the similar attention to medical history. All patients were obtained from the practice of a single referral dermatologist and are felt to be representative of our working area. The use of a single dermatologist reduces provider-associated variability.

Conclusion

According to the results of this study, OWs are more likely to develop nodular BCCs with no increased risk for superficial BCCs. The age of onset in OWs is older than in IWs. Some anatomical sites such as the trunk are more commonly affected in IWs. Truncal BCCs may have etiological factors other than UV exposure, such as a genetic predisposition. This study is useful to occupational safety representatives and physicians to stimulate the implementation of prevention strategies for this easily preventable malignancy and may encourage further research.

Basal cell carcinoma (BCC) is the most prevalent malignancy in white individuals and its incidence is rapidly increasing. Despite its low mortality rate, BCC can cause severe morbidity and remains a serious health problem with a high economic burden for health care systems. The incidence of BCC is higher in individuals who have red or blonde hair, light eye color, and/or Fitzpatrick skin types I and II. The risk for developing BCC also increases with age, and men are more frequently affected than women.^1,2 Although several factors have been implicated in the etiology of this condition, such as exposure to ionizing radiation, trauma, chemical carcinogenesis, immunosuppression, predisposing syndromes, and host factors (eg, traits that affect susceptibility to disease),^3-5 exposure to UV radiation is considered to be a major risk factor, with most BCCs presenting in sun-exposed areas of the body (eg, face, neck). Prolongate suberythrodermal UV doses, which do not burn the skin but cause erythema in the histological level, can lead to formation of pyrimidine dimers in the dermal and epidermal tissues and cause DNA mutation with potential carcinogenic effects. Due to a large number of outdoor occupations, it is likely that outdoor workers (OWs) with a history of UV exposure may develop BCCs with different features than those seen in indoor workers (IWs). However, there has been debate about the relevance of occupational UV exposure as a risk factor for BCC development.^6,7 The aim of this study was to compare the clinical and histological features of BCCs in OWs versus IWs at a referral hospital in southern Spain.

Methods

Using the electronic pathology records at a referral hospital in southern Spain, we identified medical records between May 1, 2010, and May 1, 2011, of specimens containing the term skin in the specimen box and basal cell carcinoma in the diagnosis box. We excluded patients with a history of or concomitant squamous cell carcinoma. Reexcision of incompletely excised lesions; punch, shave or incisional biopsies; and palliative excisions also were excluded. The specimens were reviewed and classified according to the differentiation pattern of BCC (ie, nodular, superficial, morpheic, micronodular). Basal cell carcinomas with mixed features were classified according to the most predominant subtype.

We also gathered information regarding the patients’ work history (ie, any job held during their lifetime with a minimum duration of 6 months). Patients were asked about the type of work and start/end dates. In patients who performed OW, we evaluated hours per day and months as well as the type of clothing worn (eg, head covering, socks/stockings during work in the summer months).

Each patient was classified as an OW or IW based on his/her stated occupation. The OWs included those who performed all or most of their work (≥6 hours per day for at least 6 months) outdoors in direct sunlight. Most patients in this group included farmers and fishermen. Indoor workers were those who performed most of their work in an indoor environment (eg, shop, factory, office, hospital, library, bank, school, laboratory). Most patients in this group included mechanics and shop assistants. A small group of individuals could not be classified as OWs or IWs and therefore were excluded from the study. Individuals with a history of exposure to ionizing radiation, chemical carcinogenesis, immunosuppression, or predisposing syndromes also were excluded.

We included variables that could be considered independent risk factors for BCC, including age, sex, eye color, natural hair color, Fitzpatrick skin type, history of sunburns, and family history. All data were collected via a personal interview performed by a single dermatologist (H.H-E.) during the follow-up with the patients conducted after obtaining all medical records and contacting eligible patients; none of the patients were lost on follow-up.

The study was approved by the hospital’s ethics committee and written consent was obtained from all recruited patients for analyzing the data acquired and accessing the relevant diagnostic documents (eg, pathology reports).

The cohorts were compared by a χ² test and Student t test, which were performed using the SPSS software version 15. Statistical significance was determined using α=.05, and all tests were 2-sided.

Results

A total of 308 patients were included in the study, comprising 178 (58%) OWs and 130 (42%) IWs. Table 1 summarizes the characteristics of each cohort with the statistical outcomes.

The mean age (SD) of the OWs was significantly higher than the IWs (75.17 [10.74] vs 69.73 [9.98] years; P<.001). The sex distribution among the 2 cohorts was significantly different (P=.002); the OW group featured a slightly higher proportion of men than women (92 [52%] vs 86 [48%]), whereas women were clearly more prevalent in the IW group than men (85 [65%] vs 45 [35%]).

No significant differences regarding eye color (blue/gray vs brown/black) between the 2 cohorts were found (P>.05). In the same way, the 2 cohorts did not show differences in the natural hair color (red/blonde vs brown/black)(P>.05).

Fitzpatrick skin type II was the most common between both cohorts (82 [46%] OWs and 75 [58%] IWs), but no statistical differences regarding the proportions of each skin type were found (P>.05).

History of sunburns (>2 episodes) was significantly different between the 2 cohorts. The incidence of second-degree sunburns in childhood was higher in IWs (P<.00001), while the incidence of second-degree sunburns in adulthood was higher in OWs (P=.002).

Most OWs had a positive family history of BCC (101 [57%]), while the majority of IWs had a negative family history of BCC (90 [69%]). This difference was statistically significant (P=.03).

Table 2 shows the distribution of anatomic sites of BCCs in OWs and IWs. The nose was the most frequently affected area in OWs (35 cases [20%]), while the cheek was the most common location (23 [18%]) in IWs. Comparison of the frequency of BCC incidence for each anatomic location revealed that only the rate for truncal BCC was significantly different; IWs had a higher incidence of truncal BCCs than OWs (P=.0035). Although the differences between groups were not statistically significant, there was a trend toward a higher incidence of BCCs on the forehead in OW (P=.06).

In both cohorts, the most prevalent histologic subtype was nodular BCC (133 [75%] OWs and 88 [68%] IWs), followed by superficial BCC (17 [10%] OWs and 27 [21%] IWs). The incidence rate of nodular BCCs was statistically different between the 2 cohorts, with OWs showing a higher incidence compared to IWs (P=.024). Regarding the superficial subtype, the opposite was observed: IWs had significantly increased risk compared to OWs (P=.05). There was a trend toward a higher incidence of morpheic BCCs in OWs than IWs, but the difference was not statistically significant (P=.07).

Comment

Skin cancer due to occupational UV exposure is more common than is generally recognized,^6,7 but occupational UV exposure as a risk factor for BCC is still an ongoing debate. In this study, we analyzed the different clinical and histological features of BCC in OWs versus IWs.

The geographic area where this study was performed is characterized by a subtropical Mediterranean climate with irregular rainfall; a short, cool to mild winter; and long, dry, hot summers. Summer temperatures usually are hot and regularly exceed 35°C (95°F). UV index (UVI) is a measure of the amount of skin-damaging UV radiation expected to reach the earth’s surface when the sun is highest in the sky (around midday) and ranges from 1 (low risk) to 10 (maximum risk). In southern Spain, the mean UVI is approximately 6 and can reach up to 9 or sometimes 10 in the summer months. Although Fitzpatrick skin types II and III are most common, the elevated UVI indicates that the general population in southern Spain is at a high risk for developing skin cancer.

In our study the mean age of IWs was lower than OWs, which suggests that IWs may develop BCC at a younger age than OWs. This finding is consistent with studies showing that cumulative occupational UV exposure has been associated with development of BCCs in older age groups, while acute intermittent recreational sun exposure, particularly sustained in childhood and adolescence, is linked with BCC in younger patients.⁶

The role of sex as a risk factor for BCC remains unclear. Some reports show that BCC is more common in men than in women.^8-10 In our study, sex distribution was statistically significant (P=.002); there were more women in the IW cohort and more men in the OW cohort. These differences may be explained by cultural and lifestyle patterns, as women who are IWs tend to have office jobs in urban settings and wear modern fashion clothes at work and for recreation. In rural settings, women have agricultural jobs and tend to wear more traditional clothes that offer sun protection.

Positive family history has been suggested to be a constitutional risk factor for BCC development.^8,11,12 In our study, we observed that positive family history was more common in OWs, while most IWs had a negative family history. These differences were significant (P=.03), and OWs had a 2.6-fold increased likelihood of having a positive family history of BCC compared to IWs. Cultural and lifestyle patterns may partially explain this finding. In rural settings, workers tend to have the same job as their parents as a traditional way of life and therefore have similar patterns of UV exposure; in urban settings, individuals may have different jobs than their parents and therefore the pattern of UV exposure may be different. However, a genetic predisposition for developing BCC cannot be excluded. In addition, we have to consider that the information on family history of BCC in the patients was self-reported and not validated, which may limit the results.

The difference in history of second-degree sunburn in childhood was significantly higher in IWs than in OWs (P<.00001). The OW group had a significant rate of sunburns in adulthood (P=.002). The relationship between UV radiation and BCC is complex, and the patterns of sun exposure and their occurrence in different periods of lifetime (ie, childhood vs adulthood) remain controversial.¹³ The overall history of severe sunburns seems to be more important than simply the tendency to burn or tan,^14,15 and a history of sunburns in childhood and adolescence has been associated with early-onset BCC.⁶ Our findings were consistent in that the age of onset of BCCs was lower in IWs who had a history of sunburns in childhood. Basal cell carcinomas developed at older ages in OWs who had a higher incidence of sunburns in adulthood. However, we have to consider that the retrospective nature of the data collection on sunburns in childhood and adulthood was potentially limited, as the information was based on the patients’ memory. Additionally, other non-UV risk factors for BCC, such as ionizing radiation exposure, were not analyzed.

The majority of BCCs developed in sun-exposed areas of the head and neck in both cohorts, and only 35 (20%) and 28 (22%) BCCs were located on the trunk, arms, or legs in OWs and IWs, respectively. In our study, the rate of BCCs on the trunk was significantly lower in OWs than in IWs (P=.0035). Basal cell carcinomas on the trunk have been suggested to be linked to genetic susceptibility^16,17 and reduced DNA repair capacity¹⁸ rather than sun exposure. Our findings support this hypothesis and suggest that occupational sun exposure has no direct relation with truncal BCC. This outcome is consistent with the result of a case-control study conducted by Pelucchi et al¹⁹ (N=1040). The authors concluded that occupational UV exposure was not associated with truncal BCC development but with head/neck BCC, indicating that there may be different etiological mechanisms between truncal and head/neck BCC.¹⁹ In the largest BCC case series published in the literature with 13,457 specimens, the authors stated that tumors on the trunk may represent a particular variant of BCC, in which the theory of chronic versus intermittent UV exposure cannot be simply extrapolated as it is for the rest of BCC sites. Other factors such as genetic predisposition could be involved in the development of truncal BCC.²⁰ Similarly, Ramos et al²¹ suggested that nonmelanoma skin cancers in sun-protected anatomic sites may occur in individuals with impairment in the DNA repair process.

The classification of histological subtypes of BCC helps to predict tumor behavior,²² which can impact the prognosis. In our study, nodular BCC was the most common subtype in both cohorts, followed by superficial BCC. The nodular subtype was increased in OWs compared to IWs, while the superficial subtype was most common in IWs. Bastiaens et al²³ and McCormack et al²⁴ have suggested that the most frequent subtypes of BCC (nodular and superficial) may represent different tumors with distinct causal factors. According to these authors, nodular subtypes are associated with cumulative UV exposure, while superficial subtypes are associated with more intense and intermittent UV exposure. The results of the current study support this hypothesis, as the OW cohort with cumulative UV exposure showed more incidence of nodular BCC than IWs, while the patients with intense and intermittent sun exposure (the IWs) showed more risk of superficial BCC.

The importance of occupational UV exposure in OWs as a risk factor for BCC is still an ongoing discussion. Our data show that occupational UV exposure may be considered an etiological factor for BCC according to histological subtype and anatomic site. Our study is limited by the retrospective nature of the data collection regarding occupation and childhood sunburns, which were based on the patients’ memory and therefore potentially biased. Data regarding family history of BCC also was self-reported and not validated. Another limiting factor was that other non-UV risk factors for BCC, such as ionizing radiation exposure, were not considered. The limited sample size also may have impacted the study results. Among the strengths of the study are the complete response rate, the similar catchment area of OWs and IWs, the common hospital setting of the 2 cohorts, and the similar attention to medical history. All patients were obtained from the practice of a single referral dermatologist and are felt to be representative of our working area. The use of a single dermatologist reduces provider-associated variability.

Conclusion

According to the results of this study, OWs are more likely to develop nodular BCCs with no increased risk for superficial BCCs. The age of onset in OWs is older than in IWs. Some anatomical sites such as the trunk are more commonly affected in IWs. Truncal BCCs may have etiological factors other than UV exposure, such as a genetic predisposition. This study is useful to occupational safety representatives and physicians to stimulate the implementation of prevention strategies for this easily preventable malignancy and may encourage further research.

Basal cell carcinoma (BCC) is the most prevalent malignancy in white individuals and its incidence is rapidly increasing. Despite its low mortality rate, BCC can cause severe morbidity and remains a serious health problem with a high economic burden for health care systems. The incidence of BCC is higher in individuals who have red or blonde hair, light eye color, and/or Fitzpatrick skin types I and II. The risk for developing BCC also increases with age, and men are more frequently affected than women.^1,2 Although several factors have been implicated in the etiology of this condition, such as exposure to ionizing radiation, trauma, chemical carcinogenesis, immunosuppression, predisposing syndromes, and host factors (eg, traits that affect susceptibility to disease),^3-5 exposure to UV radiation is considered to be a major risk factor, with most BCCs presenting in sun-exposed areas of the body (eg, face, neck). Prolongate suberythrodermal UV doses, which do not burn the skin but cause erythema in the histological level, can lead to formation of pyrimidine dimers in the dermal and epidermal tissues and cause DNA mutation with potential carcinogenic effects. Due to a large number of outdoor occupations, it is likely that outdoor workers (OWs) with a history of UV exposure may develop BCCs with different features than those seen in indoor workers (IWs). However, there has been debate about the relevance of occupational UV exposure as a risk factor for BCC development.^6,7 The aim of this study was to compare the clinical and histological features of BCCs in OWs versus IWs at a referral hospital in southern Spain.

Methods

Using the electronic pathology records at a referral hospital in southern Spain, we identified medical records between May 1, 2010, and May 1, 2011, of specimens containing the term skin in the specimen box and basal cell carcinoma in the diagnosis box. We excluded patients with a history of or concomitant squamous cell carcinoma. Reexcision of incompletely excised lesions; punch, shave or incisional biopsies; and palliative excisions also were excluded. The specimens were reviewed and classified according to the differentiation pattern of BCC (ie, nodular, superficial, morpheic, micronodular). Basal cell carcinomas with mixed features were classified according to the most predominant subtype.

We also gathered information regarding the patients’ work history (ie, any job held during their lifetime with a minimum duration of 6 months). Patients were asked about the type of work and start/end dates. In patients who performed OW, we evaluated hours per day and months as well as the type of clothing worn (eg, head covering, socks/stockings during work in the summer months).

Each patient was classified as an OW or IW based on his/her stated occupation. The OWs included those who performed all or most of their work (≥6 hours per day for at least 6 months) outdoors in direct sunlight. Most patients in this group included farmers and fishermen. Indoor workers were those who performed most of their work in an indoor environment (eg, shop, factory, office, hospital, library, bank, school, laboratory). Most patients in this group included mechanics and shop assistants. A small group of individuals could not be classified as OWs or IWs and therefore were excluded from the study. Individuals with a history of exposure to ionizing radiation, chemical carcinogenesis, immunosuppression, or predisposing syndromes also were excluded.

We included variables that could be considered independent risk factors for BCC, including age, sex, eye color, natural hair color, Fitzpatrick skin type, history of sunburns, and family history. All data were collected via a personal interview performed by a single dermatologist (H.H-E.) during the follow-up with the patients conducted after obtaining all medical records and contacting eligible patients; none of the patients were lost on follow-up.

The study was approved by the hospital’s ethics committee and written consent was obtained from all recruited patients for analyzing the data acquired and accessing the relevant diagnostic documents (eg, pathology reports).

The cohorts were compared by a χ² test and Student t test, which were performed using the SPSS software version 15. Statistical significance was determined using α=.05, and all tests were 2-sided.

Results

A total of 308 patients were included in the study, comprising 178 (58%) OWs and 130 (42%) IWs. Table 1 summarizes the characteristics of each cohort with the statistical outcomes.

The mean age (SD) of the OWs was significantly higher than the IWs (75.17 [10.74] vs 69.73 [9.98] years; P<.001). The sex distribution among the 2 cohorts was significantly different (P=.002); the OW group featured a slightly higher proportion of men than women (92 [52%] vs 86 [48%]), whereas women were clearly more prevalent in the IW group than men (85 [65%] vs 45 [35%]).

No significant differences regarding eye color (blue/gray vs brown/black) between the 2 cohorts were found (P>.05). In the same way, the 2 cohorts did not show differences in the natural hair color (red/blonde vs brown/black)(P>.05).

Fitzpatrick skin type II was the most common between both cohorts (82 [46%] OWs and 75 [58%] IWs), but no statistical differences regarding the proportions of each skin type were found (P>.05).

History of sunburns (>2 episodes) was significantly different between the 2 cohorts. The incidence of second-degree sunburns in childhood was higher in IWs (P<.00001), while the incidence of second-degree sunburns in adulthood was higher in OWs (P=.002).

Most OWs had a positive family history of BCC (101 [57%]), while the majority of IWs had a negative family history of BCC (90 [69%]). This difference was statistically significant (P=.03).

Table 2 shows the distribution of anatomic sites of BCCs in OWs and IWs. The nose was the most frequently affected area in OWs (35 cases [20%]), while the cheek was the most common location (23 [18%]) in IWs. Comparison of the frequency of BCC incidence for each anatomic location revealed that only the rate for truncal BCC was significantly different; IWs had a higher incidence of truncal BCCs than OWs (P=.0035). Although the differences between groups were not statistically significant, there was a trend toward a higher incidence of BCCs on the forehead in OW (P=.06).

In both cohorts, the most prevalent histologic subtype was nodular BCC (133 [75%] OWs and 88 [68%] IWs), followed by superficial BCC (17 [10%] OWs and 27 [21%] IWs). The incidence rate of nodular BCCs was statistically different between the 2 cohorts, with OWs showing a higher incidence compared to IWs (P=.024). Regarding the superficial subtype, the opposite was observed: IWs had significantly increased risk compared to OWs (P=.05). There was a trend toward a higher incidence of morpheic BCCs in OWs than IWs, but the difference was not statistically significant (P=.07).

Comment

Skin cancer due to occupational UV exposure is more common than is generally recognized,^6,7 but occupational UV exposure as a risk factor for BCC is still an ongoing debate. In this study, we analyzed the different clinical and histological features of BCC in OWs versus IWs.

The geographic area where this study was performed is characterized by a subtropical Mediterranean climate with irregular rainfall; a short, cool to mild winter; and long, dry, hot summers. Summer temperatures usually are hot and regularly exceed 35°C (95°F). UV index (UVI) is a measure of the amount of skin-damaging UV radiation expected to reach the earth’s surface when the sun is highest in the sky (around midday) and ranges from 1 (low risk) to 10 (maximum risk). In southern Spain, the mean UVI is approximately 6 and can reach up to 9 or sometimes 10 in the summer months. Although Fitzpatrick skin types II and III are most common, the elevated UVI indicates that the general population in southern Spain is at a high risk for developing skin cancer.

In our study the mean age of IWs was lower than OWs, which suggests that IWs may develop BCC at a younger age than OWs. This finding is consistent with studies showing that cumulative occupational UV exposure has been associated with development of BCCs in older age groups, while acute intermittent recreational sun exposure, particularly sustained in childhood and adolescence, is linked with BCC in younger patients.⁶

The role of sex as a risk factor for BCC remains unclear. Some reports show that BCC is more common in men than in women.^8-10 In our study, sex distribution was statistically significant (P=.002); there were more women in the IW cohort and more men in the OW cohort. These differences may be explained by cultural and lifestyle patterns, as women who are IWs tend to have office jobs in urban settings and wear modern fashion clothes at work and for recreation. In rural settings, women have agricultural jobs and tend to wear more traditional clothes that offer sun protection.

Positive family history has been suggested to be a constitutional risk factor for BCC development.^8,11,12 In our study, we observed that positive family history was more common in OWs, while most IWs had a negative family history. These differences were significant (P=.03), and OWs had a 2.6-fold increased likelihood of having a positive family history of BCC compared to IWs. Cultural and lifestyle patterns may partially explain this finding. In rural settings, workers tend to have the same job as their parents as a traditional way of life and therefore have similar patterns of UV exposure; in urban settings, individuals may have different jobs than their parents and therefore the pattern of UV exposure may be different. However, a genetic predisposition for developing BCC cannot be excluded. In addition, we have to consider that the information on family history of BCC in the patients was self-reported and not validated, which may limit the results.

The difference in history of second-degree sunburn in childhood was significantly higher in IWs than in OWs (P<.00001). The OW group had a significant rate of sunburns in adulthood (P=.002). The relationship between UV radiation and BCC is complex, and the patterns of sun exposure and their occurrence in different periods of lifetime (ie, childhood vs adulthood) remain controversial.¹³ The overall history of severe sunburns seems to be more important than simply the tendency to burn or tan,^14,15 and a history of sunburns in childhood and adolescence has been associated with early-onset BCC.⁶ Our findings were consistent in that the age of onset of BCCs was lower in IWs who had a history of sunburns in childhood. Basal cell carcinomas developed at older ages in OWs who had a higher incidence of sunburns in adulthood. However, we have to consider that the retrospective nature of the data collection on sunburns in childhood and adulthood was potentially limited, as the information was based on the patients’ memory. Additionally, other non-UV risk factors for BCC, such as ionizing radiation exposure, were not analyzed.

The majority of BCCs developed in sun-exposed areas of the head and neck in both cohorts, and only 35 (20%) and 28 (22%) BCCs were located on the trunk, arms, or legs in OWs and IWs, respectively. In our study, the rate of BCCs on the trunk was significantly lower in OWs than in IWs (P=.0035). Basal cell carcinomas on the trunk have been suggested to be linked to genetic susceptibility^16,17 and reduced DNA repair capacity¹⁸ rather than sun exposure. Our findings support this hypothesis and suggest that occupational sun exposure has no direct relation with truncal BCC. This outcome is consistent with the result of a case-control study conducted by Pelucchi et al¹⁹ (N=1040). The authors concluded that occupational UV exposure was not associated with truncal BCC development but with head/neck BCC, indicating that there may be different etiological mechanisms between truncal and head/neck BCC.¹⁹ In the largest BCC case series published in the literature with 13,457 specimens, the authors stated that tumors on the trunk may represent a particular variant of BCC, in which the theory of chronic versus intermittent UV exposure cannot be simply extrapolated as it is for the rest of BCC sites. Other factors such as genetic predisposition could be involved in the development of truncal BCC.²⁰ Similarly, Ramos et al²¹ suggested that nonmelanoma skin cancers in sun-protected anatomic sites may occur in individuals with impairment in the DNA repair process.

The classification of histological subtypes of BCC helps to predict tumor behavior,²² which can impact the prognosis. In our study, nodular BCC was the most common subtype in both cohorts, followed by superficial BCC. The nodular subtype was increased in OWs compared to IWs, while the superficial subtype was most common in IWs. Bastiaens et al²³ and McCormack et al²⁴ have suggested that the most frequent subtypes of BCC (nodular and superficial) may represent different tumors with distinct causal factors. According to these authors, nodular subtypes are associated with cumulative UV exposure, while superficial subtypes are associated with more intense and intermittent UV exposure. The results of the current study support this hypothesis, as the OW cohort with cumulative UV exposure showed more incidence of nodular BCC than IWs, while the patients with intense and intermittent sun exposure (the IWs) showed more risk of superficial BCC.

The importance of occupational UV exposure in OWs as a risk factor for BCC is still an ongoing discussion. Our data show that occupational UV exposure may be considered an etiological factor for BCC according to histological subtype and anatomic site. Our study is limited by the retrospective nature of the data collection regarding occupation and childhood sunburns, which were based on the patients’ memory and therefore potentially biased. Data regarding family history of BCC also was self-reported and not validated. Another limiting factor was that other non-UV risk factors for BCC, such as ionizing radiation exposure, were not considered. The limited sample size also may have impacted the study results. Among the strengths of the study are the complete response rate, the similar catchment area of OWs and IWs, the common hospital setting of the 2 cohorts, and the similar attention to medical history. All patients were obtained from the practice of a single referral dermatologist and are felt to be representative of our working area. The use of a single dermatologist reduces provider-associated variability.

Conclusion

According to the results of this study, OWs are more likely to develop nodular BCCs with no increased risk for superficial BCCs. The age of onset in OWs is older than in IWs. Some anatomical sites such as the trunk are more commonly affected in IWs. Truncal BCCs may have etiological factors other than UV exposure, such as a genetic predisposition. This study is useful to occupational safety representatives and physicians to stimulate the implementation of prevention strategies for this easily preventable malignancy and may encourage further research.

Has this ever happened to you? You are an adult neurologist who has been asked to take on the care of a pediatric neurology patient. The patient who comes to your clinic is a 20-year-old young woman with a history of moderate developmental delay and intractable epilepsy. She is on numerous medications including valproic acid with a previous trial of the ketogenic diet. You receive a report that she has focal epilepsy and is having frequent seizures and last had an MRI at age 2 years. Prior notes talk about her summer vacations but not much about the future plans for her epilepsy. You see the patient in clinic, and the family is not happy to be in the adult clinic. They are disappointed that you don’t spend more time with them or fill out myriad forms. You find out that they have not obtained legal guardianship for their daughter and have no plan for work placement after school. She also has various other medical comorbidities that were previously addressed by the pediatric neurologist.

Dr. Felton is an epilepsy specialist at the University of Wisconsin, Madison, and Dr. Kelley is director of the Pediatric Epilepsy Monitoring Unit at Johns Hopkins University, Baltimore. This editorial reflects the content of a presentation given by Dr. Felton and Dr. Kelley at the annual meeting of the American Epilepsy Society in Houston. The authors report no conflict of interest.

Has this ever happened to you? You are an adult neurologist who has been asked to take on the care of a pediatric neurology patient. The patient who comes to your clinic is a 20-year-old young woman with a history of moderate developmental delay and intractable epilepsy. She is on numerous medications including valproic acid with a previous trial of the ketogenic diet. You receive a report that she has focal epilepsy and is having frequent seizures and last had an MRI at age 2 years. Prior notes talk about her summer vacations but not much about the future plans for her epilepsy. You see the patient in clinic, and the family is not happy to be in the adult clinic. They are disappointed that you don’t spend more time with them or fill out myriad forms. You find out that they have not obtained legal guardianship for their daughter and have no plan for work placement after school. She also has various other medical comorbidities that were previously addressed by the pediatric neurologist.

Dr. Felton is an epilepsy specialist at the University of Wisconsin, Madison, and Dr. Kelley is director of the Pediatric Epilepsy Monitoring Unit at Johns Hopkins University, Baltimore. This editorial reflects the content of a presentation given by Dr. Felton and Dr. Kelley at the annual meeting of the American Epilepsy Society in Houston. The authors report no conflict of interest.

Has this ever happened to you? You are an adult neurologist who has been asked to take on the care of a pediatric neurology patient. The patient who comes to your clinic is a 20-year-old young woman with a history of moderate developmental delay and intractable epilepsy. She is on numerous medications including valproic acid with a previous trial of the ketogenic diet. You receive a report that she has focal epilepsy and is having frequent seizures and last had an MRI at age 2 years. Prior notes talk about her summer vacations but not much about the future plans for her epilepsy. You see the patient in clinic, and the family is not happy to be in the adult clinic. They are disappointed that you don’t spend more time with them or fill out myriad forms. You find out that they have not obtained legal guardianship for their daughter and have no plan for work placement after school. She also has various other medical comorbidities that were previously addressed by the pediatric neurologist.

Dr. Felton is an epilepsy specialist at the University of Wisconsin, Madison, and Dr. Kelley is director of the Pediatric Epilepsy Monitoring Unit at Johns Hopkins University, Baltimore. This editorial reflects the content of a presentation given by Dr. Felton and Dr. Kelley at the annual meeting of the American Epilepsy Society in Houston. The authors report no conflict of interest.

HOUSTON – Patients with psychogenic nonepileptic seizures who stick with evidence-based treatment have significantly fewer seizures and have less associated disability than do those who don’t make it to therapy and psychiatry visits, a study showed.

Reporting preliminary data from 59 patients in a 123-patient study, Benjamin Tolchin, MD, and his colleagues said that patients who adhered to their treatment plans were significantly more likely to experience a reduction in seizure frequency of more than 50%, compared with nonadherent patients (P = .018). Treatment dropout was positively associated with having a prior psychogenic nonepileptic seizure (PNES) diagnosis and with having less concern about the illness.

[email protected]

On Twitter @karioakes

HOUSTON – Patients with psychogenic nonepileptic seizures who stick with evidence-based treatment have significantly fewer seizures and have less associated disability than do those who don’t make it to therapy and psychiatry visits, a study showed.

Reporting preliminary data from 59 patients in a 123-patient study, Benjamin Tolchin, MD, and his colleagues said that patients who adhered to their treatment plans were significantly more likely to experience a reduction in seizure frequency of more than 50%, compared with nonadherent patients (P = .018). Treatment dropout was positively associated with having a prior psychogenic nonepileptic seizure (PNES) diagnosis and with having less concern about the illness.

[email protected]

On Twitter @karioakes

HOUSTON – Patients with psychogenic nonepileptic seizures who stick with evidence-based treatment have significantly fewer seizures and have less associated disability than do those who don’t make it to therapy and psychiatry visits, a study showed.

Reporting preliminary data from 59 patients in a 123-patient study, Benjamin Tolchin, MD, and his colleagues said that patients who adhered to their treatment plans were significantly more likely to experience a reduction in seizure frequency of more than 50%, compared with nonadherent patients (P = .018). Treatment dropout was positively associated with having a prior psychogenic nonepileptic seizure (PNES) diagnosis and with having less concern about the illness.

[email protected]

On Twitter @karioakes

The diagnosis

The radiographic and pathologic findings and the patient’s clinical presentation were most consistent with autoimmune pancreatitis and IgG4-related sclerosing cholangitis, which are manifestations of IgG4-related disease. IgG4-related disease is a fibroinflammatory condition that has been described in almost every organ system. Elevated serum IgG4 levels suggest this diagnosis, but many times remain normal.1,2 Therefore, a strong clinical suspicion should prompt a biopsy of the affected tissue, which will show a dense lymphoplasmacytic infiltrate organized in a matted and irregularly whorled pattern.2,3 Making a diagnosis requires immunohistochemical confirmation with IgG4 immunostaining of plasma cells.

The patient was started on prednisone followed by azathioprine and experienced a rapid and sustained clinical and biochemical response even after stopping immunosuppressive therapy. After treatment, repeat imaging studies were performed, which showed dramatic improvement in the above-mentioned abnormalities. Abdominal CT showed a decrease in size of the pancreatic head (Figure C) and repeat cholangiogram showed resolution of biliary stenoses (Figure D).

References

1. Oseini, A.M., Chaiteerakij, R., Shire, A.M., et al. Utility of serum immunoglobulin G4 in distinguishing immunoglobulin G4-associated cholangitis from cholangiocarcinoma. Hepatology. 2011;54:940-8.

2. Takuma, K., Kamisawa, T., Gopalakrishna, R., et al. Strategy to differentiate autoimmune pancreatitis from pancreas cancer. World J Gastroenterol. 2012;18:1015-20.

3. Stone, J.H., Zen, Y., Deshpande, V. IgG4-related disease. N Engl J Med. 2012;366:539-51.

The diagnosis

The radiographic and pathologic findings and the patient’s clinical presentation were most consistent with autoimmune pancreatitis and IgG4-related sclerosing cholangitis, which are manifestations of IgG4-related disease. IgG4-related disease is a fibroinflammatory condition that has been described in almost every organ system. Elevated serum IgG4 levels suggest this diagnosis, but many times remain normal.1,2 Therefore, a strong clinical suspicion should prompt a biopsy of the affected tissue, which will show a dense lymphoplasmacytic infiltrate organized in a matted and irregularly whorled pattern.2,3 Making a diagnosis requires immunohistochemical confirmation with IgG4 immunostaining of plasma cells.

The patient was started on prednisone followed by azathioprine and experienced a rapid and sustained clinical and biochemical response even after stopping immunosuppressive therapy. After treatment, repeat imaging studies were performed, which showed dramatic improvement in the above-mentioned abnormalities. Abdominal CT showed a decrease in size of the pancreatic head (Figure C) and repeat cholangiogram showed resolution of biliary stenoses (Figure D).

References

1. Oseini, A.M., Chaiteerakij, R., Shire, A.M., et al. Utility of serum immunoglobulin G4 in distinguishing immunoglobulin G4-associated cholangitis from cholangiocarcinoma. Hepatology. 2011;54:940-8.

2. Takuma, K., Kamisawa, T., Gopalakrishna, R., et al. Strategy to differentiate autoimmune pancreatitis from pancreas cancer. World J Gastroenterol. 2012;18:1015-20.

3. Stone, J.H., Zen, Y., Deshpande, V. IgG4-related disease. N Engl J Med. 2012;366:539-51.

The diagnosis

The radiographic and pathologic findings and the patient’s clinical presentation were most consistent with autoimmune pancreatitis and IgG4-related sclerosing cholangitis, which are manifestations of IgG4-related disease. IgG4-related disease is a fibroinflammatory condition that has been described in almost every organ system. Elevated serum IgG4 levels suggest this diagnosis, but many times remain normal.1,2 Therefore, a strong clinical suspicion should prompt a biopsy of the affected tissue, which will show a dense lymphoplasmacytic infiltrate organized in a matted and irregularly whorled pattern.2,3 Making a diagnosis requires immunohistochemical confirmation with IgG4 immunostaining of plasma cells.

The patient was started on prednisone followed by azathioprine and experienced a rapid and sustained clinical and biochemical response even after stopping immunosuppressive therapy. After treatment, repeat imaging studies were performed, which showed dramatic improvement in the above-mentioned abnormalities. Abdominal CT showed a decrease in size of the pancreatic head (Figure C) and repeat cholangiogram showed resolution of biliary stenoses (Figure D).

References

1. Oseini, A.M., Chaiteerakij, R., Shire, A.M., et al. Utility of serum immunoglobulin G4 in distinguishing immunoglobulin G4-associated cholangitis from cholangiocarcinoma. Hepatology. 2011;54:940-8.

2. Takuma, K., Kamisawa, T., Gopalakrishna, R., et al. Strategy to differentiate autoimmune pancreatitis from pancreas cancer. World J Gastroenterol. 2012;18:1015-20.

3. Stone, J.H., Zen, Y., Deshpande, V. IgG4-related disease. N Engl J Med. 2012;366:539-51.