Dermatology

CHICAGO – Apremilast was effective and well tolerated for up to 28 weeks for the treatment of oral ulcers in patients with active Behçet’s disease, based on findings from the randomized, placebo-controlled, phase 3 RELIEF trial.

At baseline, mean oral ulcer counts were 4.2 in 104 patients randomized to receive the oral phosphodiesterase-4 inhibitor and 3.9 in 103 patients in the placebo group. Mean visual analog scale (VAS) pain scores were 61.2 and 60.8 in the two groups, respectively.

The primary study endpoint of area under the curve for total number of oral ulcers over a 12-week period (AUC_Wk0-12) – a measure that reflects the number of oral ulcers that occur over time and also accounts for the recurring-remitting course of oral ulcers – was achieved. AUC_Wk0-12 was significantly lower in the apremilast group than in the placebo group (129.54 vs. 222.14, respectively; P less than .0001), Gulen Hatemi, MD, reported at the annual meeting of the American College of Rheumatology.

From baseline to week 12, apremilast treatment also resulted in a significantly lower number of oral ulcers (mean of 1.1 vs. 2.0 for placebo at 12 weeks) and significantly reduced pain from oral ulcers at every visit from week 1 through week 12 of the study, compared with placebo (mean VAS score change from baseline, –40.7 vs. –15.9), said Dr. Hatemi, a professor of medicine at Istanbul University.

“The [12-week] complete response rate ... was 53% in the apremilast group and 22.3% in the placebo group. The [12-week] partial response rate ...was 76% in the apremilast group and 48% in the placebo group,” she said, adding that the efficacy of apremilast was sustained with continued treatment through 28 weeks.

Study participants were adults (mean age, 40 years) with active Behçet’s disease and three or more oral ulcers at randomization or two or more at screening and at randomization. All had been previously treated with at least one nonbiologic medication for oral ulcers and were allowed to have received previous biologic therapies for other disease manifestations. Those with active major organ involvement were excluded.

Treatment included a 30-mg dose of apremilast twice daily for 12 weeks or placebo. After 12 weeks, all patients received apremilast through at least 28 weeks of the 64-week study.

At the 28-week analysis, patients who were initially randomized to placebo and who switched to apremilast after week 12 had benefits comparable with those seen in those randomized to apremilast at the start of the study. A complete response was seen in 59% and 62% of patients in the groups, respectively, and a partial response was seen in 90% and 85%, respectively. Additionally, the mean change in the VAS score for oral ulcer pain in the groups at that time was –40.6 and –41.9, Dr. Hatemi said.

Apremilast was well tolerated in this study; the incidence of adverse events was comparable in the treatment and placebo groups during the 12-week placebo-controlled phase of the study – 78.8% and 71.8%, respectively. The most common events were diarrhea, nausea, headache, and upper respiratory tract infection, she said.

“These were generally mild to moderate, and only two patients had to discontinue the study due to gastrointestinal adverse events,” she said, noting that no new safety signals were observed.

Behçet’s disease is a chronic, relapsing, multisystem inflammatory disorder characterized by recurrent oral ulcers that can be disabling and have a substantial effect on quality of life. These findings, which include efficacy data up to 28 weeks and safety data for at least 100 patients exposed to apremilast for at least 1 year, demonstrate the efficacy of apremilast for the treatment oral ulcers in patients with Behçet’s disease, she said, noting that “the safety findings were consistent with the known safety profile of apremilast.”

The RELIEF study was supported by Celgene. Dr. Hatemi reported receiving grant/research support from Celgene and serving as a speaker for AbbVie, Mustafa Nevzet Pharmaceuticals, and UCB.

[email protected]

SOURCE: Hatemi G et al. Arthritis Rheumatol. 2018;70(Suppl 10), Abstract 2789.

CHICAGO – Apremilast was effective and well tolerated for up to 28 weeks for the treatment of oral ulcers in patients with active Behçet’s disease, based on findings from the randomized, placebo-controlled, phase 3 RELIEF trial.

At baseline, mean oral ulcer counts were 4.2 in 104 patients randomized to receive the oral phosphodiesterase-4 inhibitor and 3.9 in 103 patients in the placebo group. Mean visual analog scale (VAS) pain scores were 61.2 and 60.8 in the two groups, respectively.

The primary study endpoint of area under the curve for total number of oral ulcers over a 12-week period (AUC_Wk0-12) – a measure that reflects the number of oral ulcers that occur over time and also accounts for the recurring-remitting course of oral ulcers – was achieved. AUC_Wk0-12 was significantly lower in the apremilast group than in the placebo group (129.54 vs. 222.14, respectively; P less than .0001), Gulen Hatemi, MD, reported at the annual meeting of the American College of Rheumatology.

From baseline to week 12, apremilast treatment also resulted in a significantly lower number of oral ulcers (mean of 1.1 vs. 2.0 for placebo at 12 weeks) and significantly reduced pain from oral ulcers at every visit from week 1 through week 12 of the study, compared with placebo (mean VAS score change from baseline, –40.7 vs. –15.9), said Dr. Hatemi, a professor of medicine at Istanbul University.

“The [12-week] complete response rate ... was 53% in the apremilast group and 22.3% in the placebo group. The [12-week] partial response rate ...was 76% in the apremilast group and 48% in the placebo group,” she said, adding that the efficacy of apremilast was sustained with continued treatment through 28 weeks.

Study participants were adults (mean age, 40 years) with active Behçet’s disease and three or more oral ulcers at randomization or two or more at screening and at randomization. All had been previously treated with at least one nonbiologic medication for oral ulcers and were allowed to have received previous biologic therapies for other disease manifestations. Those with active major organ involvement were excluded.

Treatment included a 30-mg dose of apremilast twice daily for 12 weeks or placebo. After 12 weeks, all patients received apremilast through at least 28 weeks of the 64-week study.

At the 28-week analysis, patients who were initially randomized to placebo and who switched to apremilast after week 12 had benefits comparable with those seen in those randomized to apremilast at the start of the study. A complete response was seen in 59% and 62% of patients in the groups, respectively, and a partial response was seen in 90% and 85%, respectively. Additionally, the mean change in the VAS score for oral ulcer pain in the groups at that time was –40.6 and –41.9, Dr. Hatemi said.

Apremilast was well tolerated in this study; the incidence of adverse events was comparable in the treatment and placebo groups during the 12-week placebo-controlled phase of the study – 78.8% and 71.8%, respectively. The most common events were diarrhea, nausea, headache, and upper respiratory tract infection, she said.

“These were generally mild to moderate, and only two patients had to discontinue the study due to gastrointestinal adverse events,” she said, noting that no new safety signals were observed.

Behçet’s disease is a chronic, relapsing, multisystem inflammatory disorder characterized by recurrent oral ulcers that can be disabling and have a substantial effect on quality of life. These findings, which include efficacy data up to 28 weeks and safety data for at least 100 patients exposed to apremilast for at least 1 year, demonstrate the efficacy of apremilast for the treatment oral ulcers in patients with Behçet’s disease, she said, noting that “the safety findings were consistent with the known safety profile of apremilast.”

The RELIEF study was supported by Celgene. Dr. Hatemi reported receiving grant/research support from Celgene and serving as a speaker for AbbVie, Mustafa Nevzet Pharmaceuticals, and UCB.

[email protected]

SOURCE: Hatemi G et al. Arthritis Rheumatol. 2018;70(Suppl 10), Abstract 2789.

CHICAGO – Apremilast was effective and well tolerated for up to 28 weeks for the treatment of oral ulcers in patients with active Behçet’s disease, based on findings from the randomized, placebo-controlled, phase 3 RELIEF trial.

At baseline, mean oral ulcer counts were 4.2 in 104 patients randomized to receive the oral phosphodiesterase-4 inhibitor and 3.9 in 103 patients in the placebo group. Mean visual analog scale (VAS) pain scores were 61.2 and 60.8 in the two groups, respectively.

The primary study endpoint of area under the curve for total number of oral ulcers over a 12-week period (AUC_Wk0-12) – a measure that reflects the number of oral ulcers that occur over time and also accounts for the recurring-remitting course of oral ulcers – was achieved. AUC_Wk0-12 was significantly lower in the apremilast group than in the placebo group (129.54 vs. 222.14, respectively; P less than .0001), Gulen Hatemi, MD, reported at the annual meeting of the American College of Rheumatology.

From baseline to week 12, apremilast treatment also resulted in a significantly lower number of oral ulcers (mean of 1.1 vs. 2.0 for placebo at 12 weeks) and significantly reduced pain from oral ulcers at every visit from week 1 through week 12 of the study, compared with placebo (mean VAS score change from baseline, –40.7 vs. –15.9), said Dr. Hatemi, a professor of medicine at Istanbul University.

“The [12-week] complete response rate ... was 53% in the apremilast group and 22.3% in the placebo group. The [12-week] partial response rate ...was 76% in the apremilast group and 48% in the placebo group,” she said, adding that the efficacy of apremilast was sustained with continued treatment through 28 weeks.

Study participants were adults (mean age, 40 years) with active Behçet’s disease and three or more oral ulcers at randomization or two or more at screening and at randomization. All had been previously treated with at least one nonbiologic medication for oral ulcers and were allowed to have received previous biologic therapies for other disease manifestations. Those with active major organ involvement were excluded.

Treatment included a 30-mg dose of apremilast twice daily for 12 weeks or placebo. After 12 weeks, all patients received apremilast through at least 28 weeks of the 64-week study.

At the 28-week analysis, patients who were initially randomized to placebo and who switched to apremilast after week 12 had benefits comparable with those seen in those randomized to apremilast at the start of the study. A complete response was seen in 59% and 62% of patients in the groups, respectively, and a partial response was seen in 90% and 85%, respectively. Additionally, the mean change in the VAS score for oral ulcer pain in the groups at that time was –40.6 and –41.9, Dr. Hatemi said.

Apremilast was well tolerated in this study; the incidence of adverse events was comparable in the treatment and placebo groups during the 12-week placebo-controlled phase of the study – 78.8% and 71.8%, respectively. The most common events were diarrhea, nausea, headache, and upper respiratory tract infection, she said.

“These were generally mild to moderate, and only two patients had to discontinue the study due to gastrointestinal adverse events,” she said, noting that no new safety signals were observed.

Behçet’s disease is a chronic, relapsing, multisystem inflammatory disorder characterized by recurrent oral ulcers that can be disabling and have a substantial effect on quality of life. These findings, which include efficacy data up to 28 weeks and safety data for at least 100 patients exposed to apremilast for at least 1 year, demonstrate the efficacy of apremilast for the treatment oral ulcers in patients with Behçet’s disease, she said, noting that “the safety findings were consistent with the known safety profile of apremilast.”

The RELIEF study was supported by Celgene. Dr. Hatemi reported receiving grant/research support from Celgene and serving as a speaker for AbbVie, Mustafa Nevzet Pharmaceuticals, and UCB.

[email protected]

SOURCE: Hatemi G et al. Arthritis Rheumatol. 2018;70(Suppl 10), Abstract 2789.

CHICAGO – Overweight and obese psoriasis patients have it within their power to reduce their risk of developing psoriatic arthritis through weight loss, according to a large British longitudinal study.

Bruce Jancin/MDedge News

Of the three modifiable lifestyle factors evaluated in the study as potential risk factors for the development of psoriatic arthritis in psoriasis patients – body mass index, smoking, and alcohol intake – reduction in BMI over time was clearly the winning strategy, Neil McHugh, MD, said at the annual meeting of the American College of Rheumatology.

The message from this study of 90,189 incident cases of psoriasis identified in the U.K. Clinical Practice Research Datalink was unequivocal: “If you’re overweight and have psoriasis and you lose weight, you reduce your chance of developing a nasty form of arthritis,” said Dr. McHugh, professor of pharmacoepidemiology and a rheumatologist at the University of Bath, England.

“As psoriatic arthritis affects around 20% of people with psoriasis, weight reduction amongst those who are obese may have the potential to greatly reduce their risk of psoriatic arthritis in addition to providing additional health benefits,” he added.

Among the more than 90,000 patients diagnosed with psoriasis, 1,409 subsequently developed psoriatic arthritis, with an overall incidence rate of 2.72 cases per 1,000 person-years. Baseline BMI was strongly associated in stepwise fashion with subsequent psoriatic arthritis. Psoriasis patients with a baseline BMI of 25-29.9 kg/m² were at an adjusted 1.76-fold increased risk of later developing psoriatic arthritis, compared with psoriasis patients having a BMI of less than 25. For those with a BMI of 30-34.9 kg/m², the risk of subsequent psoriatic arthritis was increased 2.04-fold. And for those with a baseline BMI of 35 kg/m² or more, the risk was increased 2.42-fold in analyses adjusted for age, sex, psoriasis duration and severity, history of trauma, and diabetes.

In contrast, the risk of developing psoriatic arthritis wasn’t significantly different between psoriasis patients who were nonsmokers, ex-smokers, or current smokers. And while there was a significantly increased risk of developing psoriatic arthritis in psoriasis patients who were current drinkers, compared with nondrinkers, the risk in ex-drinkers and heavy drinkers was similar to that in nondrinkers, a counterintuitive finding Dr. McHugh suspects was a distortion due to small numbers.

While the observed relationship between baseline BMI and subsequent risk of psoriatic arthritis was informative, it only tells part of the story, since body weight so often changes over time. Dr. McHugh and his coinvestigators had data on change in BMI over the course of 10 years of follow-up in 15,627 psoriasis patients free of psoriatic arthritis at the time their psoriasis was diagnosed. The researchers developed a BMI risk calculator that expressed the effect of change in BMI over time on the cumulative risk of developing psoriatic arthritis.

“We were able to show that if, for instance, you started with a BMI of 25 at baseline and ended up with a BMI of 30, your risk of psoriatic arthritis goes up by 13%, whereas if you start at 30 and come down to 25, your risk decreases by 13%. And the more weight you lose, the greater you reduce your risk of developing psoriatic arthritis,” the rheumatologist explained in an interview.

Indeed, with more extreme changes in BMI over the course of a decade following diagnosis of psoriasis – for example, dropping from a baseline BMI of 36 kg/m² to 23 kg/m² – the risk of developing psoriatic arthritis fell by close to 30%.

Dr. McHugh reported having no financial conflicts regarding this study, funded by the U.K. National Institute for Health Research.

[email protected]

SOURCE: Green A et al. Arthritis Rheumatol. 2018;70(Suppl 10): Abstract 2134.

CHICAGO – Overweight and obese psoriasis patients have it within their power to reduce their risk of developing psoriatic arthritis through weight loss, according to a large British longitudinal study.

Bruce Jancin/MDedge News

Of the three modifiable lifestyle factors evaluated in the study as potential risk factors for the development of psoriatic arthritis in psoriasis patients – body mass index, smoking, and alcohol intake – reduction in BMI over time was clearly the winning strategy, Neil McHugh, MD, said at the annual meeting of the American College of Rheumatology.

The message from this study of 90,189 incident cases of psoriasis identified in the U.K. Clinical Practice Research Datalink was unequivocal: “If you’re overweight and have psoriasis and you lose weight, you reduce your chance of developing a nasty form of arthritis,” said Dr. McHugh, professor of pharmacoepidemiology and a rheumatologist at the University of Bath, England.

“As psoriatic arthritis affects around 20% of people with psoriasis, weight reduction amongst those who are obese may have the potential to greatly reduce their risk of psoriatic arthritis in addition to providing additional health benefits,” he added.

Among the more than 90,000 patients diagnosed with psoriasis, 1,409 subsequently developed psoriatic arthritis, with an overall incidence rate of 2.72 cases per 1,000 person-years. Baseline BMI was strongly associated in stepwise fashion with subsequent psoriatic arthritis. Psoriasis patients with a baseline BMI of 25-29.9 kg/m² were at an adjusted 1.76-fold increased risk of later developing psoriatic arthritis, compared with psoriasis patients having a BMI of less than 25. For those with a BMI of 30-34.9 kg/m², the risk of subsequent psoriatic arthritis was increased 2.04-fold. And for those with a baseline BMI of 35 kg/m² or more, the risk was increased 2.42-fold in analyses adjusted for age, sex, psoriasis duration and severity, history of trauma, and diabetes.

In contrast, the risk of developing psoriatic arthritis wasn’t significantly different between psoriasis patients who were nonsmokers, ex-smokers, or current smokers. And while there was a significantly increased risk of developing psoriatic arthritis in psoriasis patients who were current drinkers, compared with nondrinkers, the risk in ex-drinkers and heavy drinkers was similar to that in nondrinkers, a counterintuitive finding Dr. McHugh suspects was a distortion due to small numbers.

While the observed relationship between baseline BMI and subsequent risk of psoriatic arthritis was informative, it only tells part of the story, since body weight so often changes over time. Dr. McHugh and his coinvestigators had data on change in BMI over the course of 10 years of follow-up in 15,627 psoriasis patients free of psoriatic arthritis at the time their psoriasis was diagnosed. The researchers developed a BMI risk calculator that expressed the effect of change in BMI over time on the cumulative risk of developing psoriatic arthritis.

“We were able to show that if, for instance, you started with a BMI of 25 at baseline and ended up with a BMI of 30, your risk of psoriatic arthritis goes up by 13%, whereas if you start at 30 and come down to 25, your risk decreases by 13%. And the more weight you lose, the greater you reduce your risk of developing psoriatic arthritis,” the rheumatologist explained in an interview.

Indeed, with more extreme changes in BMI over the course of a decade following diagnosis of psoriasis – for example, dropping from a baseline BMI of 36 kg/m² to 23 kg/m² – the risk of developing psoriatic arthritis fell by close to 30%.

Dr. McHugh reported having no financial conflicts regarding this study, funded by the U.K. National Institute for Health Research.

[email protected]

SOURCE: Green A et al. Arthritis Rheumatol. 2018;70(Suppl 10): Abstract 2134.

CHICAGO – Overweight and obese psoriasis patients have it within their power to reduce their risk of developing psoriatic arthritis through weight loss, according to a large British longitudinal study.

Bruce Jancin/MDedge News

Of the three modifiable lifestyle factors evaluated in the study as potential risk factors for the development of psoriatic arthritis in psoriasis patients – body mass index, smoking, and alcohol intake – reduction in BMI over time was clearly the winning strategy, Neil McHugh, MD, said at the annual meeting of the American College of Rheumatology.

The message from this study of 90,189 incident cases of psoriasis identified in the U.K. Clinical Practice Research Datalink was unequivocal: “If you’re overweight and have psoriasis and you lose weight, you reduce your chance of developing a nasty form of arthritis,” said Dr. McHugh, professor of pharmacoepidemiology and a rheumatologist at the University of Bath, England.

“As psoriatic arthritis affects around 20% of people with psoriasis, weight reduction amongst those who are obese may have the potential to greatly reduce their risk of psoriatic arthritis in addition to providing additional health benefits,” he added.

Among the more than 90,000 patients diagnosed with psoriasis, 1,409 subsequently developed psoriatic arthritis, with an overall incidence rate of 2.72 cases per 1,000 person-years. Baseline BMI was strongly associated in stepwise fashion with subsequent psoriatic arthritis. Psoriasis patients with a baseline BMI of 25-29.9 kg/m² were at an adjusted 1.76-fold increased risk of later developing psoriatic arthritis, compared with psoriasis patients having a BMI of less than 25. For those with a BMI of 30-34.9 kg/m², the risk of subsequent psoriatic arthritis was increased 2.04-fold. And for those with a baseline BMI of 35 kg/m² or more, the risk was increased 2.42-fold in analyses adjusted for age, sex, psoriasis duration and severity, history of trauma, and diabetes.

In contrast, the risk of developing psoriatic arthritis wasn’t significantly different between psoriasis patients who were nonsmokers, ex-smokers, or current smokers. And while there was a significantly increased risk of developing psoriatic arthritis in psoriasis patients who were current drinkers, compared with nondrinkers, the risk in ex-drinkers and heavy drinkers was similar to that in nondrinkers, a counterintuitive finding Dr. McHugh suspects was a distortion due to small numbers.

While the observed relationship between baseline BMI and subsequent risk of psoriatic arthritis was informative, it only tells part of the story, since body weight so often changes over time. Dr. McHugh and his coinvestigators had data on change in BMI over the course of 10 years of follow-up in 15,627 psoriasis patients free of psoriatic arthritis at the time their psoriasis was diagnosed. The researchers developed a BMI risk calculator that expressed the effect of change in BMI over time on the cumulative risk of developing psoriatic arthritis.

“We were able to show that if, for instance, you started with a BMI of 25 at baseline and ended up with a BMI of 30, your risk of psoriatic arthritis goes up by 13%, whereas if you start at 30 and come down to 25, your risk decreases by 13%. And the more weight you lose, the greater you reduce your risk of developing psoriatic arthritis,” the rheumatologist explained in an interview.

Indeed, with more extreme changes in BMI over the course of a decade following diagnosis of psoriasis – for example, dropping from a baseline BMI of 36 kg/m² to 23 kg/m² – the risk of developing psoriatic arthritis fell by close to 30%.

Dr. McHugh reported having no financial conflicts regarding this study, funded by the U.K. National Institute for Health Research.

[email protected]

SOURCE: Green A et al. Arthritis Rheumatol. 2018;70(Suppl 10): Abstract 2134.

Given its limited systemic toxicity, topical anthralin is an acceptable second-line treatment option for pediatric alopecia areata (AA), according to Sean Z. Wu, MD, of the department of dermatology, University of Cincinnati, and his associates.

In a retrospective study of 37 pediatric patients with AA, published in Pediatric Dermatology, Dr. Wu and his colleagues found that almost two-thirds experienced at least 50% regrowth of hair with topical anthralin treatment, but they described severe dermatitis and relapses as “potential drawbacks” of treatment.

The 37 patients were in the Cleveland Clinic AA areata database and began treatment with anthralin between 2004 and 2015, at aged 2-17 years (mean age 9). Over half (22) were females and most (31) were white. About 65% had patchy AA; the remainder had either alopecia totalis or alopecia universalis. Prior treatments included topical corticosteroids, minoxidil, and intralesional corticosteroids; four patients had not been treated previously. Patients were followed up from 51 days to more than 10 years, with a mean duration of 2.5 years. Treatment regimens, titrated up to achieve a mild to moderate dermatitis, included application of 0.5% cream for 5 minutes twice a week up to 1.0% cream for 30 minutes a day.

With topical anthralin, 12 (32%) of patients had complete scalp regrowth, 25 (68%) experienced at least 50% regrowth, and 5 (14%) had no response; in five patients, no follow-up information was available. Among those with at least 50% regrowth, the initial response was first noted at a mean of 3.4 months, and the mean time to maximal response was 15 months. This timeline suggests that treatment with anthralin should be continued beyond 1 year to ensure maximum beneficial results with hair regrowth, the authors wrote.

Factors associated with a positive response to treatment included less than 50% of scalp involvement. The two patients who used anthralin as monotherapy did not achieve a 50% scalp response, but the four treatment-naive patients were among those with at least 50% scalp regrowth, versus three of the five patients (60%) who had been treated previously with systemic steroids.

Two potential clinical limitations were noted during the study. Four patients had to stop treatment because of dermatitis, which suggests that patients and parents should be counseled about the potential for severe skin irritation with this treatment, the authors said. And among those who achieved at least 50% scalp regrowth, 16 of the 25 (64%) relapsed. The authors speculated that the effects of the drug could be temporary “or that the disease process may be able to overcome the anthralin effect over time.”

Dr. Wu and his coauthors cited the retrospective design and the small population size as major limitations of the study. Because some patients continued other treatments, it is “difficult to attribute scalp regrowth entirely to anthralin,” and variations in formulation and in treatment regimens are also factors to be considered, they cautioned. That AA has been found to spontaneously resolve, depending upon the severity of the disease, presents additional challenges for clinicians attempting to determine the extent to which anthralin offers therapeutic benefit, they pointed out.

In spite of the drug’s limitations, the authors concluded that the treatment was a safe and useful option as an “adjunct for those who fail first-line therapy with topical or intralesional corticosteroids.” They added that more work is needed to tailor treatment formulation, frequency, and duration to the specific needs of pediatric patients.

The authors had no relevant financial disclosures to report.

SOURCE: Wu SZ et al. Pediatr Dermatol. 2018;35:817-20.

Given its limited systemic toxicity, topical anthralin is an acceptable second-line treatment option for pediatric alopecia areata (AA), according to Sean Z. Wu, MD, of the department of dermatology, University of Cincinnati, and his associates.

In a retrospective study of 37 pediatric patients with AA, published in Pediatric Dermatology, Dr. Wu and his colleagues found that almost two-thirds experienced at least 50% regrowth of hair with topical anthralin treatment, but they described severe dermatitis and relapses as “potential drawbacks” of treatment.

The 37 patients were in the Cleveland Clinic AA areata database and began treatment with anthralin between 2004 and 2015, at aged 2-17 years (mean age 9). Over half (22) were females and most (31) were white. About 65% had patchy AA; the remainder had either alopecia totalis or alopecia universalis. Prior treatments included topical corticosteroids, minoxidil, and intralesional corticosteroids; four patients had not been treated previously. Patients were followed up from 51 days to more than 10 years, with a mean duration of 2.5 years. Treatment regimens, titrated up to achieve a mild to moderate dermatitis, included application of 0.5% cream for 5 minutes twice a week up to 1.0% cream for 30 minutes a day.

With topical anthralin, 12 (32%) of patients had complete scalp regrowth, 25 (68%) experienced at least 50% regrowth, and 5 (14%) had no response; in five patients, no follow-up information was available. Among those with at least 50% regrowth, the initial response was first noted at a mean of 3.4 months, and the mean time to maximal response was 15 months. This timeline suggests that treatment with anthralin should be continued beyond 1 year to ensure maximum beneficial results with hair regrowth, the authors wrote.

Factors associated with a positive response to treatment included less than 50% of scalp involvement. The two patients who used anthralin as monotherapy did not achieve a 50% scalp response, but the four treatment-naive patients were among those with at least 50% scalp regrowth, versus three of the five patients (60%) who had been treated previously with systemic steroids.

Two potential clinical limitations were noted during the study. Four patients had to stop treatment because of dermatitis, which suggests that patients and parents should be counseled about the potential for severe skin irritation with this treatment, the authors said. And among those who achieved at least 50% scalp regrowth, 16 of the 25 (64%) relapsed. The authors speculated that the effects of the drug could be temporary “or that the disease process may be able to overcome the anthralin effect over time.”

Dr. Wu and his coauthors cited the retrospective design and the small population size as major limitations of the study. Because some patients continued other treatments, it is “difficult to attribute scalp regrowth entirely to anthralin,” and variations in formulation and in treatment regimens are also factors to be considered, they cautioned. That AA has been found to spontaneously resolve, depending upon the severity of the disease, presents additional challenges for clinicians attempting to determine the extent to which anthralin offers therapeutic benefit, they pointed out.

In spite of the drug’s limitations, the authors concluded that the treatment was a safe and useful option as an “adjunct for those who fail first-line therapy with topical or intralesional corticosteroids.” They added that more work is needed to tailor treatment formulation, frequency, and duration to the specific needs of pediatric patients.

The authors had no relevant financial disclosures to report.

SOURCE: Wu SZ et al. Pediatr Dermatol. 2018;35:817-20.

Given its limited systemic toxicity, topical anthralin is an acceptable second-line treatment option for pediatric alopecia areata (AA), according to Sean Z. Wu, MD, of the department of dermatology, University of Cincinnati, and his associates.

In a retrospective study of 37 pediatric patients with AA, published in Pediatric Dermatology, Dr. Wu and his colleagues found that almost two-thirds experienced at least 50% regrowth of hair with topical anthralin treatment, but they described severe dermatitis and relapses as “potential drawbacks” of treatment.

The 37 patients were in the Cleveland Clinic AA areata database and began treatment with anthralin between 2004 and 2015, at aged 2-17 years (mean age 9). Over half (22) were females and most (31) were white. About 65% had patchy AA; the remainder had either alopecia totalis or alopecia universalis. Prior treatments included topical corticosteroids, minoxidil, and intralesional corticosteroids; four patients had not been treated previously. Patients were followed up from 51 days to more than 10 years, with a mean duration of 2.5 years. Treatment regimens, titrated up to achieve a mild to moderate dermatitis, included application of 0.5% cream for 5 minutes twice a week up to 1.0% cream for 30 minutes a day.

With topical anthralin, 12 (32%) of patients had complete scalp regrowth, 25 (68%) experienced at least 50% regrowth, and 5 (14%) had no response; in five patients, no follow-up information was available. Among those with at least 50% regrowth, the initial response was first noted at a mean of 3.4 months, and the mean time to maximal response was 15 months. This timeline suggests that treatment with anthralin should be continued beyond 1 year to ensure maximum beneficial results with hair regrowth, the authors wrote.

Factors associated with a positive response to treatment included less than 50% of scalp involvement. The two patients who used anthralin as monotherapy did not achieve a 50% scalp response, but the four treatment-naive patients were among those with at least 50% scalp regrowth, versus three of the five patients (60%) who had been treated previously with systemic steroids.

Two potential clinical limitations were noted during the study. Four patients had to stop treatment because of dermatitis, which suggests that patients and parents should be counseled about the potential for severe skin irritation with this treatment, the authors said. And among those who achieved at least 50% scalp regrowth, 16 of the 25 (64%) relapsed. The authors speculated that the effects of the drug could be temporary “or that the disease process may be able to overcome the anthralin effect over time.”

Dr. Wu and his coauthors cited the retrospective design and the small population size as major limitations of the study. Because some patients continued other treatments, it is “difficult to attribute scalp regrowth entirely to anthralin,” and variations in formulation and in treatment regimens are also factors to be considered, they cautioned. That AA has been found to spontaneously resolve, depending upon the severity of the disease, presents additional challenges for clinicians attempting to determine the extent to which anthralin offers therapeutic benefit, they pointed out.

In spite of the drug’s limitations, the authors concluded that the treatment was a safe and useful option as an “adjunct for those who fail first-line therapy with topical or intralesional corticosteroids.” They added that more work is needed to tailor treatment formulation, frequency, and duration to the specific needs of pediatric patients.

The authors had no relevant financial disclosures to report.

SOURCE: Wu SZ et al. Pediatr Dermatol. 2018;35:817-20.

A KOH (potassium hydroxide) test done at the visit was negative as well as a fungal culture of each toenail.

The patient was diagnosed with congenital malalignment of the great toenails (CMGTN) based on history and morphologic appearance.

Congenital malalignment of the great toenails is an underrecognized and underreported nail disorder characterized by lateral deviation of the nail plate, which is not parallel to the longitudinal axis of the distal phalanx.¹ The cause is unknown. Some reports suggest a genetic cause being transmitted in an autosomal dominant fashion with variable expression.² There have been reports of CMGTN in monozygotic and dizygotic twins making this theory likely.³ Other authors consider an external cause such as amniotic bands, neonatal asphyxia, vascular malformations, and uterine pressure. This condition also has been reported in patients with Rubinstein-Taybi syndrome.⁴

The nail changes can occur at birth but in some cases, such as our patient, the nails become dystrophic months to years after birth. Characteristic nail changes include shorter, discolored, hyperkeratotic nails with transverse groove or ridges. In some cases, the dystrophic nails may cause inflammation and tenderness and is the most common cause of ingrown toenails in children.

The differential diagnosis includes onychomycosis, traumatic nails, nail psoriasis, pachyonychia congenital (PC), and onychomadesis. Onychomycosis can present with white or yellow discoloration of the nail that in some cases can be associated with nail breakage, hyperkeratosis, onycholysis, and subungual debris. Either fungal culture or periodic acid shift stain of nail clippings can help confirm or exclude this diagnosis. Psoriatic nails present with nail pits, oils spots, and onycholysis. Traumatic nail changes may occur from using small shoes and trauma from running or playing soccer, and presents with subungual hemorrhage and nail dystrophy of the first or second toenail. PC is a genetic disorder caused by a mutation in certain keratin proteins of the skin (k6a, k6b, K16 and K17). These patients usually have other skin findings including palmoplantar keratoderma, white plaques on the mouth, and skin cysts (steatocystoma multiplex and vellus hair cysts). Nail changes characteristic of PC includes subungual hyperkeratosis that causes a wedge shape thickening of the nail bed (pincer nails).⁵ Onychomadesis can be seen after viral infections such as hand-foot-mouth disease or in patients taking chemotherapy drugs that affect nail growth.

CMGTN usually resolves with time, but some patients with severe deviation and paronychia may need surgical correction.⁶
 

Dr. Matiz is a pediatric dermatologist at Southern California Permanente Medical Group, San Diego. Email her at [email protected].

References

1. Dermatol Online J. 2014 Jan 15;20(1):21251.

2. J Dtsch Dermatol Ges. 2012 May;10(5):326-30.

3. J Am Acad Dermatol. 2007 Oct;57(4):711-5.

4. Pediatr Dermatol. 2004 Jan-Feb;21(1):44-7.

5. Curr Opin Pediatr. 2014 Aug;26(4):440-5.

6. Skin Appendage Disord. 2018 Oct;4(4):230-5.

A KOH (potassium hydroxide) test done at the visit was negative as well as a fungal culture of each toenail.

The patient was diagnosed with congenital malalignment of the great toenails (CMGTN) based on history and morphologic appearance.

Congenital malalignment of the great toenails is an underrecognized and underreported nail disorder characterized by lateral deviation of the nail plate, which is not parallel to the longitudinal axis of the distal phalanx.¹ The cause is unknown. Some reports suggest a genetic cause being transmitted in an autosomal dominant fashion with variable expression.² There have been reports of CMGTN in monozygotic and dizygotic twins making this theory likely.³ Other authors consider an external cause such as amniotic bands, neonatal asphyxia, vascular malformations, and uterine pressure. This condition also has been reported in patients with Rubinstein-Taybi syndrome.⁴

The nail changes can occur at birth but in some cases, such as our patient, the nails become dystrophic months to years after birth. Characteristic nail changes include shorter, discolored, hyperkeratotic nails with transverse groove or ridges. In some cases, the dystrophic nails may cause inflammation and tenderness and is the most common cause of ingrown toenails in children.

The differential diagnosis includes onychomycosis, traumatic nails, nail psoriasis, pachyonychia congenital (PC), and onychomadesis. Onychomycosis can present with white or yellow discoloration of the nail that in some cases can be associated with nail breakage, hyperkeratosis, onycholysis, and subungual debris. Either fungal culture or periodic acid shift stain of nail clippings can help confirm or exclude this diagnosis. Psoriatic nails present with nail pits, oils spots, and onycholysis. Traumatic nail changes may occur from using small shoes and trauma from running or playing soccer, and presents with subungual hemorrhage and nail dystrophy of the first or second toenail. PC is a genetic disorder caused by a mutation in certain keratin proteins of the skin (k6a, k6b, K16 and K17). These patients usually have other skin findings including palmoplantar keratoderma, white plaques on the mouth, and skin cysts (steatocystoma multiplex and vellus hair cysts). Nail changes characteristic of PC includes subungual hyperkeratosis that causes a wedge shape thickening of the nail bed (pincer nails).⁵ Onychomadesis can be seen after viral infections such as hand-foot-mouth disease or in patients taking chemotherapy drugs that affect nail growth.

CMGTN usually resolves with time, but some patients with severe deviation and paronychia may need surgical correction.⁶
 

Dr. Matiz is a pediatric dermatologist at Southern California Permanente Medical Group, San Diego. Email her at [email protected].

References

1. Dermatol Online J. 2014 Jan 15;20(1):21251.

2. J Dtsch Dermatol Ges. 2012 May;10(5):326-30.

3. J Am Acad Dermatol. 2007 Oct;57(4):711-5.

4. Pediatr Dermatol. 2004 Jan-Feb;21(1):44-7.

5. Curr Opin Pediatr. 2014 Aug;26(4):440-5.

6. Skin Appendage Disord. 2018 Oct;4(4):230-5.

A KOH (potassium hydroxide) test done at the visit was negative as well as a fungal culture of each toenail.

The patient was diagnosed with congenital malalignment of the great toenails (CMGTN) based on history and morphologic appearance.

Congenital malalignment of the great toenails is an underrecognized and underreported nail disorder characterized by lateral deviation of the nail plate, which is not parallel to the longitudinal axis of the distal phalanx.¹ The cause is unknown. Some reports suggest a genetic cause being transmitted in an autosomal dominant fashion with variable expression.² There have been reports of CMGTN in monozygotic and dizygotic twins making this theory likely.³ Other authors consider an external cause such as amniotic bands, neonatal asphyxia, vascular malformations, and uterine pressure. This condition also has been reported in patients with Rubinstein-Taybi syndrome.⁴

The nail changes can occur at birth but in some cases, such as our patient, the nails become dystrophic months to years after birth. Characteristic nail changes include shorter, discolored, hyperkeratotic nails with transverse groove or ridges. In some cases, the dystrophic nails may cause inflammation and tenderness and is the most common cause of ingrown toenails in children.

The differential diagnosis includes onychomycosis, traumatic nails, nail psoriasis, pachyonychia congenital (PC), and onychomadesis. Onychomycosis can present with white or yellow discoloration of the nail that in some cases can be associated with nail breakage, hyperkeratosis, onycholysis, and subungual debris. Either fungal culture or periodic acid shift stain of nail clippings can help confirm or exclude this diagnosis. Psoriatic nails present with nail pits, oils spots, and onycholysis. Traumatic nail changes may occur from using small shoes and trauma from running or playing soccer, and presents with subungual hemorrhage and nail dystrophy of the first or second toenail. PC is a genetic disorder caused by a mutation in certain keratin proteins of the skin (k6a, k6b, K16 and K17). These patients usually have other skin findings including palmoplantar keratoderma, white plaques on the mouth, and skin cysts (steatocystoma multiplex and vellus hair cysts). Nail changes characteristic of PC includes subungual hyperkeratosis that causes a wedge shape thickening of the nail bed (pincer nails).⁵ Onychomadesis can be seen after viral infections such as hand-foot-mouth disease or in patients taking chemotherapy drugs that affect nail growth.

CMGTN usually resolves with time, but some patients with severe deviation and paronychia may need surgical correction.⁶
 

Dr. Matiz is a pediatric dermatologist at Southern California Permanente Medical Group, San Diego. Email her at [email protected].

References

1. Dermatol Online J. 2014 Jan 15;20(1):21251.

2. J Dtsch Dermatol Ges. 2012 May;10(5):326-30.

3. J Am Acad Dermatol. 2007 Oct;57(4):711-5.

4. Pediatr Dermatol. 2004 Jan-Feb;21(1):44-7.

5. Curr Opin Pediatr. 2014 Aug;26(4):440-5.

6. Skin Appendage Disord. 2018 Oct;4(4):230-5.

The topical retinoid tazarotene could be an efficacious and practical alternative to microneedling for treating atrophic postacne scarring, according to a new study.

In a prospective, randomized, split-face study of adults with postacne scarring, both treatments resulted in similar efficacy after 6 months, reported T.P. Afra, MD, and associates from the department of dermatology, venereology, and leprology at the Postgraduate Institute of Medical Education and Research in Chandigarh, India. While the clinical usefulness of microneedling as a procedure for postacne scarring is well established, research exploring the effectiveness of topical therapies for acne scarring that could be used at home is lacking. “A home-based topical treatment with a comparable efficacy to microneedling and that is well tolerated would be a useful addition in the armamentarium of acne scar management,” they wrote in the study, published in JAMA Facial Plastic Surgery.

The study included 34 patients, aged 18-30 years, with grade 2-4 facial atrophic acne scars at their initial visit to the research team’s skin clinic. One side of each participants face was randomized to receive microneedling treatment for four sessions over 3 months (using a dermaroller with 1.5-mm needles). Topical tazarotene gel 0.1%, a retinoid approved by the Food and Drug Administration as a treatment for mild to moderate facial acne, was applied to the other side of their face once a night during the same time. Almost 81% were skin phototypes IV, the rest were type III or V. Patients followed up every month for 3 months, then at 6 months.

Changes in acne scar severity from baseline, the primary outcome, were assessed using Goodman and Baron quantitative and qualitative scores and a subjective dermatologist score. Patient satisfaction measured with a Patient Global Assessment (PGA) score and adverse events were secondary outcomes.

In 31 patients (91.2%), overall improvements from baseline to the 6-month visit in quantitative acne scar severity scores for both treatments were seen, with significant improvements from baseline to 6 months: A median improvement of 3 on the sides of the face treated with microneedling and a median improvement of 2.5 on the sides of the face treated with tazarotene (between-group comparison, P = .42). The qualitative acne scar severity score did not significantly improve with either treatment, the investigators noted.

The median improvement in the independent dermatologist score was also comparable for both methods at 3 and 6 months.

At 6 months, improvement in the mean PGA score was “slightly but significantly superior” for the microneedling treatment, compared with that for tazarotene (mean of 5.86 vs. 5.76, respectively; P less than .001), with both falling into the “satisfactory” range for the PGA, the investigators wrote. They also noted a positive correlation between previous exposure to oral isotretinoin and patient satisfaction.

“Although collagen accumulation has been considered a drawback of isotretinoin therapy owing to the development of hypertrophic scars, the better atrophic acne scar outcomes observed for both the present treatment groups in patients with a history of isotretinoin treatment indicates that the collagen accumulation in this case may actually be beneficial,” they wrote.

The topical retinoid was well tolerated by participants, with less than a third reporting dryness and scaling, and adverse effects associated with microneedling were described as “minimal.”

“The use of a modality such as tazarotene that prevents acne flares while addressing acne scarring is a practical addition to clinical practice,” the investigators concluded. “Tazarotene gel 0.1% would be a useful alternative to microneedling in the management of atrophic acne scars. Such a home-based medical management option for acne scarring may decrease physician dependence and health care expenditures for patients with postacne scarring.”

The study authors noted that, as collagen remodeling is a continuous process lasting more than 1 year, a limitation of their study was its short-follow-up of 6 months. However, a strength of the study was its use of validated acne scar severity scoring tools as well as patient and physician assessment of scar improvement in the outcome assessments.

The authors had no disclosures to report.

SOURCE: Afra TP et al. JAMA Facial Plast Surg. 2018 Nov 15. doi: 10.1001/jamafacial.2018.1404.

The topical retinoid tazarotene could be an efficacious and practical alternative to microneedling for treating atrophic postacne scarring, according to a new study.

In a prospective, randomized, split-face study of adults with postacne scarring, both treatments resulted in similar efficacy after 6 months, reported T.P. Afra, MD, and associates from the department of dermatology, venereology, and leprology at the Postgraduate Institute of Medical Education and Research in Chandigarh, India. While the clinical usefulness of microneedling as a procedure for postacne scarring is well established, research exploring the effectiveness of topical therapies for acne scarring that could be used at home is lacking. “A home-based topical treatment with a comparable efficacy to microneedling and that is well tolerated would be a useful addition in the armamentarium of acne scar management,” they wrote in the study, published in JAMA Facial Plastic Surgery.

The study included 34 patients, aged 18-30 years, with grade 2-4 facial atrophic acne scars at their initial visit to the research team’s skin clinic. One side of each participants face was randomized to receive microneedling treatment for four sessions over 3 months (using a dermaroller with 1.5-mm needles). Topical tazarotene gel 0.1%, a retinoid approved by the Food and Drug Administration as a treatment for mild to moderate facial acne, was applied to the other side of their face once a night during the same time. Almost 81% were skin phototypes IV, the rest were type III or V. Patients followed up every month for 3 months, then at 6 months.

Changes in acne scar severity from baseline, the primary outcome, were assessed using Goodman and Baron quantitative and qualitative scores and a subjective dermatologist score. Patient satisfaction measured with a Patient Global Assessment (PGA) score and adverse events were secondary outcomes.

In 31 patients (91.2%), overall improvements from baseline to the 6-month visit in quantitative acne scar severity scores for both treatments were seen, with significant improvements from baseline to 6 months: A median improvement of 3 on the sides of the face treated with microneedling and a median improvement of 2.5 on the sides of the face treated with tazarotene (between-group comparison, P = .42). The qualitative acne scar severity score did not significantly improve with either treatment, the investigators noted.

The median improvement in the independent dermatologist score was also comparable for both methods at 3 and 6 months.

At 6 months, improvement in the mean PGA score was “slightly but significantly superior” for the microneedling treatment, compared with that for tazarotene (mean of 5.86 vs. 5.76, respectively; P less than .001), with both falling into the “satisfactory” range for the PGA, the investigators wrote. They also noted a positive correlation between previous exposure to oral isotretinoin and patient satisfaction.

“Although collagen accumulation has been considered a drawback of isotretinoin therapy owing to the development of hypertrophic scars, the better atrophic acne scar outcomes observed for both the present treatment groups in patients with a history of isotretinoin treatment indicates that the collagen accumulation in this case may actually be beneficial,” they wrote.

The topical retinoid was well tolerated by participants, with less than a third reporting dryness and scaling, and adverse effects associated with microneedling were described as “minimal.”

“The use of a modality such as tazarotene that prevents acne flares while addressing acne scarring is a practical addition to clinical practice,” the investigators concluded. “Tazarotene gel 0.1% would be a useful alternative to microneedling in the management of atrophic acne scars. Such a home-based medical management option for acne scarring may decrease physician dependence and health care expenditures for patients with postacne scarring.”

The study authors noted that, as collagen remodeling is a continuous process lasting more than 1 year, a limitation of their study was its short-follow-up of 6 months. However, a strength of the study was its use of validated acne scar severity scoring tools as well as patient and physician assessment of scar improvement in the outcome assessments.

The authors had no disclosures to report.

SOURCE: Afra TP et al. JAMA Facial Plast Surg. 2018 Nov 15. doi: 10.1001/jamafacial.2018.1404.

The topical retinoid tazarotene could be an efficacious and practical alternative to microneedling for treating atrophic postacne scarring, according to a new study.

In a prospective, randomized, split-face study of adults with postacne scarring, both treatments resulted in similar efficacy after 6 months, reported T.P. Afra, MD, and associates from the department of dermatology, venereology, and leprology at the Postgraduate Institute of Medical Education and Research in Chandigarh, India. While the clinical usefulness of microneedling as a procedure for postacne scarring is well established, research exploring the effectiveness of topical therapies for acne scarring that could be used at home is lacking. “A home-based topical treatment with a comparable efficacy to microneedling and that is well tolerated would be a useful addition in the armamentarium of acne scar management,” they wrote in the study, published in JAMA Facial Plastic Surgery.

The study included 34 patients, aged 18-30 years, with grade 2-4 facial atrophic acne scars at their initial visit to the research team’s skin clinic. One side of each participants face was randomized to receive microneedling treatment for four sessions over 3 months (using a dermaroller with 1.5-mm needles). Topical tazarotene gel 0.1%, a retinoid approved by the Food and Drug Administration as a treatment for mild to moderate facial acne, was applied to the other side of their face once a night during the same time. Almost 81% were skin phototypes IV, the rest were type III or V. Patients followed up every month for 3 months, then at 6 months.

Changes in acne scar severity from baseline, the primary outcome, were assessed using Goodman and Baron quantitative and qualitative scores and a subjective dermatologist score. Patient satisfaction measured with a Patient Global Assessment (PGA) score and adverse events were secondary outcomes.

In 31 patients (91.2%), overall improvements from baseline to the 6-month visit in quantitative acne scar severity scores for both treatments were seen, with significant improvements from baseline to 6 months: A median improvement of 3 on the sides of the face treated with microneedling and a median improvement of 2.5 on the sides of the face treated with tazarotene (between-group comparison, P = .42). The qualitative acne scar severity score did not significantly improve with either treatment, the investigators noted.

The median improvement in the independent dermatologist score was also comparable for both methods at 3 and 6 months.

At 6 months, improvement in the mean PGA score was “slightly but significantly superior” for the microneedling treatment, compared with that for tazarotene (mean of 5.86 vs. 5.76, respectively; P less than .001), with both falling into the “satisfactory” range for the PGA, the investigators wrote. They also noted a positive correlation between previous exposure to oral isotretinoin and patient satisfaction.

“Although collagen accumulation has been considered a drawback of isotretinoin therapy owing to the development of hypertrophic scars, the better atrophic acne scar outcomes observed for both the present treatment groups in patients with a history of isotretinoin treatment indicates that the collagen accumulation in this case may actually be beneficial,” they wrote.

The topical retinoid was well tolerated by participants, with less than a third reporting dryness and scaling, and adverse effects associated with microneedling were described as “minimal.”

“The use of a modality such as tazarotene that prevents acne flares while addressing acne scarring is a practical addition to clinical practice,” the investigators concluded. “Tazarotene gel 0.1% would be a useful alternative to microneedling in the management of atrophic acne scars. Such a home-based medical management option for acne scarring may decrease physician dependence and health care expenditures for patients with postacne scarring.”

The study authors noted that, as collagen remodeling is a continuous process lasting more than 1 year, a limitation of their study was its short-follow-up of 6 months. However, a strength of the study was its use of validated acne scar severity scoring tools as well as patient and physician assessment of scar improvement in the outcome assessments.

The authors had no disclosures to report.

SOURCE: Afra TP et al. JAMA Facial Plast Surg. 2018 Nov 15. doi: 10.1001/jamafacial.2018.1404.

SAN FRANCISCO – More than a quarter of drug-induced liver injury (DILI) cases also involve skin reactions, most often drug rash with eosinophilia and system symptoms (DRESS) syndrome. These dual cases of DILI and drug-induced skin injury (DISI) underscore the need for hepatologists to pay attention to dermatologic conditions and emphasize the need for the two specialties to work together.

The findings suggest that DISI/DILI comorbidity is not uncommon, and may hint at underlying mechanisms that could be used to tailor treatment, according to Harshad Devarbhavi, MD, who presented the study at the annual meeting of the American Association for the Study of Liver Diseases. “My message was that people should work more and see if there’s any type of genotype or HLA [human leukocyte antigen] that produces this reaction. It’s a multisystem disease. It doesn’t belong to dermatologists, it’s a domain that also belongs to hepatologists,” said Dr. Devarbhavi, who is a hepatology fellow at St. John’s Medical College in Bangalore, India.

DISI is more common than DILI, and may or may not be caused by an immune response. The two conditions were previously known to co-occur, but it is rarely reported because dermatologists and hepatologists report findings in different journals.

The researchers defined DILI as a fivefold or greater increase in aspartate aminotransferase (AST) or alanine aminotransferase (ALT); a threefold or greater increase with symptoms, including cutaneous reactions; any elevation of AST, ALT, or alkaline phosphatase (ALP) accompanying a bilirubin increase of 2 mg/dL or more; or a twofold or higher increase in ALP combined with a cutaneous reaction.

They analyzed 921 DILI patients from a single registry in India, who were seen between 1997 and April 2018. All patients with skin reactions were seen by dermatologists and competing causes were excluded. A total of 28% of patients with DILI also had DISI, 13% of whom were also HIV positive; 56% developed jaundice. The mean age of patients with DILI/DISI was 35 years, compared with 42 years in DILI only patients (P = .001) and the mean duration of drug therapy was 42 days, compared with 89 days (P = .002). Twelve percent of DILI/DISI patients died, which was lower than the 17% mortality in those with DILI alone.

Of the DILI/DISI patients, 59% experienced DRESS, and 19% had Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN). Six percent of patients with DRESS died, as did 22% of those with SJS/TEN. Mortality was 16% among those with other skin manifestations. Eighteen percent of those with jaundice died, compared with 3% of those without jaundice.

Thirty patients with DILI/DISI died; 37% (11) of them had SJS/TEN, compared with 17% of survivors (P = .01). DRESS was more common in survivors (62% vs. 33%; P = .02).

Of DILI/DISI and SJS/TEN cases, 75% were associated with four drug classes: antiepileptic drugs, dapsone, antiretroviral therapies, and leflunomide.

“The liver is the biggest internal organ in the body, and skin is the largest external organ, so there is some correlation between the two, but people haven’t looked at it. People should come together and see why some drugs produce both these injuries. I think there is some mechanistic information in these drugs,” said Dr. Devarbhavi.

Source: Hepatology 2018 Oct 1;68[S1], Abstract 37.
 

SAN FRANCISCO – More than a quarter of drug-induced liver injury (DILI) cases also involve skin reactions, most often drug rash with eosinophilia and system symptoms (DRESS) syndrome. These dual cases of DILI and drug-induced skin injury (DISI) underscore the need for hepatologists to pay attention to dermatologic conditions and emphasize the need for the two specialties to work together.

The findings suggest that DISI/DILI comorbidity is not uncommon, and may hint at underlying mechanisms that could be used to tailor treatment, according to Harshad Devarbhavi, MD, who presented the study at the annual meeting of the American Association for the Study of Liver Diseases. “My message was that people should work more and see if there’s any type of genotype or HLA [human leukocyte antigen] that produces this reaction. It’s a multisystem disease. It doesn’t belong to dermatologists, it’s a domain that also belongs to hepatologists,” said Dr. Devarbhavi, who is a hepatology fellow at St. John’s Medical College in Bangalore, India.

DISI is more common than DILI, and may or may not be caused by an immune response. The two conditions were previously known to co-occur, but it is rarely reported because dermatologists and hepatologists report findings in different journals.

The researchers defined DILI as a fivefold or greater increase in aspartate aminotransferase (AST) or alanine aminotransferase (ALT); a threefold or greater increase with symptoms, including cutaneous reactions; any elevation of AST, ALT, or alkaline phosphatase (ALP) accompanying a bilirubin increase of 2 mg/dL or more; or a twofold or higher increase in ALP combined with a cutaneous reaction.

They analyzed 921 DILI patients from a single registry in India, who were seen between 1997 and April 2018. All patients with skin reactions were seen by dermatologists and competing causes were excluded. A total of 28% of patients with DILI also had DISI, 13% of whom were also HIV positive; 56% developed jaundice. The mean age of patients with DILI/DISI was 35 years, compared with 42 years in DILI only patients (P = .001) and the mean duration of drug therapy was 42 days, compared with 89 days (P = .002). Twelve percent of DILI/DISI patients died, which was lower than the 17% mortality in those with DILI alone.

Of the DILI/DISI patients, 59% experienced DRESS, and 19% had Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN). Six percent of patients with DRESS died, as did 22% of those with SJS/TEN. Mortality was 16% among those with other skin manifestations. Eighteen percent of those with jaundice died, compared with 3% of those without jaundice.

Thirty patients with DILI/DISI died; 37% (11) of them had SJS/TEN, compared with 17% of survivors (P = .01). DRESS was more common in survivors (62% vs. 33%; P = .02).

Of DILI/DISI and SJS/TEN cases, 75% were associated with four drug classes: antiepileptic drugs, dapsone, antiretroviral therapies, and leflunomide.

“The liver is the biggest internal organ in the body, and skin is the largest external organ, so there is some correlation between the two, but people haven’t looked at it. People should come together and see why some drugs produce both these injuries. I think there is some mechanistic information in these drugs,” said Dr. Devarbhavi.

Source: Hepatology 2018 Oct 1;68[S1], Abstract 37.
 

SAN FRANCISCO – More than a quarter of drug-induced liver injury (DILI) cases also involve skin reactions, most often drug rash with eosinophilia and system symptoms (DRESS) syndrome. These dual cases of DILI and drug-induced skin injury (DISI) underscore the need for hepatologists to pay attention to dermatologic conditions and emphasize the need for the two specialties to work together.

The findings suggest that DISI/DILI comorbidity is not uncommon, and may hint at underlying mechanisms that could be used to tailor treatment, according to Harshad Devarbhavi, MD, who presented the study at the annual meeting of the American Association for the Study of Liver Diseases. “My message was that people should work more and see if there’s any type of genotype or HLA [human leukocyte antigen] that produces this reaction. It’s a multisystem disease. It doesn’t belong to dermatologists, it’s a domain that also belongs to hepatologists,” said Dr. Devarbhavi, who is a hepatology fellow at St. John’s Medical College in Bangalore, India.

DISI is more common than DILI, and may or may not be caused by an immune response. The two conditions were previously known to co-occur, but it is rarely reported because dermatologists and hepatologists report findings in different journals.

The researchers defined DILI as a fivefold or greater increase in aspartate aminotransferase (AST) or alanine aminotransferase (ALT); a threefold or greater increase with symptoms, including cutaneous reactions; any elevation of AST, ALT, or alkaline phosphatase (ALP) accompanying a bilirubin increase of 2 mg/dL or more; or a twofold or higher increase in ALP combined with a cutaneous reaction.

They analyzed 921 DILI patients from a single registry in India, who were seen between 1997 and April 2018. All patients with skin reactions were seen by dermatologists and competing causes were excluded. A total of 28% of patients with DILI also had DISI, 13% of whom were also HIV positive; 56% developed jaundice. The mean age of patients with DILI/DISI was 35 years, compared with 42 years in DILI only patients (P = .001) and the mean duration of drug therapy was 42 days, compared with 89 days (P = .002). Twelve percent of DILI/DISI patients died, which was lower than the 17% mortality in those with DILI alone.

Of the DILI/DISI patients, 59% experienced DRESS, and 19% had Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN). Six percent of patients with DRESS died, as did 22% of those with SJS/TEN. Mortality was 16% among those with other skin manifestations. Eighteen percent of those with jaundice died, compared with 3% of those without jaundice.

Thirty patients with DILI/DISI died; 37% (11) of them had SJS/TEN, compared with 17% of survivors (P = .01). DRESS was more common in survivors (62% vs. 33%; P = .02).

Of DILI/DISI and SJS/TEN cases, 75% were associated with four drug classes: antiepileptic drugs, dapsone, antiretroviral therapies, and leflunomide.

“The liver is the biggest internal organ in the body, and skin is the largest external organ, so there is some correlation between the two, but people haven’t looked at it. People should come together and see why some drugs produce both these injuries. I think there is some mechanistic information in these drugs,” said Dr. Devarbhavi.

Source: Hepatology 2018 Oct 1;68[S1], Abstract 37.
 

CHICAGO – Recent randomized, placebo-controlled, phase 3 trials of tocilizumab, abatacept, and riociguat for the treatment of systemic sclerosis each failed to reach its primary endpoint of change from baseline in modified Rodnan Skin Score (mRSS).

Still, findings with respect to secondary endpoints and certain exploratory outcomes suggest each of the agents holds some promise in the systemic sclerosis (SSc) arena, according to the data presented at the annual meeting of the American College of Rheumatology.
 

Tocilizumab (Actemra)

In the double-blind portion of the phase 3 focuSSced trial of 212 patients with SSc, numerical improvement was observed for the primary endpoint of mean change in mRSS from baseline to week 48 with tocilizumab versus placebo (–6.14 vs. –4.41 points, respectively). The change in the treatment group was comparable with what was seen in the phase 2 faSScinate trial, but the decline in mRSS in the placebo group was much greater in phase 3 than in phase 2, and so the difference between the groups in the current study failed to reach statistical significance (P = .098), reported Dinesh Khanna, MBBS, a professor of medicine and director of the scleroderma program at the University of Michigan, Ann Arbor.

The interleukin-6 (IL-6) receptor–alpha antibody was previously shown in the faSScinate trial to lead to numeric improvements in skin thickening as measured by the mRSS, as well as to clinically meaningful lung function preservation as measured by percent predicted forced vital capacity (FVC).

In the current phase 3 study, key secondary end points also appeared to favor tocilizumab, but since the primary endpoint for mRSS was not met, all other P values cannot be considered statistically significant despite the strength of the evidence and were reported for informational purposes only, he noted.

The median cumulative distribution of change from baseline to week 48 in percent predicted FVC with tocilizumab versus placebo was –0.6 vs. –3.9, respectively (descriptive P = .0015), and the mean change from baseline in FVC at week 48 was –24 mL vs. –190 mL (difference of 167 mL in favor of tocilizumab; descriptive P = .0001).

Time to treatment failure also favored tocilizumab, he said (hazard ratio, 0.63; descriptive P = .082), he said.

Patients were randomly assigned to receive either weekly 162-mg injections of subcutaneous tocilizumab or placebo for 48 weeks. Escape therapy was allowed beginning at week 16 if patients experienced declines in FVC or beginning at week 24 if they experienced worsened mRSS or worsened SSc complications, Dr. Khanna said.

“The key part is that no immunotherapy was allowed. ... So it’s a true randomized, placebo-controlled trial,” he said.

Most (81%) of the patients were women, and they had a mean age of 48 years, mean SSc duration of 23 months, mean mRSS of 20.4 units on a 0-51 scale, and a normal mean percent predicted FVC of 82.1%.

“HAQ-DI showed moderate disability of 1.2,” he noted.

Safety in the study was consistent with that seen in prior tocilizumab studies; no new safety signals were identified. Serious adverse events occurred in 13% and 17% of tocilizumab and placebo group patients , respectively, and serious infections were reported by 7% and 2%.

Although clinically meaningful and consistent differences in FVC favoring tocilizumab were shown in this study, the primary endpoint was not met, Dr. Khanna said.

“There were no statistically significant differences, largely driven by unexpected improvement in the placebo group, which was different than what we found in [the faSScinate] trial,” he said, noting, however, that the FVC findings in the current study were clinically meaningful.

Also, in a separate presentation at the meeting, he explained that the differences favoring tocilizumab were statistically significant when patient-level data from the trial were analyzed based on the ACR Composite Response Index in Systemic Sclerosis (CRISS). Those findings provide validation of the novel outcomes measure, he said.

 

Abatacept (Orencia)

Dr. Khanna also reported results of the 12-month, double-blind, randomized, placebo-controlled phase 2 ASSET trial of abatacept, which showed no significant difference in mRSS in patients with early diffuse cutaneous SSc (dfSSc) who were treated with 125 mg of the recombinant fusion protein weekly and those who received placebo. However, certain secondary outcomes favored abatacept. No concomitant immunotherapy was allowed.

The adjusted mean decrease in the mRSS among patients who completed the 12-month treatment period was –6.24 vs. –4.49 in 34 patients in the abatacept group and 35 in the placebo group, respectively (P = .28).

The secondary outcome measures of mean change in Health Assessment Questionnaire Disability Index (HAQ-DI), patients global assessment, physician global assessment, and ACR CRISS scores were statistically significant or showed numerical results favoring abatacept over placebo: mean decrease in HAQ-DI, –0.17 vs. –0.11 (P = .05), respectively; mean change in physician global assessment scores, –1.30 vs. –0.35 (P = .03); median ACR CRISS index, 0.68 vs. 0.01 (P = .03), decline in percent predicted FVC of 4.13% and 1.34% (P = .11).

Escape therapy was allowed at 6 months for worsening SSc, but it did not change the outcomes trajectory, he said. A larger proportion of placebo vs. abatacept subjects required escape immunosuppressive therapy (36% vs. 16%; P = .03).

Patients were enrolled between 2014 and 2018 at 27 U.S., Canadian, and U.K. sites. At baseline, participants had a mean age of 49 years, 75% were women, and mean disease duration was very short at 1.59 years, with 60% having disease duration of 18 months or less. The mean baseline mRSS was 22.4, mean percent predicted FVC was 85.3%, and mean HAQ-DI was 1.0.

Compliance with both treatments was greater than 98%. Abatacept was well tolerated with comparable adverse events (AEs), serious AEs, and AEs of special interest such as infections and malignancies between treatments, Dr. Khanna said, noting that two deaths occurred in the abatacept group (caused by scleroderma renal crisis in both cases at days 11 and 46) and one occurred in a placebo group patient who experienced sudden cardiac arrest at day 310.

Of note, mRSS showed large variability, despite recruiting an early dcSSc population, Dr. Khanna said.

The finding with respect to the primary outcome is consistent with other recent trials because of improvement in mRSS that’s part of the natural history of the disease, including the tocilizumab findings that he reported at the meeting. The findings with respect to secondary endpoints and safety show promise.

“Stay tuned for robust ongoing work on the relationship between clinical changes and ongoing mechanistic work,” he said.
 

Riociguat (Adempas)

Similarly, in the randomized, placebo-controlled phase 2b RISE-SSc study comparing riociguat and placebo for early dcSSc, the primary efficacy endpoint of mean change in mRSS did not reach statistical significance, but exploratory data suggested that the soluble guanylate cyclase stimulator prevented disease progression in patients with early dcSSc, reported Oliver Distler, MD, head of the connective tissue diseases program at University Hospital Zurich (Switzerland).

The mean mRSS at baseline was comparable in 60 patients randomized to receive riociguat and 61 in the placebo group (16.8 and 16.71, respectively). These mean values at week 52 dropped to 14.63 vs. 15.73, respectively (P = .08).

“So it was close, but it didn’t reach significance,” he said.

The difference in the mRSS progression rate, however, suggested significant effects favoring riociguat (descriptive P = .02), he said.

Further, mean change from baseline to week 52 in percent predicted FVC was not different overall between the groups, but a large difference favoring riociguat was seen among patients with scleroderma interstitial lung disease at baseline (mean change of –2.7 vs. –8.9), he said.

No differences were seen between the groups in HAQ-DI or patient and physician global assessment. The proportion of patients with probability of improvement at 52 weeks as measured using ACR CRISS was also the same at 18% in both treatment arms, he noted, ”but the CRISS is designed more for assessing disease regression than for assessing prevention of progression.”

Treatment was, however, well tolerated. At week 52, fewer serious adverse events occurred with riociguat group than in the placebo group (15% vs. 25%, respectively), and no new safety signals were observed, he said.

Riociguat has previously shown antifibrotic effects in animal models and efficacy in patients with pulmonary arterial hypertension associated with connective tissue disease, so it was hypothesized that patients with dcSSc might benefit from riociguat therapy, Dr. Distler explained.

Study subjects had very early dcSSc (duration of 18 months or less; mean of 9 months), mRSS of 10-22 units, FVC of 45% predicted or greater, and diffusion capacity of the lung for carbon monoxide of at least 40% of predicted at screening.

Riociguat was given at an individually adjusted dose between 0.5 mg and 2.5 mg three times daily.

The findings demonstrate a numeric decrease in mRSS over time with riociguat versus placebo and a prevention of progression with riociguat; the failure to reach the primary endpoint may be related to the small study size and the higher than expected regression rate in the placebo group, Dr. Distler said.

Dr. Khanna is a consultant to Roche/Genentech and Bayer, which markets riociguat, and other companies. He has received research grants from Bayer, Bristol-Myers Squibb (which markets abatacept), and Pfizer. The ASSET trial he presented was sponsored by an National Institutes of Health/National Institute of Allergy and Infectious Diseases Clinical ACE grant and an investigator-initiated grant by Bristol-Myers Squibb. Dr. Distler has a consultancy relationship and/or has received research funding from Bayer, Roche/Genentech, and other companies. In addition, he has a patent on mir-29 for the treatment of systemic sclerosis.

[email protected]

SOURCES: Khanna D et al. Arthritis Rheumatol. 2018;70(Suppl 10): Abstract 898 and Abstract 900; Distler O et al. Arthritis Rheumatol. 2018;70(Suppl 10): Abstract 903.

CHICAGO – Recent randomized, placebo-controlled, phase 3 trials of tocilizumab, abatacept, and riociguat for the treatment of systemic sclerosis each failed to reach its primary endpoint of change from baseline in modified Rodnan Skin Score (mRSS).

Still, findings with respect to secondary endpoints and certain exploratory outcomes suggest each of the agents holds some promise in the systemic sclerosis (SSc) arena, according to the data presented at the annual meeting of the American College of Rheumatology.
 

Tocilizumab (Actemra)

In the double-blind portion of the phase 3 focuSSced trial of 212 patients with SSc, numerical improvement was observed for the primary endpoint of mean change in mRSS from baseline to week 48 with tocilizumab versus placebo (–6.14 vs. –4.41 points, respectively). The change in the treatment group was comparable with what was seen in the phase 2 faSScinate trial, but the decline in mRSS in the placebo group was much greater in phase 3 than in phase 2, and so the difference between the groups in the current study failed to reach statistical significance (P = .098), reported Dinesh Khanna, MBBS, a professor of medicine and director of the scleroderma program at the University of Michigan, Ann Arbor.

The interleukin-6 (IL-6) receptor–alpha antibody was previously shown in the faSScinate trial to lead to numeric improvements in skin thickening as measured by the mRSS, as well as to clinically meaningful lung function preservation as measured by percent predicted forced vital capacity (FVC).

In the current phase 3 study, key secondary end points also appeared to favor tocilizumab, but since the primary endpoint for mRSS was not met, all other P values cannot be considered statistically significant despite the strength of the evidence and were reported for informational purposes only, he noted.

The median cumulative distribution of change from baseline to week 48 in percent predicted FVC with tocilizumab versus placebo was –0.6 vs. –3.9, respectively (descriptive P = .0015), and the mean change from baseline in FVC at week 48 was –24 mL vs. –190 mL (difference of 167 mL in favor of tocilizumab; descriptive P = .0001).

Time to treatment failure also favored tocilizumab, he said (hazard ratio, 0.63; descriptive P = .082), he said.

Patients were randomly assigned to receive either weekly 162-mg injections of subcutaneous tocilizumab or placebo for 48 weeks. Escape therapy was allowed beginning at week 16 if patients experienced declines in FVC or beginning at week 24 if they experienced worsened mRSS or worsened SSc complications, Dr. Khanna said.

“The key part is that no immunotherapy was allowed. ... So it’s a true randomized, placebo-controlled trial,” he said.

Most (81%) of the patients were women, and they had a mean age of 48 years, mean SSc duration of 23 months, mean mRSS of 20.4 units on a 0-51 scale, and a normal mean percent predicted FVC of 82.1%.

“HAQ-DI showed moderate disability of 1.2,” he noted.

Safety in the study was consistent with that seen in prior tocilizumab studies; no new safety signals were identified. Serious adverse events occurred in 13% and 17% of tocilizumab and placebo group patients , respectively, and serious infections were reported by 7% and 2%.

Although clinically meaningful and consistent differences in FVC favoring tocilizumab were shown in this study, the primary endpoint was not met, Dr. Khanna said.

“There were no statistically significant differences, largely driven by unexpected improvement in the placebo group, which was different than what we found in [the faSScinate] trial,” he said, noting, however, that the FVC findings in the current study were clinically meaningful.

Also, in a separate presentation at the meeting, he explained that the differences favoring tocilizumab were statistically significant when patient-level data from the trial were analyzed based on the ACR Composite Response Index in Systemic Sclerosis (CRISS). Those findings provide validation of the novel outcomes measure, he said.

 

Abatacept (Orencia)

Dr. Khanna also reported results of the 12-month, double-blind, randomized, placebo-controlled phase 2 ASSET trial of abatacept, which showed no significant difference in mRSS in patients with early diffuse cutaneous SSc (dfSSc) who were treated with 125 mg of the recombinant fusion protein weekly and those who received placebo. However, certain secondary outcomes favored abatacept. No concomitant immunotherapy was allowed.

The adjusted mean decrease in the mRSS among patients who completed the 12-month treatment period was –6.24 vs. –4.49 in 34 patients in the abatacept group and 35 in the placebo group, respectively (P = .28).

The secondary outcome measures of mean change in Health Assessment Questionnaire Disability Index (HAQ-DI), patients global assessment, physician global assessment, and ACR CRISS scores were statistically significant or showed numerical results favoring abatacept over placebo: mean decrease in HAQ-DI, –0.17 vs. –0.11 (P = .05), respectively; mean change in physician global assessment scores, –1.30 vs. –0.35 (P = .03); median ACR CRISS index, 0.68 vs. 0.01 (P = .03), decline in percent predicted FVC of 4.13% and 1.34% (P = .11).

Escape therapy was allowed at 6 months for worsening SSc, but it did not change the outcomes trajectory, he said. A larger proportion of placebo vs. abatacept subjects required escape immunosuppressive therapy (36% vs. 16%; P = .03).

Patients were enrolled between 2014 and 2018 at 27 U.S., Canadian, and U.K. sites. At baseline, participants had a mean age of 49 years, 75% were women, and mean disease duration was very short at 1.59 years, with 60% having disease duration of 18 months or less. The mean baseline mRSS was 22.4, mean percent predicted FVC was 85.3%, and mean HAQ-DI was 1.0.

Compliance with both treatments was greater than 98%. Abatacept was well tolerated with comparable adverse events (AEs), serious AEs, and AEs of special interest such as infections and malignancies between treatments, Dr. Khanna said, noting that two deaths occurred in the abatacept group (caused by scleroderma renal crisis in both cases at days 11 and 46) and one occurred in a placebo group patient who experienced sudden cardiac arrest at day 310.

Of note, mRSS showed large variability, despite recruiting an early dcSSc population, Dr. Khanna said.

The finding with respect to the primary outcome is consistent with other recent trials because of improvement in mRSS that’s part of the natural history of the disease, including the tocilizumab findings that he reported at the meeting. The findings with respect to secondary endpoints and safety show promise.

“Stay tuned for robust ongoing work on the relationship between clinical changes and ongoing mechanistic work,” he said.
 

Riociguat (Adempas)

Similarly, in the randomized, placebo-controlled phase 2b RISE-SSc study comparing riociguat and placebo for early dcSSc, the primary efficacy endpoint of mean change in mRSS did not reach statistical significance, but exploratory data suggested that the soluble guanylate cyclase stimulator prevented disease progression in patients with early dcSSc, reported Oliver Distler, MD, head of the connective tissue diseases program at University Hospital Zurich (Switzerland).

The mean mRSS at baseline was comparable in 60 patients randomized to receive riociguat and 61 in the placebo group (16.8 and 16.71, respectively). These mean values at week 52 dropped to 14.63 vs. 15.73, respectively (P = .08).

“So it was close, but it didn’t reach significance,” he said.

The difference in the mRSS progression rate, however, suggested significant effects favoring riociguat (descriptive P = .02), he said.

Further, mean change from baseline to week 52 in percent predicted FVC was not different overall between the groups, but a large difference favoring riociguat was seen among patients with scleroderma interstitial lung disease at baseline (mean change of –2.7 vs. –8.9), he said.

No differences were seen between the groups in HAQ-DI or patient and physician global assessment. The proportion of patients with probability of improvement at 52 weeks as measured using ACR CRISS was also the same at 18% in both treatment arms, he noted, ”but the CRISS is designed more for assessing disease regression than for assessing prevention of progression.”

Treatment was, however, well tolerated. At week 52, fewer serious adverse events occurred with riociguat group than in the placebo group (15% vs. 25%, respectively), and no new safety signals were observed, he said.

Riociguat has previously shown antifibrotic effects in animal models and efficacy in patients with pulmonary arterial hypertension associated with connective tissue disease, so it was hypothesized that patients with dcSSc might benefit from riociguat therapy, Dr. Distler explained.

Study subjects had very early dcSSc (duration of 18 months or less; mean of 9 months), mRSS of 10-22 units, FVC of 45% predicted or greater, and diffusion capacity of the lung for carbon monoxide of at least 40% of predicted at screening.

Riociguat was given at an individually adjusted dose between 0.5 mg and 2.5 mg three times daily.

The findings demonstrate a numeric decrease in mRSS over time with riociguat versus placebo and a prevention of progression with riociguat; the failure to reach the primary endpoint may be related to the small study size and the higher than expected regression rate in the placebo group, Dr. Distler said.

Dr. Khanna is a consultant to Roche/Genentech and Bayer, which markets riociguat, and other companies. He has received research grants from Bayer, Bristol-Myers Squibb (which markets abatacept), and Pfizer. The ASSET trial he presented was sponsored by an National Institutes of Health/National Institute of Allergy and Infectious Diseases Clinical ACE grant and an investigator-initiated grant by Bristol-Myers Squibb. Dr. Distler has a consultancy relationship and/or has received research funding from Bayer, Roche/Genentech, and other companies. In addition, he has a patent on mir-29 for the treatment of systemic sclerosis.

[email protected]

SOURCES: Khanna D et al. Arthritis Rheumatol. 2018;70(Suppl 10): Abstract 898 and Abstract 900; Distler O et al. Arthritis Rheumatol. 2018;70(Suppl 10): Abstract 903.

CHICAGO – Recent randomized, placebo-controlled, phase 3 trials of tocilizumab, abatacept, and riociguat for the treatment of systemic sclerosis each failed to reach its primary endpoint of change from baseline in modified Rodnan Skin Score (mRSS).

Still, findings with respect to secondary endpoints and certain exploratory outcomes suggest each of the agents holds some promise in the systemic sclerosis (SSc) arena, according to the data presented at the annual meeting of the American College of Rheumatology.
 

Tocilizumab (Actemra)

In the double-blind portion of the phase 3 focuSSced trial of 212 patients with SSc, numerical improvement was observed for the primary endpoint of mean change in mRSS from baseline to week 48 with tocilizumab versus placebo (–6.14 vs. –4.41 points, respectively). The change in the treatment group was comparable with what was seen in the phase 2 faSScinate trial, but the decline in mRSS in the placebo group was much greater in phase 3 than in phase 2, and so the difference between the groups in the current study failed to reach statistical significance (P = .098), reported Dinesh Khanna, MBBS, a professor of medicine and director of the scleroderma program at the University of Michigan, Ann Arbor.

The interleukin-6 (IL-6) receptor–alpha antibody was previously shown in the faSScinate trial to lead to numeric improvements in skin thickening as measured by the mRSS, as well as to clinically meaningful lung function preservation as measured by percent predicted forced vital capacity (FVC).

In the current phase 3 study, key secondary end points also appeared to favor tocilizumab, but since the primary endpoint for mRSS was not met, all other P values cannot be considered statistically significant despite the strength of the evidence and were reported for informational purposes only, he noted.

The median cumulative distribution of change from baseline to week 48 in percent predicted FVC with tocilizumab versus placebo was –0.6 vs. –3.9, respectively (descriptive P = .0015), and the mean change from baseline in FVC at week 48 was –24 mL vs. –190 mL (difference of 167 mL in favor of tocilizumab; descriptive P = .0001).

Time to treatment failure also favored tocilizumab, he said (hazard ratio, 0.63; descriptive P = .082), he said.

Patients were randomly assigned to receive either weekly 162-mg injections of subcutaneous tocilizumab or placebo for 48 weeks. Escape therapy was allowed beginning at week 16 if patients experienced declines in FVC or beginning at week 24 if they experienced worsened mRSS or worsened SSc complications, Dr. Khanna said.

“The key part is that no immunotherapy was allowed. ... So it’s a true randomized, placebo-controlled trial,” he said.

Most (81%) of the patients were women, and they had a mean age of 48 years, mean SSc duration of 23 months, mean mRSS of 20.4 units on a 0-51 scale, and a normal mean percent predicted FVC of 82.1%.

“HAQ-DI showed moderate disability of 1.2,” he noted.

Safety in the study was consistent with that seen in prior tocilizumab studies; no new safety signals were identified. Serious adverse events occurred in 13% and 17% of tocilizumab and placebo group patients , respectively, and serious infections were reported by 7% and 2%.

Although clinically meaningful and consistent differences in FVC favoring tocilizumab were shown in this study, the primary endpoint was not met, Dr. Khanna said.

“There were no statistically significant differences, largely driven by unexpected improvement in the placebo group, which was different than what we found in [the faSScinate] trial,” he said, noting, however, that the FVC findings in the current study were clinically meaningful.

Also, in a separate presentation at the meeting, he explained that the differences favoring tocilizumab were statistically significant when patient-level data from the trial were analyzed based on the ACR Composite Response Index in Systemic Sclerosis (CRISS). Those findings provide validation of the novel outcomes measure, he said.

 

Abatacept (Orencia)

Dr. Khanna also reported results of the 12-month, double-blind, randomized, placebo-controlled phase 2 ASSET trial of abatacept, which showed no significant difference in mRSS in patients with early diffuse cutaneous SSc (dfSSc) who were treated with 125 mg of the recombinant fusion protein weekly and those who received placebo. However, certain secondary outcomes favored abatacept. No concomitant immunotherapy was allowed.

The adjusted mean decrease in the mRSS among patients who completed the 12-month treatment period was –6.24 vs. –4.49 in 34 patients in the abatacept group and 35 in the placebo group, respectively (P = .28).

The secondary outcome measures of mean change in Health Assessment Questionnaire Disability Index (HAQ-DI), patients global assessment, physician global assessment, and ACR CRISS scores were statistically significant or showed numerical results favoring abatacept over placebo: mean decrease in HAQ-DI, –0.17 vs. –0.11 (P = .05), respectively; mean change in physician global assessment scores, –1.30 vs. –0.35 (P = .03); median ACR CRISS index, 0.68 vs. 0.01 (P = .03), decline in percent predicted FVC of 4.13% and 1.34% (P = .11).

Escape therapy was allowed at 6 months for worsening SSc, but it did not change the outcomes trajectory, he said. A larger proportion of placebo vs. abatacept subjects required escape immunosuppressive therapy (36% vs. 16%; P = .03).

Patients were enrolled between 2014 and 2018 at 27 U.S., Canadian, and U.K. sites. At baseline, participants had a mean age of 49 years, 75% were women, and mean disease duration was very short at 1.59 years, with 60% having disease duration of 18 months or less. The mean baseline mRSS was 22.4, mean percent predicted FVC was 85.3%, and mean HAQ-DI was 1.0.

Compliance with both treatments was greater than 98%. Abatacept was well tolerated with comparable adverse events (AEs), serious AEs, and AEs of special interest such as infections and malignancies between treatments, Dr. Khanna said, noting that two deaths occurred in the abatacept group (caused by scleroderma renal crisis in both cases at days 11 and 46) and one occurred in a placebo group patient who experienced sudden cardiac arrest at day 310.

Of note, mRSS showed large variability, despite recruiting an early dcSSc population, Dr. Khanna said.

The finding with respect to the primary outcome is consistent with other recent trials because of improvement in mRSS that’s part of the natural history of the disease, including the tocilizumab findings that he reported at the meeting. The findings with respect to secondary endpoints and safety show promise.

“Stay tuned for robust ongoing work on the relationship between clinical changes and ongoing mechanistic work,” he said.
 

Riociguat (Adempas)

Similarly, in the randomized, placebo-controlled phase 2b RISE-SSc study comparing riociguat and placebo for early dcSSc, the primary efficacy endpoint of mean change in mRSS did not reach statistical significance, but exploratory data suggested that the soluble guanylate cyclase stimulator prevented disease progression in patients with early dcSSc, reported Oliver Distler, MD, head of the connective tissue diseases program at University Hospital Zurich (Switzerland).

The mean mRSS at baseline was comparable in 60 patients randomized to receive riociguat and 61 in the placebo group (16.8 and 16.71, respectively). These mean values at week 52 dropped to 14.63 vs. 15.73, respectively (P = .08).

“So it was close, but it didn’t reach significance,” he said.

The difference in the mRSS progression rate, however, suggested significant effects favoring riociguat (descriptive P = .02), he said.

Further, mean change from baseline to week 52 in percent predicted FVC was not different overall between the groups, but a large difference favoring riociguat was seen among patients with scleroderma interstitial lung disease at baseline (mean change of –2.7 vs. –8.9), he said.

No differences were seen between the groups in HAQ-DI or patient and physician global assessment. The proportion of patients with probability of improvement at 52 weeks as measured using ACR CRISS was also the same at 18% in both treatment arms, he noted, ”but the CRISS is designed more for assessing disease regression than for assessing prevention of progression.”

Treatment was, however, well tolerated. At week 52, fewer serious adverse events occurred with riociguat group than in the placebo group (15% vs. 25%, respectively), and no new safety signals were observed, he said.

Riociguat has previously shown antifibrotic effects in animal models and efficacy in patients with pulmonary arterial hypertension associated with connective tissue disease, so it was hypothesized that patients with dcSSc might benefit from riociguat therapy, Dr. Distler explained.

Study subjects had very early dcSSc (duration of 18 months or less; mean of 9 months), mRSS of 10-22 units, FVC of 45% predicted or greater, and diffusion capacity of the lung for carbon monoxide of at least 40% of predicted at screening.

Riociguat was given at an individually adjusted dose between 0.5 mg and 2.5 mg three times daily.

The findings demonstrate a numeric decrease in mRSS over time with riociguat versus placebo and a prevention of progression with riociguat; the failure to reach the primary endpoint may be related to the small study size and the higher than expected regression rate in the placebo group, Dr. Distler said.

Dr. Khanna is a consultant to Roche/Genentech and Bayer, which markets riociguat, and other companies. He has received research grants from Bayer, Bristol-Myers Squibb (which markets abatacept), and Pfizer. The ASSET trial he presented was sponsored by an National Institutes of Health/National Institute of Allergy and Infectious Diseases Clinical ACE grant and an investigator-initiated grant by Bristol-Myers Squibb. Dr. Distler has a consultancy relationship and/or has received research funding from Bayer, Roche/Genentech, and other companies. In addition, he has a patent on mir-29 for the treatment of systemic sclerosis.

[email protected]

SOURCES: Khanna D et al. Arthritis Rheumatol. 2018;70(Suppl 10): Abstract 898 and Abstract 900; Distler O et al. Arthritis Rheumatol. 2018;70(Suppl 10): Abstract 903.

A systematic literature review found an inverse association between serum vitamin D levels and severity of atopic dermatitis (AD) in children in the majority of studies, but evidence on whether supplementation can improve symptoms of the condition was inconsistent.

The data on the effect of vitamin D supplementation on AD severity “suggested potential benefit but were conflicting,” concluded Christina M. Huang, MD, of Queen’s University, Kingston, Ontario, and her coinvestigators from the department of dermatology, Hospital for Sick Children, Toronto. They reported the results of their systematic review of 21 studies published between 2008 and 2017, which included quantitative data on serum vitamin D levels or vitamin D supplementation and AD severity in patients aged 18 years or younger, in Pediatrics.

In the review, 16 studies explored the relationship between serum vitamin D status and disease severity (one was a randomized controlled trial; the rest were cohort, cross-sectional, or case control studies) in 1,847 children (average age, 5.6 years). Disease severity was measured with the SCORing Atopic Dermatitis (SCORAD) system. In 10 of the 16 studies, there was a significant inverse association between vitamin D levels and AD severity.

The studies that supported this association generally had larger sample sizes, which, the authors pointed out, suggested they were of higher quality and more reliable. However, the randomized controlled study of 89 children did not find a correlation, although in the study, vitamin D level and AD severity was a secondary outcome.

The randomized controlled trial of vitamin D supplementation used lower SCORAD cut-offs for the different severities of AD, which complicated interpretation the results, “as it may indicate that the severities reported in these articles were exaggerated as compared to other studies,” they wrote.

Six studies – four randomized controlled trials (including the study that was among the 16 studies on vitamin D and severity) and two cohort studies – with 354 participants (average age, 6.8 years) looked at the effects of oral vitamin D supplementation on the severity of AD, although dosage and duration of use varied across the studies. In four of the six studies, there were significant improvement in AD in patients given supplements, but the data were “conflicting,” partly because the largest study showing benefit used a different measure of disease severity, the Eczema Area and Severity Index (EASI), not SCORAD. “The inconsistency of tools used to measure outcomes makes it difficult to compare and understand results,” so the effects of vitamin D supplementation “are controversial and should be interpreted with caution, as certain patient populations may benefit more than others,” the authors wrote.

They also drew attention to previous research suggesting that vitamin D supplementation in the first year of life might actually increase the risk of AD in children. “Therefore, although there is a growing body of evidence supporting the beneficial effects of VD [vitamin D] supplementation, the age at which supplementation is given should be considered carefully.” The authors added that the inconclusive findings “may have been due to confounding factors that were not accounted for, such as age, season, latitude, dose, and duration. It is also possible that the lack of a true effect of VD may be contributing to the inconsistent results. Future large‐scale RCTs with consideration of these factors are needed.”

Funding and conflict of interest disclosures were not included in the study.

SOURCE: Huang C et al. Pediatr Dermatol. 2018;35: 754-60. doi: 10.1111/pde.13639.

A systematic literature review found an inverse association between serum vitamin D levels and severity of atopic dermatitis (AD) in children in the majority of studies, but evidence on whether supplementation can improve symptoms of the condition was inconsistent.

The data on the effect of vitamin D supplementation on AD severity “suggested potential benefit but were conflicting,” concluded Christina M. Huang, MD, of Queen’s University, Kingston, Ontario, and her coinvestigators from the department of dermatology, Hospital for Sick Children, Toronto. They reported the results of their systematic review of 21 studies published between 2008 and 2017, which included quantitative data on serum vitamin D levels or vitamin D supplementation and AD severity in patients aged 18 years or younger, in Pediatrics.

In the review, 16 studies explored the relationship between serum vitamin D status and disease severity (one was a randomized controlled trial; the rest were cohort, cross-sectional, or case control studies) in 1,847 children (average age, 5.6 years). Disease severity was measured with the SCORing Atopic Dermatitis (SCORAD) system. In 10 of the 16 studies, there was a significant inverse association between vitamin D levels and AD severity.

The studies that supported this association generally had larger sample sizes, which, the authors pointed out, suggested they were of higher quality and more reliable. However, the randomized controlled study of 89 children did not find a correlation, although in the study, vitamin D level and AD severity was a secondary outcome.

The randomized controlled trial of vitamin D supplementation used lower SCORAD cut-offs for the different severities of AD, which complicated interpretation the results, “as it may indicate that the severities reported in these articles were exaggerated as compared to other studies,” they wrote.

Six studies – four randomized controlled trials (including the study that was among the 16 studies on vitamin D and severity) and two cohort studies – with 354 participants (average age, 6.8 years) looked at the effects of oral vitamin D supplementation on the severity of AD, although dosage and duration of use varied across the studies. In four of the six studies, there were significant improvement in AD in patients given supplements, but the data were “conflicting,” partly because the largest study showing benefit used a different measure of disease severity, the Eczema Area and Severity Index (EASI), not SCORAD. “The inconsistency of tools used to measure outcomes makes it difficult to compare and understand results,” so the effects of vitamin D supplementation “are controversial and should be interpreted with caution, as certain patient populations may benefit more than others,” the authors wrote.

They also drew attention to previous research suggesting that vitamin D supplementation in the first year of life might actually increase the risk of AD in children. “Therefore, although there is a growing body of evidence supporting the beneficial effects of VD [vitamin D] supplementation, the age at which supplementation is given should be considered carefully.” The authors added that the inconclusive findings “may have been due to confounding factors that were not accounted for, such as age, season, latitude, dose, and duration. It is also possible that the lack of a true effect of VD may be contributing to the inconsistent results. Future large‐scale RCTs with consideration of these factors are needed.”

Funding and conflict of interest disclosures were not included in the study.

SOURCE: Huang C et al. Pediatr Dermatol. 2018;35: 754-60. doi: 10.1111/pde.13639.

A systematic literature review found an inverse association between serum vitamin D levels and severity of atopic dermatitis (AD) in children in the majority of studies, but evidence on whether supplementation can improve symptoms of the condition was inconsistent.

The data on the effect of vitamin D supplementation on AD severity “suggested potential benefit but were conflicting,” concluded Christina M. Huang, MD, of Queen’s University, Kingston, Ontario, and her coinvestigators from the department of dermatology, Hospital for Sick Children, Toronto. They reported the results of their systematic review of 21 studies published between 2008 and 2017, which included quantitative data on serum vitamin D levels or vitamin D supplementation and AD severity in patients aged 18 years or younger, in Pediatrics.

In the review, 16 studies explored the relationship between serum vitamin D status and disease severity (one was a randomized controlled trial; the rest were cohort, cross-sectional, or case control studies) in 1,847 children (average age, 5.6 years). Disease severity was measured with the SCORing Atopic Dermatitis (SCORAD) system. In 10 of the 16 studies, there was a significant inverse association between vitamin D levels and AD severity.

The studies that supported this association generally had larger sample sizes, which, the authors pointed out, suggested they were of higher quality and more reliable. However, the randomized controlled study of 89 children did not find a correlation, although in the study, vitamin D level and AD severity was a secondary outcome.

The randomized controlled trial of vitamin D supplementation used lower SCORAD cut-offs for the different severities of AD, which complicated interpretation the results, “as it may indicate that the severities reported in these articles were exaggerated as compared to other studies,” they wrote.

Six studies – four randomized controlled trials (including the study that was among the 16 studies on vitamin D and severity) and two cohort studies – with 354 participants (average age, 6.8 years) looked at the effects of oral vitamin D supplementation on the severity of AD, although dosage and duration of use varied across the studies. In four of the six studies, there were significant improvement in AD in patients given supplements, but the data were “conflicting,” partly because the largest study showing benefit used a different measure of disease severity, the Eczema Area and Severity Index (EASI), not SCORAD. “The inconsistency of tools used to measure outcomes makes it difficult to compare and understand results,” so the effects of vitamin D supplementation “are controversial and should be interpreted with caution, as certain patient populations may benefit more than others,” the authors wrote.

They also drew attention to previous research suggesting that vitamin D supplementation in the first year of life might actually increase the risk of AD in children. “Therefore, although there is a growing body of evidence supporting the beneficial effects of VD [vitamin D] supplementation, the age at which supplementation is given should be considered carefully.” The authors added that the inconclusive findings “may have been due to confounding factors that were not accounted for, such as age, season, latitude, dose, and duration. It is also possible that the lack of a true effect of VD may be contributing to the inconsistent results. Future large‐scale RCTs with consideration of these factors are needed.”

Funding and conflict of interest disclosures were not included in the study.

SOURCE: Huang C et al. Pediatr Dermatol. 2018;35: 754-60. doi: 10.1111/pde.13639.

Infection with certain viruses has been causally linked to the development of cancer. In recent years, an improved understanding of the unique pathology and molecular underpinnings of these virally associated cancers has prompted the development of more personalized treatment strategies, with a particular focus on immunotherapy. Here, we describe some of the latest developments.

The link between viruses and cancer

Suspicions about a possible role of viral infections in the development of cancer were first aroused in the early 1900s. The seminal discovery is traced back to Peyton Rous, who showed that a malignant tumor growing in a chicken could be transferred to a healthy bird by injecting it with tumor extracts that contained no actual tumor cells.¹

The infectious etiology of human cancer, however, remained controversial until many years later when the first cancer-causing virus, Epstein-Barr virus (EBV), was identified in cell cultures from patients with Burkitt lymphoma. Shortly afterward, the Rous sarcoma virus was unveiled as the oncogenic agent behind Rous’ observations.²Seven viruses have now been linked to the development of cancers and are thought to be responsible for around 12% of all cancer cases worldwide. The burden is likely to increase as technological advancements make it easier to establish a causal link between viruses and cancer development.³

In addition to making these links, researchers have also made significant headway in understanding how viruses cause cancer. Cancerous transformation of host cells occurs in only a minority of those who are infected with oncogenic viruses and often occurs in the setting of chronic infection.

Viruses can mediate carcinogenesis by direct and/or indirect mechanisms (Figure 1). Many of the hallmarks of cancer, the key attributes that drive the transformation from a normal cell to a malignant one, are compatible with the virus’s needs, such as needing to avoid cell death, increasing cell proliferation, and avoiding detection by the immune system.

Vaccines lead the charge in HPV-driven cancers

German virologist Harald zur Hausen received the Nobel Prize in 2008 for his discovery of the oncogenic role of human papillomaviruses (HPVs), a large family of more than 100 DNA viruses that infect the epithelial cells of the skin and mucous membranes. They are responsible for the largest number of virally associated cancer cases globally – around 5% (Table 1).

A number of different cancer types are linked to HPV infection, but it is best known as the cause of cervical cancer. The development of diagnostic blood tests and prophylactic vaccines for prevention and early intervention in HPV infection has helped to reduce the incidence of cervical cancer. Conversely, another type of HPV-associated cancer, head and neck squamous cell carcinoma (HNSCC), has seen increased incidence in recent years.

HPVs are categorized according to their oncogenic potential as high, intermediate, or low risk. The high-risk HPV16 and HPV18 strains are most commonly associated with cancer. They are thought to cause cancer predominantly through integration into the host genome. The HPV genome is composed of 8 genes encoding proteins that regulate viral replication and assembly. The E6 and E7 genes are the most highly oncogenic; as the HPV DNA is inserted into the host genome, the transcriptional regulator of E6/E7 is lost, leading to their increased expression. These genes have significant oncogenic potential because of their interaction with 2 tumor suppressor proteins, p53 and pRb.^6,7

The largest investment in therapeutic development for HPV-positive cancers has been in the realm of immunotherapy in an effort to boost the anti-tumor immune response. In particular, there has been a focus on the development of therapeutic vaccines, designed to prime the anti-tumor immune response to recognize viral antigens. A variety of different types of vaccines are being developed, including live, attenuated and inactivated vaccines that are protein, DNA, or peptide based. Most developed to date target the E6/E7 proteins from the HPV16/18 strains (Table 2).^8,9

Hepatocellular carcinoma: a tale of two viruses

The hepatitis viruses are a group of 5 unrelated viruses that causes inflammation of the liver. Hepatitis B (HBV), a DNA virus, and hepatitis C (HCV), an RNA virus, are also oncoviruses; HBV in particular is one of the main causes of hepatocellular carcinoma (HCC), the most common type of liver cancer.

The highly inflammatory environment fostered by HBV and HCV infection causes liver damage that often leads to cirrhosis. Continued infection can drive permanent damage to the hepatocytes, leading to genetic and epigenetic damage and driving oncogenesis. As an RNA virus, HCV doesn’t integrate into the genome and no confirmed viral oncoproteins have been identified to date, therefore it mostly drives cancer through these indirect mechanisms, which is also reflected in the fact that HCV-associated HCC predominantly occurs against a backdrop of liver cirrhosis.

HBV does integrate into the host genome. Genome sequencing studies revealed hundreds of integration sites, but most commonly they disrupted host genes involved in telomere stability and cell cycle regulation, providing some insight into the mechanisms by which HBV-associated HCC develops. In addition, HBV produces several oncoproteins, including HBx, which disrupts gene transcription, cell signaling pathways, cell cycle progress, apoptosis and other cellular processes.^15,16

Multitargeted tyrosine kinase inhibitors (TKIs) have been the focal point of therapeutic development in HCC. However, following the approval of sorafenib in 2008, there was a dearth of effective new treatment options despite substantial efforts and numerous phase 3 trials. More recently, immunotherapy has also come to the forefront, especially immune checkpoint inhibitors.

Last year marked the first new drug approvals in nearly a decade – the TKI regorafenib (Stivarga) and immune checkpoint inhibitor nivolumab (Opdivo), both in the second-line setting after failure of sorafenib. Treatment options in this setting may continue to expand, with the TKIs cabozantinib and lenvatinib and the immune checkpoint inhibitor pembrolizumab and the combination of durvalumab and tremelimumab hot on their heels.^17-20 Many of these drugs are also being evaluated in the front-line setting in comparison with sorafenib (Table 3).

Adoptive cell therapy promising in EBV-positive cancers

More than 90% of the global population is infected with EBV, making it one of the most common human viruses. It is a member of the herpesvirus family that is probably best known as the cause of infectious mononucleosis. On rare occasions, however, EBV can cause tumor development, though our understanding of its exact pathogenic role in cancer is still incomplete.

EBV is a DNA virus that doesn’t tend to integrate into the host genome, but instead remains in the nucleus in the form of episomes and produces several oncoproteins, including latent membrane protein-1. It is associated with a range of different cancer types, including Burkitt lymphoma and other B-cell malignancies. It also infects epithelial cells and can cause nasopharyngeal carcinoma and gastric cancer, however, much less is known about the molecular underpinnings of these EBV-positive cancer types.^26,27Gastric cancers actually comprise the largest group of EBV-associated tumors because of the global incidence of this cancer type. The Cancer Genome Atlas Research Network recently characterized gastric cancer on a molecular level and identified an EBV-positive subgroup as a distinct clinical entity with unique molecular characteristics.²⁹

The focus of therapeutic development has again been on immunotherapy, however in this case the idea of collecting the patients T cells, engineering them to recognize EBV, and then reinfusing them into the patient – adoptive cell therapy – has gained the most traction (Table 4).

Newest oncovirus on the block

The most recently discovered cancer-associated virus is Merkel cell polyomavirus (MCV), a DNA virus that was identified in 2008. Like EBV, virtually the whole global adult population is infected with MCV. It is linked to the development of a highly aggressive and lethal, though rare, form of skin cancer – Merkel cell carcinoma.

MCV is found in around 80% of MCC cases and in fewer than 10% of melanomas and other skin cancers. Thus far, several direct mechanisms of oncogenesis have been described, including integration of MCV into the host genome and the production of viral oncogenes, though their precise function is as yet unclear.^32-34

The American Cancer Society estimates that only 1500 cases of MCC are diagnosed each year in the United States.³⁵ Its rarity makes it difficult to conduct clinical trials with sufficient power, yet some headway has still been made.

Around half of MCCs express the programmed cell death ligand 1 (PD-L1) on their surface, making them a logical candidate for immune checkpoint inhibition. In 2017, avelumab became the first FDA-approved drug for the treatment of MCC. Approval was based on the JAVELIN Merkel 200 study in which 88 patients received avelumab. After 1 year of follow-up the ORR was 31.8%, with a CR rate of 9%.³⁶

Genome sequencing studies suggest that the mutational profile of MCV-positive tumors is quite different to those that are MCV-negative, which could have therapeutic implications. To date, these implications have not been delineated, given the challenge of small patient numbers, however an ongoing phase 1/2 trial is evaluating the combination of avelumab and radiation therapy or recombinant interferon beta, with or without MCV-specific cytotoxic T cells in patients with MCC and MCV infection.

The 2 other known cancer-causing viruses are human T-lymphotropic virus 1 (HTLV-1), a retrovirus associated with adult T-cell leukemia/lymphoma (ATL) and Kaposi sarcoma herpesvirus (KSHV). The latter is the causative agent of Kaposi sarcoma, often in combination with human immunodeficiency virus (HIV), a rare skin tumor that became renowned in the 1980s as an AIDS-defining illness.

The incidence of HTLV-1- and KSHV-positive tumors is substantially lower than the other virally associated cancers and, like MCC, this makes studying them and conducting clinical trials of novel therapeutic options a challenge. Nonetheless, several trials of targeted therapies and immunotherapies are underway.

Infection with certain viruses has been causally linked to the development of cancer. In recent years, an improved understanding of the unique pathology and molecular underpinnings of these virally associated cancers has prompted the development of more personalized treatment strategies, with a particular focus on immunotherapy. Here, we describe some of the latest developments.

The link between viruses and cancer

Suspicions about a possible role of viral infections in the development of cancer were first aroused in the early 1900s. The seminal discovery is traced back to Peyton Rous, who showed that a malignant tumor growing in a chicken could be transferred to a healthy bird by injecting it with tumor extracts that contained no actual tumor cells.¹

The infectious etiology of human cancer, however, remained controversial until many years later when the first cancer-causing virus, Epstein-Barr virus (EBV), was identified in cell cultures from patients with Burkitt lymphoma. Shortly afterward, the Rous sarcoma virus was unveiled as the oncogenic agent behind Rous’ observations.²Seven viruses have now been linked to the development of cancers and are thought to be responsible for around 12% of all cancer cases worldwide. The burden is likely to increase as technological advancements make it easier to establish a causal link between viruses and cancer development.³

In addition to making these links, researchers have also made significant headway in understanding how viruses cause cancer. Cancerous transformation of host cells occurs in only a minority of those who are infected with oncogenic viruses and often occurs in the setting of chronic infection.

Viruses can mediate carcinogenesis by direct and/or indirect mechanisms (Figure 1). Many of the hallmarks of cancer, the key attributes that drive the transformation from a normal cell to a malignant one, are compatible with the virus’s needs, such as needing to avoid cell death, increasing cell proliferation, and avoiding detection by the immune system.

Vaccines lead the charge in HPV-driven cancers

German virologist Harald zur Hausen received the Nobel Prize in 2008 for his discovery of the oncogenic role of human papillomaviruses (HPVs), a large family of more than 100 DNA viruses that infect the epithelial cells of the skin and mucous membranes. They are responsible for the largest number of virally associated cancer cases globally – around 5% (Table 1).

A number of different cancer types are linked to HPV infection, but it is best known as the cause of cervical cancer. The development of diagnostic blood tests and prophylactic vaccines for prevention and early intervention in HPV infection has helped to reduce the incidence of cervical cancer. Conversely, another type of HPV-associated cancer, head and neck squamous cell carcinoma (HNSCC), has seen increased incidence in recent years.

HPVs are categorized according to their oncogenic potential as high, intermediate, or low risk. The high-risk HPV16 and HPV18 strains are most commonly associated with cancer. They are thought to cause cancer predominantly through integration into the host genome. The HPV genome is composed of 8 genes encoding proteins that regulate viral replication and assembly. The E6 and E7 genes are the most highly oncogenic; as the HPV DNA is inserted into the host genome, the transcriptional regulator of E6/E7 is lost, leading to their increased expression. These genes have significant oncogenic potential because of their interaction with 2 tumor suppressor proteins, p53 and pRb.^6,7

The largest investment in therapeutic development for HPV-positive cancers has been in the realm of immunotherapy in an effort to boost the anti-tumor immune response. In particular, there has been a focus on the development of therapeutic vaccines, designed to prime the anti-tumor immune response to recognize viral antigens. A variety of different types of vaccines are being developed, including live, attenuated and inactivated vaccines that are protein, DNA, or peptide based. Most developed to date target the E6/E7 proteins from the HPV16/18 strains (Table 2).^8,9

Hepatocellular carcinoma: a tale of two viruses

The hepatitis viruses are a group of 5 unrelated viruses that causes inflammation of the liver. Hepatitis B (HBV), a DNA virus, and hepatitis C (HCV), an RNA virus, are also oncoviruses; HBV in particular is one of the main causes of hepatocellular carcinoma (HCC), the most common type of liver cancer.

The highly inflammatory environment fostered by HBV and HCV infection causes liver damage that often leads to cirrhosis. Continued infection can drive permanent damage to the hepatocytes, leading to genetic and epigenetic damage and driving oncogenesis. As an RNA virus, HCV doesn’t integrate into the genome and no confirmed viral oncoproteins have been identified to date, therefore it mostly drives cancer through these indirect mechanisms, which is also reflected in the fact that HCV-associated HCC predominantly occurs against a backdrop of liver cirrhosis.

HBV does integrate into the host genome. Genome sequencing studies revealed hundreds of integration sites, but most commonly they disrupted host genes involved in telomere stability and cell cycle regulation, providing some insight into the mechanisms by which HBV-associated HCC develops. In addition, HBV produces several oncoproteins, including HBx, which disrupts gene transcription, cell signaling pathways, cell cycle progress, apoptosis and other cellular processes.^15,16

Multitargeted tyrosine kinase inhibitors (TKIs) have been the focal point of therapeutic development in HCC. However, following the approval of sorafenib in 2008, there was a dearth of effective new treatment options despite substantial efforts and numerous phase 3 trials. More recently, immunotherapy has also come to the forefront, especially immune checkpoint inhibitors.

Last year marked the first new drug approvals in nearly a decade – the TKI regorafenib (Stivarga) and immune checkpoint inhibitor nivolumab (Opdivo), both in the second-line setting after failure of sorafenib. Treatment options in this setting may continue to expand, with the TKIs cabozantinib and lenvatinib and the immune checkpoint inhibitor pembrolizumab and the combination of durvalumab and tremelimumab hot on their heels.^17-20 Many of these drugs are also being evaluated in the front-line setting in comparison with sorafenib (Table 3).

Adoptive cell therapy promising in EBV-positive cancers

More than 90% of the global population is infected with EBV, making it one of the most common human viruses. It is a member of the herpesvirus family that is probably best known as the cause of infectious mononucleosis. On rare occasions, however, EBV can cause tumor development, though our understanding of its exact pathogenic role in cancer is still incomplete.

EBV is a DNA virus that doesn’t tend to integrate into the host genome, but instead remains in the nucleus in the form of episomes and produces several oncoproteins, including latent membrane protein-1. It is associated with a range of different cancer types, including Burkitt lymphoma and other B-cell malignancies. It also infects epithelial cells and can cause nasopharyngeal carcinoma and gastric cancer, however, much less is known about the molecular underpinnings of these EBV-positive cancer types.^26,27Gastric cancers actually comprise the largest group of EBV-associated tumors because of the global incidence of this cancer type. The Cancer Genome Atlas Research Network recently characterized gastric cancer on a molecular level and identified an EBV-positive subgroup as a distinct clinical entity with unique molecular characteristics.²⁹

The focus of therapeutic development has again been on immunotherapy, however in this case the idea of collecting the patients T cells, engineering them to recognize EBV, and then reinfusing them into the patient – adoptive cell therapy – has gained the most traction (Table 4).

Newest oncovirus on the block

The most recently discovered cancer-associated virus is Merkel cell polyomavirus (MCV), a DNA virus that was identified in 2008. Like EBV, virtually the whole global adult population is infected with MCV. It is linked to the development of a highly aggressive and lethal, though rare, form of skin cancer – Merkel cell carcinoma.

MCV is found in around 80% of MCC cases and in fewer than 10% of melanomas and other skin cancers. Thus far, several direct mechanisms of oncogenesis have been described, including integration of MCV into the host genome and the production of viral oncogenes, though their precise function is as yet unclear.^32-34

The American Cancer Society estimates that only 1500 cases of MCC are diagnosed each year in the United States.³⁵ Its rarity makes it difficult to conduct clinical trials with sufficient power, yet some headway has still been made.

Around half of MCCs express the programmed cell death ligand 1 (PD-L1) on their surface, making them a logical candidate for immune checkpoint inhibition. In 2017, avelumab became the first FDA-approved drug for the treatment of MCC. Approval was based on the JAVELIN Merkel 200 study in which 88 patients received avelumab. After 1 year of follow-up the ORR was 31.8%, with a CR rate of 9%.³⁶

Genome sequencing studies suggest that the mutational profile of MCV-positive tumors is quite different to those that are MCV-negative, which could have therapeutic implications. To date, these implications have not been delineated, given the challenge of small patient numbers, however an ongoing phase 1/2 trial is evaluating the combination of avelumab and radiation therapy or recombinant interferon beta, with or without MCV-specific cytotoxic T cells in patients with MCC and MCV infection.

The 2 other known cancer-causing viruses are human T-lymphotropic virus 1 (HTLV-1), a retrovirus associated with adult T-cell leukemia/lymphoma (ATL) and Kaposi sarcoma herpesvirus (KSHV). The latter is the causative agent of Kaposi sarcoma, often in combination with human immunodeficiency virus (HIV), a rare skin tumor that became renowned in the 1980s as an AIDS-defining illness.

The incidence of HTLV-1- and KSHV-positive tumors is substantially lower than the other virally associated cancers and, like MCC, this makes studying them and conducting clinical trials of novel therapeutic options a challenge. Nonetheless, several trials of targeted therapies and immunotherapies are underway.

Infection with certain viruses has been causally linked to the development of cancer. In recent years, an improved understanding of the unique pathology and molecular underpinnings of these virally associated cancers has prompted the development of more personalized treatment strategies, with a particular focus on immunotherapy. Here, we describe some of the latest developments.

The link between viruses and cancer

Suspicions about a possible role of viral infections in the development of cancer were first aroused in the early 1900s. The seminal discovery is traced back to Peyton Rous, who showed that a malignant tumor growing in a chicken could be transferred to a healthy bird by injecting it with tumor extracts that contained no actual tumor cells.¹

The infectious etiology of human cancer, however, remained controversial until many years later when the first cancer-causing virus, Epstein-Barr virus (EBV), was identified in cell cultures from patients with Burkitt lymphoma. Shortly afterward, the Rous sarcoma virus was unveiled as the oncogenic agent behind Rous’ observations.²Seven viruses have now been linked to the development of cancers and are thought to be responsible for around 12% of all cancer cases worldwide. The burden is likely to increase as technological advancements make it easier to establish a causal link between viruses and cancer development.³

In addition to making these links, researchers have also made significant headway in understanding how viruses cause cancer. Cancerous transformation of host cells occurs in only a minority of those who are infected with oncogenic viruses and often occurs in the setting of chronic infection.

Viruses can mediate carcinogenesis by direct and/or indirect mechanisms (Figure 1). Many of the hallmarks of cancer, the key attributes that drive the transformation from a normal cell to a malignant one, are compatible with the virus’s needs, such as needing to avoid cell death, increasing cell proliferation, and avoiding detection by the immune system.

Vaccines lead the charge in HPV-driven cancers

German virologist Harald zur Hausen received the Nobel Prize in 2008 for his discovery of the oncogenic role of human papillomaviruses (HPVs), a large family of more than 100 DNA viruses that infect the epithelial cells of the skin and mucous membranes. They are responsible for the largest number of virally associated cancer cases globally – around 5% (Table 1).

A number of different cancer types are linked to HPV infection, but it is best known as the cause of cervical cancer. The development of diagnostic blood tests and prophylactic vaccines for prevention and early intervention in HPV infection has helped to reduce the incidence of cervical cancer. Conversely, another type of HPV-associated cancer, head and neck squamous cell carcinoma (HNSCC), has seen increased incidence in recent years.

HPVs are categorized according to their oncogenic potential as high, intermediate, or low risk. The high-risk HPV16 and HPV18 strains are most commonly associated with cancer. They are thought to cause cancer predominantly through integration into the host genome. The HPV genome is composed of 8 genes encoding proteins that regulate viral replication and assembly. The E6 and E7 genes are the most highly oncogenic; as the HPV DNA is inserted into the host genome, the transcriptional regulator of E6/E7 is lost, leading to their increased expression. These genes have significant oncogenic potential because of their interaction with 2 tumor suppressor proteins, p53 and pRb.^6,7

The largest investment in therapeutic development for HPV-positive cancers has been in the realm of immunotherapy in an effort to boost the anti-tumor immune response. In particular, there has been a focus on the development of therapeutic vaccines, designed to prime the anti-tumor immune response to recognize viral antigens. A variety of different types of vaccines are being developed, including live, attenuated and inactivated vaccines that are protein, DNA, or peptide based. Most developed to date target the E6/E7 proteins from the HPV16/18 strains (Table 2).^8,9

Hepatocellular carcinoma: a tale of two viruses

The hepatitis viruses are a group of 5 unrelated viruses that causes inflammation of the liver. Hepatitis B (HBV), a DNA virus, and hepatitis C (HCV), an RNA virus, are also oncoviruses; HBV in particular is one of the main causes of hepatocellular carcinoma (HCC), the most common type of liver cancer.

The highly inflammatory environment fostered by HBV and HCV infection causes liver damage that often leads to cirrhosis. Continued infection can drive permanent damage to the hepatocytes, leading to genetic and epigenetic damage and driving oncogenesis. As an RNA virus, HCV doesn’t integrate into the genome and no confirmed viral oncoproteins have been identified to date, therefore it mostly drives cancer through these indirect mechanisms, which is also reflected in the fact that HCV-associated HCC predominantly occurs against a backdrop of liver cirrhosis.

HBV does integrate into the host genome. Genome sequencing studies revealed hundreds of integration sites, but most commonly they disrupted host genes involved in telomere stability and cell cycle regulation, providing some insight into the mechanisms by which HBV-associated HCC develops. In addition, HBV produces several oncoproteins, including HBx, which disrupts gene transcription, cell signaling pathways, cell cycle progress, apoptosis and other cellular processes.^15,16

Multitargeted tyrosine kinase inhibitors (TKIs) have been the focal point of therapeutic development in HCC. However, following the approval of sorafenib in 2008, there was a dearth of effective new treatment options despite substantial efforts and numerous phase 3 trials. More recently, immunotherapy has also come to the forefront, especially immune checkpoint inhibitors.

Last year marked the first new drug approvals in nearly a decade – the TKI regorafenib (Stivarga) and immune checkpoint inhibitor nivolumab (Opdivo), both in the second-line setting after failure of sorafenib. Treatment options in this setting may continue to expand, with the TKIs cabozantinib and lenvatinib and the immune checkpoint inhibitor pembrolizumab and the combination of durvalumab and tremelimumab hot on their heels.^17-20 Many of these drugs are also being evaluated in the front-line setting in comparison with sorafenib (Table 3).

Adoptive cell therapy promising in EBV-positive cancers

More than 90% of the global population is infected with EBV, making it one of the most common human viruses. It is a member of the herpesvirus family that is probably best known as the cause of infectious mononucleosis. On rare occasions, however, EBV can cause tumor development, though our understanding of its exact pathogenic role in cancer is still incomplete.

EBV is a DNA virus that doesn’t tend to integrate into the host genome, but instead remains in the nucleus in the form of episomes and produces several oncoproteins, including latent membrane protein-1. It is associated with a range of different cancer types, including Burkitt lymphoma and other B-cell malignancies. It also infects epithelial cells and can cause nasopharyngeal carcinoma and gastric cancer, however, much less is known about the molecular underpinnings of these EBV-positive cancer types.^26,27Gastric cancers actually comprise the largest group of EBV-associated tumors because of the global incidence of this cancer type. The Cancer Genome Atlas Research Network recently characterized gastric cancer on a molecular level and identified an EBV-positive subgroup as a distinct clinical entity with unique molecular characteristics.²⁹

The focus of therapeutic development has again been on immunotherapy, however in this case the idea of collecting the patients T cells, engineering them to recognize EBV, and then reinfusing them into the patient – adoptive cell therapy – has gained the most traction (Table 4).

Newest oncovirus on the block

The most recently discovered cancer-associated virus is Merkel cell polyomavirus (MCV), a DNA virus that was identified in 2008. Like EBV, virtually the whole global adult population is infected with MCV. It is linked to the development of a highly aggressive and lethal, though rare, form of skin cancer – Merkel cell carcinoma.

MCV is found in around 80% of MCC cases and in fewer than 10% of melanomas and other skin cancers. Thus far, several direct mechanisms of oncogenesis have been described, including integration of MCV into the host genome and the production of viral oncogenes, though their precise function is as yet unclear.^32-34

The American Cancer Society estimates that only 1500 cases of MCC are diagnosed each year in the United States.³⁵ Its rarity makes it difficult to conduct clinical trials with sufficient power, yet some headway has still been made.

Around half of MCCs express the programmed cell death ligand 1 (PD-L1) on their surface, making them a logical candidate for immune checkpoint inhibition. In 2017, avelumab became the first FDA-approved drug for the treatment of MCC. Approval was based on the JAVELIN Merkel 200 study in which 88 patients received avelumab. After 1 year of follow-up the ORR was 31.8%, with a CR rate of 9%.³⁶

Genome sequencing studies suggest that the mutational profile of MCV-positive tumors is quite different to those that are MCV-negative, which could have therapeutic implications. To date, these implications have not been delineated, given the challenge of small patient numbers, however an ongoing phase 1/2 trial is evaluating the combination of avelumab and radiation therapy or recombinant interferon beta, with or without MCV-specific cytotoxic T cells in patients with MCC and MCV infection.

The 2 other known cancer-causing viruses are human T-lymphotropic virus 1 (HTLV-1), a retrovirus associated with adult T-cell leukemia/lymphoma (ATL) and Kaposi sarcoma herpesvirus (KSHV). The latter is the causative agent of Kaposi sarcoma, often in combination with human immunodeficiency virus (HIV), a rare skin tumor that became renowned in the 1980s as an AIDS-defining illness.

The incidence of HTLV-1- and KSHV-positive tumors is substantially lower than the other virally associated cancers and, like MCC, this makes studying them and conducting clinical trials of novel therapeutic options a challenge. Nonetheless, several trials of targeted therapies and immunotherapies are underway.

LAS VEGAS – Alopecia is hard to bear for patients and has been difficult to treat, but “there’s been a revolution in thinking about how to treat alopecia areata,” according to Maria Hordinsky, MD.

Dr. Hordinsky, professor and chair of the department of dermatology, University of Minnesota, Minneapolis, discussed hair disorders in multiple presentations at Skin Disease Education Foundation’s annual Las Vegas Dermatology Seminar. In an interview after her session on alopecia areata, she elaborated on the state of research and treatment for patients with this diagnosis.



DERMATOLOGY NEWS: What has changed in alopecia areata treatment over the last few years?

Dr. Hordinsky: There is still no Food and Drug Administration–approved treatment for this disease. But recent studies have helped us understand how alopecia areata occurs, how important interleukin-15 is, and how to target this cytokine as well as others. At the same time, expertise has developed at several centers across the United States with using the Janus kinase inhibitor tofacitinib [Xeljanz] at 5 milligrams twice a day. This has led to more off-label use. Concurrently, many pharmaceutical companies with interest in alopecia areata have begun to study different JAK inhibitors that target different cytokine receptors. Researchers also are exploring topical JAK inhibitors.



DN: What about the high costs of these drugs?

Dr. Hordinsky: Some insurers are covering tofacitinib, and patient assistance programs are very helpful and beneficial. In my own practice, most patients taking these drugs are using those programs.



DN: Are any treatments being used less than in the past?

Dr. Hordinsky: We’re still using tools that we have in the toolbox because we don’t have an approved treatment. We use topical steroids and intralesional steroids. We also use prednisone as needed, and we use contact sensitization therapy.



DN: In your presentation, you talked about alopecia areata in body areas outside of the scalp. What should dermatologists know about the eyebrows in patients with alopecia areata?

Dr. Hordinsky: Some patients don’t care as much about the scalp hair loss because they’ve figured out how to deal with it. What really bothers some patients is their eyebrow hair loss. You can think of situations where alopecia areata creates a circle in the middle of the eyebrow on the left side, but not the right, or you lose one eyebrow but not the other. We use techniques such as intralesional steroids. If there’s some hair growth present that’s lightly pigmented, we may apply topical minoxidil or Latisse [bimatoprost] to the brow area. Patients may also do microblading.



DN: Are there eyebrow prosthetics?

Dr. Hordinsky: Yes, there are. The National Alopecia Areata Foundation provides a lot of information to patients and providers about these devices. There are devices that you can tape on your brow area. Some don’t look great cosmetically, but some look fantastic. Microblading may create the most normal appearance.



DN: What about eyelashes?

Dr. Hordinsky: Eyelash loss is tough and really bothersome to patients if they don’t wear glasses because of the protection provided by eyelashes, such as when you blink against airborne dust. If there is some hair present in the eyebrow regions, one can try to regrow hair and use something that’s safe in that region, like topical Latisse. These treatments have to be tried for a couple of months before you say yea or nay, and you and the patient have to have reasonable expectations.



DN: What about men’s beards?

Dr. Hordinsky: You can treat those areas with topical or intralesional steroids. My own experience is that you have to use intralesional steroids, and overall, this form of alopecia areata may be one of the most difficult to manage successfully.



DN: Do men complain about missing chest hair?

Dr. Hordinsky: Chest hair doesn’t come up a lot for me. For men, it’s mainly the beard area. But people with alopecia areata may sometimes minimize or not bring up discussion of loss of hair in the underarms, the genital region, or the chest. It may be because they’ve figured out how to deal with it.



DN: How do you think treatments will improve over the next 5-10 years?

Dr. Hordinsky: We have a number of companies putting JAK inhibitors into clinical trials. A major step forward will be figuring out which one works the best, and then the next hurdle will be sustainability. There are very few studies in alopecia areata about how long a response to treatment can be maintained. Another big step will be the development of a topical agent that is able to penetrate through the skin to the level of the immune attack at the lower part of the hair follicle and provide the opportunity to possibly not only grow hair but also to maintain hair growth. So there’s a lot of evolution going on right now.

Dr. Hordinsky disclosed consulting work with Procter & Gamble, Concert, and Cassiopea, and grant/research support from Aclaris, National Alopecia Areata Foundation, Allergan.

SDEF and this news organization are owned by the same parent company.

LAS VEGAS – Alopecia is hard to bear for patients and has been difficult to treat, but “there’s been a revolution in thinking about how to treat alopecia areata,” according to Maria Hordinsky, MD.

Dr. Hordinsky, professor and chair of the department of dermatology, University of Minnesota, Minneapolis, discussed hair disorders in multiple presentations at Skin Disease Education Foundation’s annual Las Vegas Dermatology Seminar. In an interview after her session on alopecia areata, she elaborated on the state of research and treatment for patients with this diagnosis.



DERMATOLOGY NEWS: What has changed in alopecia areata treatment over the last few years?

Dr. Hordinsky: There is still no Food and Drug Administration–approved treatment for this disease. But recent studies have helped us understand how alopecia areata occurs, how important interleukin-15 is, and how to target this cytokine as well as others. At the same time, expertise has developed at several centers across the United States with using the Janus kinase inhibitor tofacitinib [Xeljanz] at 5 milligrams twice a day. This has led to more off-label use. Concurrently, many pharmaceutical companies with interest in alopecia areata have begun to study different JAK inhibitors that target different cytokine receptors. Researchers also are exploring topical JAK inhibitors.



DN: What about the high costs of these drugs?

Dr. Hordinsky: Some insurers are covering tofacitinib, and patient assistance programs are very helpful and beneficial. In my own practice, most patients taking these drugs are using those programs.



DN: Are any treatments being used less than in the past?

Dr. Hordinsky: We’re still using tools that we have in the toolbox because we don’t have an approved treatment. We use topical steroids and intralesional steroids. We also use prednisone as needed, and we use contact sensitization therapy.



DN: In your presentation, you talked about alopecia areata in body areas outside of the scalp. What should dermatologists know about the eyebrows in patients with alopecia areata?

Dr. Hordinsky: Some patients don’t care as much about the scalp hair loss because they’ve figured out how to deal with it. What really bothers some patients is their eyebrow hair loss. You can think of situations where alopecia areata creates a circle in the middle of the eyebrow on the left side, but not the right, or you lose one eyebrow but not the other. We use techniques such as intralesional steroids. If there’s some hair growth present that’s lightly pigmented, we may apply topical minoxidil or Latisse [bimatoprost] to the brow area. Patients may also do microblading.



DN: Are there eyebrow prosthetics?

Dr. Hordinsky: Yes, there are. The National Alopecia Areata Foundation provides a lot of information to patients and providers about these devices. There are devices that you can tape on your brow area. Some don’t look great cosmetically, but some look fantastic. Microblading may create the most normal appearance.



DN: What about eyelashes?

Dr. Hordinsky: Eyelash loss is tough and really bothersome to patients if they don’t wear glasses because of the protection provided by eyelashes, such as when you blink against airborne dust. If there is some hair present in the eyebrow regions, one can try to regrow hair and use something that’s safe in that region, like topical Latisse. These treatments have to be tried for a couple of months before you say yea or nay, and you and the patient have to have reasonable expectations.



DN: What about men’s beards?

Dr. Hordinsky: You can treat those areas with topical or intralesional steroids. My own experience is that you have to use intralesional steroids, and overall, this form of alopecia areata may be one of the most difficult to manage successfully.



DN: Do men complain about missing chest hair?

Dr. Hordinsky: Chest hair doesn’t come up a lot for me. For men, it’s mainly the beard area. But people with alopecia areata may sometimes minimize or not bring up discussion of loss of hair in the underarms, the genital region, or the chest. It may be because they’ve figured out how to deal with it.



DN: How do you think treatments will improve over the next 5-10 years?

Dr. Hordinsky: We have a number of companies putting JAK inhibitors into clinical trials. A major step forward will be figuring out which one works the best, and then the next hurdle will be sustainability. There are very few studies in alopecia areata about how long a response to treatment can be maintained. Another big step will be the development of a topical agent that is able to penetrate through the skin to the level of the immune attack at the lower part of the hair follicle and provide the opportunity to possibly not only grow hair but also to maintain hair growth. So there’s a lot of evolution going on right now.

Dr. Hordinsky disclosed consulting work with Procter & Gamble, Concert, and Cassiopea, and grant/research support from Aclaris, National Alopecia Areata Foundation, Allergan.

SDEF and this news organization are owned by the same parent company.

LAS VEGAS – Alopecia is hard to bear for patients and has been difficult to treat, but “there’s been a revolution in thinking about how to treat alopecia areata,” according to Maria Hordinsky, MD.

Dr. Hordinsky, professor and chair of the department of dermatology, University of Minnesota, Minneapolis, discussed hair disorders in multiple presentations at Skin Disease Education Foundation’s annual Las Vegas Dermatology Seminar. In an interview after her session on alopecia areata, she elaborated on the state of research and treatment for patients with this diagnosis.



DERMATOLOGY NEWS: What has changed in alopecia areata treatment over the last few years?

Dr. Hordinsky: There is still no Food and Drug Administration–approved treatment for this disease. But recent studies have helped us understand how alopecia areata occurs, how important interleukin-15 is, and how to target this cytokine as well as others. At the same time, expertise has developed at several centers across the United States with using the Janus kinase inhibitor tofacitinib [Xeljanz] at 5 milligrams twice a day. This has led to more off-label use. Concurrently, many pharmaceutical companies with interest in alopecia areata have begun to study different JAK inhibitors that target different cytokine receptors. Researchers also are exploring topical JAK inhibitors.



DN: What about the high costs of these drugs?

Dr. Hordinsky: Some insurers are covering tofacitinib, and patient assistance programs are very helpful and beneficial. In my own practice, most patients taking these drugs are using those programs.



DN: Are any treatments being used less than in the past?

Dr. Hordinsky: We’re still using tools that we have in the toolbox because we don’t have an approved treatment. We use topical steroids and intralesional steroids. We also use prednisone as needed, and we use contact sensitization therapy.



DN: In your presentation, you talked about alopecia areata in body areas outside of the scalp. What should dermatologists know about the eyebrows in patients with alopecia areata?

Dr. Hordinsky: Some patients don’t care as much about the scalp hair loss because they’ve figured out how to deal with it. What really bothers some patients is their eyebrow hair loss. You can think of situations where alopecia areata creates a circle in the middle of the eyebrow on the left side, but not the right, or you lose one eyebrow but not the other. We use techniques such as intralesional steroids. If there’s some hair growth present that’s lightly pigmented, we may apply topical minoxidil or Latisse [bimatoprost] to the brow area. Patients may also do microblading.



DN: Are there eyebrow prosthetics?

Dr. Hordinsky: Yes, there are. The National Alopecia Areata Foundation provides a lot of information to patients and providers about these devices. There are devices that you can tape on your brow area. Some don’t look great cosmetically, but some look fantastic. Microblading may create the most normal appearance.



DN: What about eyelashes?

Dr. Hordinsky: Eyelash loss is tough and really bothersome to patients if they don’t wear glasses because of the protection provided by eyelashes, such as when you blink against airborne dust. If there is some hair present in the eyebrow regions, one can try to regrow hair and use something that’s safe in that region, like topical Latisse. These treatments have to be tried for a couple of months before you say yea or nay, and you and the patient have to have reasonable expectations.



DN: What about men’s beards?

Dr. Hordinsky: You can treat those areas with topical or intralesional steroids. My own experience is that you have to use intralesional steroids, and overall, this form of alopecia areata may be one of the most difficult to manage successfully.



DN: Do men complain about missing chest hair?

Dr. Hordinsky: Chest hair doesn’t come up a lot for me. For men, it’s mainly the beard area. But people with alopecia areata may sometimes minimize or not bring up discussion of loss of hair in the underarms, the genital region, or the chest. It may be because they’ve figured out how to deal with it.



DN: How do you think treatments will improve over the next 5-10 years?

Dr. Hordinsky: We have a number of companies putting JAK inhibitors into clinical trials. A major step forward will be figuring out which one works the best, and then the next hurdle will be sustainability. There are very few studies in alopecia areata about how long a response to treatment can be maintained. Another big step will be the development of a topical agent that is able to penetrate through the skin to the level of the immune attack at the lower part of the hair follicle and provide the opportunity to possibly not only grow hair but also to maintain hair growth. So there’s a lot of evolution going on right now.

Dr. Hordinsky disclosed consulting work with Procter & Gamble, Concert, and Cassiopea, and grant/research support from Aclaris, National Alopecia Areata Foundation, Allergan.

SDEF and this news organization are owned by the same parent company.