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Expert shares hyperhidrosis treatment pearls
Even though over-the-counter topical antiperspirants are a common go-to treatment for primary axillary hyperhidrosis, a large survey commissioned by the International Hyperhidrosis Society showed that, while OTC aluminum products are the most recommended, they offer the least satisfaction to patients.
Of the 1,985 survey respondents who self-identified as having excessive sweating, those who received treatment were most satisfied with injections and least satisfied with prescription and OTC antiperspirants and liposuction. “It’s important to recognize that, while these are not invasive, they’re simple, you need to keep up with it, and they’re really not that effective for primary hyperhidrosis,” Adam Friedman, MD, said during the virtual Orlando Dermatology Aesthetic and Clinical Conference.
A major development came in 2018, when the Food and Drug Administration approved topical glycopyrronium tosylate for the treatment of primary axillary hyperhidrosis in adults and in children as young as age 9. It marked the first topical anticholinergic approved for the condition. Results from the pivotal phase 2 ATMOS-1 and ATMOS-2 randomized, controlled trials found that, after 4 weeks of daily use, 53%-66% of patients reported a 4-point improvement or greater on the ASDD item 2, which is defined as the worst sweating they experienced in a 24-hour period on an 11-point scale.
“Patients want to know: How quickly am I going to see improvement? The answer to this can be central to treatment compliance,” said Dr. Friedman, professor and interim chair of dermatology at the George Washington University, Washington. “We have data showing that 23%-29% of patients using glycopyrronium tosylate met that primary outcome within 1 week of use. So, you can tell patients: ‘Help is on the way. You may see a response relatively soon.’ ”
The most common adverse events in the two trials were dry mouth, which affected 24% of patients, followed by mydriasis (7%), and oropharyngeal pain (6%). He advises patients to apply it once at night. “I tell my patients make this the last thing you do during your nighttime routine,” said Dr. Friedman, who coauthored a case-based clinical algorithm for approaching primary hyperhidrosis patients.
“Open it up, one swipe to the right [underarm], flip it over, one wipe of the left [underarm], toss the towelette, and wash your hands thoroughly. You don’t need to remove axillary hair or occlude the area. I tell them they may find some improvement within one week of daily use, but I give realistic expectations, usually 2-3 weeks. Tell them about the potential for side effects, which certainly can happen,” he said.
Investigators are evaluating how this product could be delivered to other body sites. Dr. Friedman said that he uses glycopyrronium tosylate off label for palmar and plantar hyperhidrosis. He advises patients to rub their hands or feet the cloth until it dries, toss the towelette, apply an occlusive agent like Aquaphor followed by gloves/socks for at least an hour, and then wash their hands or feet. “If they can keep the gloves or socks on overnight, that’s fine, but that’s very rare,” Dr. Friedman added.
“Typically, an hour or 2 of occlusive covering will get the product in where it needs to be. The upside of this product is that it’s noninvasive, there’s minimal irritation, it’s effective, and FDA approved. On the downside, it’s a long-term therapy. This is forever, so cost can be an issue, and you have to think about the anticholinergic effects as well.”
Iontophoresis is a first-line treatment for moderate to severe palmar and plantar hyperhidrosis. It’s also effective for mild hyperhidrosis with limited side effects, but it’s cumbersome, he said, requiring thrice-weekly treatment of each palm or sole for approximately 30 minutes to a controlled electric current at 15-20 mA with tap water.
There are no systemic agents approved for hyperhidrosis, only case reports or small case series. For now, the two commonly used anticholinergics are glycopyrrolate and oxybutynin. Glycopyrrolate comes in 1- and 2-mg capsules. “You can break the tablets easily and it’s pretty cheap, with an estimated cost of 2 mg/day at $756 per year,” Dr. Friedman said. “I typically start patients on 1 mg twice per day for a week, then ask how they’re doing. If they notice improvement, have minimal side effects but think they can do better, then I increase it by 1 mg and reassess. I give them autonomy, and at most, want them to max out at 6 mg per day. There is an oral solution for kids, which can make this a little more accessible.”
He prescribes oxybutynin infrequently but considers it effective. “Most patients respond to 5- to 10-mg/day dosing, but doses up to 15 or 20 mg daily may be required,” he noted.
For persistent flushing with hyperhidrosis, Dr. Friedman typically recommends treatment with clonidine. “I start patients pretty low, sometimes 0.05 mg twice per day.”
For patients who sweat because of social phobias and performance anxiety, he typically recommends treatment with a beta-adrenergic blocker. “These are highly lipophilic, so I advise patients not to take them with food,” he said. “The peak concentration is 1-1.5 hours. Usually, I start at 10 mg and I have people do a test run at home. I also take a baseline blood pressure in the office to make sure they’re not hypotensive.” The use of beta-adrenergic blockers is contraindicated in patients with bradycardia, atrioventricular block, and asthma. They can also exacerbate psoriasis.
On Sept. 20, 2020, Brickell Biotech announced the approval of sofpironium bromide gel, 5%, in Japan for the treatment of primary axillary hyperhidrosis. Sofpironium bromide is an analog of glycopyrrolate “that gets metabolized very quickly in order to limit systemic absorption of the active agent and therefore mitigate side effects,” Dr. Friedman said.
A recently published Japanese study found that 54% of patients with primary axillary hyperhidrosis who received sofpironium bromide experienced a 1- or 2-point improvement on the Hyperhidrosis Disease Severity Scale and a 50% or greater reduction in gravimetric sweat production from baseline to week 6 of treatment, compared with 36% of patients in the control group (P = .003). According to Dr. Friedman, a 15% formulation of this product is being studied in the United States, “but the experience in Japan with the 5% formulation should give us some real-world information about this product,” he said. “Out of the gate, we’re going to know something about how it’s being used.”
Dr. Friedman reported that he serves as a consultant and/or advisor to numerous pharmaceutical companies, including some that produce cannabinoids. He is also a speaker for Regeneron, Abbvie, Novartis, LRP, Dermira, and Brickel Biotech, and has received grants from Pfizer, the Dermatology Foundation, Almirall, and Janssen.
Even though over-the-counter topical antiperspirants are a common go-to treatment for primary axillary hyperhidrosis, a large survey commissioned by the International Hyperhidrosis Society showed that, while OTC aluminum products are the most recommended, they offer the least satisfaction to patients.
Of the 1,985 survey respondents who self-identified as having excessive sweating, those who received treatment were most satisfied with injections and least satisfied with prescription and OTC antiperspirants and liposuction. “It’s important to recognize that, while these are not invasive, they’re simple, you need to keep up with it, and they’re really not that effective for primary hyperhidrosis,” Adam Friedman, MD, said during the virtual Orlando Dermatology Aesthetic and Clinical Conference.
A major development came in 2018, when the Food and Drug Administration approved topical glycopyrronium tosylate for the treatment of primary axillary hyperhidrosis in adults and in children as young as age 9. It marked the first topical anticholinergic approved for the condition. Results from the pivotal phase 2 ATMOS-1 and ATMOS-2 randomized, controlled trials found that, after 4 weeks of daily use, 53%-66% of patients reported a 4-point improvement or greater on the ASDD item 2, which is defined as the worst sweating they experienced in a 24-hour period on an 11-point scale.
“Patients want to know: How quickly am I going to see improvement? The answer to this can be central to treatment compliance,” said Dr. Friedman, professor and interim chair of dermatology at the George Washington University, Washington. “We have data showing that 23%-29% of patients using glycopyrronium tosylate met that primary outcome within 1 week of use. So, you can tell patients: ‘Help is on the way. You may see a response relatively soon.’ ”
The most common adverse events in the two trials were dry mouth, which affected 24% of patients, followed by mydriasis (7%), and oropharyngeal pain (6%). He advises patients to apply it once at night. “I tell my patients make this the last thing you do during your nighttime routine,” said Dr. Friedman, who coauthored a case-based clinical algorithm for approaching primary hyperhidrosis patients.
“Open it up, one swipe to the right [underarm], flip it over, one wipe of the left [underarm], toss the towelette, and wash your hands thoroughly. You don’t need to remove axillary hair or occlude the area. I tell them they may find some improvement within one week of daily use, but I give realistic expectations, usually 2-3 weeks. Tell them about the potential for side effects, which certainly can happen,” he said.
Investigators are evaluating how this product could be delivered to other body sites. Dr. Friedman said that he uses glycopyrronium tosylate off label for palmar and plantar hyperhidrosis. He advises patients to rub their hands or feet the cloth until it dries, toss the towelette, apply an occlusive agent like Aquaphor followed by gloves/socks for at least an hour, and then wash their hands or feet. “If they can keep the gloves or socks on overnight, that’s fine, but that’s very rare,” Dr. Friedman added.
“Typically, an hour or 2 of occlusive covering will get the product in where it needs to be. The upside of this product is that it’s noninvasive, there’s minimal irritation, it’s effective, and FDA approved. On the downside, it’s a long-term therapy. This is forever, so cost can be an issue, and you have to think about the anticholinergic effects as well.”
Iontophoresis is a first-line treatment for moderate to severe palmar and plantar hyperhidrosis. It’s also effective for mild hyperhidrosis with limited side effects, but it’s cumbersome, he said, requiring thrice-weekly treatment of each palm or sole for approximately 30 minutes to a controlled electric current at 15-20 mA with tap water.
There are no systemic agents approved for hyperhidrosis, only case reports or small case series. For now, the two commonly used anticholinergics are glycopyrrolate and oxybutynin. Glycopyrrolate comes in 1- and 2-mg capsules. “You can break the tablets easily and it’s pretty cheap, with an estimated cost of 2 mg/day at $756 per year,” Dr. Friedman said. “I typically start patients on 1 mg twice per day for a week, then ask how they’re doing. If they notice improvement, have minimal side effects but think they can do better, then I increase it by 1 mg and reassess. I give them autonomy, and at most, want them to max out at 6 mg per day. There is an oral solution for kids, which can make this a little more accessible.”
He prescribes oxybutynin infrequently but considers it effective. “Most patients respond to 5- to 10-mg/day dosing, but doses up to 15 or 20 mg daily may be required,” he noted.
For persistent flushing with hyperhidrosis, Dr. Friedman typically recommends treatment with clonidine. “I start patients pretty low, sometimes 0.05 mg twice per day.”
For patients who sweat because of social phobias and performance anxiety, he typically recommends treatment with a beta-adrenergic blocker. “These are highly lipophilic, so I advise patients not to take them with food,” he said. “The peak concentration is 1-1.5 hours. Usually, I start at 10 mg and I have people do a test run at home. I also take a baseline blood pressure in the office to make sure they’re not hypotensive.” The use of beta-adrenergic blockers is contraindicated in patients with bradycardia, atrioventricular block, and asthma. They can also exacerbate psoriasis.
On Sept. 20, 2020, Brickell Biotech announced the approval of sofpironium bromide gel, 5%, in Japan for the treatment of primary axillary hyperhidrosis. Sofpironium bromide is an analog of glycopyrrolate “that gets metabolized very quickly in order to limit systemic absorption of the active agent and therefore mitigate side effects,” Dr. Friedman said.
A recently published Japanese study found that 54% of patients with primary axillary hyperhidrosis who received sofpironium bromide experienced a 1- or 2-point improvement on the Hyperhidrosis Disease Severity Scale and a 50% or greater reduction in gravimetric sweat production from baseline to week 6 of treatment, compared with 36% of patients in the control group (P = .003). According to Dr. Friedman, a 15% formulation of this product is being studied in the United States, “but the experience in Japan with the 5% formulation should give us some real-world information about this product,” he said. “Out of the gate, we’re going to know something about how it’s being used.”
Dr. Friedman reported that he serves as a consultant and/or advisor to numerous pharmaceutical companies, including some that produce cannabinoids. He is also a speaker for Regeneron, Abbvie, Novartis, LRP, Dermira, and Brickel Biotech, and has received grants from Pfizer, the Dermatology Foundation, Almirall, and Janssen.
Even though over-the-counter topical antiperspirants are a common go-to treatment for primary axillary hyperhidrosis, a large survey commissioned by the International Hyperhidrosis Society showed that, while OTC aluminum products are the most recommended, they offer the least satisfaction to patients.
Of the 1,985 survey respondents who self-identified as having excessive sweating, those who received treatment were most satisfied with injections and least satisfied with prescription and OTC antiperspirants and liposuction. “It’s important to recognize that, while these are not invasive, they’re simple, you need to keep up with it, and they’re really not that effective for primary hyperhidrosis,” Adam Friedman, MD, said during the virtual Orlando Dermatology Aesthetic and Clinical Conference.
A major development came in 2018, when the Food and Drug Administration approved topical glycopyrronium tosylate for the treatment of primary axillary hyperhidrosis in adults and in children as young as age 9. It marked the first topical anticholinergic approved for the condition. Results from the pivotal phase 2 ATMOS-1 and ATMOS-2 randomized, controlled trials found that, after 4 weeks of daily use, 53%-66% of patients reported a 4-point improvement or greater on the ASDD item 2, which is defined as the worst sweating they experienced in a 24-hour period on an 11-point scale.
“Patients want to know: How quickly am I going to see improvement? The answer to this can be central to treatment compliance,” said Dr. Friedman, professor and interim chair of dermatology at the George Washington University, Washington. “We have data showing that 23%-29% of patients using glycopyrronium tosylate met that primary outcome within 1 week of use. So, you can tell patients: ‘Help is on the way. You may see a response relatively soon.’ ”
The most common adverse events in the two trials were dry mouth, which affected 24% of patients, followed by mydriasis (7%), and oropharyngeal pain (6%). He advises patients to apply it once at night. “I tell my patients make this the last thing you do during your nighttime routine,” said Dr. Friedman, who coauthored a case-based clinical algorithm for approaching primary hyperhidrosis patients.
“Open it up, one swipe to the right [underarm], flip it over, one wipe of the left [underarm], toss the towelette, and wash your hands thoroughly. You don’t need to remove axillary hair or occlude the area. I tell them they may find some improvement within one week of daily use, but I give realistic expectations, usually 2-3 weeks. Tell them about the potential for side effects, which certainly can happen,” he said.
Investigators are evaluating how this product could be delivered to other body sites. Dr. Friedman said that he uses glycopyrronium tosylate off label for palmar and plantar hyperhidrosis. He advises patients to rub their hands or feet the cloth until it dries, toss the towelette, apply an occlusive agent like Aquaphor followed by gloves/socks for at least an hour, and then wash their hands or feet. “If they can keep the gloves or socks on overnight, that’s fine, but that’s very rare,” Dr. Friedman added.
“Typically, an hour or 2 of occlusive covering will get the product in where it needs to be. The upside of this product is that it’s noninvasive, there’s minimal irritation, it’s effective, and FDA approved. On the downside, it’s a long-term therapy. This is forever, so cost can be an issue, and you have to think about the anticholinergic effects as well.”
Iontophoresis is a first-line treatment for moderate to severe palmar and plantar hyperhidrosis. It’s also effective for mild hyperhidrosis with limited side effects, but it’s cumbersome, he said, requiring thrice-weekly treatment of each palm or sole for approximately 30 minutes to a controlled electric current at 15-20 mA with tap water.
There are no systemic agents approved for hyperhidrosis, only case reports or small case series. For now, the two commonly used anticholinergics are glycopyrrolate and oxybutynin. Glycopyrrolate comes in 1- and 2-mg capsules. “You can break the tablets easily and it’s pretty cheap, with an estimated cost of 2 mg/day at $756 per year,” Dr. Friedman said. “I typically start patients on 1 mg twice per day for a week, then ask how they’re doing. If they notice improvement, have minimal side effects but think they can do better, then I increase it by 1 mg and reassess. I give them autonomy, and at most, want them to max out at 6 mg per day. There is an oral solution for kids, which can make this a little more accessible.”
He prescribes oxybutynin infrequently but considers it effective. “Most patients respond to 5- to 10-mg/day dosing, but doses up to 15 or 20 mg daily may be required,” he noted.
For persistent flushing with hyperhidrosis, Dr. Friedman typically recommends treatment with clonidine. “I start patients pretty low, sometimes 0.05 mg twice per day.”
For patients who sweat because of social phobias and performance anxiety, he typically recommends treatment with a beta-adrenergic blocker. “These are highly lipophilic, so I advise patients not to take them with food,” he said. “The peak concentration is 1-1.5 hours. Usually, I start at 10 mg and I have people do a test run at home. I also take a baseline blood pressure in the office to make sure they’re not hypotensive.” The use of beta-adrenergic blockers is contraindicated in patients with bradycardia, atrioventricular block, and asthma. They can also exacerbate psoriasis.
On Sept. 20, 2020, Brickell Biotech announced the approval of sofpironium bromide gel, 5%, in Japan for the treatment of primary axillary hyperhidrosis. Sofpironium bromide is an analog of glycopyrrolate “that gets metabolized very quickly in order to limit systemic absorption of the active agent and therefore mitigate side effects,” Dr. Friedman said.
A recently published Japanese study found that 54% of patients with primary axillary hyperhidrosis who received sofpironium bromide experienced a 1- or 2-point improvement on the Hyperhidrosis Disease Severity Scale and a 50% or greater reduction in gravimetric sweat production from baseline to week 6 of treatment, compared with 36% of patients in the control group (P = .003). According to Dr. Friedman, a 15% formulation of this product is being studied in the United States, “but the experience in Japan with the 5% formulation should give us some real-world information about this product,” he said. “Out of the gate, we’re going to know something about how it’s being used.”
Dr. Friedman reported that he serves as a consultant and/or advisor to numerous pharmaceutical companies, including some that produce cannabinoids. He is also a speaker for Regeneron, Abbvie, Novartis, LRP, Dermira, and Brickel Biotech, and has received grants from Pfizer, the Dermatology Foundation, Almirall, and Janssen.
FROM ODAC 2021
Meta-analysis finds much less lupus than expected
The prevalence of systemic lupus erythematosus (SLE) appears to be much lower than previously believed and may pose “a potential risk to research funding for the disease,” according to results of a meta-analysis involving a network of population-based registries.
“When we started this study, a widely cited lupus statistic was that approximately 1.5 million Americans were affected. Our meta-analysis found the actual prevalence to be slightly more than 200,000: a number that approaches the [Food and Drug Administration’s] definition of a rare disease,” Emily Somers, PhD, ScM, senior author and associate professor of rheumatology and environmental health sciences at the University of Michigan, Ann Arbor, said in a written statement.
Their estimates, published online in Arthritis & Rheumatology, put the overall SLE prevalence in the United States at 72.8 per 100,000 person-years in 2018, with nearly nine times more females affected (128.7 cases per 100,000) than males (14.6 per 100,000). Race and ethnicity also play a role, as prevalence was highest among American Indian/Alaska Native and Black females, with Hispanic females lower but still higher than White and Asian/Pacific Islander females, Peter M. Izmirly, MD, MSc, of New York University, the lead author, and associates said.
SLE prevalence was distributed similarly in men, although there was a greater relative margin between American Indians/Alaska Natives (53.8 cases per 100,000 person-years) and Blacks (26.7 per 100,000), and Asians/Pacific Islanders were higher than Whites (11.2 vs. 8.9), the investigators reported.
The meta-analysis leveraged data from the Centers for Disease Control and Prevention’s national lupus registries, which include four state-specific SLE registries and a fifth in the Indian Health Service. All cases of SLE occurred in 2002-2009, and the data were age adjusted to the 2000 U.S. population and separately extrapolated to the 2018 U.S. Census population, they explained.
The analysis was funded by cooperative agreements between the New York City Department of Health and Mental Hygiene and New York University, and the CDC and National Institute of Health.
The prevalence of systemic lupus erythematosus (SLE) appears to be much lower than previously believed and may pose “a potential risk to research funding for the disease,” according to results of a meta-analysis involving a network of population-based registries.
“When we started this study, a widely cited lupus statistic was that approximately 1.5 million Americans were affected. Our meta-analysis found the actual prevalence to be slightly more than 200,000: a number that approaches the [Food and Drug Administration’s] definition of a rare disease,” Emily Somers, PhD, ScM, senior author and associate professor of rheumatology and environmental health sciences at the University of Michigan, Ann Arbor, said in a written statement.
Their estimates, published online in Arthritis & Rheumatology, put the overall SLE prevalence in the United States at 72.8 per 100,000 person-years in 2018, with nearly nine times more females affected (128.7 cases per 100,000) than males (14.6 per 100,000). Race and ethnicity also play a role, as prevalence was highest among American Indian/Alaska Native and Black females, with Hispanic females lower but still higher than White and Asian/Pacific Islander females, Peter M. Izmirly, MD, MSc, of New York University, the lead author, and associates said.
SLE prevalence was distributed similarly in men, although there was a greater relative margin between American Indians/Alaska Natives (53.8 cases per 100,000 person-years) and Blacks (26.7 per 100,000), and Asians/Pacific Islanders were higher than Whites (11.2 vs. 8.9), the investigators reported.
The meta-analysis leveraged data from the Centers for Disease Control and Prevention’s national lupus registries, which include four state-specific SLE registries and a fifth in the Indian Health Service. All cases of SLE occurred in 2002-2009, and the data were age adjusted to the 2000 U.S. population and separately extrapolated to the 2018 U.S. Census population, they explained.
The analysis was funded by cooperative agreements between the New York City Department of Health and Mental Hygiene and New York University, and the CDC and National Institute of Health.
The prevalence of systemic lupus erythematosus (SLE) appears to be much lower than previously believed and may pose “a potential risk to research funding for the disease,” according to results of a meta-analysis involving a network of population-based registries.
“When we started this study, a widely cited lupus statistic was that approximately 1.5 million Americans were affected. Our meta-analysis found the actual prevalence to be slightly more than 200,000: a number that approaches the [Food and Drug Administration’s] definition of a rare disease,” Emily Somers, PhD, ScM, senior author and associate professor of rheumatology and environmental health sciences at the University of Michigan, Ann Arbor, said in a written statement.
Their estimates, published online in Arthritis & Rheumatology, put the overall SLE prevalence in the United States at 72.8 per 100,000 person-years in 2018, with nearly nine times more females affected (128.7 cases per 100,000) than males (14.6 per 100,000). Race and ethnicity also play a role, as prevalence was highest among American Indian/Alaska Native and Black females, with Hispanic females lower but still higher than White and Asian/Pacific Islander females, Peter M. Izmirly, MD, MSc, of New York University, the lead author, and associates said.
SLE prevalence was distributed similarly in men, although there was a greater relative margin between American Indians/Alaska Natives (53.8 cases per 100,000 person-years) and Blacks (26.7 per 100,000), and Asians/Pacific Islanders were higher than Whites (11.2 vs. 8.9), the investigators reported.
The meta-analysis leveraged data from the Centers for Disease Control and Prevention’s national lupus registries, which include four state-specific SLE registries and a fifth in the Indian Health Service. All cases of SLE occurred in 2002-2009, and the data were age adjusted to the 2000 U.S. population and separately extrapolated to the 2018 U.S. Census population, they explained.
The analysis was funded by cooperative agreements between the New York City Department of Health and Mental Hygiene and New York University, and the CDC and National Institute of Health.
FROM ARTHRITIS & RHEUMATOLOGY
Expert highlights advances in DRESS
Mounting evidence suggests , Sarah Walsh, MD, said at the virtual annual congress of the European Academy of Dermatology and Venereology.
The standard dictum has been that diagnosis of this severe T-cell-mediated drug reaction requires more than a 2-week delay in symptom onset following initial drug intake. But this can steer physicians in the wrong direction and lead to stopping an innocent drug while the true culprit medication remains on board. This adversely affects patient prognosis, since a longer duration of drug exposure after symptom onset is associated with increased hospital length of stay and greater mortality risk, explained Dr. Walsh, clinical lead for dermatology at King’s College Hospital, London.
In addition to . These include clues provided by rash morphology and histopathology, HLA testing, and a novel scoring system to assess DRESS severity and the risk of potentially fatal cytomegalovirus reactivation.
Short-delay DRESS onset
In a retrospective study of 41 patients with a first episode of DRESS in three French dermatology departments, 14 (34%) had onset within 15 days or less of initial exposure to the causative drug. In 6 of 14 patients in the rapid-onset group the offending drug was an antibiotic, while in another 5 the culprit was iodinated contrast media. In the delayed-onset DRESS group, the chief sensitizers were allopurinol in 8 patients, lamotrigine in 6, carbamazepine in 4, and sulfasalazine in 2; of note, none of these 4 delayed-onset DRESS drugs were implicated in any cases of rapid-onset DRESS. There were no differences in the clinical manifestations of DRESS between the rapid- and delayed-onset groups.
Similarly, dermatologists at Government Medical College in Kerala, India, reported in a retrospective study of 100 consecutive patients with DRESS, the drug reaction emerged within 2 weeks after starting the culprit medication in 36% of cases. Indeed, 11 patients became symptomatic within 3-7 days after beginning the medication; in 10 of the 11 cases, the offending agent was an antibiotic, and in 1 patient it was terbinafine. In the 25 cases of DRESS that arose on day 8-14 of drug therapy, the culprit was phenytoin in 14, antibiotics in 6, and 1 each for clopidogrel, hydroxychloroquine, sodium valproate, lamotrigine, and vitamin D3.
Both groups of investigators concluded that a short time lag between starting a drug and development of symptoms of a drug reaction shouldn’t rule out DRESS as a possibility provided other criteria consistent with the diagnosis are present. Hallmarks of DRESS include an acute extensive rash, fever greater than 38 degrees C, enlarged lymph nodes at two or more sites, internal organ involvement, a low platelet count, elevated eosinophils, and abnormal lymphocyte levels.
Rash morphology and histology as prognostic indicators
Dr. Walsh was the lead investigator in a study that identified four distinct patterns of skin involvement in patients with DRESS. The most common type of rash in this single-center retrospective study of 27 consecutive patients was an urticated papular exanthem, present in 13 of the 27 patients. An erythema multiforme-like reaction was present in 8, exfoliative erythroderma in 3, and a morbilliform erythema in 3 others. The worst prognosis was in the subgroup with an erythema multiforme-like rash.
All 27 patients had hepatic involvement, which was severe in 9 cases. Six of the 9 with severe liver impairment had an erythema multiforme-like rash, compared with just 2 of the 18 with mild or moderate liver involvement; thus, an erythema multiforme-like skin eruption was associated with a fivefold increased likelihood of severe hepatic involvement.
“It is a clinical sign that we take seriously at presentation if atypical target lesions are present,” the dermatologist said.
Separately, Taiwanese investigators compared clinical and histopathologic features in a study of 32 patients with DRESS and 17 with maculopapular exanthem. Interface vacuolization, which was present in 29 of the 32 patients with DRESS, was far more prominent than in the comparator group. Moreover, severe dyskeratosis was significantly associated with more severe liver impairment in the DRESS group.
HLA testing
Testing for HLA haplotypes associated with severe drug reactions has a useful role as a screening tool prior to prescribing selected high-risk drugs, Dr. Walsh said. For example, it’s known that 6.8% of individuals of European ancestry carry HLA-A*32:01, an allele that was strongly associated with an increased rate of vancomycin-associated DRESS in a case-control study at Vanderbilt University, Nashville, Tenn. Indeed, 19 of 23 individuals with vancomycin-associated DRESS were HLA-A*32:01 positive, compared with none of 46 vancomycin-tolerant controls. Nineteen percent of HLA-A*32:01-positive patients developed DRESS during treatment with vancomycin, and the drug reaction occurred within 4 weeks.
The investigators noted that testing for HLA-A*32:01 is also useful in DRESS occurring in patients on vancomycin and multiple other drugs because the test’s high negative predictive value may safely allow continued therapy with this potent antibiotic for Gram-positive infections.
A DRESS prognostic scoring system
Japanese researchers have developed a scoring system for DRESS for use in monitoring severity of the drug reaction, predicting prognosis, and estimating the risk of developing cytomegalovirus disease and its potentially fatal complications. The scoring system incorporates patient factors, including age, duration of drug exposure after symptom onset; rash characteristics, such as percentage of body surface area involved and presence or absence of erythroderma; appetite loss; and laboratory values.
“It yields a prognostic score that can be used to determine treatment choices, such as immediate intervention with anti-CMV agents. It’s a very useful tool,” Dr. Walsh said.
She reported having no financial conflicts regarding her presentation.
Mounting evidence suggests , Sarah Walsh, MD, said at the virtual annual congress of the European Academy of Dermatology and Venereology.
The standard dictum has been that diagnosis of this severe T-cell-mediated drug reaction requires more than a 2-week delay in symptom onset following initial drug intake. But this can steer physicians in the wrong direction and lead to stopping an innocent drug while the true culprit medication remains on board. This adversely affects patient prognosis, since a longer duration of drug exposure after symptom onset is associated with increased hospital length of stay and greater mortality risk, explained Dr. Walsh, clinical lead for dermatology at King’s College Hospital, London.
In addition to . These include clues provided by rash morphology and histopathology, HLA testing, and a novel scoring system to assess DRESS severity and the risk of potentially fatal cytomegalovirus reactivation.
Short-delay DRESS onset
In a retrospective study of 41 patients with a first episode of DRESS in three French dermatology departments, 14 (34%) had onset within 15 days or less of initial exposure to the causative drug. In 6 of 14 patients in the rapid-onset group the offending drug was an antibiotic, while in another 5 the culprit was iodinated contrast media. In the delayed-onset DRESS group, the chief sensitizers were allopurinol in 8 patients, lamotrigine in 6, carbamazepine in 4, and sulfasalazine in 2; of note, none of these 4 delayed-onset DRESS drugs were implicated in any cases of rapid-onset DRESS. There were no differences in the clinical manifestations of DRESS between the rapid- and delayed-onset groups.
Similarly, dermatologists at Government Medical College in Kerala, India, reported in a retrospective study of 100 consecutive patients with DRESS, the drug reaction emerged within 2 weeks after starting the culprit medication in 36% of cases. Indeed, 11 patients became symptomatic within 3-7 days after beginning the medication; in 10 of the 11 cases, the offending agent was an antibiotic, and in 1 patient it was terbinafine. In the 25 cases of DRESS that arose on day 8-14 of drug therapy, the culprit was phenytoin in 14, antibiotics in 6, and 1 each for clopidogrel, hydroxychloroquine, sodium valproate, lamotrigine, and vitamin D3.
Both groups of investigators concluded that a short time lag between starting a drug and development of symptoms of a drug reaction shouldn’t rule out DRESS as a possibility provided other criteria consistent with the diagnosis are present. Hallmarks of DRESS include an acute extensive rash, fever greater than 38 degrees C, enlarged lymph nodes at two or more sites, internal organ involvement, a low platelet count, elevated eosinophils, and abnormal lymphocyte levels.
Rash morphology and histology as prognostic indicators
Dr. Walsh was the lead investigator in a study that identified four distinct patterns of skin involvement in patients with DRESS. The most common type of rash in this single-center retrospective study of 27 consecutive patients was an urticated papular exanthem, present in 13 of the 27 patients. An erythema multiforme-like reaction was present in 8, exfoliative erythroderma in 3, and a morbilliform erythema in 3 others. The worst prognosis was in the subgroup with an erythema multiforme-like rash.
All 27 patients had hepatic involvement, which was severe in 9 cases. Six of the 9 with severe liver impairment had an erythema multiforme-like rash, compared with just 2 of the 18 with mild or moderate liver involvement; thus, an erythema multiforme-like skin eruption was associated with a fivefold increased likelihood of severe hepatic involvement.
“It is a clinical sign that we take seriously at presentation if atypical target lesions are present,” the dermatologist said.
Separately, Taiwanese investigators compared clinical and histopathologic features in a study of 32 patients with DRESS and 17 with maculopapular exanthem. Interface vacuolization, which was present in 29 of the 32 patients with DRESS, was far more prominent than in the comparator group. Moreover, severe dyskeratosis was significantly associated with more severe liver impairment in the DRESS group.
HLA testing
Testing for HLA haplotypes associated with severe drug reactions has a useful role as a screening tool prior to prescribing selected high-risk drugs, Dr. Walsh said. For example, it’s known that 6.8% of individuals of European ancestry carry HLA-A*32:01, an allele that was strongly associated with an increased rate of vancomycin-associated DRESS in a case-control study at Vanderbilt University, Nashville, Tenn. Indeed, 19 of 23 individuals with vancomycin-associated DRESS were HLA-A*32:01 positive, compared with none of 46 vancomycin-tolerant controls. Nineteen percent of HLA-A*32:01-positive patients developed DRESS during treatment with vancomycin, and the drug reaction occurred within 4 weeks.
The investigators noted that testing for HLA-A*32:01 is also useful in DRESS occurring in patients on vancomycin and multiple other drugs because the test’s high negative predictive value may safely allow continued therapy with this potent antibiotic for Gram-positive infections.
A DRESS prognostic scoring system
Japanese researchers have developed a scoring system for DRESS for use in monitoring severity of the drug reaction, predicting prognosis, and estimating the risk of developing cytomegalovirus disease and its potentially fatal complications. The scoring system incorporates patient factors, including age, duration of drug exposure after symptom onset; rash characteristics, such as percentage of body surface area involved and presence or absence of erythroderma; appetite loss; and laboratory values.
“It yields a prognostic score that can be used to determine treatment choices, such as immediate intervention with anti-CMV agents. It’s a very useful tool,” Dr. Walsh said.
She reported having no financial conflicts regarding her presentation.
Mounting evidence suggests , Sarah Walsh, MD, said at the virtual annual congress of the European Academy of Dermatology and Venereology.
The standard dictum has been that diagnosis of this severe T-cell-mediated drug reaction requires more than a 2-week delay in symptom onset following initial drug intake. But this can steer physicians in the wrong direction and lead to stopping an innocent drug while the true culprit medication remains on board. This adversely affects patient prognosis, since a longer duration of drug exposure after symptom onset is associated with increased hospital length of stay and greater mortality risk, explained Dr. Walsh, clinical lead for dermatology at King’s College Hospital, London.
In addition to . These include clues provided by rash morphology and histopathology, HLA testing, and a novel scoring system to assess DRESS severity and the risk of potentially fatal cytomegalovirus reactivation.
Short-delay DRESS onset
In a retrospective study of 41 patients with a first episode of DRESS in three French dermatology departments, 14 (34%) had onset within 15 days or less of initial exposure to the causative drug. In 6 of 14 patients in the rapid-onset group the offending drug was an antibiotic, while in another 5 the culprit was iodinated contrast media. In the delayed-onset DRESS group, the chief sensitizers were allopurinol in 8 patients, lamotrigine in 6, carbamazepine in 4, and sulfasalazine in 2; of note, none of these 4 delayed-onset DRESS drugs were implicated in any cases of rapid-onset DRESS. There were no differences in the clinical manifestations of DRESS between the rapid- and delayed-onset groups.
Similarly, dermatologists at Government Medical College in Kerala, India, reported in a retrospective study of 100 consecutive patients with DRESS, the drug reaction emerged within 2 weeks after starting the culprit medication in 36% of cases. Indeed, 11 patients became symptomatic within 3-7 days after beginning the medication; in 10 of the 11 cases, the offending agent was an antibiotic, and in 1 patient it was terbinafine. In the 25 cases of DRESS that arose on day 8-14 of drug therapy, the culprit was phenytoin in 14, antibiotics in 6, and 1 each for clopidogrel, hydroxychloroquine, sodium valproate, lamotrigine, and vitamin D3.
Both groups of investigators concluded that a short time lag between starting a drug and development of symptoms of a drug reaction shouldn’t rule out DRESS as a possibility provided other criteria consistent with the diagnosis are present. Hallmarks of DRESS include an acute extensive rash, fever greater than 38 degrees C, enlarged lymph nodes at two or more sites, internal organ involvement, a low platelet count, elevated eosinophils, and abnormal lymphocyte levels.
Rash morphology and histology as prognostic indicators
Dr. Walsh was the lead investigator in a study that identified four distinct patterns of skin involvement in patients with DRESS. The most common type of rash in this single-center retrospective study of 27 consecutive patients was an urticated papular exanthem, present in 13 of the 27 patients. An erythema multiforme-like reaction was present in 8, exfoliative erythroderma in 3, and a morbilliform erythema in 3 others. The worst prognosis was in the subgroup with an erythema multiforme-like rash.
All 27 patients had hepatic involvement, which was severe in 9 cases. Six of the 9 with severe liver impairment had an erythema multiforme-like rash, compared with just 2 of the 18 with mild or moderate liver involvement; thus, an erythema multiforme-like skin eruption was associated with a fivefold increased likelihood of severe hepatic involvement.
“It is a clinical sign that we take seriously at presentation if atypical target lesions are present,” the dermatologist said.
Separately, Taiwanese investigators compared clinical and histopathologic features in a study of 32 patients with DRESS and 17 with maculopapular exanthem. Interface vacuolization, which was present in 29 of the 32 patients with DRESS, was far more prominent than in the comparator group. Moreover, severe dyskeratosis was significantly associated with more severe liver impairment in the DRESS group.
HLA testing
Testing for HLA haplotypes associated with severe drug reactions has a useful role as a screening tool prior to prescribing selected high-risk drugs, Dr. Walsh said. For example, it’s known that 6.8% of individuals of European ancestry carry HLA-A*32:01, an allele that was strongly associated with an increased rate of vancomycin-associated DRESS in a case-control study at Vanderbilt University, Nashville, Tenn. Indeed, 19 of 23 individuals with vancomycin-associated DRESS were HLA-A*32:01 positive, compared with none of 46 vancomycin-tolerant controls. Nineteen percent of HLA-A*32:01-positive patients developed DRESS during treatment with vancomycin, and the drug reaction occurred within 4 weeks.
The investigators noted that testing for HLA-A*32:01 is also useful in DRESS occurring in patients on vancomycin and multiple other drugs because the test’s high negative predictive value may safely allow continued therapy with this potent antibiotic for Gram-positive infections.
A DRESS prognostic scoring system
Japanese researchers have developed a scoring system for DRESS for use in monitoring severity of the drug reaction, predicting prognosis, and estimating the risk of developing cytomegalovirus disease and its potentially fatal complications. The scoring system incorporates patient factors, including age, duration of drug exposure after symptom onset; rash characteristics, such as percentage of body surface area involved and presence or absence of erythroderma; appetite loss; and laboratory values.
“It yields a prognostic score that can be used to determine treatment choices, such as immediate intervention with anti-CMV agents. It’s a very useful tool,” Dr. Walsh said.
She reported having no financial conflicts regarding her presentation.
FROM THE EADV CONGRESS
Oral JAK1 inhibitor shows promise for hidradenitis suppurativa
A (HS) in a pair of small, randomized, phase 2 studies that established proof-of-concept for the novel agent, Afsaneh Alavi, MD, reported at the virtual annual congress of the European Academy of Dermatology and Venereology.
These favorable clinical findings were buttressed by a proteomic analysis demonstrating dose-dependent reductions in circulating inflammatory mediators, added Dr. Alavi, a dermatologist at the Mayo Clinic in Rochester, Minn.
The investigational oral small molecule, known for now as INCB54707, is 52 times more selective for JAK1 than JAK2.
Both multicenter studies entailed 8 weeks of active treatment with INCB54707 followed by a 4-week safety observation. In one study, 10 patients received 15 mg of the investigational agent once daily in open-label fashion. The other trial randomized 35 patients to the JAK1 inhibitor at 30 mg, 60 mg, or 90 mg per day or placebo. About 70% of participants in the studies had Hurley stage II HS; the rest were stage III.
Safety and tolerability were the primary outcomes in the two studies. One patient in the open-label study dropped out because of a flare of fibromyalgia. In the larger randomized trial, four patients – all in the group assigned to 90 mg/day of the JAK1 inhibitor – developed thrombocytopenia, resulting in temporary discontinuation of treatment for up to 2 weeks. In all four instances, the laboratory abnormality was reversed after temporary interruption of treatment, with no sequelae upon restarting the drug. There were no serious treatment-emergent adverse events in either study.
In the low-dose, open-label study, four of nine completers (44%) experienced a Hidradenitis Suppurativa Clinical Response (HiSCR) at week 8, defined as at least a 50% reduction in inflammatory lesion count with no increase in abscesses or draining fistulae compared to baseline. In the randomized trial, the week-8 HiSCR rate was 57% in placebo-treated controls, 56% in those on 30 mg/day or 60 mg/day of the JAK1 inhibitor, and significantly better at 88% in the group on 90 mg/day.
The rapidity of response to the JAK1 inhibitor was noteworthy. After just 1 week of treatment, an abscess and inflammatory nodule count of zero to two lesions was present in 22% of patients on INCB54707 at 60 mg/day and 29% of those on 90 mg/day, compared with none of the patients on 30 mg/day or placebo. At week 2, an abscess and nodule count of 0-2 was documented in 33% of participants on the JAK1 inhibitor at 30 mg/day, 58% at 60 mg/day, and 50% with 90 mg/day. At week 8, the rates were 57% with placebo, 44% with active treatment at 30 or 60 mg/day, and 63% in patients on 90 mg/day.
A dose-dependent significant improvement in Hidradenitis Suppurativa Quality of Life scores was documented in response to the JAK1 inhibitor.
There is an unmet need for effective therapies for HS, a chronic, extremely painful inflammatory condition with a large negative impact on quality of life. At present, the only Food and Drug Administration–approved medication for HS is the tumor necrosis factor inhibitor, adalimumab (Humira), noted Dr. Alavi. Ongoing studies are evaluating other JAK inhibitors, as well as TNF inhibitors and interleukin-17 and -23 blockers.
She reported receiving research funding from and serving as a consultant to Incyte, the studies’ sponsor, and more than a dozen other pharmaceutical companies.
A (HS) in a pair of small, randomized, phase 2 studies that established proof-of-concept for the novel agent, Afsaneh Alavi, MD, reported at the virtual annual congress of the European Academy of Dermatology and Venereology.
These favorable clinical findings were buttressed by a proteomic analysis demonstrating dose-dependent reductions in circulating inflammatory mediators, added Dr. Alavi, a dermatologist at the Mayo Clinic in Rochester, Minn.
The investigational oral small molecule, known for now as INCB54707, is 52 times more selective for JAK1 than JAK2.
Both multicenter studies entailed 8 weeks of active treatment with INCB54707 followed by a 4-week safety observation. In one study, 10 patients received 15 mg of the investigational agent once daily in open-label fashion. The other trial randomized 35 patients to the JAK1 inhibitor at 30 mg, 60 mg, or 90 mg per day or placebo. About 70% of participants in the studies had Hurley stage II HS; the rest were stage III.
Safety and tolerability were the primary outcomes in the two studies. One patient in the open-label study dropped out because of a flare of fibromyalgia. In the larger randomized trial, four patients – all in the group assigned to 90 mg/day of the JAK1 inhibitor – developed thrombocytopenia, resulting in temporary discontinuation of treatment for up to 2 weeks. In all four instances, the laboratory abnormality was reversed after temporary interruption of treatment, with no sequelae upon restarting the drug. There were no serious treatment-emergent adverse events in either study.
In the low-dose, open-label study, four of nine completers (44%) experienced a Hidradenitis Suppurativa Clinical Response (HiSCR) at week 8, defined as at least a 50% reduction in inflammatory lesion count with no increase in abscesses or draining fistulae compared to baseline. In the randomized trial, the week-8 HiSCR rate was 57% in placebo-treated controls, 56% in those on 30 mg/day or 60 mg/day of the JAK1 inhibitor, and significantly better at 88% in the group on 90 mg/day.
The rapidity of response to the JAK1 inhibitor was noteworthy. After just 1 week of treatment, an abscess and inflammatory nodule count of zero to two lesions was present in 22% of patients on INCB54707 at 60 mg/day and 29% of those on 90 mg/day, compared with none of the patients on 30 mg/day or placebo. At week 2, an abscess and nodule count of 0-2 was documented in 33% of participants on the JAK1 inhibitor at 30 mg/day, 58% at 60 mg/day, and 50% with 90 mg/day. At week 8, the rates were 57% with placebo, 44% with active treatment at 30 or 60 mg/day, and 63% in patients on 90 mg/day.
A dose-dependent significant improvement in Hidradenitis Suppurativa Quality of Life scores was documented in response to the JAK1 inhibitor.
There is an unmet need for effective therapies for HS, a chronic, extremely painful inflammatory condition with a large negative impact on quality of life. At present, the only Food and Drug Administration–approved medication for HS is the tumor necrosis factor inhibitor, adalimumab (Humira), noted Dr. Alavi. Ongoing studies are evaluating other JAK inhibitors, as well as TNF inhibitors and interleukin-17 and -23 blockers.
She reported receiving research funding from and serving as a consultant to Incyte, the studies’ sponsor, and more than a dozen other pharmaceutical companies.
A (HS) in a pair of small, randomized, phase 2 studies that established proof-of-concept for the novel agent, Afsaneh Alavi, MD, reported at the virtual annual congress of the European Academy of Dermatology and Venereology.
These favorable clinical findings were buttressed by a proteomic analysis demonstrating dose-dependent reductions in circulating inflammatory mediators, added Dr. Alavi, a dermatologist at the Mayo Clinic in Rochester, Minn.
The investigational oral small molecule, known for now as INCB54707, is 52 times more selective for JAK1 than JAK2.
Both multicenter studies entailed 8 weeks of active treatment with INCB54707 followed by a 4-week safety observation. In one study, 10 patients received 15 mg of the investigational agent once daily in open-label fashion. The other trial randomized 35 patients to the JAK1 inhibitor at 30 mg, 60 mg, or 90 mg per day or placebo. About 70% of participants in the studies had Hurley stage II HS; the rest were stage III.
Safety and tolerability were the primary outcomes in the two studies. One patient in the open-label study dropped out because of a flare of fibromyalgia. In the larger randomized trial, four patients – all in the group assigned to 90 mg/day of the JAK1 inhibitor – developed thrombocytopenia, resulting in temporary discontinuation of treatment for up to 2 weeks. In all four instances, the laboratory abnormality was reversed after temporary interruption of treatment, with no sequelae upon restarting the drug. There were no serious treatment-emergent adverse events in either study.
In the low-dose, open-label study, four of nine completers (44%) experienced a Hidradenitis Suppurativa Clinical Response (HiSCR) at week 8, defined as at least a 50% reduction in inflammatory lesion count with no increase in abscesses or draining fistulae compared to baseline. In the randomized trial, the week-8 HiSCR rate was 57% in placebo-treated controls, 56% in those on 30 mg/day or 60 mg/day of the JAK1 inhibitor, and significantly better at 88% in the group on 90 mg/day.
The rapidity of response to the JAK1 inhibitor was noteworthy. After just 1 week of treatment, an abscess and inflammatory nodule count of zero to two lesions was present in 22% of patients on INCB54707 at 60 mg/day and 29% of those on 90 mg/day, compared with none of the patients on 30 mg/day or placebo. At week 2, an abscess and nodule count of 0-2 was documented in 33% of participants on the JAK1 inhibitor at 30 mg/day, 58% at 60 mg/day, and 50% with 90 mg/day. At week 8, the rates were 57% with placebo, 44% with active treatment at 30 or 60 mg/day, and 63% in patients on 90 mg/day.
A dose-dependent significant improvement in Hidradenitis Suppurativa Quality of Life scores was documented in response to the JAK1 inhibitor.
There is an unmet need for effective therapies for HS, a chronic, extremely painful inflammatory condition with a large negative impact on quality of life. At present, the only Food and Drug Administration–approved medication for HS is the tumor necrosis factor inhibitor, adalimumab (Humira), noted Dr. Alavi. Ongoing studies are evaluating other JAK inhibitors, as well as TNF inhibitors and interleukin-17 and -23 blockers.
She reported receiving research funding from and serving as a consultant to Incyte, the studies’ sponsor, and more than a dozen other pharmaceutical companies.
FROM THE EADV CONGRESS
Severe renal arteriosclerosis may indicate cardiovascular risk in lupus nephritis
Severe renal arteriosclerosis was associated with a ninefold increased risk of atherosclerotic cardiovascular disease in patients with lupus nephritis, based on data from an observational study of 189 individuals.
Atherosclerotic cardiovascular disease (ASCVD) has traditionally been thought to be a late complication of systemic lupus erythematosus (SLE), but this has been challenged in recent population-based studies of patients with SLE and lupus nephritis (LN) that indicated an early and increased risk of ASCVD at the time of diagnosis. However, it is unclear which early risk factors may predispose patients to ASCVD, Shivani Garg, MD, of the University of Wisconsin, Madison, and colleagues wrote in a study published in Arthritis Care & Research.
In patients with IgA nephropathy and renal transplantation, previous studies have shown that severe renal arteriosclerosis (r-ASCL) based on kidney biopsies at the time of diagnosis predicts ASCVD, but “a few studies including LN biopsies failed to report a similar association between the presence of severe r-ASCL and ASCVD occurrence,” possibly because of underreporting of r-ASCL. Dr. Garg and colleagues also noted the problem of underreporting of r-ASCL in their own previous study of its prevalence in LN patients at the time of diagnosis.
To get a more detailed view of how r-ASCL may be linked to early occurrence of ASCVD in LN patients, Dr. Garg and coauthors identified 189 consecutive patients with incident LN who underwent diagnostic biopsies between 1994 and 2017. The median age of the patients was 25 years, 78% were women, and 73% were white. The researchers developed a composite score for r-ASCL severity based on reported and overread biopsies.
Overall, 31% of the patients had any reported r-ASCL, and 7% had moderate-severe r-ASCL. After incorporating systematically reexamined r-ASCL grades, the prevalence of any and moderate-severe r-ASCL increased to 39% and 12%, respectively.
Based on their composite of reported and overread r-ASCL grade, severe r-ASCL in diagnostic LN biopsies was associated with a ninefold increased risk of ASCVD.
The researchers identified 22 incident ASCVD events over an 11-year follow-up for an overall 12% incidence of ASCVD in LN. ASCVD was defined as ischemic heart disease (including myocardial infarction, coronary artery revascularization, abnormal stress test, abnormal angiogram, and events documented by a cardiologist); stroke and transient ischemic attack (TIA); and peripheral vascular disease. Incident ASCVD was defined as the first ASCVD event between 1 and 10 years after LN diagnosis.
The most common ASCVD events were stroke or TIA (12 patients), events related to ischemic heart disease (7 patients), and events related to peripheral vascular disease (3 patients).
Lack of statin use
The researchers also hypothesized that the presence of gaps in statin use among eligible LN patients would be present in their study population. “Among the 20 patients with incident ASCVD events after LN diagnosis in our cohort, none was on statin therapy at the time of LN diagnosis,” the researchers said, noting that current guidelines from the American College of Rheumatology and the European League Against Rheumatism (now known as the European Alliance of Associations for Rheumatology) recommend initiating statin therapy at the time of LN diagnosis in all patients who have hyperlipidemia and chronic kidney disease (CKD) stage ≥3. “Further, 11 patients (55%) met high-risk criteria (hyperlipidemia and CKD stage ≥3) to implement statin therapy at the time of LN diagnosis, yet only one patient (9%) was initiated on statin therapy.” In addition, patients with stage 3 or higher CKD were more likely to develop ASCVD than patients without stage 3 or higher CKD, they said.
The study findings were limited by several factors including the majority white study population, the ability to overread only 25% of the biopsies, and the lack of data on the potential role of chronic lesions in ASCVD, the researchers noted. However, the results were strengthened by the use of a validated LN cohort, and the data provide “the basis to establish severe composite r-ASCL as a predictor of ASCVD events using a larger sample size in different cohorts,” they said.
The study received no outside funding. The researchers had no financial conflicts to disclose.
Severe renal arteriosclerosis was associated with a ninefold increased risk of atherosclerotic cardiovascular disease in patients with lupus nephritis, based on data from an observational study of 189 individuals.
Atherosclerotic cardiovascular disease (ASCVD) has traditionally been thought to be a late complication of systemic lupus erythematosus (SLE), but this has been challenged in recent population-based studies of patients with SLE and lupus nephritis (LN) that indicated an early and increased risk of ASCVD at the time of diagnosis. However, it is unclear which early risk factors may predispose patients to ASCVD, Shivani Garg, MD, of the University of Wisconsin, Madison, and colleagues wrote in a study published in Arthritis Care & Research.
In patients with IgA nephropathy and renal transplantation, previous studies have shown that severe renal arteriosclerosis (r-ASCL) based on kidney biopsies at the time of diagnosis predicts ASCVD, but “a few studies including LN biopsies failed to report a similar association between the presence of severe r-ASCL and ASCVD occurrence,” possibly because of underreporting of r-ASCL. Dr. Garg and colleagues also noted the problem of underreporting of r-ASCL in their own previous study of its prevalence in LN patients at the time of diagnosis.
To get a more detailed view of how r-ASCL may be linked to early occurrence of ASCVD in LN patients, Dr. Garg and coauthors identified 189 consecutive patients with incident LN who underwent diagnostic biopsies between 1994 and 2017. The median age of the patients was 25 years, 78% were women, and 73% were white. The researchers developed a composite score for r-ASCL severity based on reported and overread biopsies.
Overall, 31% of the patients had any reported r-ASCL, and 7% had moderate-severe r-ASCL. After incorporating systematically reexamined r-ASCL grades, the prevalence of any and moderate-severe r-ASCL increased to 39% and 12%, respectively.
Based on their composite of reported and overread r-ASCL grade, severe r-ASCL in diagnostic LN biopsies was associated with a ninefold increased risk of ASCVD.
The researchers identified 22 incident ASCVD events over an 11-year follow-up for an overall 12% incidence of ASCVD in LN. ASCVD was defined as ischemic heart disease (including myocardial infarction, coronary artery revascularization, abnormal stress test, abnormal angiogram, and events documented by a cardiologist); stroke and transient ischemic attack (TIA); and peripheral vascular disease. Incident ASCVD was defined as the first ASCVD event between 1 and 10 years after LN diagnosis.
The most common ASCVD events were stroke or TIA (12 patients), events related to ischemic heart disease (7 patients), and events related to peripheral vascular disease (3 patients).
Lack of statin use
The researchers also hypothesized that the presence of gaps in statin use among eligible LN patients would be present in their study population. “Among the 20 patients with incident ASCVD events after LN diagnosis in our cohort, none was on statin therapy at the time of LN diagnosis,” the researchers said, noting that current guidelines from the American College of Rheumatology and the European League Against Rheumatism (now known as the European Alliance of Associations for Rheumatology) recommend initiating statin therapy at the time of LN diagnosis in all patients who have hyperlipidemia and chronic kidney disease (CKD) stage ≥3. “Further, 11 patients (55%) met high-risk criteria (hyperlipidemia and CKD stage ≥3) to implement statin therapy at the time of LN diagnosis, yet only one patient (9%) was initiated on statin therapy.” In addition, patients with stage 3 or higher CKD were more likely to develop ASCVD than patients without stage 3 or higher CKD, they said.
The study findings were limited by several factors including the majority white study population, the ability to overread only 25% of the biopsies, and the lack of data on the potential role of chronic lesions in ASCVD, the researchers noted. However, the results were strengthened by the use of a validated LN cohort, and the data provide “the basis to establish severe composite r-ASCL as a predictor of ASCVD events using a larger sample size in different cohorts,” they said.
The study received no outside funding. The researchers had no financial conflicts to disclose.
Severe renal arteriosclerosis was associated with a ninefold increased risk of atherosclerotic cardiovascular disease in patients with lupus nephritis, based on data from an observational study of 189 individuals.
Atherosclerotic cardiovascular disease (ASCVD) has traditionally been thought to be a late complication of systemic lupus erythematosus (SLE), but this has been challenged in recent population-based studies of patients with SLE and lupus nephritis (LN) that indicated an early and increased risk of ASCVD at the time of diagnosis. However, it is unclear which early risk factors may predispose patients to ASCVD, Shivani Garg, MD, of the University of Wisconsin, Madison, and colleagues wrote in a study published in Arthritis Care & Research.
In patients with IgA nephropathy and renal transplantation, previous studies have shown that severe renal arteriosclerosis (r-ASCL) based on kidney biopsies at the time of diagnosis predicts ASCVD, but “a few studies including LN biopsies failed to report a similar association between the presence of severe r-ASCL and ASCVD occurrence,” possibly because of underreporting of r-ASCL. Dr. Garg and colleagues also noted the problem of underreporting of r-ASCL in their own previous study of its prevalence in LN patients at the time of diagnosis.
To get a more detailed view of how r-ASCL may be linked to early occurrence of ASCVD in LN patients, Dr. Garg and coauthors identified 189 consecutive patients with incident LN who underwent diagnostic biopsies between 1994 and 2017. The median age of the patients was 25 years, 78% were women, and 73% were white. The researchers developed a composite score for r-ASCL severity based on reported and overread biopsies.
Overall, 31% of the patients had any reported r-ASCL, and 7% had moderate-severe r-ASCL. After incorporating systematically reexamined r-ASCL grades, the prevalence of any and moderate-severe r-ASCL increased to 39% and 12%, respectively.
Based on their composite of reported and overread r-ASCL grade, severe r-ASCL in diagnostic LN biopsies was associated with a ninefold increased risk of ASCVD.
The researchers identified 22 incident ASCVD events over an 11-year follow-up for an overall 12% incidence of ASCVD in LN. ASCVD was defined as ischemic heart disease (including myocardial infarction, coronary artery revascularization, abnormal stress test, abnormal angiogram, and events documented by a cardiologist); stroke and transient ischemic attack (TIA); and peripheral vascular disease. Incident ASCVD was defined as the first ASCVD event between 1 and 10 years after LN diagnosis.
The most common ASCVD events were stroke or TIA (12 patients), events related to ischemic heart disease (7 patients), and events related to peripheral vascular disease (3 patients).
Lack of statin use
The researchers also hypothesized that the presence of gaps in statin use among eligible LN patients would be present in their study population. “Among the 20 patients with incident ASCVD events after LN diagnosis in our cohort, none was on statin therapy at the time of LN diagnosis,” the researchers said, noting that current guidelines from the American College of Rheumatology and the European League Against Rheumatism (now known as the European Alliance of Associations for Rheumatology) recommend initiating statin therapy at the time of LN diagnosis in all patients who have hyperlipidemia and chronic kidney disease (CKD) stage ≥3. “Further, 11 patients (55%) met high-risk criteria (hyperlipidemia and CKD stage ≥3) to implement statin therapy at the time of LN diagnosis, yet only one patient (9%) was initiated on statin therapy.” In addition, patients with stage 3 or higher CKD were more likely to develop ASCVD than patients without stage 3 or higher CKD, they said.
The study findings were limited by several factors including the majority white study population, the ability to overread only 25% of the biopsies, and the lack of data on the potential role of chronic lesions in ASCVD, the researchers noted. However, the results were strengthened by the use of a validated LN cohort, and the data provide “the basis to establish severe composite r-ASCL as a predictor of ASCVD events using a larger sample size in different cohorts,” they said.
The study received no outside funding. The researchers had no financial conflicts to disclose.
FROM ARTHRITIS CARE & RESEARCH
Patients dislike prurigo nodularis treatment options, survey finds
.
The eye-opening results of the 406-patient, 12-country European patient survey indicate “high levels of disbelief in currently available treatment options and an overall dissatisfaction with treatment,” Manuel P. Pereira, MD, PhD, said in presenting the findings at the annual congress of the European Academy of Dermatology and Venereology.
Only 5.3% of patients pronounced themselves “very satisfied” with their treatment. Another 28% were “rather satisfied.”
“Remarkably, almost 10% of patients were not being treated for prurigo despite having active disease,” said Dr. Pereira, a dermatologist at the Center for Chronic Pruritus at University Hospital Münster (Germany).
When survey participants were asked to identify their most important unmet treatment needs, 79.5% named improvement of itch, 57.2% sought improvement in skin lesions, and 30.5% wanted better sleep.
The most widely used treatments were emollients, prescribed in 84.5% of patients; topical steroids, in 55.7%; antihistamines, 55.2%; and phototherapy, 42.1%. Far fewer patients were on more potent medications: Cyclosporine, systemic corticosteroids, or other immunosuppressants were prescribed for 21.9% of patients; gabapentin and related compounds in 17%; and topical immunomodulators in 8.6%. Twenty-three percent of patients were on antidepressants.
None of the available treatment options, all of which are off label, received high marks from patients. For example, only 1 in 10 patients on antihistamines during the last 6 months rated the drugs as effective. Topical immunomodulators were deemed effective by 1.1% of patients with active prurigo nodularis; gabapentinoids by 3.1%; phototherapy by 9.9%; and antidepressants were rated as effective for the chronic skin disease by only 2.3% of patients. The top-rated therapies were topical steroids, deemed effective by 12.8% of patients; systemic immunosuppressants, favored by 12.2%; and emollients, deemed effective by 10.5% of patients, even though more than 80% of survey participants were using them.
Dr. Pereira said the survey results highlight a pressing need for guidelines aimed at improving clinical care for patients with chronic prurigo nodularis. The first-ever such guidelines on the diagnosis and management of this debilitating disease, developed by Dr. Pereira and other members of the International Forum for the Study of Itch (IFSI), were recently published in the journal Itch. The new guidelines advocate a multimodal treatment approach incorporating a combination of topical and systemic therapies.
At present, there is no approved treatment for prurigo nodularis. Given the unmet need, however, the pace of research has quickened. Innovative potential treatments in the developmental pipeline include Janus kinase inhibitors, topical phosphodiesterase-4 inhibitors, systemic opioid receptor modulators, and neurokinin-1 receptor antagonists.
The patient survey was funded by the EADV and carried out by the EADV’s Pruritus Task Force as part of the European Prurigo Project. Dr. Pereira reported receiving research funding from the EADV and the German Research Foundation. He is a paid speaker for AbbVie, Galderma, Menlo Therapeutics (now VYNE Therapeutics), Novartis, and Trevi.
.
The eye-opening results of the 406-patient, 12-country European patient survey indicate “high levels of disbelief in currently available treatment options and an overall dissatisfaction with treatment,” Manuel P. Pereira, MD, PhD, said in presenting the findings at the annual congress of the European Academy of Dermatology and Venereology.
Only 5.3% of patients pronounced themselves “very satisfied” with their treatment. Another 28% were “rather satisfied.”
“Remarkably, almost 10% of patients were not being treated for prurigo despite having active disease,” said Dr. Pereira, a dermatologist at the Center for Chronic Pruritus at University Hospital Münster (Germany).
When survey participants were asked to identify their most important unmet treatment needs, 79.5% named improvement of itch, 57.2% sought improvement in skin lesions, and 30.5% wanted better sleep.
The most widely used treatments were emollients, prescribed in 84.5% of patients; topical steroids, in 55.7%; antihistamines, 55.2%; and phototherapy, 42.1%. Far fewer patients were on more potent medications: Cyclosporine, systemic corticosteroids, or other immunosuppressants were prescribed for 21.9% of patients; gabapentin and related compounds in 17%; and topical immunomodulators in 8.6%. Twenty-three percent of patients were on antidepressants.
None of the available treatment options, all of which are off label, received high marks from patients. For example, only 1 in 10 patients on antihistamines during the last 6 months rated the drugs as effective. Topical immunomodulators were deemed effective by 1.1% of patients with active prurigo nodularis; gabapentinoids by 3.1%; phototherapy by 9.9%; and antidepressants were rated as effective for the chronic skin disease by only 2.3% of patients. The top-rated therapies were topical steroids, deemed effective by 12.8% of patients; systemic immunosuppressants, favored by 12.2%; and emollients, deemed effective by 10.5% of patients, even though more than 80% of survey participants were using them.
Dr. Pereira said the survey results highlight a pressing need for guidelines aimed at improving clinical care for patients with chronic prurigo nodularis. The first-ever such guidelines on the diagnosis and management of this debilitating disease, developed by Dr. Pereira and other members of the International Forum for the Study of Itch (IFSI), were recently published in the journal Itch. The new guidelines advocate a multimodal treatment approach incorporating a combination of topical and systemic therapies.
At present, there is no approved treatment for prurigo nodularis. Given the unmet need, however, the pace of research has quickened. Innovative potential treatments in the developmental pipeline include Janus kinase inhibitors, topical phosphodiesterase-4 inhibitors, systemic opioid receptor modulators, and neurokinin-1 receptor antagonists.
The patient survey was funded by the EADV and carried out by the EADV’s Pruritus Task Force as part of the European Prurigo Project. Dr. Pereira reported receiving research funding from the EADV and the German Research Foundation. He is a paid speaker for AbbVie, Galderma, Menlo Therapeutics (now VYNE Therapeutics), Novartis, and Trevi.
.
The eye-opening results of the 406-patient, 12-country European patient survey indicate “high levels of disbelief in currently available treatment options and an overall dissatisfaction with treatment,” Manuel P. Pereira, MD, PhD, said in presenting the findings at the annual congress of the European Academy of Dermatology and Venereology.
Only 5.3% of patients pronounced themselves “very satisfied” with their treatment. Another 28% were “rather satisfied.”
“Remarkably, almost 10% of patients were not being treated for prurigo despite having active disease,” said Dr. Pereira, a dermatologist at the Center for Chronic Pruritus at University Hospital Münster (Germany).
When survey participants were asked to identify their most important unmet treatment needs, 79.5% named improvement of itch, 57.2% sought improvement in skin lesions, and 30.5% wanted better sleep.
The most widely used treatments were emollients, prescribed in 84.5% of patients; topical steroids, in 55.7%; antihistamines, 55.2%; and phototherapy, 42.1%. Far fewer patients were on more potent medications: Cyclosporine, systemic corticosteroids, or other immunosuppressants were prescribed for 21.9% of patients; gabapentin and related compounds in 17%; and topical immunomodulators in 8.6%. Twenty-three percent of patients were on antidepressants.
None of the available treatment options, all of which are off label, received high marks from patients. For example, only 1 in 10 patients on antihistamines during the last 6 months rated the drugs as effective. Topical immunomodulators were deemed effective by 1.1% of patients with active prurigo nodularis; gabapentinoids by 3.1%; phototherapy by 9.9%; and antidepressants were rated as effective for the chronic skin disease by only 2.3% of patients. The top-rated therapies were topical steroids, deemed effective by 12.8% of patients; systemic immunosuppressants, favored by 12.2%; and emollients, deemed effective by 10.5% of patients, even though more than 80% of survey participants were using them.
Dr. Pereira said the survey results highlight a pressing need for guidelines aimed at improving clinical care for patients with chronic prurigo nodularis. The first-ever such guidelines on the diagnosis and management of this debilitating disease, developed by Dr. Pereira and other members of the International Forum for the Study of Itch (IFSI), were recently published in the journal Itch. The new guidelines advocate a multimodal treatment approach incorporating a combination of topical and systemic therapies.
At present, there is no approved treatment for prurigo nodularis. Given the unmet need, however, the pace of research has quickened. Innovative potential treatments in the developmental pipeline include Janus kinase inhibitors, topical phosphodiesterase-4 inhibitors, systemic opioid receptor modulators, and neurokinin-1 receptor antagonists.
The patient survey was funded by the EADV and carried out by the EADV’s Pruritus Task Force as part of the European Prurigo Project. Dr. Pereira reported receiving research funding from the EADV and the German Research Foundation. He is a paid speaker for AbbVie, Galderma, Menlo Therapeutics (now VYNE Therapeutics), Novartis, and Trevi.
FROM THE EADV CONGRESS
A 67-year-old White woman presented with 2 weeks of bullae on her lower feet
Bullous arthropod assault
Insect-bite reactions are commonly seen in dermatology practice. Most often, they present as pruritic papules. Vesicles and bullae can be seen as well but are less common. Flea bites are the most likely to cause blisters.1 Lesions may be grouped or in a linear pattern. Children tend to have more severe reactions than adults. Body temperature and odor may make some people more susceptible than others to bites. Of note, patients with chronic lymphocytic leukemia tend to have more severe, bullous reactions.2 The differential diagnosis includes bullous pemphigoid, bullous impetigo, bullous tinea, bullous fixed drug, and bullous diabeticorum.
In general, bullous arthropod reactions begin as intraepidermal vesicles that can progress to subepidermal blisters. Eosinophils can be present. Flame figures are often seen in patients with chronic lymphocytic leukemia.3 Histopathology in this patient revealed a subepidermal vesicular dermatitis with minimal inflammation. Periodic acid–Schiff (PAS) stain was negative. Direct immunofluorescence was negative for IgG, C3, IgA, IgM, and fibrinogen. Of note, systemic steroids may alter histologic and immunologic findings.
Bullous pemphigoid is an autoimmune blistering disorder where patients develop widespread tense bullae. Histopathology revealed a subepidermal blister with numerous eosinophils. Direct immunofluorescence study of perilesional skin showed linear IgG and C3 deposits at the basal membrane level. Systemic steroids, tetracyclines, and immunosuppressive medications are a mainstay of treatment. In bullous impetigo, the toxin of Staphylococcus aureus causes blister formation. It is treated with antistaphylococcal antibiotics. Bullous tinea reveals hyphae with PAS staining. Topical or systemic antifungals are used for treatment.
In severe cases, systemic steroids can be used as well. Bacterial culture was negative in this patient. The patient was treated with 1 week of oral prednisone prior to biopsy and topical betamethasone ointment. Her lesions subsequently resolved with no recurrence.
This case and photo were submitted by Brooke Resh Sateesh, MD, San Diego Family Dermatology.
Dr. Bilu Martin is a board-certified dermatologist in private practice at Premier Dermatology, MD, in Aventura, Fla. More diagnostic cases are available at mdedge.com/dermatology. To submit a case for possible publication, send an email to [email protected].
References
1-3. “Dermatology” 2nd ed. (Maryland Heights, Mo.: Mosby, 2008).
Bullous arthropod assault
Insect-bite reactions are commonly seen in dermatology practice. Most often, they present as pruritic papules. Vesicles and bullae can be seen as well but are less common. Flea bites are the most likely to cause blisters.1 Lesions may be grouped or in a linear pattern. Children tend to have more severe reactions than adults. Body temperature and odor may make some people more susceptible than others to bites. Of note, patients with chronic lymphocytic leukemia tend to have more severe, bullous reactions.2 The differential diagnosis includes bullous pemphigoid, bullous impetigo, bullous tinea, bullous fixed drug, and bullous diabeticorum.
In general, bullous arthropod reactions begin as intraepidermal vesicles that can progress to subepidermal blisters. Eosinophils can be present. Flame figures are often seen in patients with chronic lymphocytic leukemia.3 Histopathology in this patient revealed a subepidermal vesicular dermatitis with minimal inflammation. Periodic acid–Schiff (PAS) stain was negative. Direct immunofluorescence was negative for IgG, C3, IgA, IgM, and fibrinogen. Of note, systemic steroids may alter histologic and immunologic findings.
Bullous pemphigoid is an autoimmune blistering disorder where patients develop widespread tense bullae. Histopathology revealed a subepidermal blister with numerous eosinophils. Direct immunofluorescence study of perilesional skin showed linear IgG and C3 deposits at the basal membrane level. Systemic steroids, tetracyclines, and immunosuppressive medications are a mainstay of treatment. In bullous impetigo, the toxin of Staphylococcus aureus causes blister formation. It is treated with antistaphylococcal antibiotics. Bullous tinea reveals hyphae with PAS staining. Topical or systemic antifungals are used for treatment.
In severe cases, systemic steroids can be used as well. Bacterial culture was negative in this patient. The patient was treated with 1 week of oral prednisone prior to biopsy and topical betamethasone ointment. Her lesions subsequently resolved with no recurrence.
This case and photo were submitted by Brooke Resh Sateesh, MD, San Diego Family Dermatology.
Dr. Bilu Martin is a board-certified dermatologist in private practice at Premier Dermatology, MD, in Aventura, Fla. More diagnostic cases are available at mdedge.com/dermatology. To submit a case for possible publication, send an email to [email protected].
References
1-3. “Dermatology” 2nd ed. (Maryland Heights, Mo.: Mosby, 2008).
Bullous arthropod assault
Insect-bite reactions are commonly seen in dermatology practice. Most often, they present as pruritic papules. Vesicles and bullae can be seen as well but are less common. Flea bites are the most likely to cause blisters.1 Lesions may be grouped or in a linear pattern. Children tend to have more severe reactions than adults. Body temperature and odor may make some people more susceptible than others to bites. Of note, patients with chronic lymphocytic leukemia tend to have more severe, bullous reactions.2 The differential diagnosis includes bullous pemphigoid, bullous impetigo, bullous tinea, bullous fixed drug, and bullous diabeticorum.
In general, bullous arthropod reactions begin as intraepidermal vesicles that can progress to subepidermal blisters. Eosinophils can be present. Flame figures are often seen in patients with chronic lymphocytic leukemia.3 Histopathology in this patient revealed a subepidermal vesicular dermatitis with minimal inflammation. Periodic acid–Schiff (PAS) stain was negative. Direct immunofluorescence was negative for IgG, C3, IgA, IgM, and fibrinogen. Of note, systemic steroids may alter histologic and immunologic findings.
Bullous pemphigoid is an autoimmune blistering disorder where patients develop widespread tense bullae. Histopathology revealed a subepidermal blister with numerous eosinophils. Direct immunofluorescence study of perilesional skin showed linear IgG and C3 deposits at the basal membrane level. Systemic steroids, tetracyclines, and immunosuppressive medications are a mainstay of treatment. In bullous impetigo, the toxin of Staphylococcus aureus causes blister formation. It is treated with antistaphylococcal antibiotics. Bullous tinea reveals hyphae with PAS staining. Topical or systemic antifungals are used for treatment.
In severe cases, systemic steroids can be used as well. Bacterial culture was negative in this patient. The patient was treated with 1 week of oral prednisone prior to biopsy and topical betamethasone ointment. Her lesions subsequently resolved with no recurrence.
This case and photo were submitted by Brooke Resh Sateesh, MD, San Diego Family Dermatology.
Dr. Bilu Martin is a board-certified dermatologist in private practice at Premier Dermatology, MD, in Aventura, Fla. More diagnostic cases are available at mdedge.com/dermatology. To submit a case for possible publication, send an email to [email protected].
References
1-3. “Dermatology” 2nd ed. (Maryland Heights, Mo.: Mosby, 2008).
High hydroxychloroquine blood level may lower thrombosis risk in lupus
Maintaining an average hydroxychloroquine whole blood level above 1,068 ng/mL significantly reduced the risk of thrombosis in adults with systemic lupus erythematosus, based on data from 739 patients.
Hydroxychloroquine (HCQ) is a common treatment for systemic lupus erythematosus (SLE); studies suggest that it may protect against thrombosis, but the optimal dosing for this purpose remains unknown, wrote Michelle Petri, MD, of Johns Hopkins University, Baltimore, and colleagues. In a study published in Arthritis & Rheumatology, the researchers examined data on HCQ levels from 739 adults with SLE who were part of the Hopkins Lupus Cohort, a longitudinal study of outcomes in SLE patients. Of these, 38 (5.1%) developed thrombosis during 2,330 person-years of follow-up.
Overall, the average HCQ blood level was significantly lower in patients who experienced thrombosis, compared to those who did not (720 ng/mL vs. 935 ng/mL; P = .025). “Prescribed hydroxychloroquine doses did not predict hydroxychloroquine blood levels,” the researchers noted.
In addition, Dr. Petri and associates found a dose-response relationship in which the thrombosis rate declined approximately 13% for every 200-ng/mL increase in the mean HCQ blood level measurement and for the most recent HCQ blood level measurement after controlling for factors that included age, ethnicity, lupus anticoagulant, low C3, and hypertension.
In a multivariate analysis, thrombotic events decreased by 69% in patients with mean HCQ blood levels greater than 1,068 ng/mL, compared to those with average HCQ blood levels less than 648 ng/mL.
The average age of the patients at the time HCQ measurements began was 43 years, 93% were female, and 46% were White. Patients visited a clinic every 3 months, and HCQ levels were determined by liquid chromatography-tandem mass spectrometry.
“Between-person and within-person correlation coefficients were used to measure the strength of the linear association between HCQ blood levels and commonly prescribed HCQ doses from 4.5 to 6.5 mg/kg,” the researchers said.
Higher doses of HCQ have been associated with increased risk for retinopathy, and current guidelines recommend using less than 5 mg/kg of ideal body weight, the researchers said. “Importantly, there was no correlation between the prescribed dose and the hydroxychloroquine blood level over the range (4.5 to 6.5 mg/kg) used in clinical practice, highlighting the need for personalized hydroxychloroquine drug level-guided therapy and dose adjustment,” they emphasized.
The study findings were limited by several factors, including the observational design and potential confounding from variables not included in the model, as well as the small sample size, single site, and single rheumatologist involved in the study, the researchers noted.
The results suggest that aiming for a blood HCQ level of 1,068 ng/mL can be done safely to help prevent thrombosis in patients with SLE, the researchers said. “Routine clinical integration of hydroxychloroquine blood level measurement offers an opportunity for personalized drug dosing and risk management beyond rigid empirical dosing recommendations in patients with SLE,” they concluded.
The study was supported in part by grants from the National Institutes of Health and the National Institute of Arthritis and Musculoskeletal and Skin Diseases. The researchers had no relevant financial conflicts to disclose.
SOURCE: Petri M et al. Arthritis Rheumatol. 2021 Jan 6. doi: 10.1002/ART.41621.
Maintaining an average hydroxychloroquine whole blood level above 1,068 ng/mL significantly reduced the risk of thrombosis in adults with systemic lupus erythematosus, based on data from 739 patients.
Hydroxychloroquine (HCQ) is a common treatment for systemic lupus erythematosus (SLE); studies suggest that it may protect against thrombosis, but the optimal dosing for this purpose remains unknown, wrote Michelle Petri, MD, of Johns Hopkins University, Baltimore, and colleagues. In a study published in Arthritis & Rheumatology, the researchers examined data on HCQ levels from 739 adults with SLE who were part of the Hopkins Lupus Cohort, a longitudinal study of outcomes in SLE patients. Of these, 38 (5.1%) developed thrombosis during 2,330 person-years of follow-up.
Overall, the average HCQ blood level was significantly lower in patients who experienced thrombosis, compared to those who did not (720 ng/mL vs. 935 ng/mL; P = .025). “Prescribed hydroxychloroquine doses did not predict hydroxychloroquine blood levels,” the researchers noted.
In addition, Dr. Petri and associates found a dose-response relationship in which the thrombosis rate declined approximately 13% for every 200-ng/mL increase in the mean HCQ blood level measurement and for the most recent HCQ blood level measurement after controlling for factors that included age, ethnicity, lupus anticoagulant, low C3, and hypertension.
In a multivariate analysis, thrombotic events decreased by 69% in patients with mean HCQ blood levels greater than 1,068 ng/mL, compared to those with average HCQ blood levels less than 648 ng/mL.
The average age of the patients at the time HCQ measurements began was 43 years, 93% were female, and 46% were White. Patients visited a clinic every 3 months, and HCQ levels were determined by liquid chromatography-tandem mass spectrometry.
“Between-person and within-person correlation coefficients were used to measure the strength of the linear association between HCQ blood levels and commonly prescribed HCQ doses from 4.5 to 6.5 mg/kg,” the researchers said.
Higher doses of HCQ have been associated with increased risk for retinopathy, and current guidelines recommend using less than 5 mg/kg of ideal body weight, the researchers said. “Importantly, there was no correlation between the prescribed dose and the hydroxychloroquine blood level over the range (4.5 to 6.5 mg/kg) used in clinical practice, highlighting the need for personalized hydroxychloroquine drug level-guided therapy and dose adjustment,” they emphasized.
The study findings were limited by several factors, including the observational design and potential confounding from variables not included in the model, as well as the small sample size, single site, and single rheumatologist involved in the study, the researchers noted.
The results suggest that aiming for a blood HCQ level of 1,068 ng/mL can be done safely to help prevent thrombosis in patients with SLE, the researchers said. “Routine clinical integration of hydroxychloroquine blood level measurement offers an opportunity for personalized drug dosing and risk management beyond rigid empirical dosing recommendations in patients with SLE,” they concluded.
The study was supported in part by grants from the National Institutes of Health and the National Institute of Arthritis and Musculoskeletal and Skin Diseases. The researchers had no relevant financial conflicts to disclose.
SOURCE: Petri M et al. Arthritis Rheumatol. 2021 Jan 6. doi: 10.1002/ART.41621.
Maintaining an average hydroxychloroquine whole blood level above 1,068 ng/mL significantly reduced the risk of thrombosis in adults with systemic lupus erythematosus, based on data from 739 patients.
Hydroxychloroquine (HCQ) is a common treatment for systemic lupus erythematosus (SLE); studies suggest that it may protect against thrombosis, but the optimal dosing for this purpose remains unknown, wrote Michelle Petri, MD, of Johns Hopkins University, Baltimore, and colleagues. In a study published in Arthritis & Rheumatology, the researchers examined data on HCQ levels from 739 adults with SLE who were part of the Hopkins Lupus Cohort, a longitudinal study of outcomes in SLE patients. Of these, 38 (5.1%) developed thrombosis during 2,330 person-years of follow-up.
Overall, the average HCQ blood level was significantly lower in patients who experienced thrombosis, compared to those who did not (720 ng/mL vs. 935 ng/mL; P = .025). “Prescribed hydroxychloroquine doses did not predict hydroxychloroquine blood levels,” the researchers noted.
In addition, Dr. Petri and associates found a dose-response relationship in which the thrombosis rate declined approximately 13% for every 200-ng/mL increase in the mean HCQ blood level measurement and for the most recent HCQ blood level measurement after controlling for factors that included age, ethnicity, lupus anticoagulant, low C3, and hypertension.
In a multivariate analysis, thrombotic events decreased by 69% in patients with mean HCQ blood levels greater than 1,068 ng/mL, compared to those with average HCQ blood levels less than 648 ng/mL.
The average age of the patients at the time HCQ measurements began was 43 years, 93% were female, and 46% were White. Patients visited a clinic every 3 months, and HCQ levels were determined by liquid chromatography-tandem mass spectrometry.
“Between-person and within-person correlation coefficients were used to measure the strength of the linear association between HCQ blood levels and commonly prescribed HCQ doses from 4.5 to 6.5 mg/kg,” the researchers said.
Higher doses of HCQ have been associated with increased risk for retinopathy, and current guidelines recommend using less than 5 mg/kg of ideal body weight, the researchers said. “Importantly, there was no correlation between the prescribed dose and the hydroxychloroquine blood level over the range (4.5 to 6.5 mg/kg) used in clinical practice, highlighting the need for personalized hydroxychloroquine drug level-guided therapy and dose adjustment,” they emphasized.
The study findings were limited by several factors, including the observational design and potential confounding from variables not included in the model, as well as the small sample size, single site, and single rheumatologist involved in the study, the researchers noted.
The results suggest that aiming for a blood HCQ level of 1,068 ng/mL can be done safely to help prevent thrombosis in patients with SLE, the researchers said. “Routine clinical integration of hydroxychloroquine blood level measurement offers an opportunity for personalized drug dosing and risk management beyond rigid empirical dosing recommendations in patients with SLE,” they concluded.
The study was supported in part by grants from the National Institutes of Health and the National Institute of Arthritis and Musculoskeletal and Skin Diseases. The researchers had no relevant financial conflicts to disclose.
SOURCE: Petri M et al. Arthritis Rheumatol. 2021 Jan 6. doi: 10.1002/ART.41621.
FROM ARTHRITIS & RHEUMATOLOGY
Key clinical point: Higher blood levels of hydroxychloroquine (HCQ) were protective against thrombosis in adults with systemic lupus erythematosus (SLE).
Major finding: The average HCQ in SLE patients who developed thrombosis was 720 ng/mL, compared to 935 ng/mL in those without thrombosis (P = .025).
Study details: The data come from an observational study of 739 adults with SLE; 5.1% developed thrombosis during the study period.
Disclosures: The study was supported in part by grants from the National Institutes of Health and the National Institute of Arthritis and Musculoskeletal and Skin Diseases. The researchers had no relevant financial conflicts to disclose.
Source: Petri M et al. Arthritis Rheumatol. 2021 Jan 6. doi: 10.1002/ART.41621.
Why a mycosis fungoides diagnosis takes so long
Dermatopathologist Michi M. Shinohara, MD, is often asked why it takes so long to diagnose mycosis fungoides. Her reply: Early histopathologic findings in mycosis fungoides (MF) can be subtle, and accurate diagnosis is aided by taking multiple skin biopsies from different sites sequentially over time when there’s diagnostic uncertainty.
“Take multiple biopsies. There is clear literature that taking multiple biopsies from different areas of the body can really increase the sensitivity and specificity of TCR/PCR [T-cell receptor gene PCR clonality studies],” she said at a virtual forum on cutaneous malignancies jointly presented by the Postgraduate Institute for Medicine and Global Academy for Medical Education.
Patients with MF carry multiple subclones, and by taking multiple skin biopsies, different expression patterns may be revealed.
“MF is incredibly mutationally complex, and that has implications for therapy. There is certainly no single, nor even a few, targetable mutations. There are over 50 driver mutations known in CTCL [cutaneous T-cell lymphoma] involving more than a dozen signaling pathways,” said Dr. Shinohara, codirector of the cutaneous lymphoma clinic at the Seattle Cancer Care Alliance and director of dermatopathology at the University of Washington, Seattle.
MF is a lymphoma of skin-resident memory T-cells, the same T-cells involved in the pathogenesis of fixed drug eruption. MF accounts for about half of primary CTCLs. Traditionally, the average time from appearance of skin lesions to definitive diagnosis of MF is 3-6 years.
The International Society for Cutaneous Lymphomas diagnostic algorithm emphasizes that accurate diagnosis of MF requires clinical and histopathologic correlation supported by immunohistochemistry and TCR/PCR or other molecular studies. In an independent validation study, the algorithm demonstrated a sensitivity of 87.5% and specificity of 60% for diagnosis of MF.
Using this algorithm, a diagnosis of MF requires 4 points or more. A maximum of 2 points is available for the key clinical findings of variably sized persistent patches and/or plaques on non–sun-exposed areas, with poikiloderma. Another maximum of 2 points is awarded for the classic histopathologic findings consistent with MF and other forms of cutaneous T-cell lymphoma – namely, a superficial lymphoid infiltrate with epidermotropic but not spongiotic atypia. A positive immunohistochemical study is worth 1 point, and another point is granted for a positive result from a molecular study; both the immunohistochemical and molecular studies should “almost always” be done in patients with suspected MF, whereas a bone marrow biopsy is almost never appropriate.
The challenge for dermatopathologists in making an early diagnosis of MF is that, in patch-stage disease, many of the patient’s own cytotoxic CD8+ T-cells are present in the biopsy specimen battling the malignancy. These tumor-fighting cells often mask the malignant T-cells, clouding the picture under the microscope and putting the 2-point maximum for histopathologic findings out of reach. However, as the patient progresses to plaques, tumors, and erythroderma, the proportion of malignant T-cells increases and the diagnosis becomes easier, Dr. Shinohara explained.
In cases where histopathologic uncertainty exists, the immunohistochemistry and molecular studies become particularly important because, when positive, they can raise a patient’s score up to the 4-point diagnostic threshold. Dr. Shinohara focused on recent advances in molecular studies because that’s where the action is of late in the field of MF diagnostics.
High-throughput sequencing and other molecular studies
Three molecular study options are available for the diagnosis of MF: TCR/PCR, which is the traditional clonality study; next-generation high-throughput DNA sequencing; and flow cytometry.
A TCR/PCR study showing a monoclonal T-cell clone on a more subdued polyclonal background is highly suggestive of MF, as opposed to other inflammatory dermatoses. Early in the disease, however, the pattern can be oligoclonal, an inconclusive result. This point is where taking multiple biopsies from different skin sites becomes extremely helpful to amplify TCR/PCR’s sensitivity and specificity. Indeed, investigators at Stanford (Calif.) University have reported that TCR/PCR analysis showing an identical T-cell clone in biopsy specimens from two different skin sites had 82.6% sensitivity and 95.7% specificity for unequivocal MF.
High-throughput sequencing of the T-cell receptor gene has greater specificity for diagnosis of MF than TCR/PCR, and with similar sensitivity.
“The sensitivity of high-throughput sequencing is okay, but really we want it to be helpful in those wishy washy cases where we get an oligoclonal result on TCR/PCR; that’s, I think, an ideal use for it,” Dr. Shinohara said.
In addition to its role in establishing the diagnosis of MF, high-throughput sequencing shows promise for two other potential applications: detection of residual disease following stem cell transplantation and risk stratification in patients with early-stage disease.
Citing a landmark Stanford retrospective cohort analysis of actuarial disease-specific survival in 525 patients with MF and Sezary syndrome, she noted that the majority of patients had stage IA or IB disease – meaning patches and/or plaques on less than or more than 10% of their body surface area – and the survival curves of these patients with early-stage CTCL were flat.
“Most patients are going to live for decades with their disease if they have early disease, and that’s very reassuring for patients,” the dermatopathologist observed.
And yet, early-stage disease does not follow an indolent lifelong course in a subset of patients; rather, their disease becomes aggressive and resistant to all treatments short of stem cell transplantation. Investigators at Harvard University, Boston, have reported that high-throughput sequencing of the T-cell receptor beta gene in lesional skin biopsies is a powerful tool for early identification of this high-risk subpopulation of patients with early-stage MF. They demonstrated in a cohort of 141 patients with early-stage MF, then again in a validation cohort of 69 others, that a tumor clone frequency (TCF) greater than 25% in lesional skin, as measured by high-throughput sequencing, was a more powerful predictor of disease progression than any of the established prognostic factors.
In the discovery set, a TCF in excess of 25% was associated with a 4.9-fold increased likelihood of reduced progression-free survival; in the validation set, the risk was 10-fold greater than in patients with a lesser TCF. These were significantly greater risks than those seen with other proposed biomarkers of diminished progression-free survival, including the presence of plaques; stage IB, as opposed to IA, disease; large-cell transformation; age greater than 60 years; and elevated lactate dehydrogenase levels.
Although this groundbreaking work requires confirmation in another dataset, “this may be something we evolve towards doing in patients with early disease to pick out those who may have bad outcomes later,” Dr. Shinohara commented.
Still, she stressed, molecular studies will never replace histopathologic analysis for diagnosis of MF. “Judicious use of molecular studies may help in establishing the diagnosis, but I don’t think any one molecular study is ever going to be our home run,” she said.
She reported no financial conflicts regarding her presentation.
Global Academy for Medical Education and this news organization are owned by the same company.
Dermatopathologist Michi M. Shinohara, MD, is often asked why it takes so long to diagnose mycosis fungoides. Her reply: Early histopathologic findings in mycosis fungoides (MF) can be subtle, and accurate diagnosis is aided by taking multiple skin biopsies from different sites sequentially over time when there’s diagnostic uncertainty.
“Take multiple biopsies. There is clear literature that taking multiple biopsies from different areas of the body can really increase the sensitivity and specificity of TCR/PCR [T-cell receptor gene PCR clonality studies],” she said at a virtual forum on cutaneous malignancies jointly presented by the Postgraduate Institute for Medicine and Global Academy for Medical Education.
Patients with MF carry multiple subclones, and by taking multiple skin biopsies, different expression patterns may be revealed.
“MF is incredibly mutationally complex, and that has implications for therapy. There is certainly no single, nor even a few, targetable mutations. There are over 50 driver mutations known in CTCL [cutaneous T-cell lymphoma] involving more than a dozen signaling pathways,” said Dr. Shinohara, codirector of the cutaneous lymphoma clinic at the Seattle Cancer Care Alliance and director of dermatopathology at the University of Washington, Seattle.
MF is a lymphoma of skin-resident memory T-cells, the same T-cells involved in the pathogenesis of fixed drug eruption. MF accounts for about half of primary CTCLs. Traditionally, the average time from appearance of skin lesions to definitive diagnosis of MF is 3-6 years.
The International Society for Cutaneous Lymphomas diagnostic algorithm emphasizes that accurate diagnosis of MF requires clinical and histopathologic correlation supported by immunohistochemistry and TCR/PCR or other molecular studies. In an independent validation study, the algorithm demonstrated a sensitivity of 87.5% and specificity of 60% for diagnosis of MF.
Using this algorithm, a diagnosis of MF requires 4 points or more. A maximum of 2 points is available for the key clinical findings of variably sized persistent patches and/or plaques on non–sun-exposed areas, with poikiloderma. Another maximum of 2 points is awarded for the classic histopathologic findings consistent with MF and other forms of cutaneous T-cell lymphoma – namely, a superficial lymphoid infiltrate with epidermotropic but not spongiotic atypia. A positive immunohistochemical study is worth 1 point, and another point is granted for a positive result from a molecular study; both the immunohistochemical and molecular studies should “almost always” be done in patients with suspected MF, whereas a bone marrow biopsy is almost never appropriate.
The challenge for dermatopathologists in making an early diagnosis of MF is that, in patch-stage disease, many of the patient’s own cytotoxic CD8+ T-cells are present in the biopsy specimen battling the malignancy. These tumor-fighting cells often mask the malignant T-cells, clouding the picture under the microscope and putting the 2-point maximum for histopathologic findings out of reach. However, as the patient progresses to plaques, tumors, and erythroderma, the proportion of malignant T-cells increases and the diagnosis becomes easier, Dr. Shinohara explained.
In cases where histopathologic uncertainty exists, the immunohistochemistry and molecular studies become particularly important because, when positive, they can raise a patient’s score up to the 4-point diagnostic threshold. Dr. Shinohara focused on recent advances in molecular studies because that’s where the action is of late in the field of MF diagnostics.
High-throughput sequencing and other molecular studies
Three molecular study options are available for the diagnosis of MF: TCR/PCR, which is the traditional clonality study; next-generation high-throughput DNA sequencing; and flow cytometry.
A TCR/PCR study showing a monoclonal T-cell clone on a more subdued polyclonal background is highly suggestive of MF, as opposed to other inflammatory dermatoses. Early in the disease, however, the pattern can be oligoclonal, an inconclusive result. This point is where taking multiple biopsies from different skin sites becomes extremely helpful to amplify TCR/PCR’s sensitivity and specificity. Indeed, investigators at Stanford (Calif.) University have reported that TCR/PCR analysis showing an identical T-cell clone in biopsy specimens from two different skin sites had 82.6% sensitivity and 95.7% specificity for unequivocal MF.
High-throughput sequencing of the T-cell receptor gene has greater specificity for diagnosis of MF than TCR/PCR, and with similar sensitivity.
“The sensitivity of high-throughput sequencing is okay, but really we want it to be helpful in those wishy washy cases where we get an oligoclonal result on TCR/PCR; that’s, I think, an ideal use for it,” Dr. Shinohara said.
In addition to its role in establishing the diagnosis of MF, high-throughput sequencing shows promise for two other potential applications: detection of residual disease following stem cell transplantation and risk stratification in patients with early-stage disease.
Citing a landmark Stanford retrospective cohort analysis of actuarial disease-specific survival in 525 patients with MF and Sezary syndrome, she noted that the majority of patients had stage IA or IB disease – meaning patches and/or plaques on less than or more than 10% of their body surface area – and the survival curves of these patients with early-stage CTCL were flat.
“Most patients are going to live for decades with their disease if they have early disease, and that’s very reassuring for patients,” the dermatopathologist observed.
And yet, early-stage disease does not follow an indolent lifelong course in a subset of patients; rather, their disease becomes aggressive and resistant to all treatments short of stem cell transplantation. Investigators at Harvard University, Boston, have reported that high-throughput sequencing of the T-cell receptor beta gene in lesional skin biopsies is a powerful tool for early identification of this high-risk subpopulation of patients with early-stage MF. They demonstrated in a cohort of 141 patients with early-stage MF, then again in a validation cohort of 69 others, that a tumor clone frequency (TCF) greater than 25% in lesional skin, as measured by high-throughput sequencing, was a more powerful predictor of disease progression than any of the established prognostic factors.
In the discovery set, a TCF in excess of 25% was associated with a 4.9-fold increased likelihood of reduced progression-free survival; in the validation set, the risk was 10-fold greater than in patients with a lesser TCF. These were significantly greater risks than those seen with other proposed biomarkers of diminished progression-free survival, including the presence of plaques; stage IB, as opposed to IA, disease; large-cell transformation; age greater than 60 years; and elevated lactate dehydrogenase levels.
Although this groundbreaking work requires confirmation in another dataset, “this may be something we evolve towards doing in patients with early disease to pick out those who may have bad outcomes later,” Dr. Shinohara commented.
Still, she stressed, molecular studies will never replace histopathologic analysis for diagnosis of MF. “Judicious use of molecular studies may help in establishing the diagnosis, but I don’t think any one molecular study is ever going to be our home run,” she said.
She reported no financial conflicts regarding her presentation.
Global Academy for Medical Education and this news organization are owned by the same company.
Dermatopathologist Michi M. Shinohara, MD, is often asked why it takes so long to diagnose mycosis fungoides. Her reply: Early histopathologic findings in mycosis fungoides (MF) can be subtle, and accurate diagnosis is aided by taking multiple skin biopsies from different sites sequentially over time when there’s diagnostic uncertainty.
“Take multiple biopsies. There is clear literature that taking multiple biopsies from different areas of the body can really increase the sensitivity and specificity of TCR/PCR [T-cell receptor gene PCR clonality studies],” she said at a virtual forum on cutaneous malignancies jointly presented by the Postgraduate Institute for Medicine and Global Academy for Medical Education.
Patients with MF carry multiple subclones, and by taking multiple skin biopsies, different expression patterns may be revealed.
“MF is incredibly mutationally complex, and that has implications for therapy. There is certainly no single, nor even a few, targetable mutations. There are over 50 driver mutations known in CTCL [cutaneous T-cell lymphoma] involving more than a dozen signaling pathways,” said Dr. Shinohara, codirector of the cutaneous lymphoma clinic at the Seattle Cancer Care Alliance and director of dermatopathology at the University of Washington, Seattle.
MF is a lymphoma of skin-resident memory T-cells, the same T-cells involved in the pathogenesis of fixed drug eruption. MF accounts for about half of primary CTCLs. Traditionally, the average time from appearance of skin lesions to definitive diagnosis of MF is 3-6 years.
The International Society for Cutaneous Lymphomas diagnostic algorithm emphasizes that accurate diagnosis of MF requires clinical and histopathologic correlation supported by immunohistochemistry and TCR/PCR or other molecular studies. In an independent validation study, the algorithm demonstrated a sensitivity of 87.5% and specificity of 60% for diagnosis of MF.
Using this algorithm, a diagnosis of MF requires 4 points or more. A maximum of 2 points is available for the key clinical findings of variably sized persistent patches and/or plaques on non–sun-exposed areas, with poikiloderma. Another maximum of 2 points is awarded for the classic histopathologic findings consistent with MF and other forms of cutaneous T-cell lymphoma – namely, a superficial lymphoid infiltrate with epidermotropic but not spongiotic atypia. A positive immunohistochemical study is worth 1 point, and another point is granted for a positive result from a molecular study; both the immunohistochemical and molecular studies should “almost always” be done in patients with suspected MF, whereas a bone marrow biopsy is almost never appropriate.
The challenge for dermatopathologists in making an early diagnosis of MF is that, in patch-stage disease, many of the patient’s own cytotoxic CD8+ T-cells are present in the biopsy specimen battling the malignancy. These tumor-fighting cells often mask the malignant T-cells, clouding the picture under the microscope and putting the 2-point maximum for histopathologic findings out of reach. However, as the patient progresses to plaques, tumors, and erythroderma, the proportion of malignant T-cells increases and the diagnosis becomes easier, Dr. Shinohara explained.
In cases where histopathologic uncertainty exists, the immunohistochemistry and molecular studies become particularly important because, when positive, they can raise a patient’s score up to the 4-point diagnostic threshold. Dr. Shinohara focused on recent advances in molecular studies because that’s where the action is of late in the field of MF diagnostics.
High-throughput sequencing and other molecular studies
Three molecular study options are available for the diagnosis of MF: TCR/PCR, which is the traditional clonality study; next-generation high-throughput DNA sequencing; and flow cytometry.
A TCR/PCR study showing a monoclonal T-cell clone on a more subdued polyclonal background is highly suggestive of MF, as opposed to other inflammatory dermatoses. Early in the disease, however, the pattern can be oligoclonal, an inconclusive result. This point is where taking multiple biopsies from different skin sites becomes extremely helpful to amplify TCR/PCR’s sensitivity and specificity. Indeed, investigators at Stanford (Calif.) University have reported that TCR/PCR analysis showing an identical T-cell clone in biopsy specimens from two different skin sites had 82.6% sensitivity and 95.7% specificity for unequivocal MF.
High-throughput sequencing of the T-cell receptor gene has greater specificity for diagnosis of MF than TCR/PCR, and with similar sensitivity.
“The sensitivity of high-throughput sequencing is okay, but really we want it to be helpful in those wishy washy cases where we get an oligoclonal result on TCR/PCR; that’s, I think, an ideal use for it,” Dr. Shinohara said.
In addition to its role in establishing the diagnosis of MF, high-throughput sequencing shows promise for two other potential applications: detection of residual disease following stem cell transplantation and risk stratification in patients with early-stage disease.
Citing a landmark Stanford retrospective cohort analysis of actuarial disease-specific survival in 525 patients with MF and Sezary syndrome, she noted that the majority of patients had stage IA or IB disease – meaning patches and/or plaques on less than or more than 10% of their body surface area – and the survival curves of these patients with early-stage CTCL were flat.
“Most patients are going to live for decades with their disease if they have early disease, and that’s very reassuring for patients,” the dermatopathologist observed.
And yet, early-stage disease does not follow an indolent lifelong course in a subset of patients; rather, their disease becomes aggressive and resistant to all treatments short of stem cell transplantation. Investigators at Harvard University, Boston, have reported that high-throughput sequencing of the T-cell receptor beta gene in lesional skin biopsies is a powerful tool for early identification of this high-risk subpopulation of patients with early-stage MF. They demonstrated in a cohort of 141 patients with early-stage MF, then again in a validation cohort of 69 others, that a tumor clone frequency (TCF) greater than 25% in lesional skin, as measured by high-throughput sequencing, was a more powerful predictor of disease progression than any of the established prognostic factors.
In the discovery set, a TCF in excess of 25% was associated with a 4.9-fold increased likelihood of reduced progression-free survival; in the validation set, the risk was 10-fold greater than in patients with a lesser TCF. These were significantly greater risks than those seen with other proposed biomarkers of diminished progression-free survival, including the presence of plaques; stage IB, as opposed to IA, disease; large-cell transformation; age greater than 60 years; and elevated lactate dehydrogenase levels.
Although this groundbreaking work requires confirmation in another dataset, “this may be something we evolve towards doing in patients with early disease to pick out those who may have bad outcomes later,” Dr. Shinohara commented.
Still, she stressed, molecular studies will never replace histopathologic analysis for diagnosis of MF. “Judicious use of molecular studies may help in establishing the diagnosis, but I don’t think any one molecular study is ever going to be our home run,” she said.
She reported no financial conflicts regarding her presentation.
Global Academy for Medical Education and this news organization are owned by the same company.
FROM THE CUTANEOUS MALIGNANCIES FORUM
New AK treatments: Local reactions are the price for greater clearance rates
, according to an expert speaking at the annual Coastal Dermatology Symposium, held virtually.
This relationship is not new. In a review of treatments for AKs, Neal Bhatia, MD, a dermatologist and researcher at Therapeutics Dermatology, San Diego, advised that most effective agents trade a higher risk of inflammatory reactions – including erythema, flaking, and scaling – for greater therapeutic gain. In many cases, local skin reactions are an inevitable consequence of their mechanism of action.
Data from the completed phase 3 trials of tirbanibulin 1% ointment (KX01-AK-003 and KX01-AK-004), are illustrative. (Tirbanibulin 1% ointment was approved by the Food and Drug Administration in mid-December, after the Coastal Derm meeting was held.)
In the phase 3 trials, which have not yet been published, tirbanibulin, an inhibitor of Src kinase, which has an antiproliferative action, was four to five times more effective than vehicle by day 57 for overall complete clearance (P < .0001) of AKs and complete clearance of the face (P < .0001), but rates of local skin reactions were generally two to three times higher, according to Dr. Bhatia.
In the KX01-AK-004 trial, for example, 61% of patients had complete clearance of the face, versus 14% of those randomized to vehicle. The difference for overall partial clearance (76% vs. 20%; P < .0001), partial clearance of the face (80% vs. 22%; P < .0001), and partial clearance of the scalp (69% vs. 15%; P < .0001) was even greater. When compared with placebo, tirbanibulin was also associated with greater rates of erythema (90% vs. 31%), crusting (45% vs. 8%), flaking (84% vs. 35%), swelling (38% vs. 2%) and erosions or ulcers (12% vs. 1%).
Although these events might be a challenge with regard to tolerability for some patients, they might best be described as evidence that the drug is working.
“Local skin reactions are anticipated. They are not adverse events. They are not side effects,” Dr. Bhatia said at the meeting, jointly presented by the University of Louisville and Global Academy for Medical Education. “Patients are going to get red, and you need to counsel patients about the 5 days when they can expected to be red. It is a sign of the civil war, if you will, that your skin is taking on with the actinic keratoses.”
Both 3- and 5-day courses of the drug were tested in the clinical trials. (The approved prescribing information recommends treatment on the face or scalp once a day for 5 consecutive days).
Other studies evaluating treatments for AKs have also associated an increased risk of local skin reactions with greater efficacy, Dr. Bhatia noted. As an example, he cited a phase 4 study comparing 0.015% ingenol mebutate gel to diclofenac sodium 3% gel in people with facial and scalp AK lesions.
At the end of the 3-month study, complete clearance was higher among those on ingenol mebutate, which was applied for 3 days, when compared with diclofenac sodium gel, which was applied daily for 3 months (34% vs. 23%; P = .006). However, patients randomized to ingenol mebutate gel had to first weather a higher rate of application-site erythema (19% vs. 12%) before achieving a greater level of clearance.
The correlation between efficacy and local reactions at the site of treatment application emphasizes the importance of educating patients about this relationship and in engaging in shared decision-making, Dr. Bhatia said.
“It is basically a tradeoff between local skin reactions, between frequency [of applications], compliance, and, of course, duration of therapy, even though both drugs served their purposes well,” said Dr. Bhatia, referring to the comparison of the ingenol mebutate and diclofenac gels.
Although not absolute, efficacy and tolerability were also generally inversely related in a recent four-treatment comparison of four commonly used field-directed therapies. In that trial, the primary endpoint was at least a 75% reduction from baseline in the number of AKs to 12 months after treatment ended.
For that outcome, 5% fluorouracil (5-FU) cream (74.7%) was significantly more effective than 5% imiquimod cream (53.9%), methyl aminolevulinate photodynamic therapy (37.7%), and 0.015% ingenol mebutate gel (28.9%). Also, 5-FU treatment was associated with the moderate or severe erythema (81.5%), severe pain (16.%), and a severe burning sensation (21.5%).
Other therapies on the horizon, some of which are already available in Europe or Canada, show a relationship between efficacy and local skin reactions. Of two that Dr. Bhatia cited, 5-FU and salicylic acid combined in a solution and 5-FU and calcipotriene combined in an ointment have demonstrated high rates of efficacy but at the cost of substantial rates of erythema and flaking.
Transient skin reactions can be made acceptable to patients who are informed of the goals of clearing AKs, which includes lowering the risk of cancer, as well as cosmetic improvement. In the phase 4 study comparing ingenol mebutate gel to diclofenac sodium gel, the end-of-study global satisfaction rates were higher (P < .001) for those randomized to the most effective therapy despite the local skin reactions.
Preparing patients for the consequences of therapy for AKs is essential, because optimal therapy involves treating uninvolved skin, according to Hassan Galadari, MD, assistant professor of dermatology, United Arab Emirates University, Dubai. A coauthor of a recent review article on actinic keratoses, Dr. Galadari said in an interview that field treatment means patients might have local skin reactions where they did not previously have lesions.
“Actinic damage may not be visible with the naked eye. That is why field treatment, which is applying medicine in adjacent areas that may appear normal, is indicated,” he said. As a result, “areas that otherwise may have appeared as normal start to react by becoming red, itchy, and even inflamed.”
He agreed with Dr. Bhatia that local skin reactions are typically the price paid for effective control of these precancerous lesions.
This publication and Global Academy for Medical Education are owned by the same parent company.
Dr. Bhatia reports financial relationships with more than 30 pharmaceutical companies with dermatologic products, including Almirall and other companies with products relevant to AK therapies.
, according to an expert speaking at the annual Coastal Dermatology Symposium, held virtually.
This relationship is not new. In a review of treatments for AKs, Neal Bhatia, MD, a dermatologist and researcher at Therapeutics Dermatology, San Diego, advised that most effective agents trade a higher risk of inflammatory reactions – including erythema, flaking, and scaling – for greater therapeutic gain. In many cases, local skin reactions are an inevitable consequence of their mechanism of action.
Data from the completed phase 3 trials of tirbanibulin 1% ointment (KX01-AK-003 and KX01-AK-004), are illustrative. (Tirbanibulin 1% ointment was approved by the Food and Drug Administration in mid-December, after the Coastal Derm meeting was held.)
In the phase 3 trials, which have not yet been published, tirbanibulin, an inhibitor of Src kinase, which has an antiproliferative action, was four to five times more effective than vehicle by day 57 for overall complete clearance (P < .0001) of AKs and complete clearance of the face (P < .0001), but rates of local skin reactions were generally two to three times higher, according to Dr. Bhatia.
In the KX01-AK-004 trial, for example, 61% of patients had complete clearance of the face, versus 14% of those randomized to vehicle. The difference for overall partial clearance (76% vs. 20%; P < .0001), partial clearance of the face (80% vs. 22%; P < .0001), and partial clearance of the scalp (69% vs. 15%; P < .0001) was even greater. When compared with placebo, tirbanibulin was also associated with greater rates of erythema (90% vs. 31%), crusting (45% vs. 8%), flaking (84% vs. 35%), swelling (38% vs. 2%) and erosions or ulcers (12% vs. 1%).
Although these events might be a challenge with regard to tolerability for some patients, they might best be described as evidence that the drug is working.
“Local skin reactions are anticipated. They are not adverse events. They are not side effects,” Dr. Bhatia said at the meeting, jointly presented by the University of Louisville and Global Academy for Medical Education. “Patients are going to get red, and you need to counsel patients about the 5 days when they can expected to be red. It is a sign of the civil war, if you will, that your skin is taking on with the actinic keratoses.”
Both 3- and 5-day courses of the drug were tested in the clinical trials. (The approved prescribing information recommends treatment on the face or scalp once a day for 5 consecutive days).
Other studies evaluating treatments for AKs have also associated an increased risk of local skin reactions with greater efficacy, Dr. Bhatia noted. As an example, he cited a phase 4 study comparing 0.015% ingenol mebutate gel to diclofenac sodium 3% gel in people with facial and scalp AK lesions.
At the end of the 3-month study, complete clearance was higher among those on ingenol mebutate, which was applied for 3 days, when compared with diclofenac sodium gel, which was applied daily for 3 months (34% vs. 23%; P = .006). However, patients randomized to ingenol mebutate gel had to first weather a higher rate of application-site erythema (19% vs. 12%) before achieving a greater level of clearance.
The correlation between efficacy and local reactions at the site of treatment application emphasizes the importance of educating patients about this relationship and in engaging in shared decision-making, Dr. Bhatia said.
“It is basically a tradeoff between local skin reactions, between frequency [of applications], compliance, and, of course, duration of therapy, even though both drugs served their purposes well,” said Dr. Bhatia, referring to the comparison of the ingenol mebutate and diclofenac gels.
Although not absolute, efficacy and tolerability were also generally inversely related in a recent four-treatment comparison of four commonly used field-directed therapies. In that trial, the primary endpoint was at least a 75% reduction from baseline in the number of AKs to 12 months after treatment ended.
For that outcome, 5% fluorouracil (5-FU) cream (74.7%) was significantly more effective than 5% imiquimod cream (53.9%), methyl aminolevulinate photodynamic therapy (37.7%), and 0.015% ingenol mebutate gel (28.9%). Also, 5-FU treatment was associated with the moderate or severe erythema (81.5%), severe pain (16.%), and a severe burning sensation (21.5%).
Other therapies on the horizon, some of which are already available in Europe or Canada, show a relationship between efficacy and local skin reactions. Of two that Dr. Bhatia cited, 5-FU and salicylic acid combined in a solution and 5-FU and calcipotriene combined in an ointment have demonstrated high rates of efficacy but at the cost of substantial rates of erythema and flaking.
Transient skin reactions can be made acceptable to patients who are informed of the goals of clearing AKs, which includes lowering the risk of cancer, as well as cosmetic improvement. In the phase 4 study comparing ingenol mebutate gel to diclofenac sodium gel, the end-of-study global satisfaction rates were higher (P < .001) for those randomized to the most effective therapy despite the local skin reactions.
Preparing patients for the consequences of therapy for AKs is essential, because optimal therapy involves treating uninvolved skin, according to Hassan Galadari, MD, assistant professor of dermatology, United Arab Emirates University, Dubai. A coauthor of a recent review article on actinic keratoses, Dr. Galadari said in an interview that field treatment means patients might have local skin reactions where they did not previously have lesions.
“Actinic damage may not be visible with the naked eye. That is why field treatment, which is applying medicine in adjacent areas that may appear normal, is indicated,” he said. As a result, “areas that otherwise may have appeared as normal start to react by becoming red, itchy, and even inflamed.”
He agreed with Dr. Bhatia that local skin reactions are typically the price paid for effective control of these precancerous lesions.
This publication and Global Academy for Medical Education are owned by the same parent company.
Dr. Bhatia reports financial relationships with more than 30 pharmaceutical companies with dermatologic products, including Almirall and other companies with products relevant to AK therapies.
, according to an expert speaking at the annual Coastal Dermatology Symposium, held virtually.
This relationship is not new. In a review of treatments for AKs, Neal Bhatia, MD, a dermatologist and researcher at Therapeutics Dermatology, San Diego, advised that most effective agents trade a higher risk of inflammatory reactions – including erythema, flaking, and scaling – for greater therapeutic gain. In many cases, local skin reactions are an inevitable consequence of their mechanism of action.
Data from the completed phase 3 trials of tirbanibulin 1% ointment (KX01-AK-003 and KX01-AK-004), are illustrative. (Tirbanibulin 1% ointment was approved by the Food and Drug Administration in mid-December, after the Coastal Derm meeting was held.)
In the phase 3 trials, which have not yet been published, tirbanibulin, an inhibitor of Src kinase, which has an antiproliferative action, was four to five times more effective than vehicle by day 57 for overall complete clearance (P < .0001) of AKs and complete clearance of the face (P < .0001), but rates of local skin reactions were generally two to three times higher, according to Dr. Bhatia.
In the KX01-AK-004 trial, for example, 61% of patients had complete clearance of the face, versus 14% of those randomized to vehicle. The difference for overall partial clearance (76% vs. 20%; P < .0001), partial clearance of the face (80% vs. 22%; P < .0001), and partial clearance of the scalp (69% vs. 15%; P < .0001) was even greater. When compared with placebo, tirbanibulin was also associated with greater rates of erythema (90% vs. 31%), crusting (45% vs. 8%), flaking (84% vs. 35%), swelling (38% vs. 2%) and erosions or ulcers (12% vs. 1%).
Although these events might be a challenge with regard to tolerability for some patients, they might best be described as evidence that the drug is working.
“Local skin reactions are anticipated. They are not adverse events. They are not side effects,” Dr. Bhatia said at the meeting, jointly presented by the University of Louisville and Global Academy for Medical Education. “Patients are going to get red, and you need to counsel patients about the 5 days when they can expected to be red. It is a sign of the civil war, if you will, that your skin is taking on with the actinic keratoses.”
Both 3- and 5-day courses of the drug were tested in the clinical trials. (The approved prescribing information recommends treatment on the face or scalp once a day for 5 consecutive days).
Other studies evaluating treatments for AKs have also associated an increased risk of local skin reactions with greater efficacy, Dr. Bhatia noted. As an example, he cited a phase 4 study comparing 0.015% ingenol mebutate gel to diclofenac sodium 3% gel in people with facial and scalp AK lesions.
At the end of the 3-month study, complete clearance was higher among those on ingenol mebutate, which was applied for 3 days, when compared with diclofenac sodium gel, which was applied daily for 3 months (34% vs. 23%; P = .006). However, patients randomized to ingenol mebutate gel had to first weather a higher rate of application-site erythema (19% vs. 12%) before achieving a greater level of clearance.
The correlation between efficacy and local reactions at the site of treatment application emphasizes the importance of educating patients about this relationship and in engaging in shared decision-making, Dr. Bhatia said.
“It is basically a tradeoff between local skin reactions, between frequency [of applications], compliance, and, of course, duration of therapy, even though both drugs served their purposes well,” said Dr. Bhatia, referring to the comparison of the ingenol mebutate and diclofenac gels.
Although not absolute, efficacy and tolerability were also generally inversely related in a recent four-treatment comparison of four commonly used field-directed therapies. In that trial, the primary endpoint was at least a 75% reduction from baseline in the number of AKs to 12 months after treatment ended.
For that outcome, 5% fluorouracil (5-FU) cream (74.7%) was significantly more effective than 5% imiquimod cream (53.9%), methyl aminolevulinate photodynamic therapy (37.7%), and 0.015% ingenol mebutate gel (28.9%). Also, 5-FU treatment was associated with the moderate or severe erythema (81.5%), severe pain (16.%), and a severe burning sensation (21.5%).
Other therapies on the horizon, some of which are already available in Europe or Canada, show a relationship between efficacy and local skin reactions. Of two that Dr. Bhatia cited, 5-FU and salicylic acid combined in a solution and 5-FU and calcipotriene combined in an ointment have demonstrated high rates of efficacy but at the cost of substantial rates of erythema and flaking.
Transient skin reactions can be made acceptable to patients who are informed of the goals of clearing AKs, which includes lowering the risk of cancer, as well as cosmetic improvement. In the phase 4 study comparing ingenol mebutate gel to diclofenac sodium gel, the end-of-study global satisfaction rates were higher (P < .001) for those randomized to the most effective therapy despite the local skin reactions.
Preparing patients for the consequences of therapy for AKs is essential, because optimal therapy involves treating uninvolved skin, according to Hassan Galadari, MD, assistant professor of dermatology, United Arab Emirates University, Dubai. A coauthor of a recent review article on actinic keratoses, Dr. Galadari said in an interview that field treatment means patients might have local skin reactions where they did not previously have lesions.
“Actinic damage may not be visible with the naked eye. That is why field treatment, which is applying medicine in adjacent areas that may appear normal, is indicated,” he said. As a result, “areas that otherwise may have appeared as normal start to react by becoming red, itchy, and even inflamed.”
He agreed with Dr. Bhatia that local skin reactions are typically the price paid for effective control of these precancerous lesions.
This publication and Global Academy for Medical Education are owned by the same parent company.
Dr. Bhatia reports financial relationships with more than 30 pharmaceutical companies with dermatologic products, including Almirall and other companies with products relevant to AK therapies.
FROM COASTAL DERM