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Early post-ACS bleeding may signal cancer
PARIS –, according to work presented at the annual congress of the European Society of Cardiology.
Of 3,644 patients discharged with dual-antiplatelet therapy after acute coronary syndrome (ACS), 1,215 (33%) had postdischarge bleeding. Taken together, patients who bled had a hazard ratio (HR) of 3.43 for a new cancer diagnosis (P less than .001).
Of the patients in the post-ACS cohort, 227 were newly diagnosed with cancer after discharge, making up 1% of the patients who did not bleed after discharge, and 3.9% of the patients who experienced postdischarge bleeding. Put another way, “[t]he positive predictive value for cancer diagnosis of post-discharge bleeding was 7.7%,” wrote Isabel Muñoz Pousa, MD, and her colleagues in the poster accompanying the presentation.
This elevated risk for cancer diagnosis was driven primarily by the 827 incidents of spontaneous bleeding; here, the HR was 4.38 (P less than .001). The 389 bleeds occuring after trauma, such as bladder catheterization or a fall, did not carry an increased risk for a new cancer diagnosis.
“Spontaneous post-discharge bleeding in ACS patients is strongly associated with subsequent cancer diagnosis within the first 6 months,” wrote Dr. Muñoz Pousa and her colleagues of the Hospital Universitario Alvaro Cunqueiro, Vigo, Spain. The investigators found a median time of 4.6 months from the bleeding episode to cancer diagnosis.
Of all anatomic locations, genitourinary bleeds were the most strongly associated with new cancer: 228 patients saw a HR of 8.63 for a new cancer diagnosis (P less than .001). Bronchopulmonary bleeds, sustained by 56 patients, carried a HR of 4.26 for new cancer diagnosis, and gastrointestinal bleeds a HR of 3.78 (P = .001 and P less than .001, respectively). Dr. Muñoz Pousa and her coinvestigators aggregated data from patients who had bleeding at other sites and saw no significant association with new cancers in this group of patients.
Though patients were initially discharged on dual-antiplatelet therapy, many patients stopped taking the medication over the mean 56.2 months of follow-up. The risk of bleeding did not differ significantly between those who were taking DAPT and those off DAPT, wrote Dr. Muñoz Pousa and her colleagues, adding: “We found a higher incidence of cancer in the first six months after discharge regardless of whether patients were taking dual-antiplatelet therapy or not.”
In their statistical analysis, Dr. Muñoz Pousa and colleagues adjusted for potential confounders, and looked at the effect of bleeding as a time-varying covariate on subsequent cancer diagnosis, using Cox regression models.
“Most of the bleeding episodes in the study were mild,” noted Dr. Munoz Pousa in a press statement. However, she said, “The bleeding events more strongly related with a new cancer diagnosis were severe hemorrhages of unknown cause requiring surgery – for example digestive bleeding needing endoscopic treatment.”
Breaking bleeding severity down by Bleeding Academic Research Consortium (BARC) criteria, the investigators found that most patients had relatively mild bleeding episodes categorized as BARC 1 or 2, with about half of all bleeding falling into the BARC 1 category.
Still, the 436 patients who had BARC 2 bleeding had a hazard ratio of 4.88 for cancer diagnosis, and the 71 BARC 3A patients saw the HR climb to 7.30. The risk for cancer subsequent to bleeding peaked at BARC 3B, with a HR of 12.29 for these 46 individuals (P less than .001 for all). Just 37 patients experienced BARC 3C bleeds, which were associated with a nonsignificant HR of 3.17 for new cancer diagnosis.
Although it’s not known why the post ACS–cancer bleeding association exists, Dr. Munoz Pousa put forward a plausible reason for the link. “A possible explanation is that there is a preexisting subclinical lesion in an organ that is triggered to become cancer by antiplatelet drugs or a stressful situation such as heart attack,” she said in the press release.
Antiplatelet therapy should be taken as prescribed post-ACS, and the physician threshold for further evaluation should be low when a significant spontaneous bleed is seen soon after ACS. “A prompt evaluation of bleeding could be useful for enabling an early detection of cancer in these patients,” said Dr. Munoz Pousa and her colleagues. “Our results suggest that patients should seek medical advice if they experience bleeding after discharge for a heart attack.”
The authors reported no conflicts of interest.
SOURCE: Munoz Pousa, I. et al. ESC Congress 2019, Abstract P677.
PARIS –, according to work presented at the annual congress of the European Society of Cardiology.
Of 3,644 patients discharged with dual-antiplatelet therapy after acute coronary syndrome (ACS), 1,215 (33%) had postdischarge bleeding. Taken together, patients who bled had a hazard ratio (HR) of 3.43 for a new cancer diagnosis (P less than .001).
Of the patients in the post-ACS cohort, 227 were newly diagnosed with cancer after discharge, making up 1% of the patients who did not bleed after discharge, and 3.9% of the patients who experienced postdischarge bleeding. Put another way, “[t]he positive predictive value for cancer diagnosis of post-discharge bleeding was 7.7%,” wrote Isabel Muñoz Pousa, MD, and her colleagues in the poster accompanying the presentation.
This elevated risk for cancer diagnosis was driven primarily by the 827 incidents of spontaneous bleeding; here, the HR was 4.38 (P less than .001). The 389 bleeds occuring after trauma, such as bladder catheterization or a fall, did not carry an increased risk for a new cancer diagnosis.
“Spontaneous post-discharge bleeding in ACS patients is strongly associated with subsequent cancer diagnosis within the first 6 months,” wrote Dr. Muñoz Pousa and her colleagues of the Hospital Universitario Alvaro Cunqueiro, Vigo, Spain. The investigators found a median time of 4.6 months from the bleeding episode to cancer diagnosis.
Of all anatomic locations, genitourinary bleeds were the most strongly associated with new cancer: 228 patients saw a HR of 8.63 for a new cancer diagnosis (P less than .001). Bronchopulmonary bleeds, sustained by 56 patients, carried a HR of 4.26 for new cancer diagnosis, and gastrointestinal bleeds a HR of 3.78 (P = .001 and P less than .001, respectively). Dr. Muñoz Pousa and her coinvestigators aggregated data from patients who had bleeding at other sites and saw no significant association with new cancers in this group of patients.
Though patients were initially discharged on dual-antiplatelet therapy, many patients stopped taking the medication over the mean 56.2 months of follow-up. The risk of bleeding did not differ significantly between those who were taking DAPT and those off DAPT, wrote Dr. Muñoz Pousa and her colleagues, adding: “We found a higher incidence of cancer in the first six months after discharge regardless of whether patients were taking dual-antiplatelet therapy or not.”
In their statistical analysis, Dr. Muñoz Pousa and colleagues adjusted for potential confounders, and looked at the effect of bleeding as a time-varying covariate on subsequent cancer diagnosis, using Cox regression models.
“Most of the bleeding episodes in the study were mild,” noted Dr. Munoz Pousa in a press statement. However, she said, “The bleeding events more strongly related with a new cancer diagnosis were severe hemorrhages of unknown cause requiring surgery – for example digestive bleeding needing endoscopic treatment.”
Breaking bleeding severity down by Bleeding Academic Research Consortium (BARC) criteria, the investigators found that most patients had relatively mild bleeding episodes categorized as BARC 1 or 2, with about half of all bleeding falling into the BARC 1 category.
Still, the 436 patients who had BARC 2 bleeding had a hazard ratio of 4.88 for cancer diagnosis, and the 71 BARC 3A patients saw the HR climb to 7.30. The risk for cancer subsequent to bleeding peaked at BARC 3B, with a HR of 12.29 for these 46 individuals (P less than .001 for all). Just 37 patients experienced BARC 3C bleeds, which were associated with a nonsignificant HR of 3.17 for new cancer diagnosis.
Although it’s not known why the post ACS–cancer bleeding association exists, Dr. Munoz Pousa put forward a plausible reason for the link. “A possible explanation is that there is a preexisting subclinical lesion in an organ that is triggered to become cancer by antiplatelet drugs or a stressful situation such as heart attack,” she said in the press release.
Antiplatelet therapy should be taken as prescribed post-ACS, and the physician threshold for further evaluation should be low when a significant spontaneous bleed is seen soon after ACS. “A prompt evaluation of bleeding could be useful for enabling an early detection of cancer in these patients,” said Dr. Munoz Pousa and her colleagues. “Our results suggest that patients should seek medical advice if they experience bleeding after discharge for a heart attack.”
The authors reported no conflicts of interest.
SOURCE: Munoz Pousa, I. et al. ESC Congress 2019, Abstract P677.
PARIS –, according to work presented at the annual congress of the European Society of Cardiology.
Of 3,644 patients discharged with dual-antiplatelet therapy after acute coronary syndrome (ACS), 1,215 (33%) had postdischarge bleeding. Taken together, patients who bled had a hazard ratio (HR) of 3.43 for a new cancer diagnosis (P less than .001).
Of the patients in the post-ACS cohort, 227 were newly diagnosed with cancer after discharge, making up 1% of the patients who did not bleed after discharge, and 3.9% of the patients who experienced postdischarge bleeding. Put another way, “[t]he positive predictive value for cancer diagnosis of post-discharge bleeding was 7.7%,” wrote Isabel Muñoz Pousa, MD, and her colleagues in the poster accompanying the presentation.
This elevated risk for cancer diagnosis was driven primarily by the 827 incidents of spontaneous bleeding; here, the HR was 4.38 (P less than .001). The 389 bleeds occuring after trauma, such as bladder catheterization or a fall, did not carry an increased risk for a new cancer diagnosis.
“Spontaneous post-discharge bleeding in ACS patients is strongly associated with subsequent cancer diagnosis within the first 6 months,” wrote Dr. Muñoz Pousa and her colleagues of the Hospital Universitario Alvaro Cunqueiro, Vigo, Spain. The investigators found a median time of 4.6 months from the bleeding episode to cancer diagnosis.
Of all anatomic locations, genitourinary bleeds were the most strongly associated with new cancer: 228 patients saw a HR of 8.63 for a new cancer diagnosis (P less than .001). Bronchopulmonary bleeds, sustained by 56 patients, carried a HR of 4.26 for new cancer diagnosis, and gastrointestinal bleeds a HR of 3.78 (P = .001 and P less than .001, respectively). Dr. Muñoz Pousa and her coinvestigators aggregated data from patients who had bleeding at other sites and saw no significant association with new cancers in this group of patients.
Though patients were initially discharged on dual-antiplatelet therapy, many patients stopped taking the medication over the mean 56.2 months of follow-up. The risk of bleeding did not differ significantly between those who were taking DAPT and those off DAPT, wrote Dr. Muñoz Pousa and her colleagues, adding: “We found a higher incidence of cancer in the first six months after discharge regardless of whether patients were taking dual-antiplatelet therapy or not.”
In their statistical analysis, Dr. Muñoz Pousa and colleagues adjusted for potential confounders, and looked at the effect of bleeding as a time-varying covariate on subsequent cancer diagnosis, using Cox regression models.
“Most of the bleeding episodes in the study were mild,” noted Dr. Munoz Pousa in a press statement. However, she said, “The bleeding events more strongly related with a new cancer diagnosis were severe hemorrhages of unknown cause requiring surgery – for example digestive bleeding needing endoscopic treatment.”
Breaking bleeding severity down by Bleeding Academic Research Consortium (BARC) criteria, the investigators found that most patients had relatively mild bleeding episodes categorized as BARC 1 or 2, with about half of all bleeding falling into the BARC 1 category.
Still, the 436 patients who had BARC 2 bleeding had a hazard ratio of 4.88 for cancer diagnosis, and the 71 BARC 3A patients saw the HR climb to 7.30. The risk for cancer subsequent to bleeding peaked at BARC 3B, with a HR of 12.29 for these 46 individuals (P less than .001 for all). Just 37 patients experienced BARC 3C bleeds, which were associated with a nonsignificant HR of 3.17 for new cancer diagnosis.
Although it’s not known why the post ACS–cancer bleeding association exists, Dr. Munoz Pousa put forward a plausible reason for the link. “A possible explanation is that there is a preexisting subclinical lesion in an organ that is triggered to become cancer by antiplatelet drugs or a stressful situation such as heart attack,” she said in the press release.
Antiplatelet therapy should be taken as prescribed post-ACS, and the physician threshold for further evaluation should be low when a significant spontaneous bleed is seen soon after ACS. “A prompt evaluation of bleeding could be useful for enabling an early detection of cancer in these patients,” said Dr. Munoz Pousa and her colleagues. “Our results suggest that patients should seek medical advice if they experience bleeding after discharge for a heart attack.”
The authors reported no conflicts of interest.
SOURCE: Munoz Pousa, I. et al. ESC Congress 2019, Abstract P677.
FROM ESC CONGRESS 2019
Over decades, low physical activity boosts mortality risk
PARIS – , according to results from a prospective cohort study that followed more than 23,000 adults for over 2 decades.
“Individuals who remained physically inactive, or who decreased their physical activity over 22 years, had substantially increased risk of dying from all causes, and from cardiovascular disease,” Trine Moholdt, PhD, said at a press conference at the annual congress of the European Society of Cardiology.
“The bad news is that sustained inactivity was associated with a 99% increase in all-cause mortality and 168% increase in cardiovascular deaths” compared with sustained physical activity, she said.
The news was similarly bad for individuals who had been highly active and then became inactive; this cohort had an increase in all-cause mortality of 116% and sustained a 173% increase in cardiovascular deaths. “Previous activity levels – they don’t count. You have to keep it up,” said Dr. Moholdt, speaking in a video interview.
However, the risk associated with inactivity was attenuated for those patients who became more active over the course of the study period; their risk was still higher than that of those who had sustained activity, but lower than those who remained inactive. “It’s never too late to start being physically active,” said Dr. Moholdt.
All groups were compared with individuals who remained highly active over the study period; this reference group had the lowest risk of both cardiovascular and all-cause death.
Dr. Moholdt noted a limitation of most previous research into how physical activity relates to cardiovascular and all-cause mortality: Data are obtained just at baseline, and then associated with a downstream outcome. “But people change!” she said, so it’s important to track how activity levels change over time.
To that end, the Nord-Trøndelag Health Study (HUNT study) measured activity levels for 23,156 participants at two points, and then assessed cardiovascular and all-cause mortality, over a period of 22 years.
Dr. Moholdt, head of the Exercise, Cardiometabolic Health and Reproduction research group at Norwegian University of Science and Technology, Trondheim, and her collaborators asked individuals about physical activity in 1985, and again in 2007. At each time point, investigators asked participants to report how many hours per week they spent in “mosjon,” the Norwegian word for “motion”; Dr. Moholdt explained that the word carries the connotation of purposeful, health-promoting physical activity.
Individuals were grouped into one of three activity levels at each time point: Inactive participants reported no purposeful physical activity, moderately active participants reported less than 2 hours per week of this activity, and the most highly active group was active for 2 or more hours per week.
Patients who were in each of the three activity groupings at baseline might have changed their activity levels by the second assessment, so the investigators tracked a total of nine categories of exercise trends over time.
The mean age of participants in the Nord-Trøndelag Health Study (HUNT study) was 39 years, and the mean body mass index was 24 kg/m2. Of the 23,156 participants, 12,665 were women. Dr. Moholdt and her colleagues used statistical analysis to adjust for age, sex, body mass index, smoking, educational status, and systolic blood pressure.
However, Dr. Moholdt acknowledged at the press conference that comorbidities not captured in the study design might impact changes in activity levels, particularly for formerly highly active patients who became inactive over the study period.
The study was presented in a poster session at the congress. Dr. Moholdt reported no conflicts of interest. The study was funded by Health Central Norway (Helse-Midt Norge), a state entity that operates health care facilities in the region of Norway where the HUNT study was conducted.
SOURCE: Moholdt T. et al. ESC Congress 2019, Abstract P627.
PARIS – , according to results from a prospective cohort study that followed more than 23,000 adults for over 2 decades.
“Individuals who remained physically inactive, or who decreased their physical activity over 22 years, had substantially increased risk of dying from all causes, and from cardiovascular disease,” Trine Moholdt, PhD, said at a press conference at the annual congress of the European Society of Cardiology.
“The bad news is that sustained inactivity was associated with a 99% increase in all-cause mortality and 168% increase in cardiovascular deaths” compared with sustained physical activity, she said.
The news was similarly bad for individuals who had been highly active and then became inactive; this cohort had an increase in all-cause mortality of 116% and sustained a 173% increase in cardiovascular deaths. “Previous activity levels – they don’t count. You have to keep it up,” said Dr. Moholdt, speaking in a video interview.
However, the risk associated with inactivity was attenuated for those patients who became more active over the course of the study period; their risk was still higher than that of those who had sustained activity, but lower than those who remained inactive. “It’s never too late to start being physically active,” said Dr. Moholdt.
All groups were compared with individuals who remained highly active over the study period; this reference group had the lowest risk of both cardiovascular and all-cause death.
Dr. Moholdt noted a limitation of most previous research into how physical activity relates to cardiovascular and all-cause mortality: Data are obtained just at baseline, and then associated with a downstream outcome. “But people change!” she said, so it’s important to track how activity levels change over time.
To that end, the Nord-Trøndelag Health Study (HUNT study) measured activity levels for 23,156 participants at two points, and then assessed cardiovascular and all-cause mortality, over a period of 22 years.
Dr. Moholdt, head of the Exercise, Cardiometabolic Health and Reproduction research group at Norwegian University of Science and Technology, Trondheim, and her collaborators asked individuals about physical activity in 1985, and again in 2007. At each time point, investigators asked participants to report how many hours per week they spent in “mosjon,” the Norwegian word for “motion”; Dr. Moholdt explained that the word carries the connotation of purposeful, health-promoting physical activity.
Individuals were grouped into one of three activity levels at each time point: Inactive participants reported no purposeful physical activity, moderately active participants reported less than 2 hours per week of this activity, and the most highly active group was active for 2 or more hours per week.
Patients who were in each of the three activity groupings at baseline might have changed their activity levels by the second assessment, so the investigators tracked a total of nine categories of exercise trends over time.
The mean age of participants in the Nord-Trøndelag Health Study (HUNT study) was 39 years, and the mean body mass index was 24 kg/m2. Of the 23,156 participants, 12,665 were women. Dr. Moholdt and her colleagues used statistical analysis to adjust for age, sex, body mass index, smoking, educational status, and systolic blood pressure.
However, Dr. Moholdt acknowledged at the press conference that comorbidities not captured in the study design might impact changes in activity levels, particularly for formerly highly active patients who became inactive over the study period.
The study was presented in a poster session at the congress. Dr. Moholdt reported no conflicts of interest. The study was funded by Health Central Norway (Helse-Midt Norge), a state entity that operates health care facilities in the region of Norway where the HUNT study was conducted.
SOURCE: Moholdt T. et al. ESC Congress 2019, Abstract P627.
PARIS – , according to results from a prospective cohort study that followed more than 23,000 adults for over 2 decades.
“Individuals who remained physically inactive, or who decreased their physical activity over 22 years, had substantially increased risk of dying from all causes, and from cardiovascular disease,” Trine Moholdt, PhD, said at a press conference at the annual congress of the European Society of Cardiology.
“The bad news is that sustained inactivity was associated with a 99% increase in all-cause mortality and 168% increase in cardiovascular deaths” compared with sustained physical activity, she said.
The news was similarly bad for individuals who had been highly active and then became inactive; this cohort had an increase in all-cause mortality of 116% and sustained a 173% increase in cardiovascular deaths. “Previous activity levels – they don’t count. You have to keep it up,” said Dr. Moholdt, speaking in a video interview.
However, the risk associated with inactivity was attenuated for those patients who became more active over the course of the study period; their risk was still higher than that of those who had sustained activity, but lower than those who remained inactive. “It’s never too late to start being physically active,” said Dr. Moholdt.
All groups were compared with individuals who remained highly active over the study period; this reference group had the lowest risk of both cardiovascular and all-cause death.
Dr. Moholdt noted a limitation of most previous research into how physical activity relates to cardiovascular and all-cause mortality: Data are obtained just at baseline, and then associated with a downstream outcome. “But people change!” she said, so it’s important to track how activity levels change over time.
To that end, the Nord-Trøndelag Health Study (HUNT study) measured activity levels for 23,156 participants at two points, and then assessed cardiovascular and all-cause mortality, over a period of 22 years.
Dr. Moholdt, head of the Exercise, Cardiometabolic Health and Reproduction research group at Norwegian University of Science and Technology, Trondheim, and her collaborators asked individuals about physical activity in 1985, and again in 2007. At each time point, investigators asked participants to report how many hours per week they spent in “mosjon,” the Norwegian word for “motion”; Dr. Moholdt explained that the word carries the connotation of purposeful, health-promoting physical activity.
Individuals were grouped into one of three activity levels at each time point: Inactive participants reported no purposeful physical activity, moderately active participants reported less than 2 hours per week of this activity, and the most highly active group was active for 2 or more hours per week.
Patients who were in each of the three activity groupings at baseline might have changed their activity levels by the second assessment, so the investigators tracked a total of nine categories of exercise trends over time.
The mean age of participants in the Nord-Trøndelag Health Study (HUNT study) was 39 years, and the mean body mass index was 24 kg/m2. Of the 23,156 participants, 12,665 were women. Dr. Moholdt and her colleagues used statistical analysis to adjust for age, sex, body mass index, smoking, educational status, and systolic blood pressure.
However, Dr. Moholdt acknowledged at the press conference that comorbidities not captured in the study design might impact changes in activity levels, particularly for formerly highly active patients who became inactive over the study period.
The study was presented in a poster session at the congress. Dr. Moholdt reported no conflicts of interest. The study was funded by Health Central Norway (Helse-Midt Norge), a state entity that operates health care facilities in the region of Norway where the HUNT study was conducted.
SOURCE: Moholdt T. et al. ESC Congress 2019, Abstract P627.
AT THE ESC CONGRESS 2019
In vasculitis, the skin tells the story
MILAN – , Robert Micheletti, MD, said at the World Congress of Dermatology.
In granulomatous vasculitis, histiocytes and giant cells can play a significant role, explained Dr. Micheletti, director of the cutaneous vasculitis clinic at the University of Pennsylvania, Philadelphia. The condition may be secondary to an autoimmune disease such as lupus erythematosus or RA; a granulomatous disease such as Crohn’s disease or sarcoidosis; infections such as tuberculosis, a fungal disease, or herpes or zoster viruses, or lymphoma, Dr. Micheletti said.
However, a primary systemic vasculitis such as granulomatosis with polyangiitis (GPA; formerly known as Wegener’s polyangiitis) or eosinophilic granulomatosis with polyangiitis (EGPA; also known as Churg-Strauss vasculitis), giant cell arteritis, or Takayasu arteritis may also be responsible, he said. Occasionally, the culprit can also be a drug-induced vasculitis.
The physical examination gives clues to the size of involved vessels, which in turn helps to classify the vasculitis, Dr. Micheletti said.
When vasculitis affects small vessels, the skin findings will be palpable purpura, urticarial papules, vesicles, and petechiae, he said, adding that “The small vessel involvement accounts for the small size of the lesions, and complement cascade and inflammation account for the palpability of the lesions and the symptomatology.” As red blood cells extravasate from the affected vessels, nonblanching purpura develop, and gravity’s effect on the deposition of immune complex material dictates how lesions are distributed.
“Manifestations more typical of medium vessel vasculitis include subcutaneous nodules, livedo reticularis, retiform purpura, larger hemorrhagic bullae, and more significant ulceration and necrosis,” he said. “If such lesions are seen, suspect medium-vessel vasculitis or vasculitis overlapping small and medium vessels.” Cutaneous or systemic polyarteritis nodosa, antineutrophilic cytoplasmic autoantibody (ANCA)–associated vasculitis, and cryoglobulinemic vasculitis are examples, he added.
The particularities of renal manifestations of vasculitis also offer clues to the vessels involved. When a vasculitis patient has glomerulonephritis, suspect small-vessel involvement, Dr. Micheletti said. However, vasculitis affecting medium-sized vessels will cause renovascular hypertension and, potentially renal arterial aneurysms.
Nerves are typically spared in small-vessel vasculitis, while wrist or foot drop can be seen in mononeuritis multiplex.
Recently, the Diagnostic and Classification Criteria in Vasculitis Study (DCVAS) looked at more than 6,800 patients at over 130 sites around the world, proposing new classification criteria for ANCA-associated vasculitis (AAV) and large-vessel vasculitis. The study found that skin findings are common in AAV, with 30%-50% of cases presenting initially with skin lesions. Petechiae and/or purpura are the most common of the skin manifestations, he said. By contrast, for EGPA, allergic and nonspecific findings were the most common findings.
Although skin biopsy can confirm the diagnosis in up to 94% of AAV cases, it’s underutilized and performed in less than half (24%-44%) of cases, Dr. Micheletti said. The study’s findings “demonstrate the importance of a good skin exam, as well as its utility for diagnosis” of vasculitis, he said.
An additional finding form the DCVAS study was that skin lesions can give clues to severity of vasculitis: “Among 1,184 patients with ANCA-associated vasculitis, those with cutaneous involvement were more likely to have systemic manifestations of disease, more likely to have such severe manifestations as glomerulonephritis, alveolar hemorrhage, and mononeuritis,” said Dr. Micheletti, with a hazard ratio of 2.0 among those individuals who had EGPA or GPA.
“Skin findings have diagnostic and, potentially, prognostic importance,” he said. “Use the physician exam and your clinical acumen to your advantage,” but always confirm vasculitis with a biopsy. “Clinicopathologic correlation is key.” A simple urinalysis will screen for renal involvement, and is of “paramount importance,” he added.
Dr. Micheletti reported that he had no relevant disclosures.
MILAN – , Robert Micheletti, MD, said at the World Congress of Dermatology.
In granulomatous vasculitis, histiocytes and giant cells can play a significant role, explained Dr. Micheletti, director of the cutaneous vasculitis clinic at the University of Pennsylvania, Philadelphia. The condition may be secondary to an autoimmune disease such as lupus erythematosus or RA; a granulomatous disease such as Crohn’s disease or sarcoidosis; infections such as tuberculosis, a fungal disease, or herpes or zoster viruses, or lymphoma, Dr. Micheletti said.
However, a primary systemic vasculitis such as granulomatosis with polyangiitis (GPA; formerly known as Wegener’s polyangiitis) or eosinophilic granulomatosis with polyangiitis (EGPA; also known as Churg-Strauss vasculitis), giant cell arteritis, or Takayasu arteritis may also be responsible, he said. Occasionally, the culprit can also be a drug-induced vasculitis.
The physical examination gives clues to the size of involved vessels, which in turn helps to classify the vasculitis, Dr. Micheletti said.
When vasculitis affects small vessels, the skin findings will be palpable purpura, urticarial papules, vesicles, and petechiae, he said, adding that “The small vessel involvement accounts for the small size of the lesions, and complement cascade and inflammation account for the palpability of the lesions and the symptomatology.” As red blood cells extravasate from the affected vessels, nonblanching purpura develop, and gravity’s effect on the deposition of immune complex material dictates how lesions are distributed.
“Manifestations more typical of medium vessel vasculitis include subcutaneous nodules, livedo reticularis, retiform purpura, larger hemorrhagic bullae, and more significant ulceration and necrosis,” he said. “If such lesions are seen, suspect medium-vessel vasculitis or vasculitis overlapping small and medium vessels.” Cutaneous or systemic polyarteritis nodosa, antineutrophilic cytoplasmic autoantibody (ANCA)–associated vasculitis, and cryoglobulinemic vasculitis are examples, he added.
The particularities of renal manifestations of vasculitis also offer clues to the vessels involved. When a vasculitis patient has glomerulonephritis, suspect small-vessel involvement, Dr. Micheletti said. However, vasculitis affecting medium-sized vessels will cause renovascular hypertension and, potentially renal arterial aneurysms.
Nerves are typically spared in small-vessel vasculitis, while wrist or foot drop can be seen in mononeuritis multiplex.
Recently, the Diagnostic and Classification Criteria in Vasculitis Study (DCVAS) looked at more than 6,800 patients at over 130 sites around the world, proposing new classification criteria for ANCA-associated vasculitis (AAV) and large-vessel vasculitis. The study found that skin findings are common in AAV, with 30%-50% of cases presenting initially with skin lesions. Petechiae and/or purpura are the most common of the skin manifestations, he said. By contrast, for EGPA, allergic and nonspecific findings were the most common findings.
Although skin biopsy can confirm the diagnosis in up to 94% of AAV cases, it’s underutilized and performed in less than half (24%-44%) of cases, Dr. Micheletti said. The study’s findings “demonstrate the importance of a good skin exam, as well as its utility for diagnosis” of vasculitis, he said.
An additional finding form the DCVAS study was that skin lesions can give clues to severity of vasculitis: “Among 1,184 patients with ANCA-associated vasculitis, those with cutaneous involvement were more likely to have systemic manifestations of disease, more likely to have such severe manifestations as glomerulonephritis, alveolar hemorrhage, and mononeuritis,” said Dr. Micheletti, with a hazard ratio of 2.0 among those individuals who had EGPA or GPA.
“Skin findings have diagnostic and, potentially, prognostic importance,” he said. “Use the physician exam and your clinical acumen to your advantage,” but always confirm vasculitis with a biopsy. “Clinicopathologic correlation is key.” A simple urinalysis will screen for renal involvement, and is of “paramount importance,” he added.
Dr. Micheletti reported that he had no relevant disclosures.
MILAN – , Robert Micheletti, MD, said at the World Congress of Dermatology.
In granulomatous vasculitis, histiocytes and giant cells can play a significant role, explained Dr. Micheletti, director of the cutaneous vasculitis clinic at the University of Pennsylvania, Philadelphia. The condition may be secondary to an autoimmune disease such as lupus erythematosus or RA; a granulomatous disease such as Crohn’s disease or sarcoidosis; infections such as tuberculosis, a fungal disease, or herpes or zoster viruses, or lymphoma, Dr. Micheletti said.
However, a primary systemic vasculitis such as granulomatosis with polyangiitis (GPA; formerly known as Wegener’s polyangiitis) or eosinophilic granulomatosis with polyangiitis (EGPA; also known as Churg-Strauss vasculitis), giant cell arteritis, or Takayasu arteritis may also be responsible, he said. Occasionally, the culprit can also be a drug-induced vasculitis.
The physical examination gives clues to the size of involved vessels, which in turn helps to classify the vasculitis, Dr. Micheletti said.
When vasculitis affects small vessels, the skin findings will be palpable purpura, urticarial papules, vesicles, and petechiae, he said, adding that “The small vessel involvement accounts for the small size of the lesions, and complement cascade and inflammation account for the palpability of the lesions and the symptomatology.” As red blood cells extravasate from the affected vessels, nonblanching purpura develop, and gravity’s effect on the deposition of immune complex material dictates how lesions are distributed.
“Manifestations more typical of medium vessel vasculitis include subcutaneous nodules, livedo reticularis, retiform purpura, larger hemorrhagic bullae, and more significant ulceration and necrosis,” he said. “If such lesions are seen, suspect medium-vessel vasculitis or vasculitis overlapping small and medium vessels.” Cutaneous or systemic polyarteritis nodosa, antineutrophilic cytoplasmic autoantibody (ANCA)–associated vasculitis, and cryoglobulinemic vasculitis are examples, he added.
The particularities of renal manifestations of vasculitis also offer clues to the vessels involved. When a vasculitis patient has glomerulonephritis, suspect small-vessel involvement, Dr. Micheletti said. However, vasculitis affecting medium-sized vessels will cause renovascular hypertension and, potentially renal arterial aneurysms.
Nerves are typically spared in small-vessel vasculitis, while wrist or foot drop can be seen in mononeuritis multiplex.
Recently, the Diagnostic and Classification Criteria in Vasculitis Study (DCVAS) looked at more than 6,800 patients at over 130 sites around the world, proposing new classification criteria for ANCA-associated vasculitis (AAV) and large-vessel vasculitis. The study found that skin findings are common in AAV, with 30%-50% of cases presenting initially with skin lesions. Petechiae and/or purpura are the most common of the skin manifestations, he said. By contrast, for EGPA, allergic and nonspecific findings were the most common findings.
Although skin biopsy can confirm the diagnosis in up to 94% of AAV cases, it’s underutilized and performed in less than half (24%-44%) of cases, Dr. Micheletti said. The study’s findings “demonstrate the importance of a good skin exam, as well as its utility for diagnosis” of vasculitis, he said.
An additional finding form the DCVAS study was that skin lesions can give clues to severity of vasculitis: “Among 1,184 patients with ANCA-associated vasculitis, those with cutaneous involvement were more likely to have systemic manifestations of disease, more likely to have such severe manifestations as glomerulonephritis, alveolar hemorrhage, and mononeuritis,” said Dr. Micheletti, with a hazard ratio of 2.0 among those individuals who had EGPA or GPA.
“Skin findings have diagnostic and, potentially, prognostic importance,” he said. “Use the physician exam and your clinical acumen to your advantage,” but always confirm vasculitis with a biopsy. “Clinicopathologic correlation is key.” A simple urinalysis will screen for renal involvement, and is of “paramount importance,” he added.
Dr. Micheletti reported that he had no relevant disclosures.
AT WCD2019
FDA panel backs Descovy as HIV PrEP for men and transgender women who have sex with men
The Food and Drug Administration’s Antimicrobial Drugs Advisory Committee backed the fixed dose combination of emtricitabine and tenofovir alafenamide (TAF; Descovy, Gilead) for pre-exposure prophylaxis (PrEP) against HIV for men and transgender women who have sex with men.
In a discussion after a 16-2 vote, committee members cited analysis by the study’s sponsor and the FDA showing efficacy and a generally good safety profile in the DISCOVER trial, the single new clinical trial conducted to support TAF’s use for pre-exposure prophylaxis (PrEP).
However, this trial included no cisgender women; the sponsor asked for approval based primarily on extrapolation from the DISCOVER results and previous results with tenofovir disoproxil fumarate (TDF) in cisgender women. Both formulations of tenofovir are prodrugs and converted to tenofovir diphosphate intracellularly in peripheral blood mononuclear cells, though many aspects of their pharmacokinetics differ.
The committee voted 10-8 against the proposition that these data supported an indication of TAF for PrEP in cisgender women, in a narrowly worded question from the FDA.
Many members who voted on either side of the question had strongly worded reservations about the lack of data for cisgender women. Said committee chair Lindsey R. Baden, MD, director of the infectious disease service at Dana-Farber Cancer Institute, Boston, who voted against the indication for cisgender women, “We’ve failed women. To be at this point and not have the data to guide decision-making is a shame on all of us.”
Ighovwerha Ofotokun, MD, who voted yes, concurred: “I agree it is a terrible failure that the agency, as well as the sponsor, would come to this committee with a lack of data on women.” But for Dr. Ofotokun, a professor of infectious diseases at Emory University, Atlanta, not including cisgender women in the approval was a distasteful proposition. “Creating a two-tier prevention and treatment hierarchy would not be helpful. We should remind ourselves that there are more women living with HIV in the world than there are men, and the risk of new HIV infection is higher among women than among men, if you look at this globally,” he said.
“I find it disrespectful and an issue of research equity. Women deserve the same quality of data about the safety and efficacy of the drugs they are exposed to that men get and that is not the situation we find ourselves in at the moment,” said Dawn K. Smith, MD, MPH, a lead scientist at the Centers for Disease Control and Prevention (CDC), Atlanta, who voted against approval for cisgender women.
Michael Green, MD, MPH, professor of pediatrics, surgery and clinical and translational science at the University of Pittsburgh, echoed the frustration of many committee members when he said, “I voted yes, almost abstained, then almost voted no.” He, along with all who voted yes, emphasized the importance of mandatory postmarketing studies in cisgender women to ensure efficacy data are obtained.
Transgender women made up only about 1% of the DISCOVER population, a fact that also gave many committee members pause.
If TAF is approved, labeling and package materials should be clear that the data support only noninferiority, not superiority, compared with TDF, said several advisory committee members who voted for approval for men and transgender women who have sex with men. “My expectation of this approval is that it should be marketed responsibly from the perspective of not creating these disparities and having Truvada be a drug for poor people and Descovy be a drug for rich people,” said Demetre Dasklalakis, MD, assistant commissioner of the Bureau of HIV/AIDS Prevention and Control at the city of New York’s Department of Health and Hygiene, and of the Icahn School of Medicine at Mount Sinai, N.Y. Truvada is slated to be offered as a generic drug in 2020, according to a Securities and Exchange Commission filing by Gilead Sciences.
The CDC reported earlier in 2019 that rates of new HIV infections have plateaued in recent years. Uptake of PrEP has been particularly low among at-risk members of minority populations, in rural areas, and in the South, according to a CDC report.
The DISCOVER trial is a 96-week ongoing trial to test TAF’s noninferiority to a fixed-drug combination of emcitrabine and tenofovir dimethyl fumarate (TDF; Truvada, Gilead) for PrEP. Both drugs are already approved to treat HIV infection, and TDF is approved for PrEP. Non-inferiority was preestablished at a rate ratio of HIV incidence of 1.62 (TAF:TDF) between the two study arms.
DISCOVER has enrolled 5,387 men and transgender women who have sex with men and are deemed at high risk for HIV, and found an incidence rate ratio of 0.47, with the upper bound of the confidence interval at 1.15. Since this figure was less than the prespecified noninferiority margin, both Gilead presenters and the FDA agreed, TAF’s noninferiority for efficacy was established.
Characteristics were similar between patients in the TAF arm (N = 2,694) and the TDF arm (N = 2,693). About 60% of patients in each arm reported having receptive anal sex with at least two partners in the previous 12 weeks, and recent rectal gonorrhea, syphilis, and chlamydia rates were 9-13% at baseline. Two thirds of participants reported recreational drug use, and about one in four reported binge drinking.
Sexual behavior and sexually transmitted infection rates continued generally unchanged from baseline during the study period.
The median age was 34 years, and most participants (84%) were white. Black participants made up 9% of the study population, and about 25% were of Hispanic or Latin ethnic origin.
Known decreases in bone mineral density occur with TDF; these were not seen with TAF, and bone mineral density increased while on TAF for the DISCOVER population aged 19-25 years.
Renal biomarkers of concern with TDF included two proteins linked with proximal tubule dysfunction, as well as estimated glomerular filtration rate. According to the sponsor’s analysis, eGFR fell by 2.3 mL/min for the TAF group, compared with a 1.8 mL/min rise while on TDF (P less than .001). Changes of similar statistical significance were seen for proximal tubular proteinuria. Also, improvements were seen in renal measures for the subset of patients enrolled who were on TDF PrEP at baseline but switched to TAF, in a prespecified subgroup analysis.
However, patients who were on TDF had a significant decrease in total cholesterol and both low- and high-density lipoprotein cholesterol compared with those on TAF, who had minimal changes or slight increases in lipids (P less than .001 for all). Triglycerides rose for those on TAF and remained unchanged for those on TDF (P = .002).
The PrEP indication sought by Gilead includes adults and adolescents, defined as those who weigh more than 35 kg. A nonvoting question put before the committee asked whether the totality of tenofovir data supported an indication of TAF for cisgender men who have insertive vaginal sex; though this extrapolation didn’t give the committee as much pause as the request for approval in cisgender women, they cited similar concerns and noted that cervicovaginal mucosa are different in many ways from rectal mucosa.
The study included no cisgender women, for a host of reasons cited by the sponsor and the FDA. These included high nonadherence rates among this population, relatively lower HIV infection rates among cisgender women in the United States, and mixed efficacy results in previous tenofovir clinical trials; the latter point made establishing a noninferiority margin problematic, according to the FDA.
For Dr. Baden, “The optics of approval for population A but not for population B are problematic.” Speaking to both the sponsor and the FDA, he said, “Everyone agrees there needs to be actual data. Please do the study as quickly as possible.” What’s needed is the collective will to make it happen, he added: “I don’t accept that it’s too big, too hard, too difficult.”
The FDA usually follows the recommendations of its advisory committees.
This article was updated 8/8/19.
The Food and Drug Administration’s Antimicrobial Drugs Advisory Committee backed the fixed dose combination of emtricitabine and tenofovir alafenamide (TAF; Descovy, Gilead) for pre-exposure prophylaxis (PrEP) against HIV for men and transgender women who have sex with men.
In a discussion after a 16-2 vote, committee members cited analysis by the study’s sponsor and the FDA showing efficacy and a generally good safety profile in the DISCOVER trial, the single new clinical trial conducted to support TAF’s use for pre-exposure prophylaxis (PrEP).
However, this trial included no cisgender women; the sponsor asked for approval based primarily on extrapolation from the DISCOVER results and previous results with tenofovir disoproxil fumarate (TDF) in cisgender women. Both formulations of tenofovir are prodrugs and converted to tenofovir diphosphate intracellularly in peripheral blood mononuclear cells, though many aspects of their pharmacokinetics differ.
The committee voted 10-8 against the proposition that these data supported an indication of TAF for PrEP in cisgender women, in a narrowly worded question from the FDA.
Many members who voted on either side of the question had strongly worded reservations about the lack of data for cisgender women. Said committee chair Lindsey R. Baden, MD, director of the infectious disease service at Dana-Farber Cancer Institute, Boston, who voted against the indication for cisgender women, “We’ve failed women. To be at this point and not have the data to guide decision-making is a shame on all of us.”
Ighovwerha Ofotokun, MD, who voted yes, concurred: “I agree it is a terrible failure that the agency, as well as the sponsor, would come to this committee with a lack of data on women.” But for Dr. Ofotokun, a professor of infectious diseases at Emory University, Atlanta, not including cisgender women in the approval was a distasteful proposition. “Creating a two-tier prevention and treatment hierarchy would not be helpful. We should remind ourselves that there are more women living with HIV in the world than there are men, and the risk of new HIV infection is higher among women than among men, if you look at this globally,” he said.
“I find it disrespectful and an issue of research equity. Women deserve the same quality of data about the safety and efficacy of the drugs they are exposed to that men get and that is not the situation we find ourselves in at the moment,” said Dawn K. Smith, MD, MPH, a lead scientist at the Centers for Disease Control and Prevention (CDC), Atlanta, who voted against approval for cisgender women.
Michael Green, MD, MPH, professor of pediatrics, surgery and clinical and translational science at the University of Pittsburgh, echoed the frustration of many committee members when he said, “I voted yes, almost abstained, then almost voted no.” He, along with all who voted yes, emphasized the importance of mandatory postmarketing studies in cisgender women to ensure efficacy data are obtained.
Transgender women made up only about 1% of the DISCOVER population, a fact that also gave many committee members pause.
If TAF is approved, labeling and package materials should be clear that the data support only noninferiority, not superiority, compared with TDF, said several advisory committee members who voted for approval for men and transgender women who have sex with men. “My expectation of this approval is that it should be marketed responsibly from the perspective of not creating these disparities and having Truvada be a drug for poor people and Descovy be a drug for rich people,” said Demetre Dasklalakis, MD, assistant commissioner of the Bureau of HIV/AIDS Prevention and Control at the city of New York’s Department of Health and Hygiene, and of the Icahn School of Medicine at Mount Sinai, N.Y. Truvada is slated to be offered as a generic drug in 2020, according to a Securities and Exchange Commission filing by Gilead Sciences.
The CDC reported earlier in 2019 that rates of new HIV infections have plateaued in recent years. Uptake of PrEP has been particularly low among at-risk members of minority populations, in rural areas, and in the South, according to a CDC report.
The DISCOVER trial is a 96-week ongoing trial to test TAF’s noninferiority to a fixed-drug combination of emcitrabine and tenofovir dimethyl fumarate (TDF; Truvada, Gilead) for PrEP. Both drugs are already approved to treat HIV infection, and TDF is approved for PrEP. Non-inferiority was preestablished at a rate ratio of HIV incidence of 1.62 (TAF:TDF) between the two study arms.
DISCOVER has enrolled 5,387 men and transgender women who have sex with men and are deemed at high risk for HIV, and found an incidence rate ratio of 0.47, with the upper bound of the confidence interval at 1.15. Since this figure was less than the prespecified noninferiority margin, both Gilead presenters and the FDA agreed, TAF’s noninferiority for efficacy was established.
Characteristics were similar between patients in the TAF arm (N = 2,694) and the TDF arm (N = 2,693). About 60% of patients in each arm reported having receptive anal sex with at least two partners in the previous 12 weeks, and recent rectal gonorrhea, syphilis, and chlamydia rates were 9-13% at baseline. Two thirds of participants reported recreational drug use, and about one in four reported binge drinking.
Sexual behavior and sexually transmitted infection rates continued generally unchanged from baseline during the study period.
The median age was 34 years, and most participants (84%) were white. Black participants made up 9% of the study population, and about 25% were of Hispanic or Latin ethnic origin.
Known decreases in bone mineral density occur with TDF; these were not seen with TAF, and bone mineral density increased while on TAF for the DISCOVER population aged 19-25 years.
Renal biomarkers of concern with TDF included two proteins linked with proximal tubule dysfunction, as well as estimated glomerular filtration rate. According to the sponsor’s analysis, eGFR fell by 2.3 mL/min for the TAF group, compared with a 1.8 mL/min rise while on TDF (P less than .001). Changes of similar statistical significance were seen for proximal tubular proteinuria. Also, improvements were seen in renal measures for the subset of patients enrolled who were on TDF PrEP at baseline but switched to TAF, in a prespecified subgroup analysis.
However, patients who were on TDF had a significant decrease in total cholesterol and both low- and high-density lipoprotein cholesterol compared with those on TAF, who had minimal changes or slight increases in lipids (P less than .001 for all). Triglycerides rose for those on TAF and remained unchanged for those on TDF (P = .002).
The PrEP indication sought by Gilead includes adults and adolescents, defined as those who weigh more than 35 kg. A nonvoting question put before the committee asked whether the totality of tenofovir data supported an indication of TAF for cisgender men who have insertive vaginal sex; though this extrapolation didn’t give the committee as much pause as the request for approval in cisgender women, they cited similar concerns and noted that cervicovaginal mucosa are different in many ways from rectal mucosa.
The study included no cisgender women, for a host of reasons cited by the sponsor and the FDA. These included high nonadherence rates among this population, relatively lower HIV infection rates among cisgender women in the United States, and mixed efficacy results in previous tenofovir clinical trials; the latter point made establishing a noninferiority margin problematic, according to the FDA.
For Dr. Baden, “The optics of approval for population A but not for population B are problematic.” Speaking to both the sponsor and the FDA, he said, “Everyone agrees there needs to be actual data. Please do the study as quickly as possible.” What’s needed is the collective will to make it happen, he added: “I don’t accept that it’s too big, too hard, too difficult.”
The FDA usually follows the recommendations of its advisory committees.
This article was updated 8/8/19.
The Food and Drug Administration’s Antimicrobial Drugs Advisory Committee backed the fixed dose combination of emtricitabine and tenofovir alafenamide (TAF; Descovy, Gilead) for pre-exposure prophylaxis (PrEP) against HIV for men and transgender women who have sex with men.
In a discussion after a 16-2 vote, committee members cited analysis by the study’s sponsor and the FDA showing efficacy and a generally good safety profile in the DISCOVER trial, the single new clinical trial conducted to support TAF’s use for pre-exposure prophylaxis (PrEP).
However, this trial included no cisgender women; the sponsor asked for approval based primarily on extrapolation from the DISCOVER results and previous results with tenofovir disoproxil fumarate (TDF) in cisgender women. Both formulations of tenofovir are prodrugs and converted to tenofovir diphosphate intracellularly in peripheral blood mononuclear cells, though many aspects of their pharmacokinetics differ.
The committee voted 10-8 against the proposition that these data supported an indication of TAF for PrEP in cisgender women, in a narrowly worded question from the FDA.
Many members who voted on either side of the question had strongly worded reservations about the lack of data for cisgender women. Said committee chair Lindsey R. Baden, MD, director of the infectious disease service at Dana-Farber Cancer Institute, Boston, who voted against the indication for cisgender women, “We’ve failed women. To be at this point and not have the data to guide decision-making is a shame on all of us.”
Ighovwerha Ofotokun, MD, who voted yes, concurred: “I agree it is a terrible failure that the agency, as well as the sponsor, would come to this committee with a lack of data on women.” But for Dr. Ofotokun, a professor of infectious diseases at Emory University, Atlanta, not including cisgender women in the approval was a distasteful proposition. “Creating a two-tier prevention and treatment hierarchy would not be helpful. We should remind ourselves that there are more women living with HIV in the world than there are men, and the risk of new HIV infection is higher among women than among men, if you look at this globally,” he said.
“I find it disrespectful and an issue of research equity. Women deserve the same quality of data about the safety and efficacy of the drugs they are exposed to that men get and that is not the situation we find ourselves in at the moment,” said Dawn K. Smith, MD, MPH, a lead scientist at the Centers for Disease Control and Prevention (CDC), Atlanta, who voted against approval for cisgender women.
Michael Green, MD, MPH, professor of pediatrics, surgery and clinical and translational science at the University of Pittsburgh, echoed the frustration of many committee members when he said, “I voted yes, almost abstained, then almost voted no.” He, along with all who voted yes, emphasized the importance of mandatory postmarketing studies in cisgender women to ensure efficacy data are obtained.
Transgender women made up only about 1% of the DISCOVER population, a fact that also gave many committee members pause.
If TAF is approved, labeling and package materials should be clear that the data support only noninferiority, not superiority, compared with TDF, said several advisory committee members who voted for approval for men and transgender women who have sex with men. “My expectation of this approval is that it should be marketed responsibly from the perspective of not creating these disparities and having Truvada be a drug for poor people and Descovy be a drug for rich people,” said Demetre Dasklalakis, MD, assistant commissioner of the Bureau of HIV/AIDS Prevention and Control at the city of New York’s Department of Health and Hygiene, and of the Icahn School of Medicine at Mount Sinai, N.Y. Truvada is slated to be offered as a generic drug in 2020, according to a Securities and Exchange Commission filing by Gilead Sciences.
The CDC reported earlier in 2019 that rates of new HIV infections have plateaued in recent years. Uptake of PrEP has been particularly low among at-risk members of minority populations, in rural areas, and in the South, according to a CDC report.
The DISCOVER trial is a 96-week ongoing trial to test TAF’s noninferiority to a fixed-drug combination of emcitrabine and tenofovir dimethyl fumarate (TDF; Truvada, Gilead) for PrEP. Both drugs are already approved to treat HIV infection, and TDF is approved for PrEP. Non-inferiority was preestablished at a rate ratio of HIV incidence of 1.62 (TAF:TDF) between the two study arms.
DISCOVER has enrolled 5,387 men and transgender women who have sex with men and are deemed at high risk for HIV, and found an incidence rate ratio of 0.47, with the upper bound of the confidence interval at 1.15. Since this figure was less than the prespecified noninferiority margin, both Gilead presenters and the FDA agreed, TAF’s noninferiority for efficacy was established.
Characteristics were similar between patients in the TAF arm (N = 2,694) and the TDF arm (N = 2,693). About 60% of patients in each arm reported having receptive anal sex with at least two partners in the previous 12 weeks, and recent rectal gonorrhea, syphilis, and chlamydia rates were 9-13% at baseline. Two thirds of participants reported recreational drug use, and about one in four reported binge drinking.
Sexual behavior and sexually transmitted infection rates continued generally unchanged from baseline during the study period.
The median age was 34 years, and most participants (84%) were white. Black participants made up 9% of the study population, and about 25% were of Hispanic or Latin ethnic origin.
Known decreases in bone mineral density occur with TDF; these were not seen with TAF, and bone mineral density increased while on TAF for the DISCOVER population aged 19-25 years.
Renal biomarkers of concern with TDF included two proteins linked with proximal tubule dysfunction, as well as estimated glomerular filtration rate. According to the sponsor’s analysis, eGFR fell by 2.3 mL/min for the TAF group, compared with a 1.8 mL/min rise while on TDF (P less than .001). Changes of similar statistical significance were seen for proximal tubular proteinuria. Also, improvements were seen in renal measures for the subset of patients enrolled who were on TDF PrEP at baseline but switched to TAF, in a prespecified subgroup analysis.
However, patients who were on TDF had a significant decrease in total cholesterol and both low- and high-density lipoprotein cholesterol compared with those on TAF, who had minimal changes or slight increases in lipids (P less than .001 for all). Triglycerides rose for those on TAF and remained unchanged for those on TDF (P = .002).
The PrEP indication sought by Gilead includes adults and adolescents, defined as those who weigh more than 35 kg. A nonvoting question put before the committee asked whether the totality of tenofovir data supported an indication of TAF for cisgender men who have insertive vaginal sex; though this extrapolation didn’t give the committee as much pause as the request for approval in cisgender women, they cited similar concerns and noted that cervicovaginal mucosa are different in many ways from rectal mucosa.
The study included no cisgender women, for a host of reasons cited by the sponsor and the FDA. These included high nonadherence rates among this population, relatively lower HIV infection rates among cisgender women in the United States, and mixed efficacy results in previous tenofovir clinical trials; the latter point made establishing a noninferiority margin problematic, according to the FDA.
For Dr. Baden, “The optics of approval for population A but not for population B are problematic.” Speaking to both the sponsor and the FDA, he said, “Everyone agrees there needs to be actual data. Please do the study as quickly as possible.” What’s needed is the collective will to make it happen, he added: “I don’t accept that it’s too big, too hard, too difficult.”
The FDA usually follows the recommendations of its advisory committees.
This article was updated 8/8/19.
FROM AN FDA ADVISORY COMMITTEE MEETING
Most authors of endoscopy practice guidelines have undisclosed financial conflicts
SAN DIEGO – Authors of endoscopy clinical practice guidelines (CPGs) received many more payments from industry than they disclosed, according to a new review of publicly available data.
Additionally, many of the payments came from pharmaceutical companies or medical device manufacturers whose products were directly related to the practice guideline topic at hand, said Amir Rumann, MD, and coauthors, who presented their findings in a poster session at the annual Digestive Disease Week®.
The researchers found that, of 581 authors listed in 38 CPGs, 127 had initially disclosed payments when the guidelines were published. A search of the federal Open Payments database, however, found that 452 of these authors had payments that they did not disclose in the CPG publication process.
For authors with undisclosed payments, the median value of the total undisclosed amounts was $2,445, from a median of 2.5 unique companies, according to records maintained by the Centers for Medicare & Medicaid Services. The interquartile range for payments was $167-$10,380.
“There is a high burden of undisclosed payments by pharmaceutical and medical device manufacturers to authors of endoscopy guidelines in the United States,” wrote Dr. Rumman and coauthors at the University of Toronto, where Dr. Rumann is a gastroenterology resident.
Of the authors who disclosed payments, 20 (16%) disclosed payments from sources directly related to the CPG in the publication. But the Open Payments database search yielded 314 (54%) disclosed payments that were judged directly related to the CPG topic at hand.
Of the 38 CPGs included in the analysis, 24 were from the American Society for Gastrointestinal Endoscopy (ASGE), and 4 were from the American Gastroenterological Association (AGA). According to the analysis performed by Dr. Rumman and his coauthors, 23 of these guidelines adhered to standards proposed by the National Academy of Medicine for development of “trustworthy” CPGs.
“The prevalence of conflicts of interest in the form of industry payments among physicians is well described in academic literature. A number of studies, including several from our group, have found there is a high burden of these payments among authors and chairs of CPGs in various therapeutic areas,” commented senior author Samir Grover, MD, a gastroenterologist at the University of Toronto. “Additionally, the existing literature has shown that many of these payments go undisclosed in the CPG themselves. This is concerning. Although the presence of these payments doesn’t necessarily indicate any obvious wrongdoing on the part of the recipients, it can undermine public and professional trust in guidelines.”
In its 2011 report, the National Academy of Medicine outlined three criteria for trustworthy guidelines. These include ensuring that committee chairs do not have financial conflicts of interest (COIs), limiting authors who do have financial COIs to less than half of the guideline drafting panel, and disclosing financially motivated relationships between individual health care providers and members of industry. “To our surprise, our findings demonstrated that none of the CPGs we identified met all of these criteria,” noted Dr. Grover, adding that “this finding highlights the importance of accountability at both the contributor level (to ensure conflicts are appropriately declared) and at the level of the sponsoring society (to ensure that guideline committee members and chairs are selected a priori for reasons that include impact of conflicts).”
Dr. Rumann and his colleagues conducted a cross-sectional study, including all endoscopy-related CPGs from AGA and ASGE published from 2014 through 2017. They performed a manual reconciliation between financial COIs disclosed in CPG documents and those reported in the Open Payments database maintained by CMS, which includes data from August 2013 to December 2017. “We decided to focus on CPGs of relevance to endoscopy, as the majority of the work to date has revolved around pharma and not devices, a potentially significant other source for industry payments to physicians,” explained Dr. Grover.
In the Open Payments database, payment types are recorded as general payments, research payments, or ownerships or investments. For each payment transaction, the type, amount, and date of payment are recorded, as is the payer.
In all, 91 individuals appeared as authors 581 times. The median number of CPGs per author was 2 with a range of 1-26.
About 80% of authors had payments reported in the Open Payments database. Though Dr. Grover acknowledged that reporting errors may exist in the Open Payments database, this fact, he said, “highlights the need for greater involvement of physicians in correct declaration of their payments.”
Among the guideline authors, 119 (20.5%) had originally disclosed general payments. However, more than three times that many authors had undisclosed records of general payments that showed up in the Open Payments database query. In all, 399 authors (68.6%) had received general payments, according to the database.
Though all 12 of the ownership or investment payments seen on Open Payments were disclosed, just 40 of 74 research payments were disclosed, said Dr. Rumann and coauthors.
“Given the potential impact of these undisclosed payments on CPGs, stricter policies on conflict of interest disclosures are needed,” they wrote.
When asked whether he would expect change to come from the findings, Dr. Grover replied, “First and foremost, we want to increase the awareness of the issue, among both the health professions and the public. While we believe that more research into COI in general is required, our study, along with similar papers in the field, show that CPGs authors need to be more cognizant of declaration of potential conflicts. In addition to being hopeful that readers of the article will be prompted to exert more diligence in tracking and declaring any payments they have received, we are hopeful that sponsoring societies self-regulate the membership of CPG committees and the choice of chairs in accordance with established criteria to mitigate conflicts.”
Dr. Rumann and other coauthors reported no conflicts of interest. Senior author Samir Grover, MD, reported financial relationships with several pharmaceutical companies.
SOURCE: Rumann A et al. DDW 2019, poster Sa1004.
The authors bring awareness to an important issue. Conflict of interest (COI) in guideline development has received a lot of attention over the past few years. COI, whether actual or perceived, can lead to mistrust of recommendations, limit uptake and dissemination of guidelines, and possibly lead to low-quality care.
As part of the AGA Institute’s mission, the Clinical Guidelines Committee (CGC) is charged with advancing the practice of gastroenterology through developing clinical practice guidelines that promote high-quality, evidence-based care. In accordance with the National Academies of Medicine (formerly Institute of Medicine) report for trustworthy guidelines, the CGC’s COI policy is in agreement with the following standards: more than 50% of guideline members have no financial COI, the methodologist cochair is completely free of COI, and the guideline cochair has no direct clincal practice guideline–relevant financial COI.
Guidelines developed by the AGA CGC are informed by a technical review or evidence synthesis. All panel members considered for the technical review and guideline panel must go through a stringent vetting process, which includes completion of a comprehensive COI disclosure form. All authors are asked to report any financial and intellectual interests from the past 3 years including stocks/stock options, speaking engagements, board and committee memberships, legal testimony, research grants, employment, patents, or intellectual property. A review of the Centers for Medicare & Medicaid Services Open Payments database is also performed. Open Payments is a national disclosure program and public database established in 2014 that reports financial relationships and lists any payment or gift to U.S. health care providers (physicians and teaching hospitals) valued at more than $10. While the AGA strives to form technical review and guideline panels that are free from financial and intellectual COI, technical review panels may, on occasion, include recognized clinical experts who have relationships deemed to be manageable because technical review authors serve as content experts and do not contribute to the actual recommendations in the guideline.
Furthermore, all official journals of the AGA Institute adhere to the standards set forth by the Committee on Publication Ethics and the International Committee of Medical Journal Editors. As such, at the time of publication, a uniform detailed self-report disclosure form is used to publicly disclose all relevant financial and nonfinancial COIs.
In light of the negative impact of perceived COI, substantial efforts have been made by professional organizations and medical editors to ensure proper disclosure of conflicts and the AGA CGC committee strengthened its COI policy further in 2018. The AGA CGC is committing to minimizing panel members with financial and nonfinancial COI and ensuring adequate disclosure and management of COI when present.
Shahnaz Sultan, MD, MHSc, AGAF, chair of the AGA Clinical Guideline Committee, and Yngve Falck-Ytter, MD, AGAF, chair emeritus of the AGA Clinical Guideline Committee.
The authors bring awareness to an important issue. Conflict of interest (COI) in guideline development has received a lot of attention over the past few years. COI, whether actual or perceived, can lead to mistrust of recommendations, limit uptake and dissemination of guidelines, and possibly lead to low-quality care.
As part of the AGA Institute’s mission, the Clinical Guidelines Committee (CGC) is charged with advancing the practice of gastroenterology through developing clinical practice guidelines that promote high-quality, evidence-based care. In accordance with the National Academies of Medicine (formerly Institute of Medicine) report for trustworthy guidelines, the CGC’s COI policy is in agreement with the following standards: more than 50% of guideline members have no financial COI, the methodologist cochair is completely free of COI, and the guideline cochair has no direct clincal practice guideline–relevant financial COI.
Guidelines developed by the AGA CGC are informed by a technical review or evidence synthesis. All panel members considered for the technical review and guideline panel must go through a stringent vetting process, which includes completion of a comprehensive COI disclosure form. All authors are asked to report any financial and intellectual interests from the past 3 years including stocks/stock options, speaking engagements, board and committee memberships, legal testimony, research grants, employment, patents, or intellectual property. A review of the Centers for Medicare & Medicaid Services Open Payments database is also performed. Open Payments is a national disclosure program and public database established in 2014 that reports financial relationships and lists any payment or gift to U.S. health care providers (physicians and teaching hospitals) valued at more than $10. While the AGA strives to form technical review and guideline panels that are free from financial and intellectual COI, technical review panels may, on occasion, include recognized clinical experts who have relationships deemed to be manageable because technical review authors serve as content experts and do not contribute to the actual recommendations in the guideline.
Furthermore, all official journals of the AGA Institute adhere to the standards set forth by the Committee on Publication Ethics and the International Committee of Medical Journal Editors. As such, at the time of publication, a uniform detailed self-report disclosure form is used to publicly disclose all relevant financial and nonfinancial COIs.
In light of the negative impact of perceived COI, substantial efforts have been made by professional organizations and medical editors to ensure proper disclosure of conflicts and the AGA CGC committee strengthened its COI policy further in 2018. The AGA CGC is committing to minimizing panel members with financial and nonfinancial COI and ensuring adequate disclosure and management of COI when present.
Shahnaz Sultan, MD, MHSc, AGAF, chair of the AGA Clinical Guideline Committee, and Yngve Falck-Ytter, MD, AGAF, chair emeritus of the AGA Clinical Guideline Committee.
The authors bring awareness to an important issue. Conflict of interest (COI) in guideline development has received a lot of attention over the past few years. COI, whether actual or perceived, can lead to mistrust of recommendations, limit uptake and dissemination of guidelines, and possibly lead to low-quality care.
As part of the AGA Institute’s mission, the Clinical Guidelines Committee (CGC) is charged with advancing the practice of gastroenterology through developing clinical practice guidelines that promote high-quality, evidence-based care. In accordance with the National Academies of Medicine (formerly Institute of Medicine) report for trustworthy guidelines, the CGC’s COI policy is in agreement with the following standards: more than 50% of guideline members have no financial COI, the methodologist cochair is completely free of COI, and the guideline cochair has no direct clincal practice guideline–relevant financial COI.
Guidelines developed by the AGA CGC are informed by a technical review or evidence synthesis. All panel members considered for the technical review and guideline panel must go through a stringent vetting process, which includes completion of a comprehensive COI disclosure form. All authors are asked to report any financial and intellectual interests from the past 3 years including stocks/stock options, speaking engagements, board and committee memberships, legal testimony, research grants, employment, patents, or intellectual property. A review of the Centers for Medicare & Medicaid Services Open Payments database is also performed. Open Payments is a national disclosure program and public database established in 2014 that reports financial relationships and lists any payment or gift to U.S. health care providers (physicians and teaching hospitals) valued at more than $10. While the AGA strives to form technical review and guideline panels that are free from financial and intellectual COI, technical review panels may, on occasion, include recognized clinical experts who have relationships deemed to be manageable because technical review authors serve as content experts and do not contribute to the actual recommendations in the guideline.
Furthermore, all official journals of the AGA Institute adhere to the standards set forth by the Committee on Publication Ethics and the International Committee of Medical Journal Editors. As such, at the time of publication, a uniform detailed self-report disclosure form is used to publicly disclose all relevant financial and nonfinancial COIs.
In light of the negative impact of perceived COI, substantial efforts have been made by professional organizations and medical editors to ensure proper disclosure of conflicts and the AGA CGC committee strengthened its COI policy further in 2018. The AGA CGC is committing to minimizing panel members with financial and nonfinancial COI and ensuring adequate disclosure and management of COI when present.
Shahnaz Sultan, MD, MHSc, AGAF, chair of the AGA Clinical Guideline Committee, and Yngve Falck-Ytter, MD, AGAF, chair emeritus of the AGA Clinical Guideline Committee.
SAN DIEGO – Authors of endoscopy clinical practice guidelines (CPGs) received many more payments from industry than they disclosed, according to a new review of publicly available data.
Additionally, many of the payments came from pharmaceutical companies or medical device manufacturers whose products were directly related to the practice guideline topic at hand, said Amir Rumann, MD, and coauthors, who presented their findings in a poster session at the annual Digestive Disease Week®.
The researchers found that, of 581 authors listed in 38 CPGs, 127 had initially disclosed payments when the guidelines were published. A search of the federal Open Payments database, however, found that 452 of these authors had payments that they did not disclose in the CPG publication process.
For authors with undisclosed payments, the median value of the total undisclosed amounts was $2,445, from a median of 2.5 unique companies, according to records maintained by the Centers for Medicare & Medicaid Services. The interquartile range for payments was $167-$10,380.
“There is a high burden of undisclosed payments by pharmaceutical and medical device manufacturers to authors of endoscopy guidelines in the United States,” wrote Dr. Rumman and coauthors at the University of Toronto, where Dr. Rumann is a gastroenterology resident.
Of the authors who disclosed payments, 20 (16%) disclosed payments from sources directly related to the CPG in the publication. But the Open Payments database search yielded 314 (54%) disclosed payments that were judged directly related to the CPG topic at hand.
Of the 38 CPGs included in the analysis, 24 were from the American Society for Gastrointestinal Endoscopy (ASGE), and 4 were from the American Gastroenterological Association (AGA). According to the analysis performed by Dr. Rumman and his coauthors, 23 of these guidelines adhered to standards proposed by the National Academy of Medicine for development of “trustworthy” CPGs.
“The prevalence of conflicts of interest in the form of industry payments among physicians is well described in academic literature. A number of studies, including several from our group, have found there is a high burden of these payments among authors and chairs of CPGs in various therapeutic areas,” commented senior author Samir Grover, MD, a gastroenterologist at the University of Toronto. “Additionally, the existing literature has shown that many of these payments go undisclosed in the CPG themselves. This is concerning. Although the presence of these payments doesn’t necessarily indicate any obvious wrongdoing on the part of the recipients, it can undermine public and professional trust in guidelines.”
In its 2011 report, the National Academy of Medicine outlined three criteria for trustworthy guidelines. These include ensuring that committee chairs do not have financial conflicts of interest (COIs), limiting authors who do have financial COIs to less than half of the guideline drafting panel, and disclosing financially motivated relationships between individual health care providers and members of industry. “To our surprise, our findings demonstrated that none of the CPGs we identified met all of these criteria,” noted Dr. Grover, adding that “this finding highlights the importance of accountability at both the contributor level (to ensure conflicts are appropriately declared) and at the level of the sponsoring society (to ensure that guideline committee members and chairs are selected a priori for reasons that include impact of conflicts).”
Dr. Rumann and his colleagues conducted a cross-sectional study, including all endoscopy-related CPGs from AGA and ASGE published from 2014 through 2017. They performed a manual reconciliation between financial COIs disclosed in CPG documents and those reported in the Open Payments database maintained by CMS, which includes data from August 2013 to December 2017. “We decided to focus on CPGs of relevance to endoscopy, as the majority of the work to date has revolved around pharma and not devices, a potentially significant other source for industry payments to physicians,” explained Dr. Grover.
In the Open Payments database, payment types are recorded as general payments, research payments, or ownerships or investments. For each payment transaction, the type, amount, and date of payment are recorded, as is the payer.
In all, 91 individuals appeared as authors 581 times. The median number of CPGs per author was 2 with a range of 1-26.
About 80% of authors had payments reported in the Open Payments database. Though Dr. Grover acknowledged that reporting errors may exist in the Open Payments database, this fact, he said, “highlights the need for greater involvement of physicians in correct declaration of their payments.”
Among the guideline authors, 119 (20.5%) had originally disclosed general payments. However, more than three times that many authors had undisclosed records of general payments that showed up in the Open Payments database query. In all, 399 authors (68.6%) had received general payments, according to the database.
Though all 12 of the ownership or investment payments seen on Open Payments were disclosed, just 40 of 74 research payments were disclosed, said Dr. Rumann and coauthors.
“Given the potential impact of these undisclosed payments on CPGs, stricter policies on conflict of interest disclosures are needed,” they wrote.
When asked whether he would expect change to come from the findings, Dr. Grover replied, “First and foremost, we want to increase the awareness of the issue, among both the health professions and the public. While we believe that more research into COI in general is required, our study, along with similar papers in the field, show that CPGs authors need to be more cognizant of declaration of potential conflicts. In addition to being hopeful that readers of the article will be prompted to exert more diligence in tracking and declaring any payments they have received, we are hopeful that sponsoring societies self-regulate the membership of CPG committees and the choice of chairs in accordance with established criteria to mitigate conflicts.”
Dr. Rumann and other coauthors reported no conflicts of interest. Senior author Samir Grover, MD, reported financial relationships with several pharmaceutical companies.
SOURCE: Rumann A et al. DDW 2019, poster Sa1004.
SAN DIEGO – Authors of endoscopy clinical practice guidelines (CPGs) received many more payments from industry than they disclosed, according to a new review of publicly available data.
Additionally, many of the payments came from pharmaceutical companies or medical device manufacturers whose products were directly related to the practice guideline topic at hand, said Amir Rumann, MD, and coauthors, who presented their findings in a poster session at the annual Digestive Disease Week®.
The researchers found that, of 581 authors listed in 38 CPGs, 127 had initially disclosed payments when the guidelines were published. A search of the federal Open Payments database, however, found that 452 of these authors had payments that they did not disclose in the CPG publication process.
For authors with undisclosed payments, the median value of the total undisclosed amounts was $2,445, from a median of 2.5 unique companies, according to records maintained by the Centers for Medicare & Medicaid Services. The interquartile range for payments was $167-$10,380.
“There is a high burden of undisclosed payments by pharmaceutical and medical device manufacturers to authors of endoscopy guidelines in the United States,” wrote Dr. Rumman and coauthors at the University of Toronto, where Dr. Rumann is a gastroenterology resident.
Of the authors who disclosed payments, 20 (16%) disclosed payments from sources directly related to the CPG in the publication. But the Open Payments database search yielded 314 (54%) disclosed payments that were judged directly related to the CPG topic at hand.
Of the 38 CPGs included in the analysis, 24 were from the American Society for Gastrointestinal Endoscopy (ASGE), and 4 were from the American Gastroenterological Association (AGA). According to the analysis performed by Dr. Rumman and his coauthors, 23 of these guidelines adhered to standards proposed by the National Academy of Medicine for development of “trustworthy” CPGs.
“The prevalence of conflicts of interest in the form of industry payments among physicians is well described in academic literature. A number of studies, including several from our group, have found there is a high burden of these payments among authors and chairs of CPGs in various therapeutic areas,” commented senior author Samir Grover, MD, a gastroenterologist at the University of Toronto. “Additionally, the existing literature has shown that many of these payments go undisclosed in the CPG themselves. This is concerning. Although the presence of these payments doesn’t necessarily indicate any obvious wrongdoing on the part of the recipients, it can undermine public and professional trust in guidelines.”
In its 2011 report, the National Academy of Medicine outlined three criteria for trustworthy guidelines. These include ensuring that committee chairs do not have financial conflicts of interest (COIs), limiting authors who do have financial COIs to less than half of the guideline drafting panel, and disclosing financially motivated relationships between individual health care providers and members of industry. “To our surprise, our findings demonstrated that none of the CPGs we identified met all of these criteria,” noted Dr. Grover, adding that “this finding highlights the importance of accountability at both the contributor level (to ensure conflicts are appropriately declared) and at the level of the sponsoring society (to ensure that guideline committee members and chairs are selected a priori for reasons that include impact of conflicts).”
Dr. Rumann and his colleagues conducted a cross-sectional study, including all endoscopy-related CPGs from AGA and ASGE published from 2014 through 2017. They performed a manual reconciliation between financial COIs disclosed in CPG documents and those reported in the Open Payments database maintained by CMS, which includes data from August 2013 to December 2017. “We decided to focus on CPGs of relevance to endoscopy, as the majority of the work to date has revolved around pharma and not devices, a potentially significant other source for industry payments to physicians,” explained Dr. Grover.
In the Open Payments database, payment types are recorded as general payments, research payments, or ownerships or investments. For each payment transaction, the type, amount, and date of payment are recorded, as is the payer.
In all, 91 individuals appeared as authors 581 times. The median number of CPGs per author was 2 with a range of 1-26.
About 80% of authors had payments reported in the Open Payments database. Though Dr. Grover acknowledged that reporting errors may exist in the Open Payments database, this fact, he said, “highlights the need for greater involvement of physicians in correct declaration of their payments.”
Among the guideline authors, 119 (20.5%) had originally disclosed general payments. However, more than three times that many authors had undisclosed records of general payments that showed up in the Open Payments database query. In all, 399 authors (68.6%) had received general payments, according to the database.
Though all 12 of the ownership or investment payments seen on Open Payments were disclosed, just 40 of 74 research payments were disclosed, said Dr. Rumann and coauthors.
“Given the potential impact of these undisclosed payments on CPGs, stricter policies on conflict of interest disclosures are needed,” they wrote.
When asked whether he would expect change to come from the findings, Dr. Grover replied, “First and foremost, we want to increase the awareness of the issue, among both the health professions and the public. While we believe that more research into COI in general is required, our study, along with similar papers in the field, show that CPGs authors need to be more cognizant of declaration of potential conflicts. In addition to being hopeful that readers of the article will be prompted to exert more diligence in tracking and declaring any payments they have received, we are hopeful that sponsoring societies self-regulate the membership of CPG committees and the choice of chairs in accordance with established criteria to mitigate conflicts.”
Dr. Rumann and other coauthors reported no conflicts of interest. Senior author Samir Grover, MD, reported financial relationships with several pharmaceutical companies.
SOURCE: Rumann A et al. DDW 2019, poster Sa1004.
REPORTING FROM DDW 2019
Clues to eczematous cheilitis may lie in the history
NEW YORK – , but patients may be slow to seek help, Bethanee Schlosser, MD, PhD, said at the American Academy of Dermatology summer meeting.
One of the challenges in helping patients with lip problems is that lips are constantly in motion and constantly interacting with the outside world, said Dr. Schlosser, of the department of dermatology, Northwestern University, Chicago. There’s ongoing low-level trauma with phonation, eating, drinking, and general environmental exposure, she said. Eczematous cheilitis will present with scaling and erythema of the vermilion lips, with lower lip involvement often more pronounced than symptoms on the upper lip. Fissuring and erosion are sometimes, but not always, present as well.
In addition to flaking and redness, Dr. Schlosser noted that patients will complain of dry lips, irritation, itching, and sometimes tingling.
Sorting out the etiology of eczematous cheilitis requires a thorough history. “Ask about habits, such as lip licking, picking, or biting,” she said. Recent dental work, braces, or other appliances for alignment or temporomandibular joint problems can introduce both mechanical irritation and potential allergens, and even musical instruments can be culprits, such as when an oboe reed causes an allergic reaction.
Personal hygiene products, cosmetics, gum chewing, and candy consumption can be the irritant culprits, noted Dr. Schlosser. Careful questioning of patients and examination of the products used can provide clues, since dyes and pigments in cosmetics and gum may provoke reactions.
History taking should also include questions about tobacco in all forms, marijuana, and prescription medication, which can cause lip problems. And it’s important to ask about skin disease in general, to determine if symptoms are present in other anatomic locations, and to ask about any family history of skin disease, she said.
Endogenous contributors can include true atopic dermatitis, psoriasis, and nutritional deficiencies. Psoriatic cheilitis can have prominent crusting and exfoliation. In a Brazilian study that evaluated patents with cutaneous psoriasis and age-, race-, and sex-matched controls with no history of skin disease, psoriasis was associated with geographic tongue, with an odds ratio of 5.0 (95% CI 1.5-16.8). Geographic stomatitis can also be seen, said Dr. Schlosser. Tongue fissures were also more common among those with psoriasis cheilitis (OR 2.7, 95% confidence interval, 1.3-5.6) in the same study (Med Oral Patol Oral Cir Bucal. 2009 Aug 1;14[8]:e371-5).
For psoriatic cheilitis, looking beyond the lips can help refine the diagnosis, she noted. There may be intra-oral signs or signs of extra-oral involvement, especially on the scalp, ears, and genitalia. Koebnerization may be difficult to detect on the lips, but may be present elsewhere. A family history of psoriasis may also tip the scales toward this diagnosis.
Exogenous causes of eczematous cheilitis are much more common and can include contact with irritants and allergens, factitial cheilitis, and cheilitis medicamentosa, Dr Schlosser pointed out.
Allergic contact dermatitis can come from local exposure (to cosmetics and other personal care items, for example) or from incidental exposures. Components of saliva can become concentrated when saliva dries outside the oral cavity, so for chronic lip lickers, saliva alone can be sufficiently irritating to provoke a cheilitis, Dr. Schlosser said.
Transfer of an irritant or allergen is also possible from other body sites, as when a nail-chewer develops allergic cheilitis from an ingredient in nail polish. Transfer from products used on other facial areas and the hair is also possible, as is “connubial transfer,” when an allergen is transferred from an intimate partner.
Cutaneous patch tests can be helpful in pinpointing the offending agent, or agents, according to Dr. Schlosser. She cited a study of 91 patients (77% of whom were female) who underwent patch testing for eczematous cheilitis. The researchers determined that 45% of patients had allergic contact cheilitis (Int J Dermatol. 2016 Jul;55[7]:e386-91).
The patch testing revealed that fragrances, balsam of Peru (Myroxylon pereirae resin), preservatives, and even metals such as nickel and gold were common allergens. The findings echo those in another database review that showed fragrances, M. pereirae, and nickel as the top three allergens on patch testing for lip cheilitis.
Dr. Schlosser said that the most common offending sources are lipsticks, makeup, other cosmetic products, and moisturizer, which are responsible for 10% or more of reactions.
Whatever the etiology, the treatment of eczematous cheilitis can be divided conceptually into two phases. During the induction phase, use of a low- to mid-potency topical corticosteroid ointment quiets inflammation. Examples include alclometasone 0.05%, desonide 0.05%, fluticasone 0.005%, or triamcinolone 0.1%. “Ointment formulations are preferred,” said Dr. Schlosser, since they won’t dissolve so easily with lip licking and will adhere well to the surface of the vermilion lip.
Next, a topical calcineurin inhibitor such as tacrolimus 0.1% can be used for maintenance. Other topical medications, especially topical anesthetics, should be used with caution, she said.
For psoriatic cheilitis, induction with 5% salicylic acid ointment can be followed by the topical calcineurin inhibitor phase, said Dr. Schlosser.
Dr. Schlosser disclosed financial relationships with Beiersdorf, Decision Support in Medicine, and UpToDate.
[email protected]
NEW YORK – , but patients may be slow to seek help, Bethanee Schlosser, MD, PhD, said at the American Academy of Dermatology summer meeting.
One of the challenges in helping patients with lip problems is that lips are constantly in motion and constantly interacting with the outside world, said Dr. Schlosser, of the department of dermatology, Northwestern University, Chicago. There’s ongoing low-level trauma with phonation, eating, drinking, and general environmental exposure, she said. Eczematous cheilitis will present with scaling and erythema of the vermilion lips, with lower lip involvement often more pronounced than symptoms on the upper lip. Fissuring and erosion are sometimes, but not always, present as well.
In addition to flaking and redness, Dr. Schlosser noted that patients will complain of dry lips, irritation, itching, and sometimes tingling.
Sorting out the etiology of eczematous cheilitis requires a thorough history. “Ask about habits, such as lip licking, picking, or biting,” she said. Recent dental work, braces, or other appliances for alignment or temporomandibular joint problems can introduce both mechanical irritation and potential allergens, and even musical instruments can be culprits, such as when an oboe reed causes an allergic reaction.
Personal hygiene products, cosmetics, gum chewing, and candy consumption can be the irritant culprits, noted Dr. Schlosser. Careful questioning of patients and examination of the products used can provide clues, since dyes and pigments in cosmetics and gum may provoke reactions.
History taking should also include questions about tobacco in all forms, marijuana, and prescription medication, which can cause lip problems. And it’s important to ask about skin disease in general, to determine if symptoms are present in other anatomic locations, and to ask about any family history of skin disease, she said.
Endogenous contributors can include true atopic dermatitis, psoriasis, and nutritional deficiencies. Psoriatic cheilitis can have prominent crusting and exfoliation. In a Brazilian study that evaluated patents with cutaneous psoriasis and age-, race-, and sex-matched controls with no history of skin disease, psoriasis was associated with geographic tongue, with an odds ratio of 5.0 (95% CI 1.5-16.8). Geographic stomatitis can also be seen, said Dr. Schlosser. Tongue fissures were also more common among those with psoriasis cheilitis (OR 2.7, 95% confidence interval, 1.3-5.6) in the same study (Med Oral Patol Oral Cir Bucal. 2009 Aug 1;14[8]:e371-5).
For psoriatic cheilitis, looking beyond the lips can help refine the diagnosis, she noted. There may be intra-oral signs or signs of extra-oral involvement, especially on the scalp, ears, and genitalia. Koebnerization may be difficult to detect on the lips, but may be present elsewhere. A family history of psoriasis may also tip the scales toward this diagnosis.
Exogenous causes of eczematous cheilitis are much more common and can include contact with irritants and allergens, factitial cheilitis, and cheilitis medicamentosa, Dr Schlosser pointed out.
Allergic contact dermatitis can come from local exposure (to cosmetics and other personal care items, for example) or from incidental exposures. Components of saliva can become concentrated when saliva dries outside the oral cavity, so for chronic lip lickers, saliva alone can be sufficiently irritating to provoke a cheilitis, Dr. Schlosser said.
Transfer of an irritant or allergen is also possible from other body sites, as when a nail-chewer develops allergic cheilitis from an ingredient in nail polish. Transfer from products used on other facial areas and the hair is also possible, as is “connubial transfer,” when an allergen is transferred from an intimate partner.
Cutaneous patch tests can be helpful in pinpointing the offending agent, or agents, according to Dr. Schlosser. She cited a study of 91 patients (77% of whom were female) who underwent patch testing for eczematous cheilitis. The researchers determined that 45% of patients had allergic contact cheilitis (Int J Dermatol. 2016 Jul;55[7]:e386-91).
The patch testing revealed that fragrances, balsam of Peru (Myroxylon pereirae resin), preservatives, and even metals such as nickel and gold were common allergens. The findings echo those in another database review that showed fragrances, M. pereirae, and nickel as the top three allergens on patch testing for lip cheilitis.
Dr. Schlosser said that the most common offending sources are lipsticks, makeup, other cosmetic products, and moisturizer, which are responsible for 10% or more of reactions.
Whatever the etiology, the treatment of eczematous cheilitis can be divided conceptually into two phases. During the induction phase, use of a low- to mid-potency topical corticosteroid ointment quiets inflammation. Examples include alclometasone 0.05%, desonide 0.05%, fluticasone 0.005%, or triamcinolone 0.1%. “Ointment formulations are preferred,” said Dr. Schlosser, since they won’t dissolve so easily with lip licking and will adhere well to the surface of the vermilion lip.
Next, a topical calcineurin inhibitor such as tacrolimus 0.1% can be used for maintenance. Other topical medications, especially topical anesthetics, should be used with caution, she said.
For psoriatic cheilitis, induction with 5% salicylic acid ointment can be followed by the topical calcineurin inhibitor phase, said Dr. Schlosser.
Dr. Schlosser disclosed financial relationships with Beiersdorf, Decision Support in Medicine, and UpToDate.
[email protected]
NEW YORK – , but patients may be slow to seek help, Bethanee Schlosser, MD, PhD, said at the American Academy of Dermatology summer meeting.
One of the challenges in helping patients with lip problems is that lips are constantly in motion and constantly interacting with the outside world, said Dr. Schlosser, of the department of dermatology, Northwestern University, Chicago. There’s ongoing low-level trauma with phonation, eating, drinking, and general environmental exposure, she said. Eczematous cheilitis will present with scaling and erythema of the vermilion lips, with lower lip involvement often more pronounced than symptoms on the upper lip. Fissuring and erosion are sometimes, but not always, present as well.
In addition to flaking and redness, Dr. Schlosser noted that patients will complain of dry lips, irritation, itching, and sometimes tingling.
Sorting out the etiology of eczematous cheilitis requires a thorough history. “Ask about habits, such as lip licking, picking, or biting,” she said. Recent dental work, braces, or other appliances for alignment or temporomandibular joint problems can introduce both mechanical irritation and potential allergens, and even musical instruments can be culprits, such as when an oboe reed causes an allergic reaction.
Personal hygiene products, cosmetics, gum chewing, and candy consumption can be the irritant culprits, noted Dr. Schlosser. Careful questioning of patients and examination of the products used can provide clues, since dyes and pigments in cosmetics and gum may provoke reactions.
History taking should also include questions about tobacco in all forms, marijuana, and prescription medication, which can cause lip problems. And it’s important to ask about skin disease in general, to determine if symptoms are present in other anatomic locations, and to ask about any family history of skin disease, she said.
Endogenous contributors can include true atopic dermatitis, psoriasis, and nutritional deficiencies. Psoriatic cheilitis can have prominent crusting and exfoliation. In a Brazilian study that evaluated patents with cutaneous psoriasis and age-, race-, and sex-matched controls with no history of skin disease, psoriasis was associated with geographic tongue, with an odds ratio of 5.0 (95% CI 1.5-16.8). Geographic stomatitis can also be seen, said Dr. Schlosser. Tongue fissures were also more common among those with psoriasis cheilitis (OR 2.7, 95% confidence interval, 1.3-5.6) in the same study (Med Oral Patol Oral Cir Bucal. 2009 Aug 1;14[8]:e371-5).
For psoriatic cheilitis, looking beyond the lips can help refine the diagnosis, she noted. There may be intra-oral signs or signs of extra-oral involvement, especially on the scalp, ears, and genitalia. Koebnerization may be difficult to detect on the lips, but may be present elsewhere. A family history of psoriasis may also tip the scales toward this diagnosis.
Exogenous causes of eczematous cheilitis are much more common and can include contact with irritants and allergens, factitial cheilitis, and cheilitis medicamentosa, Dr Schlosser pointed out.
Allergic contact dermatitis can come from local exposure (to cosmetics and other personal care items, for example) or from incidental exposures. Components of saliva can become concentrated when saliva dries outside the oral cavity, so for chronic lip lickers, saliva alone can be sufficiently irritating to provoke a cheilitis, Dr. Schlosser said.
Transfer of an irritant or allergen is also possible from other body sites, as when a nail-chewer develops allergic cheilitis from an ingredient in nail polish. Transfer from products used on other facial areas and the hair is also possible, as is “connubial transfer,” when an allergen is transferred from an intimate partner.
Cutaneous patch tests can be helpful in pinpointing the offending agent, or agents, according to Dr. Schlosser. She cited a study of 91 patients (77% of whom were female) who underwent patch testing for eczematous cheilitis. The researchers determined that 45% of patients had allergic contact cheilitis (Int J Dermatol. 2016 Jul;55[7]:e386-91).
The patch testing revealed that fragrances, balsam of Peru (Myroxylon pereirae resin), preservatives, and even metals such as nickel and gold were common allergens. The findings echo those in another database review that showed fragrances, M. pereirae, and nickel as the top three allergens on patch testing for lip cheilitis.
Dr. Schlosser said that the most common offending sources are lipsticks, makeup, other cosmetic products, and moisturizer, which are responsible for 10% or more of reactions.
Whatever the etiology, the treatment of eczematous cheilitis can be divided conceptually into two phases. During the induction phase, use of a low- to mid-potency topical corticosteroid ointment quiets inflammation. Examples include alclometasone 0.05%, desonide 0.05%, fluticasone 0.005%, or triamcinolone 0.1%. “Ointment formulations are preferred,” said Dr. Schlosser, since they won’t dissolve so easily with lip licking and will adhere well to the surface of the vermilion lip.
Next, a topical calcineurin inhibitor such as tacrolimus 0.1% can be used for maintenance. Other topical medications, especially topical anesthetics, should be used with caution, she said.
For psoriatic cheilitis, induction with 5% salicylic acid ointment can be followed by the topical calcineurin inhibitor phase, said Dr. Schlosser.
Dr. Schlosser disclosed financial relationships with Beiersdorf, Decision Support in Medicine, and UpToDate.
[email protected]
EXPERT ANALYSIS FROM SUMMER AAD 2019
What’s the best way to sort out red nail discoloration?
NEW YORK – Nail discoloration, in all its variety, has a wide differential. And while that differential narrows when a patient presents with concerns about nails with red discoloration, there’s still a long list of diagnoses to consider.
During a nail-focused session at the American Academy of Dermatology summer meeting, Shari Lipner, MD, PhD, took attendees through a presentation-based approach that gets to the root etiology of erythronychia and guides diagnosis and treatment options.
“However, regardless of the etiology, erythronychia shares a common pathogenesis,” said Dr. Lipner, a dermatologist at New York–Presbyterian Hospital and Weil Cornell Medicine. The process begins in the distal nail matrix, resulting in a thin long strip of ventral nail becoming discolored, with the nail bed filling in the concavity. The engorged nail bed also makes the affected nail unit prone to splinter hemorrhages, and the thinned, transparent nail makes the erythema more visible, she explained.
Polydactylous longitudinal erythronychia
For erythronychia affecting several nails, onychotillomania is among the possible causes. This condition “often goes hand in hand with onychophagia,” and trichotillomania, skin-picking, or other self-mutilating disorders may also be present, she said. In both the adult and pediatric population, onychotillomania can accompany psychiatric disorders, including depression and obsessive-compulsive disorder, and may be associated with suicidal ideation, she added.
When onychotillomania is the cause, erythronychia may be accompanied by paronychia, and patients will often have a shortened nail bed and an atrophic nail plate. Dorsal pterygium may also be present.
Dermoscopy can provide some clues that onychotillomania is the culprit, said Dr. Lipner, citing a study that looked at dermoscopic images of 36 cases, which found scales in 94%, absence of the nail plate in 83%, and characteristic wavy lines in 69% (J Am Acad Dermatol. 2018 Oct;79[4]:702-5). Other frequent dermoscopy findings included hemorrhages (64%), crusts (61%), nail bed pigmentation (47%), and speckled dots (39%).
Lichen planus can also affect the nails, with erythronychia among its manifestations, she noted. Though lichen planus is thought of as a disease of middle or older age, usually affecting those aged 50-70 years, “15% of those affected are less than 20 years old,” she said.
The erythronychia of lichen planus is often accompanied by longitudinal riding, splitting, and atrophy of the nail plate, she said. Pterygium can also be present, representing a scar in the nail matrix. Dermatopathology will reveal a patchy, bandlike lichenoid infiltrate, with variable sawtooth hypergranulosis and hyperplasia.
“There’s not much evidence about how to treat lichen planus of the nails,” noted Dr. Lipner. Options can include intralesional corticosteroid injections at the nail matrix, topical corticosteroids, oral methotrexate, and retinoids.
Darier disease, an inherited condition caused by mutations in ATP2A2, has both skin and nail manifestations. Characteristic skin signs include hyperkeratotic papules, cobblestone papules, and palmar pits, she said. When nails are affected – as they are in up to 95% of Darier disease patients – they can have a characteristic “candy cane” appearance, with bands of longitudinal erythronychia alternating with normal-colored nail. The nails can also have V-shaped notching, she added.
Patients with systemic lupus erythematosus can also have longitudinal erythronychia; here, dermoscopy will show the characteristic prominent capillary loops in the proximal nail folds, she said.
Foreign substances such as nail polish and dyes, when they’re the source of erythronychia in one or several nails, can usually be wiped off with alcohol or acetone; also, “the proximal margin of discoloration will follow the same pattern as the nail fold,” said Dr. Lipner.
Localized longitudinal erythronychia
When the red discoloration is limited to a single nail, the differential shifts, said Dr. Lipner. With a hematoma, there’s often a history of trauma, and dermoscopy will show characteristic globules and streaks.
The first clue that erythronychia caused by onychopapilloma can be seen at the lunula: There will often be a comet- or pencil-shaped point to the discoloration in that region. But, she said, “the key is to do dermoscopy at the free edge of the nail plate. In 100 percent of cases, there will be a subungual hyperkeratotic papule” that will solidify the diagnosis.
Histopathology of onychopapillomas – a relatively recently recognized entity – will show nail bed and distal matrix acanthosis, with the distal nail bed showing matrix metaplasia, Dr. Lipner said.
Glomus tumors arise from cells of the glomus body, a specialized vascular apparatus that is involved in temperature regulation. “These structures are abundant in the digits and the subungual region,” said Dr. Lipner, which means that glomus tumors – a benign lesion – may develop subungually. Glomus tumors can be idiopathic, but she added, “think neurofibromatosis type 1 if you see multiple glomus tumors.”
Glomus tumors will present with longitudinal erythronychia, with a distal split of the nail sometimes accompanying the discoloration. A round bluish to gray nodule can also be seen. A thorough history and exam can help solidify the diagnosis, said Dr. Lipner; there’s a characteristic triad of point tenderness with the application of pressure to the nail, pain, and cold hypersensitivity.
Classically, the point tenderness is assessed by Love’s test, which elicits severe pain when the subungual tumor is pressed with a small object like the end of paper clip or a ballpoint pen. Application of a tourniquet to the arm after elevation, termed Hildreth’s test, should alleviate subungual glomus tumor pain, and release of the tourniquet causes an abrupt and marked recurrence of pain. Immersing the patient’s affected hand in cold water also increases glomus tumor pain.
“Imaging can be quite helpful” to confirm a glomus tumor diagnosis, said Dr. Lipner. “X-ray is cheap, and you can see erosions in 50% of patients.” However, she added, doppler ultrasound and magnetic resonance imaging are more sensitive, detecting tumors as small as 2 mm.
“Biopsy with histopathology is the gold standard in making the diagnosis” of glomus tumor, though, she noted. Pathologic examination will show monomorphic cells with small caliber vascular channels.
Malignancy is actually uncommon with erythronychia, though it’s always in the differential diagnosis, she said.
In one case series examining subungual squamous cell carcinomas, common findings included onycholysis and localized hyperkeratosis, along with longitudinal erythronychia. “This may be subtle; splinter hemorrhages can also be present,” noted Dr. Lipner, adding, “If there are any symptoms, or an evolving band, a biopsy is indicated.”
“Even with erythronychia, the presentation can be quite variable,” she said. Nail unit melanoma can count erythronychia among the presenting signs. Clues that should raise suspicion for melanoma can include a wide band and prominent onycholysis, especially distal onycholysis and splintering. Again, she said, “biopsy with histopathology is the gold standard in making the diagnosis”; any symptoms or evidence of an evolving band should trigger a biopsy.
Dr. Lipner had no conflicts of interest relevant to her presentation.
SOURCE: Lipner S. Summer AAD 2019, Presentation F035.
NEW YORK – Nail discoloration, in all its variety, has a wide differential. And while that differential narrows when a patient presents with concerns about nails with red discoloration, there’s still a long list of diagnoses to consider.
During a nail-focused session at the American Academy of Dermatology summer meeting, Shari Lipner, MD, PhD, took attendees through a presentation-based approach that gets to the root etiology of erythronychia and guides diagnosis and treatment options.
“However, regardless of the etiology, erythronychia shares a common pathogenesis,” said Dr. Lipner, a dermatologist at New York–Presbyterian Hospital and Weil Cornell Medicine. The process begins in the distal nail matrix, resulting in a thin long strip of ventral nail becoming discolored, with the nail bed filling in the concavity. The engorged nail bed also makes the affected nail unit prone to splinter hemorrhages, and the thinned, transparent nail makes the erythema more visible, she explained.
Polydactylous longitudinal erythronychia
For erythronychia affecting several nails, onychotillomania is among the possible causes. This condition “often goes hand in hand with onychophagia,” and trichotillomania, skin-picking, or other self-mutilating disorders may also be present, she said. In both the adult and pediatric population, onychotillomania can accompany psychiatric disorders, including depression and obsessive-compulsive disorder, and may be associated with suicidal ideation, she added.
When onychotillomania is the cause, erythronychia may be accompanied by paronychia, and patients will often have a shortened nail bed and an atrophic nail plate. Dorsal pterygium may also be present.
Dermoscopy can provide some clues that onychotillomania is the culprit, said Dr. Lipner, citing a study that looked at dermoscopic images of 36 cases, which found scales in 94%, absence of the nail plate in 83%, and characteristic wavy lines in 69% (J Am Acad Dermatol. 2018 Oct;79[4]:702-5). Other frequent dermoscopy findings included hemorrhages (64%), crusts (61%), nail bed pigmentation (47%), and speckled dots (39%).
Lichen planus can also affect the nails, with erythronychia among its manifestations, she noted. Though lichen planus is thought of as a disease of middle or older age, usually affecting those aged 50-70 years, “15% of those affected are less than 20 years old,” she said.
The erythronychia of lichen planus is often accompanied by longitudinal riding, splitting, and atrophy of the nail plate, she said. Pterygium can also be present, representing a scar in the nail matrix. Dermatopathology will reveal a patchy, bandlike lichenoid infiltrate, with variable sawtooth hypergranulosis and hyperplasia.
“There’s not much evidence about how to treat lichen planus of the nails,” noted Dr. Lipner. Options can include intralesional corticosteroid injections at the nail matrix, topical corticosteroids, oral methotrexate, and retinoids.
Darier disease, an inherited condition caused by mutations in ATP2A2, has both skin and nail manifestations. Characteristic skin signs include hyperkeratotic papules, cobblestone papules, and palmar pits, she said. When nails are affected – as they are in up to 95% of Darier disease patients – they can have a characteristic “candy cane” appearance, with bands of longitudinal erythronychia alternating with normal-colored nail. The nails can also have V-shaped notching, she added.
Patients with systemic lupus erythematosus can also have longitudinal erythronychia; here, dermoscopy will show the characteristic prominent capillary loops in the proximal nail folds, she said.
Foreign substances such as nail polish and dyes, when they’re the source of erythronychia in one or several nails, can usually be wiped off with alcohol or acetone; also, “the proximal margin of discoloration will follow the same pattern as the nail fold,” said Dr. Lipner.
Localized longitudinal erythronychia
When the red discoloration is limited to a single nail, the differential shifts, said Dr. Lipner. With a hematoma, there’s often a history of trauma, and dermoscopy will show characteristic globules and streaks.
The first clue that erythronychia caused by onychopapilloma can be seen at the lunula: There will often be a comet- or pencil-shaped point to the discoloration in that region. But, she said, “the key is to do dermoscopy at the free edge of the nail plate. In 100 percent of cases, there will be a subungual hyperkeratotic papule” that will solidify the diagnosis.
Histopathology of onychopapillomas – a relatively recently recognized entity – will show nail bed and distal matrix acanthosis, with the distal nail bed showing matrix metaplasia, Dr. Lipner said.
Glomus tumors arise from cells of the glomus body, a specialized vascular apparatus that is involved in temperature regulation. “These structures are abundant in the digits and the subungual region,” said Dr. Lipner, which means that glomus tumors – a benign lesion – may develop subungually. Glomus tumors can be idiopathic, but she added, “think neurofibromatosis type 1 if you see multiple glomus tumors.”
Glomus tumors will present with longitudinal erythronychia, with a distal split of the nail sometimes accompanying the discoloration. A round bluish to gray nodule can also be seen. A thorough history and exam can help solidify the diagnosis, said Dr. Lipner; there’s a characteristic triad of point tenderness with the application of pressure to the nail, pain, and cold hypersensitivity.
Classically, the point tenderness is assessed by Love’s test, which elicits severe pain when the subungual tumor is pressed with a small object like the end of paper clip or a ballpoint pen. Application of a tourniquet to the arm after elevation, termed Hildreth’s test, should alleviate subungual glomus tumor pain, and release of the tourniquet causes an abrupt and marked recurrence of pain. Immersing the patient’s affected hand in cold water also increases glomus tumor pain.
“Imaging can be quite helpful” to confirm a glomus tumor diagnosis, said Dr. Lipner. “X-ray is cheap, and you can see erosions in 50% of patients.” However, she added, doppler ultrasound and magnetic resonance imaging are more sensitive, detecting tumors as small as 2 mm.
“Biopsy with histopathology is the gold standard in making the diagnosis” of glomus tumor, though, she noted. Pathologic examination will show monomorphic cells with small caliber vascular channels.
Malignancy is actually uncommon with erythronychia, though it’s always in the differential diagnosis, she said.
In one case series examining subungual squamous cell carcinomas, common findings included onycholysis and localized hyperkeratosis, along with longitudinal erythronychia. “This may be subtle; splinter hemorrhages can also be present,” noted Dr. Lipner, adding, “If there are any symptoms, or an evolving band, a biopsy is indicated.”
“Even with erythronychia, the presentation can be quite variable,” she said. Nail unit melanoma can count erythronychia among the presenting signs. Clues that should raise suspicion for melanoma can include a wide band and prominent onycholysis, especially distal onycholysis and splintering. Again, she said, “biopsy with histopathology is the gold standard in making the diagnosis”; any symptoms or evidence of an evolving band should trigger a biopsy.
Dr. Lipner had no conflicts of interest relevant to her presentation.
SOURCE: Lipner S. Summer AAD 2019, Presentation F035.
NEW YORK – Nail discoloration, in all its variety, has a wide differential. And while that differential narrows when a patient presents with concerns about nails with red discoloration, there’s still a long list of diagnoses to consider.
During a nail-focused session at the American Academy of Dermatology summer meeting, Shari Lipner, MD, PhD, took attendees through a presentation-based approach that gets to the root etiology of erythronychia and guides diagnosis and treatment options.
“However, regardless of the etiology, erythronychia shares a common pathogenesis,” said Dr. Lipner, a dermatologist at New York–Presbyterian Hospital and Weil Cornell Medicine. The process begins in the distal nail matrix, resulting in a thin long strip of ventral nail becoming discolored, with the nail bed filling in the concavity. The engorged nail bed also makes the affected nail unit prone to splinter hemorrhages, and the thinned, transparent nail makes the erythema more visible, she explained.
Polydactylous longitudinal erythronychia
For erythronychia affecting several nails, onychotillomania is among the possible causes. This condition “often goes hand in hand with onychophagia,” and trichotillomania, skin-picking, or other self-mutilating disorders may also be present, she said. In both the adult and pediatric population, onychotillomania can accompany psychiatric disorders, including depression and obsessive-compulsive disorder, and may be associated with suicidal ideation, she added.
When onychotillomania is the cause, erythronychia may be accompanied by paronychia, and patients will often have a shortened nail bed and an atrophic nail plate. Dorsal pterygium may also be present.
Dermoscopy can provide some clues that onychotillomania is the culprit, said Dr. Lipner, citing a study that looked at dermoscopic images of 36 cases, which found scales in 94%, absence of the nail plate in 83%, and characteristic wavy lines in 69% (J Am Acad Dermatol. 2018 Oct;79[4]:702-5). Other frequent dermoscopy findings included hemorrhages (64%), crusts (61%), nail bed pigmentation (47%), and speckled dots (39%).
Lichen planus can also affect the nails, with erythronychia among its manifestations, she noted. Though lichen planus is thought of as a disease of middle or older age, usually affecting those aged 50-70 years, “15% of those affected are less than 20 years old,” she said.
The erythronychia of lichen planus is often accompanied by longitudinal riding, splitting, and atrophy of the nail plate, she said. Pterygium can also be present, representing a scar in the nail matrix. Dermatopathology will reveal a patchy, bandlike lichenoid infiltrate, with variable sawtooth hypergranulosis and hyperplasia.
“There’s not much evidence about how to treat lichen planus of the nails,” noted Dr. Lipner. Options can include intralesional corticosteroid injections at the nail matrix, topical corticosteroids, oral methotrexate, and retinoids.
Darier disease, an inherited condition caused by mutations in ATP2A2, has both skin and nail manifestations. Characteristic skin signs include hyperkeratotic papules, cobblestone papules, and palmar pits, she said. When nails are affected – as they are in up to 95% of Darier disease patients – they can have a characteristic “candy cane” appearance, with bands of longitudinal erythronychia alternating with normal-colored nail. The nails can also have V-shaped notching, she added.
Patients with systemic lupus erythematosus can also have longitudinal erythronychia; here, dermoscopy will show the characteristic prominent capillary loops in the proximal nail folds, she said.
Foreign substances such as nail polish and dyes, when they’re the source of erythronychia in one or several nails, can usually be wiped off with alcohol or acetone; also, “the proximal margin of discoloration will follow the same pattern as the nail fold,” said Dr. Lipner.
Localized longitudinal erythronychia
When the red discoloration is limited to a single nail, the differential shifts, said Dr. Lipner. With a hematoma, there’s often a history of trauma, and dermoscopy will show characteristic globules and streaks.
The first clue that erythronychia caused by onychopapilloma can be seen at the lunula: There will often be a comet- or pencil-shaped point to the discoloration in that region. But, she said, “the key is to do dermoscopy at the free edge of the nail plate. In 100 percent of cases, there will be a subungual hyperkeratotic papule” that will solidify the diagnosis.
Histopathology of onychopapillomas – a relatively recently recognized entity – will show nail bed and distal matrix acanthosis, with the distal nail bed showing matrix metaplasia, Dr. Lipner said.
Glomus tumors arise from cells of the glomus body, a specialized vascular apparatus that is involved in temperature regulation. “These structures are abundant in the digits and the subungual region,” said Dr. Lipner, which means that glomus tumors – a benign lesion – may develop subungually. Glomus tumors can be idiopathic, but she added, “think neurofibromatosis type 1 if you see multiple glomus tumors.”
Glomus tumors will present with longitudinal erythronychia, with a distal split of the nail sometimes accompanying the discoloration. A round bluish to gray nodule can also be seen. A thorough history and exam can help solidify the diagnosis, said Dr. Lipner; there’s a characteristic triad of point tenderness with the application of pressure to the nail, pain, and cold hypersensitivity.
Classically, the point tenderness is assessed by Love’s test, which elicits severe pain when the subungual tumor is pressed with a small object like the end of paper clip or a ballpoint pen. Application of a tourniquet to the arm after elevation, termed Hildreth’s test, should alleviate subungual glomus tumor pain, and release of the tourniquet causes an abrupt and marked recurrence of pain. Immersing the patient’s affected hand in cold water also increases glomus tumor pain.
“Imaging can be quite helpful” to confirm a glomus tumor diagnosis, said Dr. Lipner. “X-ray is cheap, and you can see erosions in 50% of patients.” However, she added, doppler ultrasound and magnetic resonance imaging are more sensitive, detecting tumors as small as 2 mm.
“Biopsy with histopathology is the gold standard in making the diagnosis” of glomus tumor, though, she noted. Pathologic examination will show monomorphic cells with small caliber vascular channels.
Malignancy is actually uncommon with erythronychia, though it’s always in the differential diagnosis, she said.
In one case series examining subungual squamous cell carcinomas, common findings included onycholysis and localized hyperkeratosis, along with longitudinal erythronychia. “This may be subtle; splinter hemorrhages can also be present,” noted Dr. Lipner, adding, “If there are any symptoms, or an evolving band, a biopsy is indicated.”
“Even with erythronychia, the presentation can be quite variable,” she said. Nail unit melanoma can count erythronychia among the presenting signs. Clues that should raise suspicion for melanoma can include a wide band and prominent onycholysis, especially distal onycholysis and splintering. Again, she said, “biopsy with histopathology is the gold standard in making the diagnosis”; any symptoms or evidence of an evolving band should trigger a biopsy.
Dr. Lipner had no conflicts of interest relevant to her presentation.
SOURCE: Lipner S. Summer AAD 2019, Presentation F035.
EXPERT ANALYSIS FROM SUMMER AAD 2019
Consider adding chemical peels for your acne patients
MILAN – according to Dee Anna Glaser, MD.
Speaking at the World Congress of Dermatology, Dr. Glaser, director of clinical research and interim chair of the department of dermatology at Saint Louis University, said that in her practice, acne and actinic keratosis are the most common medical indications for chemical peels and that “acne is just a winner all the way around.”
For acne, she added: “Chemical peels can help both the comedonal and the inflammatory component. It should probably be combined with other therapies, and it does produce both an exfoliative and an anti-inflammatory benefit,.”
A variety of chemical peel formulations can be considered for acne, Dr. Glaser noted. “Typically, you’re going to use a light chemical peel,” such as glycolic or salicylic acid. Other options include Jessner’s solution or a light trichloroacetic acid formulation, she said, adding that tretinoin alone can also be considered.
In choosing between glycolic and salicylic acid, Dr. Glaser said, “salicylic acid should theoretically be the best agent because it is lipophilic and the glycolic acid is hydrophilic.” The reality of how these agents perform clinically, though, may sort out differently.
Dr. Glaser pointed to a double-blind, randomized controlled trial of the two agents in 20 women with facial acne. The severity of participants’ inflammatory acne was mild to moderate, with an average of 27 inflammatory lesions, and they had been on a stable prescription or over-the-counter acne regimen for at least 2 months (Dermatol Surg. 2008 Jan;34[1]:45-50).
Patients received six peels – one every 2 weeks – with 30% glycolic acid (an alpha-hydroxy acid) and 30% salicylic acid (a beta-hydroxy acid) in the split-face study.
All participants started at 4 minutes of exposure and increased up to 5 minutes as tolerated, although timing is only really important for glycolic acid, the same duration of exposure was maintained for each agent for the sake of consistency between arms, said Dr. Glaser, one of the investigators.
Sharing photographs of study participants, she observed that after six peels, “there really isn’t a significant difference.” Therefore, she added, “even though salicylic acid should be better, you can see that glycolic acid really held its own in this study.”
Dr. Glaser pointed out that a trend was seen for slightly better results with salicylic acid and results with this agent were more durable than those seen with glycolic acid. Patients reported fewer side effects on the beta-hydroxy–treated side as well.
She referred to another study, conducted in Japan, that used a double-blind, split-face design to compare 40% glycolic acid with a placebo that had a similarly low pH of 2.0. The 26 patients with moderate acne received five peels on a biweekly schedule, with glycolic acid significantly outperforming placebo. Among acne subtypes, noninflammatory acne improved more than inflammatory acne with glycolic acid (Dermatol Surg. 2014 Mar;40[3]:314-22).
Dr. Glaser said that in her own practice, she still tries to use salicylic acid for her acne patients,” though some patients prefer the experience of a glycolic acid peel, with which there’s likely to be less pain. “So if you have a preference, or your patient has a preference, you will probably be able to use the acid that works best for you,” she said.
Whatever peel is chosen, it should be considered an adjuvant to other topical and systemic acne therapies, Dr. Glaser stressed. “To maintain the results, you really do need to maintain the patient on some sort of standard acne therapy that you would normally do.”
Peels can also be an effective part of a multipronged approach that includes laser therapy and intralesional steroids, she said. However, peels can be considered for monotherapy in patients who don’t tolerate other acne therapies, and they can be used safely in pregnancy, she said.
As with all such treatments, dermatologists should remember to consider and counsel about herpes simplex virus prophylaxis and sun protection.
Dr. Glaser reported financial relationships with Galderma, Ulthera, Ortho, Allergan, Cellgene, and other pharmaceutical companies.
MILAN – according to Dee Anna Glaser, MD.
Speaking at the World Congress of Dermatology, Dr. Glaser, director of clinical research and interim chair of the department of dermatology at Saint Louis University, said that in her practice, acne and actinic keratosis are the most common medical indications for chemical peels and that “acne is just a winner all the way around.”
For acne, she added: “Chemical peels can help both the comedonal and the inflammatory component. It should probably be combined with other therapies, and it does produce both an exfoliative and an anti-inflammatory benefit,.”
A variety of chemical peel formulations can be considered for acne, Dr. Glaser noted. “Typically, you’re going to use a light chemical peel,” such as glycolic or salicylic acid. Other options include Jessner’s solution or a light trichloroacetic acid formulation, she said, adding that tretinoin alone can also be considered.
In choosing between glycolic and salicylic acid, Dr. Glaser said, “salicylic acid should theoretically be the best agent because it is lipophilic and the glycolic acid is hydrophilic.” The reality of how these agents perform clinically, though, may sort out differently.
Dr. Glaser pointed to a double-blind, randomized controlled trial of the two agents in 20 women with facial acne. The severity of participants’ inflammatory acne was mild to moderate, with an average of 27 inflammatory lesions, and they had been on a stable prescription or over-the-counter acne regimen for at least 2 months (Dermatol Surg. 2008 Jan;34[1]:45-50).
Patients received six peels – one every 2 weeks – with 30% glycolic acid (an alpha-hydroxy acid) and 30% salicylic acid (a beta-hydroxy acid) in the split-face study.
All participants started at 4 minutes of exposure and increased up to 5 minutes as tolerated, although timing is only really important for glycolic acid, the same duration of exposure was maintained for each agent for the sake of consistency between arms, said Dr. Glaser, one of the investigators.
Sharing photographs of study participants, she observed that after six peels, “there really isn’t a significant difference.” Therefore, she added, “even though salicylic acid should be better, you can see that glycolic acid really held its own in this study.”
Dr. Glaser pointed out that a trend was seen for slightly better results with salicylic acid and results with this agent were more durable than those seen with glycolic acid. Patients reported fewer side effects on the beta-hydroxy–treated side as well.
She referred to another study, conducted in Japan, that used a double-blind, split-face design to compare 40% glycolic acid with a placebo that had a similarly low pH of 2.0. The 26 patients with moderate acne received five peels on a biweekly schedule, with glycolic acid significantly outperforming placebo. Among acne subtypes, noninflammatory acne improved more than inflammatory acne with glycolic acid (Dermatol Surg. 2014 Mar;40[3]:314-22).
Dr. Glaser said that in her own practice, she still tries to use salicylic acid for her acne patients,” though some patients prefer the experience of a glycolic acid peel, with which there’s likely to be less pain. “So if you have a preference, or your patient has a preference, you will probably be able to use the acid that works best for you,” she said.
Whatever peel is chosen, it should be considered an adjuvant to other topical and systemic acne therapies, Dr. Glaser stressed. “To maintain the results, you really do need to maintain the patient on some sort of standard acne therapy that you would normally do.”
Peels can also be an effective part of a multipronged approach that includes laser therapy and intralesional steroids, she said. However, peels can be considered for monotherapy in patients who don’t tolerate other acne therapies, and they can be used safely in pregnancy, she said.
As with all such treatments, dermatologists should remember to consider and counsel about herpes simplex virus prophylaxis and sun protection.
Dr. Glaser reported financial relationships with Galderma, Ulthera, Ortho, Allergan, Cellgene, and other pharmaceutical companies.
MILAN – according to Dee Anna Glaser, MD.
Speaking at the World Congress of Dermatology, Dr. Glaser, director of clinical research and interim chair of the department of dermatology at Saint Louis University, said that in her practice, acne and actinic keratosis are the most common medical indications for chemical peels and that “acne is just a winner all the way around.”
For acne, she added: “Chemical peels can help both the comedonal and the inflammatory component. It should probably be combined with other therapies, and it does produce both an exfoliative and an anti-inflammatory benefit,.”
A variety of chemical peel formulations can be considered for acne, Dr. Glaser noted. “Typically, you’re going to use a light chemical peel,” such as glycolic or salicylic acid. Other options include Jessner’s solution or a light trichloroacetic acid formulation, she said, adding that tretinoin alone can also be considered.
In choosing between glycolic and salicylic acid, Dr. Glaser said, “salicylic acid should theoretically be the best agent because it is lipophilic and the glycolic acid is hydrophilic.” The reality of how these agents perform clinically, though, may sort out differently.
Dr. Glaser pointed to a double-blind, randomized controlled trial of the two agents in 20 women with facial acne. The severity of participants’ inflammatory acne was mild to moderate, with an average of 27 inflammatory lesions, and they had been on a stable prescription or over-the-counter acne regimen for at least 2 months (Dermatol Surg. 2008 Jan;34[1]:45-50).
Patients received six peels – one every 2 weeks – with 30% glycolic acid (an alpha-hydroxy acid) and 30% salicylic acid (a beta-hydroxy acid) in the split-face study.
All participants started at 4 minutes of exposure and increased up to 5 minutes as tolerated, although timing is only really important for glycolic acid, the same duration of exposure was maintained for each agent for the sake of consistency between arms, said Dr. Glaser, one of the investigators.
Sharing photographs of study participants, she observed that after six peels, “there really isn’t a significant difference.” Therefore, she added, “even though salicylic acid should be better, you can see that glycolic acid really held its own in this study.”
Dr. Glaser pointed out that a trend was seen for slightly better results with salicylic acid and results with this agent were more durable than those seen with glycolic acid. Patients reported fewer side effects on the beta-hydroxy–treated side as well.
She referred to another study, conducted in Japan, that used a double-blind, split-face design to compare 40% glycolic acid with a placebo that had a similarly low pH of 2.0. The 26 patients with moderate acne received five peels on a biweekly schedule, with glycolic acid significantly outperforming placebo. Among acne subtypes, noninflammatory acne improved more than inflammatory acne with glycolic acid (Dermatol Surg. 2014 Mar;40[3]:314-22).
Dr. Glaser said that in her own practice, she still tries to use salicylic acid for her acne patients,” though some patients prefer the experience of a glycolic acid peel, with which there’s likely to be less pain. “So if you have a preference, or your patient has a preference, you will probably be able to use the acid that works best for you,” she said.
Whatever peel is chosen, it should be considered an adjuvant to other topical and systemic acne therapies, Dr. Glaser stressed. “To maintain the results, you really do need to maintain the patient on some sort of standard acne therapy that you would normally do.”
Peels can also be an effective part of a multipronged approach that includes laser therapy and intralesional steroids, she said. However, peels can be considered for monotherapy in patients who don’t tolerate other acne therapies, and they can be used safely in pregnancy, she said.
As with all such treatments, dermatologists should remember to consider and counsel about herpes simplex virus prophylaxis and sun protection.
Dr. Glaser reported financial relationships with Galderma, Ulthera, Ortho, Allergan, Cellgene, and other pharmaceutical companies.
EXPERT ANALYSIS FROM WCD2019
Beyond C. difficile: The future of fecal microbial transplantation
SAN DIEGO – Two leading figures in microbiome research took time during the annual Digestive Disease Week to share their perspective with members of the press. Identifying key research presented at the meeting and painting a broader picture of trends and challenges in research on the interplay with the microbiota with gut health, Colleen Kelly, MD, of Brown University, Providence, R.I., cochair and principal investigator, AGA FMT Registry Steering Committee, led off the round table with a discussion of human research on fecal microbial transplantation (FMT) and obesity.
Purna Kashyap, MBBS, of the Mayo Clinic, Rochester, Minn., member, AGA Center for Gut Microbiome Research and Education Scientific Advisory Board, delved into the potential for donor microbiota transplant to address small bowel disorders, such as small intestinal bacterial overgrowth, and provided commentary regarding the potential – and limitations – of using FMT in functional bowel disorders such as irritable bowel syndrome (IBS).
Obesity
Dr. Kelly noted that two abstracts at the conference presented data about FMT in obesity. The first study was presented by Jessica Allegretti, MD, a gastroenterologist at Brigham and Women’s Hospital, Boston; the second study was presented by Elaine Yu, MD, an endocrinologist at Massachusetts General Hospital, Boston.
The two studies shared some similarities, but had some differences, said Dr. Kelly. “They both used lean donor encapsulated FMT ... and they both were placebo controlled, using placebo capsules.” The first study looked at metabolically healthy obese patients, while the second study included patients with mild to moderate insulin resistance.
Dr. Allegretti’s work looked at the effect that FMT from lean donors had on levels of a satiety peptide, glucagonlike peptide–1 (GLP-1), while also looking at changes in weight and microbiota, as well as safety. Patients received an initial 30-capsule dose as well as two later doses of 12 capsules each. The 22-patient study, in which individuals were randomized 1:1 to FMT or placebo capsules, didn’t show statistically significant changes in GLP-1 levels or body mass index with FMT over the 12-week study period. “But they were able to show engraftment, which I think is an important thing that you do wonder about – over this period of time, the bacteria that came from the lean donor actually engrafted into the recipient and affected the diversity. The recipient became more similar to the donor,” said Dr. Kelly.
There were some clues among the findings that engraftment was effecting metabolic change in the recipient, she said, including differences in bile acid conversion among gut bacteria; also, lower levels of the primary bile acid taurocholic acid in recipients after FMT. “So it was a negative study in what she was looking for, but an example of these smaller studies kind of pushing the field along.”
In discussing the study presented by Dr. Yu that examined lean donor FMT in individuals with insulin resistance, Dr. Kelly said, “It was actually pretty sophisticated.” By using hyperinsulinemic euglycemic clamping, the investigators were able to measure insulin sensitivity based on glucose load. In this study of 24 individuals randomized 1:1 to receive FMT or placebo capsules, recipients received weekly doses over a period of 6 weeks. Here again, though Dr. Yu and colleagues again found engraftment, “they did not find the big changes in metabolic parameters that they hoped that they would,” said Dr. Kelly.
These two studies furthered previous work completed in the Netherlands examining lean donor FMT for individuals with metabolic syndrome. “Those [studies] did show both engraftment and some changes in insulin resistance,” but they were also small studies, noted Dr. Kelly. Dr. Kashyap pointed out that the earlier studies had shown in a subgroup analysis that response to FMT was limited to those patients who lacked microbial diversity pretransplant.
This makes some mechanistic sense when thinking about FMT’s greatest success to date: Treating Clostridioides difficile infection, a condition whose very hallmark is dysbiosis characterized by monospecies gut domination, noted Dr. Kashyap.
Added Dr. Kelly, “I think everyone’s hoping there’s going to be this pill that’s going to make us skinny, but I don’t think we’re going to find that with FMT and obesity. I do think these studies are important, because there’s so much animal data already, and we’re kind of like, ‘How much more can you do in mice?’ ” By translating this preclinical work into humans, the mechanisms of obesity and the role of the microbiome can be better understood.
IBS
Turning to functional bowel disorders, Dr. Kelly pointed out a new study examining FMT for IBS. “So far, the research has been pretty disappointing,” she noted. The study, presented by Prashant Singh, MBBS, a gastroenterology fellow at Beth Israel Deaconess Medical Center, Boston, examined FMT for patients with moderate to severe diarrhea-predominant IBS. The study had four arms, randomizing the 44 participants to FMT alone; pretreatment with metronidazole and ciprofloxacin or rifaximin, each followed by FMT; or placebo. “It really didn’t show any differences in their severity of IBS in any group; so no effect: a negative study,” said Dr. Kelly.
“It’s challenging. FMT is an appealing strategy because we don’t have to put a lot of thought process into it,” said Dr. Kashyap, but it’s no panacea. “We aren’t going to be able to treat everybody with FMT.
“The challenge with IBS is that if we look at all the compositional studies, the majority of them show that at least a big subset of patients with IBS already have a normal-appearing microbiome,” said Dr. Kashyap. In those patients, “It’s very hard to know what FMT is doing.” He noted that IBS subclassifications are made by pathophysiology, without regard to the intestinal microbiome, so these classifications may not be useful for determining who may benefit from FMT.
“Again, there’s always an opportunity to learn from these studies,” whether they’re positive or negative, as long as they’re well done, said Dr. Kashyap. “There’s always an opportunity to go back and see, was there a specific subgroup of patients who responded, where there might be one or more causes which might be more amenable” to FMT.
Small intestine
And most intestinal microbial research to date, noted Dr. Kelly, has focused on the colon. “Most of our knowledge is of fecal microbiota.” New techniques including double-balloon enteroscopy of the small bowel have promise to “provide completely new information about patterns of bacteria throughout the small bowel,” and of the role of small bowel bacteria in overall gut health, she said.
“The role of the small bowel has been ignored because of accessibility,” agreed Dr. Kashyap. There’s a current focus on research into enteroscopy and other techniques to sample small intestine microbiota, he said.
In a podium presentation, Eugene Chang, MD, Martin Boyer Professor in the University of Chicago’s department of medicine, gave a broad overview of how the small intestine microbiome modulates lipid regulation. This choice of topic for the Charles M. Mansbach Memorial Lecture shows that gastroenterologists are recognizing the importance of microbiome along the entire span of the gut, said Dr. Kashyap. Dr. Chang’s approach, he added, represents a departure in that “it’s not simply just looking at what’s present and what’s not, but seeing what’s functionally relevant to metabolism.”
“We always have known that the small intestine is the workhorse; that’s where everything happens” in terms of motility, absorption, and digestion, said Dr. Kashyap. “But because of our inability to reach it easily we’ve always chosen to ignore it; we always go after the low-hanging fruit.” Despite challenges, more microbiome research should be small-bowel focused. “Eventually, it’s no pain, no gain.”
Dr. Kashyap is on the advisory board of uBiome, and is an ad hoc advisory board member for Salix Pharmaceuticals. Dr. Kelly reported no conflicts of interest.
This story was updated on July 30, 2019.
SAN DIEGO – Two leading figures in microbiome research took time during the annual Digestive Disease Week to share their perspective with members of the press. Identifying key research presented at the meeting and painting a broader picture of trends and challenges in research on the interplay with the microbiota with gut health, Colleen Kelly, MD, of Brown University, Providence, R.I., cochair and principal investigator, AGA FMT Registry Steering Committee, led off the round table with a discussion of human research on fecal microbial transplantation (FMT) and obesity.
Purna Kashyap, MBBS, of the Mayo Clinic, Rochester, Minn., member, AGA Center for Gut Microbiome Research and Education Scientific Advisory Board, delved into the potential for donor microbiota transplant to address small bowel disorders, such as small intestinal bacterial overgrowth, and provided commentary regarding the potential – and limitations – of using FMT in functional bowel disorders such as irritable bowel syndrome (IBS).
Obesity
Dr. Kelly noted that two abstracts at the conference presented data about FMT in obesity. The first study was presented by Jessica Allegretti, MD, a gastroenterologist at Brigham and Women’s Hospital, Boston; the second study was presented by Elaine Yu, MD, an endocrinologist at Massachusetts General Hospital, Boston.
The two studies shared some similarities, but had some differences, said Dr. Kelly. “They both used lean donor encapsulated FMT ... and they both were placebo controlled, using placebo capsules.” The first study looked at metabolically healthy obese patients, while the second study included patients with mild to moderate insulin resistance.
Dr. Allegretti’s work looked at the effect that FMT from lean donors had on levels of a satiety peptide, glucagonlike peptide–1 (GLP-1), while also looking at changes in weight and microbiota, as well as safety. Patients received an initial 30-capsule dose as well as two later doses of 12 capsules each. The 22-patient study, in which individuals were randomized 1:1 to FMT or placebo capsules, didn’t show statistically significant changes in GLP-1 levels or body mass index with FMT over the 12-week study period. “But they were able to show engraftment, which I think is an important thing that you do wonder about – over this period of time, the bacteria that came from the lean donor actually engrafted into the recipient and affected the diversity. The recipient became more similar to the donor,” said Dr. Kelly.
There were some clues among the findings that engraftment was effecting metabolic change in the recipient, she said, including differences in bile acid conversion among gut bacteria; also, lower levels of the primary bile acid taurocholic acid in recipients after FMT. “So it was a negative study in what she was looking for, but an example of these smaller studies kind of pushing the field along.”
In discussing the study presented by Dr. Yu that examined lean donor FMT in individuals with insulin resistance, Dr. Kelly said, “It was actually pretty sophisticated.” By using hyperinsulinemic euglycemic clamping, the investigators were able to measure insulin sensitivity based on glucose load. In this study of 24 individuals randomized 1:1 to receive FMT or placebo capsules, recipients received weekly doses over a period of 6 weeks. Here again, though Dr. Yu and colleagues again found engraftment, “they did not find the big changes in metabolic parameters that they hoped that they would,” said Dr. Kelly.
These two studies furthered previous work completed in the Netherlands examining lean donor FMT for individuals with metabolic syndrome. “Those [studies] did show both engraftment and some changes in insulin resistance,” but they were also small studies, noted Dr. Kelly. Dr. Kashyap pointed out that the earlier studies had shown in a subgroup analysis that response to FMT was limited to those patients who lacked microbial diversity pretransplant.
This makes some mechanistic sense when thinking about FMT’s greatest success to date: Treating Clostridioides difficile infection, a condition whose very hallmark is dysbiosis characterized by monospecies gut domination, noted Dr. Kashyap.
Added Dr. Kelly, “I think everyone’s hoping there’s going to be this pill that’s going to make us skinny, but I don’t think we’re going to find that with FMT and obesity. I do think these studies are important, because there’s so much animal data already, and we’re kind of like, ‘How much more can you do in mice?’ ” By translating this preclinical work into humans, the mechanisms of obesity and the role of the microbiome can be better understood.
IBS
Turning to functional bowel disorders, Dr. Kelly pointed out a new study examining FMT for IBS. “So far, the research has been pretty disappointing,” she noted. The study, presented by Prashant Singh, MBBS, a gastroenterology fellow at Beth Israel Deaconess Medical Center, Boston, examined FMT for patients with moderate to severe diarrhea-predominant IBS. The study had four arms, randomizing the 44 participants to FMT alone; pretreatment with metronidazole and ciprofloxacin or rifaximin, each followed by FMT; or placebo. “It really didn’t show any differences in their severity of IBS in any group; so no effect: a negative study,” said Dr. Kelly.
“It’s challenging. FMT is an appealing strategy because we don’t have to put a lot of thought process into it,” said Dr. Kashyap, but it’s no panacea. “We aren’t going to be able to treat everybody with FMT.
“The challenge with IBS is that if we look at all the compositional studies, the majority of them show that at least a big subset of patients with IBS already have a normal-appearing microbiome,” said Dr. Kashyap. In those patients, “It’s very hard to know what FMT is doing.” He noted that IBS subclassifications are made by pathophysiology, without regard to the intestinal microbiome, so these classifications may not be useful for determining who may benefit from FMT.
“Again, there’s always an opportunity to learn from these studies,” whether they’re positive or negative, as long as they’re well done, said Dr. Kashyap. “There’s always an opportunity to go back and see, was there a specific subgroup of patients who responded, where there might be one or more causes which might be more amenable” to FMT.
Small intestine
And most intestinal microbial research to date, noted Dr. Kelly, has focused on the colon. “Most of our knowledge is of fecal microbiota.” New techniques including double-balloon enteroscopy of the small bowel have promise to “provide completely new information about patterns of bacteria throughout the small bowel,” and of the role of small bowel bacteria in overall gut health, she said.
“The role of the small bowel has been ignored because of accessibility,” agreed Dr. Kashyap. There’s a current focus on research into enteroscopy and other techniques to sample small intestine microbiota, he said.
In a podium presentation, Eugene Chang, MD, Martin Boyer Professor in the University of Chicago’s department of medicine, gave a broad overview of how the small intestine microbiome modulates lipid regulation. This choice of topic for the Charles M. Mansbach Memorial Lecture shows that gastroenterologists are recognizing the importance of microbiome along the entire span of the gut, said Dr. Kashyap. Dr. Chang’s approach, he added, represents a departure in that “it’s not simply just looking at what’s present and what’s not, but seeing what’s functionally relevant to metabolism.”
“We always have known that the small intestine is the workhorse; that’s where everything happens” in terms of motility, absorption, and digestion, said Dr. Kashyap. “But because of our inability to reach it easily we’ve always chosen to ignore it; we always go after the low-hanging fruit.” Despite challenges, more microbiome research should be small-bowel focused. “Eventually, it’s no pain, no gain.”
Dr. Kashyap is on the advisory board of uBiome, and is an ad hoc advisory board member for Salix Pharmaceuticals. Dr. Kelly reported no conflicts of interest.
This story was updated on July 30, 2019.
SAN DIEGO – Two leading figures in microbiome research took time during the annual Digestive Disease Week to share their perspective with members of the press. Identifying key research presented at the meeting and painting a broader picture of trends and challenges in research on the interplay with the microbiota with gut health, Colleen Kelly, MD, of Brown University, Providence, R.I., cochair and principal investigator, AGA FMT Registry Steering Committee, led off the round table with a discussion of human research on fecal microbial transplantation (FMT) and obesity.
Purna Kashyap, MBBS, of the Mayo Clinic, Rochester, Minn., member, AGA Center for Gut Microbiome Research and Education Scientific Advisory Board, delved into the potential for donor microbiota transplant to address small bowel disorders, such as small intestinal bacterial overgrowth, and provided commentary regarding the potential – and limitations – of using FMT in functional bowel disorders such as irritable bowel syndrome (IBS).
Obesity
Dr. Kelly noted that two abstracts at the conference presented data about FMT in obesity. The first study was presented by Jessica Allegretti, MD, a gastroenterologist at Brigham and Women’s Hospital, Boston; the second study was presented by Elaine Yu, MD, an endocrinologist at Massachusetts General Hospital, Boston.
The two studies shared some similarities, but had some differences, said Dr. Kelly. “They both used lean donor encapsulated FMT ... and they both were placebo controlled, using placebo capsules.” The first study looked at metabolically healthy obese patients, while the second study included patients with mild to moderate insulin resistance.
Dr. Allegretti’s work looked at the effect that FMT from lean donors had on levels of a satiety peptide, glucagonlike peptide–1 (GLP-1), while also looking at changes in weight and microbiota, as well as safety. Patients received an initial 30-capsule dose as well as two later doses of 12 capsules each. The 22-patient study, in which individuals were randomized 1:1 to FMT or placebo capsules, didn’t show statistically significant changes in GLP-1 levels or body mass index with FMT over the 12-week study period. “But they were able to show engraftment, which I think is an important thing that you do wonder about – over this period of time, the bacteria that came from the lean donor actually engrafted into the recipient and affected the diversity. The recipient became more similar to the donor,” said Dr. Kelly.
There were some clues among the findings that engraftment was effecting metabolic change in the recipient, she said, including differences in bile acid conversion among gut bacteria; also, lower levels of the primary bile acid taurocholic acid in recipients after FMT. “So it was a negative study in what she was looking for, but an example of these smaller studies kind of pushing the field along.”
In discussing the study presented by Dr. Yu that examined lean donor FMT in individuals with insulin resistance, Dr. Kelly said, “It was actually pretty sophisticated.” By using hyperinsulinemic euglycemic clamping, the investigators were able to measure insulin sensitivity based on glucose load. In this study of 24 individuals randomized 1:1 to receive FMT or placebo capsules, recipients received weekly doses over a period of 6 weeks. Here again, though Dr. Yu and colleagues again found engraftment, “they did not find the big changes in metabolic parameters that they hoped that they would,” said Dr. Kelly.
These two studies furthered previous work completed in the Netherlands examining lean donor FMT for individuals with metabolic syndrome. “Those [studies] did show both engraftment and some changes in insulin resistance,” but they were also small studies, noted Dr. Kelly. Dr. Kashyap pointed out that the earlier studies had shown in a subgroup analysis that response to FMT was limited to those patients who lacked microbial diversity pretransplant.
This makes some mechanistic sense when thinking about FMT’s greatest success to date: Treating Clostridioides difficile infection, a condition whose very hallmark is dysbiosis characterized by monospecies gut domination, noted Dr. Kashyap.
Added Dr. Kelly, “I think everyone’s hoping there’s going to be this pill that’s going to make us skinny, but I don’t think we’re going to find that with FMT and obesity. I do think these studies are important, because there’s so much animal data already, and we’re kind of like, ‘How much more can you do in mice?’ ” By translating this preclinical work into humans, the mechanisms of obesity and the role of the microbiome can be better understood.
IBS
Turning to functional bowel disorders, Dr. Kelly pointed out a new study examining FMT for IBS. “So far, the research has been pretty disappointing,” she noted. The study, presented by Prashant Singh, MBBS, a gastroenterology fellow at Beth Israel Deaconess Medical Center, Boston, examined FMT for patients with moderate to severe diarrhea-predominant IBS. The study had four arms, randomizing the 44 participants to FMT alone; pretreatment with metronidazole and ciprofloxacin or rifaximin, each followed by FMT; or placebo. “It really didn’t show any differences in their severity of IBS in any group; so no effect: a negative study,” said Dr. Kelly.
“It’s challenging. FMT is an appealing strategy because we don’t have to put a lot of thought process into it,” said Dr. Kashyap, but it’s no panacea. “We aren’t going to be able to treat everybody with FMT.
“The challenge with IBS is that if we look at all the compositional studies, the majority of them show that at least a big subset of patients with IBS already have a normal-appearing microbiome,” said Dr. Kashyap. In those patients, “It’s very hard to know what FMT is doing.” He noted that IBS subclassifications are made by pathophysiology, without regard to the intestinal microbiome, so these classifications may not be useful for determining who may benefit from FMT.
“Again, there’s always an opportunity to learn from these studies,” whether they’re positive or negative, as long as they’re well done, said Dr. Kashyap. “There’s always an opportunity to go back and see, was there a specific subgroup of patients who responded, where there might be one or more causes which might be more amenable” to FMT.
Small intestine
And most intestinal microbial research to date, noted Dr. Kelly, has focused on the colon. “Most of our knowledge is of fecal microbiota.” New techniques including double-balloon enteroscopy of the small bowel have promise to “provide completely new information about patterns of bacteria throughout the small bowel,” and of the role of small bowel bacteria in overall gut health, she said.
“The role of the small bowel has been ignored because of accessibility,” agreed Dr. Kashyap. There’s a current focus on research into enteroscopy and other techniques to sample small intestine microbiota, he said.
In a podium presentation, Eugene Chang, MD, Martin Boyer Professor in the University of Chicago’s department of medicine, gave a broad overview of how the small intestine microbiome modulates lipid regulation. This choice of topic for the Charles M. Mansbach Memorial Lecture shows that gastroenterologists are recognizing the importance of microbiome along the entire span of the gut, said Dr. Kashyap. Dr. Chang’s approach, he added, represents a departure in that “it’s not simply just looking at what’s present and what’s not, but seeing what’s functionally relevant to metabolism.”
“We always have known that the small intestine is the workhorse; that’s where everything happens” in terms of motility, absorption, and digestion, said Dr. Kashyap. “But because of our inability to reach it easily we’ve always chosen to ignore it; we always go after the low-hanging fruit.” Despite challenges, more microbiome research should be small-bowel focused. “Eventually, it’s no pain, no gain.”
Dr. Kashyap is on the advisory board of uBiome, and is an ad hoc advisory board member for Salix Pharmaceuticals. Dr. Kelly reported no conflicts of interest.
This story was updated on July 30, 2019.
EXPERT ANALYSIS FROM DDW 2019
Lenabasum, a novel cannabinoid, shows promise in dermatomyositis
MILAN – according to Victoria Werth, MD, who presented early-stage findings at the World Congress of Dermatology.
Lenabasum – previously known as anabasum – is a synthetic cannabinoid that binds to the CB2 receptor present on a variety of cells, including lymphocytes, explained Dr. Werth, professor of medicine at the University of Pennsylvania, Philadelphia, and chief of dermatology at the Philadelphia Veterans Administration Hospital. The nonpsychoactive compound’s mechanism of action helps prevent tissue thickening and fibrosis. In addition to its potential for dermatomyositis treatment, it is also being investigated as a treatment for cystic fibrosis, scleroderma, and lupus.
Dr. Werth added that earlier in vitro work with peripheral blood mononuclear cells of patients with dermatomyositis showed that lenabasum markedly suppressed the cells’ secretion of tumor necrosis factor–alpha, interferon-alpha, and interferon-beta (J Invest Dermatol. 2017 Nov;137[11]:2445-7). A randomized, placebo-controlled trial tested lenabasum, known in the trial as JBT-101, in 22 patients with skin-predominant myositis. The study was structured so patients took a half dose of lenabasum for 1 month, followed by 2 months of taking a full dose, and finally 1 month with no lenabasum dosing. Compared with placebo, scores on the Cutaneous Dermatomyositis Disease Area and Severity Index (CDASI) were significantly improved with full dosing of lenabasum (P = .02), Dr. Werth said.
In this 16-week trial, the mean change in CDASI score dropped for participants in both the lenabasum and placebo groups for the first 4 weeks. After that, however, those taking lenabasum saw an improvement of about 8 points from baseline CDASI score at 8 weeks, while those taking placebo had a decline of 3 points (P = .05). The differences remained significant at trial’s end.
Patient-reported outcomes for pain were significantly better with lenabasum, with patients on lenabasum recording a decrease on the Patient-Reported Outcomes Measurement Information System–29 pain interference scale, while patients on placebo reported an increase in pain by the end of the study period (P = .026). Scores on two other patient-reported dermatomyositis scales were numerically improved for patients taking lenabasum, but the differences from the patients on placebo were not statistically significant, Dr. Werth said.
However, patients in the initial clinical trial were given the opportunity to continue in a long-term extension arm, and that group has seen the clinician-rated CDASI scores continue to fall, with a mean decrease of 22 points from baseline (about 12 further points from the mean for those on lenabasum in the initial trial) at the 68-week mark, she added.
Itch scores continued to drop as well, with a reduction of 3.7 points on the 5-D Itch scale by 68 weeks; at 16 weeks, the reduction for the lenabasum arm had been 1.3 points.
Skin samples taken from trial participants showed many fewer CD4 cells in those taking lenabasum, compared with placebo at week 12 of the initial study. Interferon-beta and -gamma levels also dropped in those taking lenabasum, but not in the placebo arm.
“Lenabasum has effects on cytokine signatures and inflammatory cells correlating with response to therapy,” Dr. Werth said, adding that the findings gave support for a planned global phase 3 clinical trial of lenabasum in dermatomyositis.
Dr. Werth reported receiving grants from Pfizer and Corbus, and consulting fees from Pfizer, Janssen, Neovacs, Idera Pharmaceuticals, Octapharma, CSL Behring, and Corbus Pharmaceuticals. The study was funded by Corbus, the National Institutes of Health, and the University of Pennsylvania.
Cannabinoids represent a broad class of chemical compounds originally comprised only phytocannabinoids – cannabinoids produced by the cannabis plant. The best-known and most-studied cannabinoids are tetrahydrocannabinol and cannabidiol, which are plant-derived, or “phyto”, cannabinoids. While tetrahydrocannabinol is best known for its mind-altering, munchy-causing properties, it was in fact the study of this illegal substance that led to the groundbreaking discovery of the human endocannabinoid system. (Meaning, we make our very own cannabinoids and receptors for them, which make up an extraordinary biological network that play a role in everything from sensations of pain and itch to mood, inflammation regulation, and wound healing.) Gold star for drugs?
It was this understanding that led to the development of synthetic cannabinoids, like ajulemic acid (aka lenabasum), all of which has created a flurry of investigative productivity and creativity to capitalize on these bioactive agents. That said, development, research and development, and even education in/on this area has been hindered for many years because of both regulatory limitations and negative public perceptions, given the Schedule 1 designation of every component of the cannabis plant (even nonpsychoactive actives) up until a few months ago with the passing of the Farm Bill (which made hemp legal).
However, the interest level among consumers, patients, and physicians is quickly growing regarding the effectiveness of cannabinoids in the treatment of a laundry list of skin conditions and symptoms, including psoriasis, atopic dermatitis, and wound healing. But there are just so many unanswered questions for anyone to be certain about the benefits. We recently published a study surveying 531 dermatologists to get a better idea about our community’s attitude and awareness on cannabinoids as therapeutics, and it turned out there’s a lot we all need to learn (J Drugs Dermatol. 2018 Dec 1;17[12]:1273-8). Some highlights of our findings:
- Dermatologists are being approached by their patients with questions on this subject matter, and this is more likely to occur in states where medical cannabis is legalized.
- While more than 90% of respondents agreed that this is an important area for research and development and 86% thought medical cannabinoids should be legal, more than 80% were not comfortable with their understanding or knowledge on this subject matter, which is not surprising given that 64% of respondents incorrectly responded that cannabidiol has psychoactive effects.
With the fast-tracking of lenabasum down the Food and Drug Administration approval pathway for not one but two diseases we as dermatologists manage, I am optimistic that this addition to our much needed armament will serve as further stimulus to expand the role of cannabinoids in the management of dermatologic diseases and spotlight the need for more education and research in this vastly underrecognized yet intriguing and promising space.
Adam Friedman, MD, is professor and interim chair of dermatology, director of translational research, and director of the supportive oncodermatology clinic at George Washington University, Washington, and is on the board of Dermatology News. Dr. Friedman is on the scientific advisory board for Corbus Pharmaceuticals.
Cannabinoids represent a broad class of chemical compounds originally comprised only phytocannabinoids – cannabinoids produced by the cannabis plant. The best-known and most-studied cannabinoids are tetrahydrocannabinol and cannabidiol, which are plant-derived, or “phyto”, cannabinoids. While tetrahydrocannabinol is best known for its mind-altering, munchy-causing properties, it was in fact the study of this illegal substance that led to the groundbreaking discovery of the human endocannabinoid system. (Meaning, we make our very own cannabinoids and receptors for them, which make up an extraordinary biological network that play a role in everything from sensations of pain and itch to mood, inflammation regulation, and wound healing.) Gold star for drugs?
It was this understanding that led to the development of synthetic cannabinoids, like ajulemic acid (aka lenabasum), all of which has created a flurry of investigative productivity and creativity to capitalize on these bioactive agents. That said, development, research and development, and even education in/on this area has been hindered for many years because of both regulatory limitations and negative public perceptions, given the Schedule 1 designation of every component of the cannabis plant (even nonpsychoactive actives) up until a few months ago with the passing of the Farm Bill (which made hemp legal).
However, the interest level among consumers, patients, and physicians is quickly growing regarding the effectiveness of cannabinoids in the treatment of a laundry list of skin conditions and symptoms, including psoriasis, atopic dermatitis, and wound healing. But there are just so many unanswered questions for anyone to be certain about the benefits. We recently published a study surveying 531 dermatologists to get a better idea about our community’s attitude and awareness on cannabinoids as therapeutics, and it turned out there’s a lot we all need to learn (J Drugs Dermatol. 2018 Dec 1;17[12]:1273-8). Some highlights of our findings:
- Dermatologists are being approached by their patients with questions on this subject matter, and this is more likely to occur in states where medical cannabis is legalized.
- While more than 90% of respondents agreed that this is an important area for research and development and 86% thought medical cannabinoids should be legal, more than 80% were not comfortable with their understanding or knowledge on this subject matter, which is not surprising given that 64% of respondents incorrectly responded that cannabidiol has psychoactive effects.
With the fast-tracking of lenabasum down the Food and Drug Administration approval pathway for not one but two diseases we as dermatologists manage, I am optimistic that this addition to our much needed armament will serve as further stimulus to expand the role of cannabinoids in the management of dermatologic diseases and spotlight the need for more education and research in this vastly underrecognized yet intriguing and promising space.
Adam Friedman, MD, is professor and interim chair of dermatology, director of translational research, and director of the supportive oncodermatology clinic at George Washington University, Washington, and is on the board of Dermatology News. Dr. Friedman is on the scientific advisory board for Corbus Pharmaceuticals.
Cannabinoids represent a broad class of chemical compounds originally comprised only phytocannabinoids – cannabinoids produced by the cannabis plant. The best-known and most-studied cannabinoids are tetrahydrocannabinol and cannabidiol, which are plant-derived, or “phyto”, cannabinoids. While tetrahydrocannabinol is best known for its mind-altering, munchy-causing properties, it was in fact the study of this illegal substance that led to the groundbreaking discovery of the human endocannabinoid system. (Meaning, we make our very own cannabinoids and receptors for them, which make up an extraordinary biological network that play a role in everything from sensations of pain and itch to mood, inflammation regulation, and wound healing.) Gold star for drugs?
It was this understanding that led to the development of synthetic cannabinoids, like ajulemic acid (aka lenabasum), all of which has created a flurry of investigative productivity and creativity to capitalize on these bioactive agents. That said, development, research and development, and even education in/on this area has been hindered for many years because of both regulatory limitations and negative public perceptions, given the Schedule 1 designation of every component of the cannabis plant (even nonpsychoactive actives) up until a few months ago with the passing of the Farm Bill (which made hemp legal).
However, the interest level among consumers, patients, and physicians is quickly growing regarding the effectiveness of cannabinoids in the treatment of a laundry list of skin conditions and symptoms, including psoriasis, atopic dermatitis, and wound healing. But there are just so many unanswered questions for anyone to be certain about the benefits. We recently published a study surveying 531 dermatologists to get a better idea about our community’s attitude and awareness on cannabinoids as therapeutics, and it turned out there’s a lot we all need to learn (J Drugs Dermatol. 2018 Dec 1;17[12]:1273-8). Some highlights of our findings:
- Dermatologists are being approached by their patients with questions on this subject matter, and this is more likely to occur in states where medical cannabis is legalized.
- While more than 90% of respondents agreed that this is an important area for research and development and 86% thought medical cannabinoids should be legal, more than 80% were not comfortable with their understanding or knowledge on this subject matter, which is not surprising given that 64% of respondents incorrectly responded that cannabidiol has psychoactive effects.
With the fast-tracking of lenabasum down the Food and Drug Administration approval pathway for not one but two diseases we as dermatologists manage, I am optimistic that this addition to our much needed armament will serve as further stimulus to expand the role of cannabinoids in the management of dermatologic diseases and spotlight the need for more education and research in this vastly underrecognized yet intriguing and promising space.
Adam Friedman, MD, is professor and interim chair of dermatology, director of translational research, and director of the supportive oncodermatology clinic at George Washington University, Washington, and is on the board of Dermatology News. Dr. Friedman is on the scientific advisory board for Corbus Pharmaceuticals.
MILAN – according to Victoria Werth, MD, who presented early-stage findings at the World Congress of Dermatology.
Lenabasum – previously known as anabasum – is a synthetic cannabinoid that binds to the CB2 receptor present on a variety of cells, including lymphocytes, explained Dr. Werth, professor of medicine at the University of Pennsylvania, Philadelphia, and chief of dermatology at the Philadelphia Veterans Administration Hospital. The nonpsychoactive compound’s mechanism of action helps prevent tissue thickening and fibrosis. In addition to its potential for dermatomyositis treatment, it is also being investigated as a treatment for cystic fibrosis, scleroderma, and lupus.
Dr. Werth added that earlier in vitro work with peripheral blood mononuclear cells of patients with dermatomyositis showed that lenabasum markedly suppressed the cells’ secretion of tumor necrosis factor–alpha, interferon-alpha, and interferon-beta (J Invest Dermatol. 2017 Nov;137[11]:2445-7). A randomized, placebo-controlled trial tested lenabasum, known in the trial as JBT-101, in 22 patients with skin-predominant myositis. The study was structured so patients took a half dose of lenabasum for 1 month, followed by 2 months of taking a full dose, and finally 1 month with no lenabasum dosing. Compared with placebo, scores on the Cutaneous Dermatomyositis Disease Area and Severity Index (CDASI) were significantly improved with full dosing of lenabasum (P = .02), Dr. Werth said.
In this 16-week trial, the mean change in CDASI score dropped for participants in both the lenabasum and placebo groups for the first 4 weeks. After that, however, those taking lenabasum saw an improvement of about 8 points from baseline CDASI score at 8 weeks, while those taking placebo had a decline of 3 points (P = .05). The differences remained significant at trial’s end.
Patient-reported outcomes for pain were significantly better with lenabasum, with patients on lenabasum recording a decrease on the Patient-Reported Outcomes Measurement Information System–29 pain interference scale, while patients on placebo reported an increase in pain by the end of the study period (P = .026). Scores on two other patient-reported dermatomyositis scales were numerically improved for patients taking lenabasum, but the differences from the patients on placebo were not statistically significant, Dr. Werth said.
However, patients in the initial clinical trial were given the opportunity to continue in a long-term extension arm, and that group has seen the clinician-rated CDASI scores continue to fall, with a mean decrease of 22 points from baseline (about 12 further points from the mean for those on lenabasum in the initial trial) at the 68-week mark, she added.
Itch scores continued to drop as well, with a reduction of 3.7 points on the 5-D Itch scale by 68 weeks; at 16 weeks, the reduction for the lenabasum arm had been 1.3 points.
Skin samples taken from trial participants showed many fewer CD4 cells in those taking lenabasum, compared with placebo at week 12 of the initial study. Interferon-beta and -gamma levels also dropped in those taking lenabasum, but not in the placebo arm.
“Lenabasum has effects on cytokine signatures and inflammatory cells correlating with response to therapy,” Dr. Werth said, adding that the findings gave support for a planned global phase 3 clinical trial of lenabasum in dermatomyositis.
Dr. Werth reported receiving grants from Pfizer and Corbus, and consulting fees from Pfizer, Janssen, Neovacs, Idera Pharmaceuticals, Octapharma, CSL Behring, and Corbus Pharmaceuticals. The study was funded by Corbus, the National Institutes of Health, and the University of Pennsylvania.
MILAN – according to Victoria Werth, MD, who presented early-stage findings at the World Congress of Dermatology.
Lenabasum – previously known as anabasum – is a synthetic cannabinoid that binds to the CB2 receptor present on a variety of cells, including lymphocytes, explained Dr. Werth, professor of medicine at the University of Pennsylvania, Philadelphia, and chief of dermatology at the Philadelphia Veterans Administration Hospital. The nonpsychoactive compound’s mechanism of action helps prevent tissue thickening and fibrosis. In addition to its potential for dermatomyositis treatment, it is also being investigated as a treatment for cystic fibrosis, scleroderma, and lupus.
Dr. Werth added that earlier in vitro work with peripheral blood mononuclear cells of patients with dermatomyositis showed that lenabasum markedly suppressed the cells’ secretion of tumor necrosis factor–alpha, interferon-alpha, and interferon-beta (J Invest Dermatol. 2017 Nov;137[11]:2445-7). A randomized, placebo-controlled trial tested lenabasum, known in the trial as JBT-101, in 22 patients with skin-predominant myositis. The study was structured so patients took a half dose of lenabasum for 1 month, followed by 2 months of taking a full dose, and finally 1 month with no lenabasum dosing. Compared with placebo, scores on the Cutaneous Dermatomyositis Disease Area and Severity Index (CDASI) were significantly improved with full dosing of lenabasum (P = .02), Dr. Werth said.
In this 16-week trial, the mean change in CDASI score dropped for participants in both the lenabasum and placebo groups for the first 4 weeks. After that, however, those taking lenabasum saw an improvement of about 8 points from baseline CDASI score at 8 weeks, while those taking placebo had a decline of 3 points (P = .05). The differences remained significant at trial’s end.
Patient-reported outcomes for pain were significantly better with lenabasum, with patients on lenabasum recording a decrease on the Patient-Reported Outcomes Measurement Information System–29 pain interference scale, while patients on placebo reported an increase in pain by the end of the study period (P = .026). Scores on two other patient-reported dermatomyositis scales were numerically improved for patients taking lenabasum, but the differences from the patients on placebo were not statistically significant, Dr. Werth said.
However, patients in the initial clinical trial were given the opportunity to continue in a long-term extension arm, and that group has seen the clinician-rated CDASI scores continue to fall, with a mean decrease of 22 points from baseline (about 12 further points from the mean for those on lenabasum in the initial trial) at the 68-week mark, she added.
Itch scores continued to drop as well, with a reduction of 3.7 points on the 5-D Itch scale by 68 weeks; at 16 weeks, the reduction for the lenabasum arm had been 1.3 points.
Skin samples taken from trial participants showed many fewer CD4 cells in those taking lenabasum, compared with placebo at week 12 of the initial study. Interferon-beta and -gamma levels also dropped in those taking lenabasum, but not in the placebo arm.
“Lenabasum has effects on cytokine signatures and inflammatory cells correlating with response to therapy,” Dr. Werth said, adding that the findings gave support for a planned global phase 3 clinical trial of lenabasum in dermatomyositis.
Dr. Werth reported receiving grants from Pfizer and Corbus, and consulting fees from Pfizer, Janssen, Neovacs, Idera Pharmaceuticals, Octapharma, CSL Behring, and Corbus Pharmaceuticals. The study was funded by Corbus, the National Institutes of Health, and the University of Pennsylvania.
EXPERT ANALYSIS FROM WCD2019