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PREDIX HER2 trial: Similar efficacy, less toxicity with T-DM1 for HER2+, HR+ breast cancer
CHICAGO – Targeted neoadjuvant therapy with trastuzumab emtansine (T-DM1) had similar efficacy with less toxicity, compared with a standard chemotherapy–based regimen for patients with HER2- and hormone receptor–positive breast cancers in the phase 2 Swedish PREDIX HER2 trial.
The pathologic complete response (pCR) rate was 45% among 98 participants who were randomized to received T-DM1, and 47% in those randomized to receive docetaxel, trastuzumab, and pertuzumab (DTP), Jonas C.S. Bergh, MD, PhD, reported at the annual meeting of the American Society of Clinical Oncology.
The pCR rate in hormone receptor(HR) –positive tumors was 36% in both groups, and the rates in HR-negative tumors were 59% and 67% in the T-DM1 and DTP arms, respectively; any differences in pCR rates between the groups were not statistically significant, said Dr. Bergh of the Karolinska Institute and University Hospital, Stockholm.
Patients were adults with HER2-positive breast cancer and tumor size greater than 20 mm or verified lymph node metastases at enrollment, and 62.6% of tumors were HR positive. Both treatment arms received their assigned therapy every 3 weeks for a planned total of six courses, but the protocol allowed a switch to the competing treatment upon progression, lack of response, or drug-related severe toxicity. All received postoperative epirubicin+cyclophosphamide every 3 weeks, with the T-DM1 arm receiving 4 courses and the DTP arm receiving 2 courses, and both arms also received adjuvant trastuzumab for 11 courses.
Age (median of 52 years), menopausal status, and histological type and grade were well balanced between the treatment groups.
Grade 3/4 adverse events occurred on 63 occasions in the DTP arm, compared with 10 in the T-DM1 arm; febrile neutropenia accounted for 26 and 3 of the events in the groups, respectively. All events, with the exception of liver toxicity, occurred more frequently in the DTP arm, Dr. Bergh said.
Ultimately, 9 patients switched from T-DM1 to DTP – 7 for progression or lack of response and 2 because of toxicity, and 18 switched from DTP to T-DM1 because of either progression or lack of response, and 14 because of toxicity. One patient in each group achieved pCR after switching, he noted.
“There was clearly better quality of life [during the study] for the T-DM1 group,” he added, noting that the quality of life data were reported separately at the meeting.
Additionally, an exploratory analysis demonstrated an early steep decrease of F-FDG uptake, suggesting that PET/CT may be a useful tool for predicting pCR.
Although neoadjuvant therapy produces high pCR rates and is the standard of care in HER2 positive breast cancer, the optimal treatment regimen remains to be established; but the current findings, along with prior data showing efficacy with T-DM1 in patients who fail to respond to two or more lines of anti-HER2 therapies, suggest it is a potential new standard for neoadjuvant therapy, particularly for patients with HER2- and HR-positive disease, he concluded.
Dr. Bergh reported a financial relationship with UpToDate, and research funding to his institution from Amgen, AstraZeneca, Bayer, Merck, Pfizer, Roche, and Sanofi.
SOURCE: Bergh J et al. ASCO 2019, Abstract 501.
CHICAGO – Targeted neoadjuvant therapy with trastuzumab emtansine (T-DM1) had similar efficacy with less toxicity, compared with a standard chemotherapy–based regimen for patients with HER2- and hormone receptor–positive breast cancers in the phase 2 Swedish PREDIX HER2 trial.
The pathologic complete response (pCR) rate was 45% among 98 participants who were randomized to received T-DM1, and 47% in those randomized to receive docetaxel, trastuzumab, and pertuzumab (DTP), Jonas C.S. Bergh, MD, PhD, reported at the annual meeting of the American Society of Clinical Oncology.
The pCR rate in hormone receptor(HR) –positive tumors was 36% in both groups, and the rates in HR-negative tumors were 59% and 67% in the T-DM1 and DTP arms, respectively; any differences in pCR rates between the groups were not statistically significant, said Dr. Bergh of the Karolinska Institute and University Hospital, Stockholm.
Patients were adults with HER2-positive breast cancer and tumor size greater than 20 mm or verified lymph node metastases at enrollment, and 62.6% of tumors were HR positive. Both treatment arms received their assigned therapy every 3 weeks for a planned total of six courses, but the protocol allowed a switch to the competing treatment upon progression, lack of response, or drug-related severe toxicity. All received postoperative epirubicin+cyclophosphamide every 3 weeks, with the T-DM1 arm receiving 4 courses and the DTP arm receiving 2 courses, and both arms also received adjuvant trastuzumab for 11 courses.
Age (median of 52 years), menopausal status, and histological type and grade were well balanced between the treatment groups.
Grade 3/4 adverse events occurred on 63 occasions in the DTP arm, compared with 10 in the T-DM1 arm; febrile neutropenia accounted for 26 and 3 of the events in the groups, respectively. All events, with the exception of liver toxicity, occurred more frequently in the DTP arm, Dr. Bergh said.
Ultimately, 9 patients switched from T-DM1 to DTP – 7 for progression or lack of response and 2 because of toxicity, and 18 switched from DTP to T-DM1 because of either progression or lack of response, and 14 because of toxicity. One patient in each group achieved pCR after switching, he noted.
“There was clearly better quality of life [during the study] for the T-DM1 group,” he added, noting that the quality of life data were reported separately at the meeting.
Additionally, an exploratory analysis demonstrated an early steep decrease of F-FDG uptake, suggesting that PET/CT may be a useful tool for predicting pCR.
Although neoadjuvant therapy produces high pCR rates and is the standard of care in HER2 positive breast cancer, the optimal treatment regimen remains to be established; but the current findings, along with prior data showing efficacy with T-DM1 in patients who fail to respond to two or more lines of anti-HER2 therapies, suggest it is a potential new standard for neoadjuvant therapy, particularly for patients with HER2- and HR-positive disease, he concluded.
Dr. Bergh reported a financial relationship with UpToDate, and research funding to his institution from Amgen, AstraZeneca, Bayer, Merck, Pfizer, Roche, and Sanofi.
SOURCE: Bergh J et al. ASCO 2019, Abstract 501.
CHICAGO – Targeted neoadjuvant therapy with trastuzumab emtansine (T-DM1) had similar efficacy with less toxicity, compared with a standard chemotherapy–based regimen for patients with HER2- and hormone receptor–positive breast cancers in the phase 2 Swedish PREDIX HER2 trial.
The pathologic complete response (pCR) rate was 45% among 98 participants who were randomized to received T-DM1, and 47% in those randomized to receive docetaxel, trastuzumab, and pertuzumab (DTP), Jonas C.S. Bergh, MD, PhD, reported at the annual meeting of the American Society of Clinical Oncology.
The pCR rate in hormone receptor(HR) –positive tumors was 36% in both groups, and the rates in HR-negative tumors were 59% and 67% in the T-DM1 and DTP arms, respectively; any differences in pCR rates between the groups were not statistically significant, said Dr. Bergh of the Karolinska Institute and University Hospital, Stockholm.
Patients were adults with HER2-positive breast cancer and tumor size greater than 20 mm or verified lymph node metastases at enrollment, and 62.6% of tumors were HR positive. Both treatment arms received their assigned therapy every 3 weeks for a planned total of six courses, but the protocol allowed a switch to the competing treatment upon progression, lack of response, or drug-related severe toxicity. All received postoperative epirubicin+cyclophosphamide every 3 weeks, with the T-DM1 arm receiving 4 courses and the DTP arm receiving 2 courses, and both arms also received adjuvant trastuzumab for 11 courses.
Age (median of 52 years), menopausal status, and histological type and grade were well balanced between the treatment groups.
Grade 3/4 adverse events occurred on 63 occasions in the DTP arm, compared with 10 in the T-DM1 arm; febrile neutropenia accounted for 26 and 3 of the events in the groups, respectively. All events, with the exception of liver toxicity, occurred more frequently in the DTP arm, Dr. Bergh said.
Ultimately, 9 patients switched from T-DM1 to DTP – 7 for progression or lack of response and 2 because of toxicity, and 18 switched from DTP to T-DM1 because of either progression or lack of response, and 14 because of toxicity. One patient in each group achieved pCR after switching, he noted.
“There was clearly better quality of life [during the study] for the T-DM1 group,” he added, noting that the quality of life data were reported separately at the meeting.
Additionally, an exploratory analysis demonstrated an early steep decrease of F-FDG uptake, suggesting that PET/CT may be a useful tool for predicting pCR.
Although neoadjuvant therapy produces high pCR rates and is the standard of care in HER2 positive breast cancer, the optimal treatment regimen remains to be established; but the current findings, along with prior data showing efficacy with T-DM1 in patients who fail to respond to two or more lines of anti-HER2 therapies, suggest it is a potential new standard for neoadjuvant therapy, particularly for patients with HER2- and HR-positive disease, he concluded.
Dr. Bergh reported a financial relationship with UpToDate, and research funding to his institution from Amgen, AstraZeneca, Bayer, Merck, Pfizer, Roche, and Sanofi.
SOURCE: Bergh J et al. ASCO 2019, Abstract 501.
REPORTING FROM ASCO 2019
FDA invites sample submission for FDA-ARGOS database
which seeks to support research and regulatory decisions regarding DNA testing for pathogens with quality-controlled and curated genomic sequence data. Such testing and devices could be used as medical countermeasures against biothreats such as Ebola and Zika.
Infectious disease next-generation sequencing could use DNA analysis to help identify pathogens – from viruses to parasites – faster and more efficiently by, in theory, accomplishing with one test what was only possible before with many, according to the FDA. In order to not only further development of such tests and devices but also aid regulatory and scientific review of them, the FDA has collaborated with the Department of Defense, the National Center for Biotechnology Information, and Institute for Genome Sciences at the University of Maryland, Baltimore, to create FDA-ARGOS.
However, the FDA and its collaborators need samples of pathogens to continue developing the database, so they’ve invited health care professionals to submit samples for that purpose. More information, including preferred organism list and submission guidelines, can be found on the FDA-ARGOS website.
which seeks to support research and regulatory decisions regarding DNA testing for pathogens with quality-controlled and curated genomic sequence data. Such testing and devices could be used as medical countermeasures against biothreats such as Ebola and Zika.
Infectious disease next-generation sequencing could use DNA analysis to help identify pathogens – from viruses to parasites – faster and more efficiently by, in theory, accomplishing with one test what was only possible before with many, according to the FDA. In order to not only further development of such tests and devices but also aid regulatory and scientific review of them, the FDA has collaborated with the Department of Defense, the National Center for Biotechnology Information, and Institute for Genome Sciences at the University of Maryland, Baltimore, to create FDA-ARGOS.
However, the FDA and its collaborators need samples of pathogens to continue developing the database, so they’ve invited health care professionals to submit samples for that purpose. More information, including preferred organism list and submission guidelines, can be found on the FDA-ARGOS website.
which seeks to support research and regulatory decisions regarding DNA testing for pathogens with quality-controlled and curated genomic sequence data. Such testing and devices could be used as medical countermeasures against biothreats such as Ebola and Zika.
Infectious disease next-generation sequencing could use DNA analysis to help identify pathogens – from viruses to parasites – faster and more efficiently by, in theory, accomplishing with one test what was only possible before with many, according to the FDA. In order to not only further development of such tests and devices but also aid regulatory and scientific review of them, the FDA has collaborated with the Department of Defense, the National Center for Biotechnology Information, and Institute for Genome Sciences at the University of Maryland, Baltimore, to create FDA-ARGOS.
However, the FDA and its collaborators need samples of pathogens to continue developing the database, so they’ve invited health care professionals to submit samples for that purpose. More information, including preferred organism list and submission guidelines, can be found on the FDA-ARGOS website.
HEAD-US system shows promise for assessing joint bleeding
Results from a prospective study appear to confirm the utility of the Haemophilia Early Arthropathy Detection by UltraSound (HEAD‐US) scoring system to evaluate joint bleeding rates in patients with hemophilia A who are treated exclusively with secondary or tertiary prophylaxis.
HEAD-US showed a strong correlation with the joint bleeding rate over a 3 year period for ankles and knees, but not for elbows.
“Primary prophylaxis is considered the most effective regimen in preventing arthropathy formation. However, due to social and economic reasons, a considerable number of children and young adults with haemophilia worldwide are currently treated by secondary or tertiary prophylaxis,” Atanas Banchev, MD, of University Hospital Tsaritsa Giovanna – ISUL, Bulgaria, and colleagues, wrote in a letter to the editor in Haemophilia. “Due to its wide availability and low cost, the sonographic score Haemophilia Early Arthropathy Detection by UltraSound (HEAD‐US) has recently become an attractive tool for assessment of joint status.”
The researchers conducted a prospective study of 42 patients with moderate to severe hemophilia A. The patients were treated with secondary or tertiary prophylaxis for a minimum of 5 years and had no history of inhibitors or factor VIII inhibitor antibodies.
The team collected data on patient demographics, disease characteristics, and prophylactic therapy. Patients were assessed at regular intervals at various treatment facilities throughout Bulgaria.
The scoring was based on three markers: synovitis (score 0‐2), cartilage (score 0‐4) and subchondral bone (score of 0‐2) with a maximum score of eight points per joint, according to the researchers.
A total of 250 joints were evaluated via the HEAD‐US scoring system. Dr. Banchev and colleagues reported that articular damage was present in 34% (n = 85) of joints evaluated with the tool. No defects were detected in the remaining joints (n = 165).
Mean HEAD‐US scores for each specific joint were 2.2 (range 0‐8) for ankles, 0.96 (range 0‐8) for knees, and 0.73 (range 0‐6) for elbows.
The researchers reported a strong correlation between the assessed joint bleeding rates for 3 years and the corresponding HEAD-US scores in ankles and knees. For ankles, the Spearman’s correlation coefficient was 0.545 (P less than .001) and for knees it was 0.692 (P less than .001).
They found no statistically significant correlation between the HEAD-US score and the assessed joint bleeding rates for 3 years in elbows (coefficient 0.161, P = .143).
One key limitation of the study was the nonconsideration of therapeutic compliance in the outcome assessment.
No funding sources were reported. The authors reported having no conflicts of interest.
SOURCE: Banchev A et al. Haemophilia. 2019 May 27. doi: 10.1111/hae.13771.
Results from a prospective study appear to confirm the utility of the Haemophilia Early Arthropathy Detection by UltraSound (HEAD‐US) scoring system to evaluate joint bleeding rates in patients with hemophilia A who are treated exclusively with secondary or tertiary prophylaxis.
HEAD-US showed a strong correlation with the joint bleeding rate over a 3 year period for ankles and knees, but not for elbows.
“Primary prophylaxis is considered the most effective regimen in preventing arthropathy formation. However, due to social and economic reasons, a considerable number of children and young adults with haemophilia worldwide are currently treated by secondary or tertiary prophylaxis,” Atanas Banchev, MD, of University Hospital Tsaritsa Giovanna – ISUL, Bulgaria, and colleagues, wrote in a letter to the editor in Haemophilia. “Due to its wide availability and low cost, the sonographic score Haemophilia Early Arthropathy Detection by UltraSound (HEAD‐US) has recently become an attractive tool for assessment of joint status.”
The researchers conducted a prospective study of 42 patients with moderate to severe hemophilia A. The patients were treated with secondary or tertiary prophylaxis for a minimum of 5 years and had no history of inhibitors or factor VIII inhibitor antibodies.
The team collected data on patient demographics, disease characteristics, and prophylactic therapy. Patients were assessed at regular intervals at various treatment facilities throughout Bulgaria.
The scoring was based on three markers: synovitis (score 0‐2), cartilage (score 0‐4) and subchondral bone (score of 0‐2) with a maximum score of eight points per joint, according to the researchers.
A total of 250 joints were evaluated via the HEAD‐US scoring system. Dr. Banchev and colleagues reported that articular damage was present in 34% (n = 85) of joints evaluated with the tool. No defects were detected in the remaining joints (n = 165).
Mean HEAD‐US scores for each specific joint were 2.2 (range 0‐8) for ankles, 0.96 (range 0‐8) for knees, and 0.73 (range 0‐6) for elbows.
The researchers reported a strong correlation between the assessed joint bleeding rates for 3 years and the corresponding HEAD-US scores in ankles and knees. For ankles, the Spearman’s correlation coefficient was 0.545 (P less than .001) and for knees it was 0.692 (P less than .001).
They found no statistically significant correlation between the HEAD-US score and the assessed joint bleeding rates for 3 years in elbows (coefficient 0.161, P = .143).
One key limitation of the study was the nonconsideration of therapeutic compliance in the outcome assessment.
No funding sources were reported. The authors reported having no conflicts of interest.
SOURCE: Banchev A et al. Haemophilia. 2019 May 27. doi: 10.1111/hae.13771.
Results from a prospective study appear to confirm the utility of the Haemophilia Early Arthropathy Detection by UltraSound (HEAD‐US) scoring system to evaluate joint bleeding rates in patients with hemophilia A who are treated exclusively with secondary or tertiary prophylaxis.
HEAD-US showed a strong correlation with the joint bleeding rate over a 3 year period for ankles and knees, but not for elbows.
“Primary prophylaxis is considered the most effective regimen in preventing arthropathy formation. However, due to social and economic reasons, a considerable number of children and young adults with haemophilia worldwide are currently treated by secondary or tertiary prophylaxis,” Atanas Banchev, MD, of University Hospital Tsaritsa Giovanna – ISUL, Bulgaria, and colleagues, wrote in a letter to the editor in Haemophilia. “Due to its wide availability and low cost, the sonographic score Haemophilia Early Arthropathy Detection by UltraSound (HEAD‐US) has recently become an attractive tool for assessment of joint status.”
The researchers conducted a prospective study of 42 patients with moderate to severe hemophilia A. The patients were treated with secondary or tertiary prophylaxis for a minimum of 5 years and had no history of inhibitors or factor VIII inhibitor antibodies.
The team collected data on patient demographics, disease characteristics, and prophylactic therapy. Patients were assessed at regular intervals at various treatment facilities throughout Bulgaria.
The scoring was based on three markers: synovitis (score 0‐2), cartilage (score 0‐4) and subchondral bone (score of 0‐2) with a maximum score of eight points per joint, according to the researchers.
A total of 250 joints were evaluated via the HEAD‐US scoring system. Dr. Banchev and colleagues reported that articular damage was present in 34% (n = 85) of joints evaluated with the tool. No defects were detected in the remaining joints (n = 165).
Mean HEAD‐US scores for each specific joint were 2.2 (range 0‐8) for ankles, 0.96 (range 0‐8) for knees, and 0.73 (range 0‐6) for elbows.
The researchers reported a strong correlation between the assessed joint bleeding rates for 3 years and the corresponding HEAD-US scores in ankles and knees. For ankles, the Spearman’s correlation coefficient was 0.545 (P less than .001) and for knees it was 0.692 (P less than .001).
They found no statistically significant correlation between the HEAD-US score and the assessed joint bleeding rates for 3 years in elbows (coefficient 0.161, P = .143).
One key limitation of the study was the nonconsideration of therapeutic compliance in the outcome assessment.
No funding sources were reported. The authors reported having no conflicts of interest.
SOURCE: Banchev A et al. Haemophilia. 2019 May 27. doi: 10.1111/hae.13771.
FROM HAEMOPHILIA
Drastic weight loss prevents progression to type 2 diabetes, PREVIEW data suggest
SAN FRANCISCO – And to the surprise of researchers, the results were the same regardless of dietary and exercise interventions more than 3 years after the initial weight loss.
There’s a big limitation, though: About half of the participants who initially lost weight dropped out during the 3-year study, and data about them are not yet available. Still, only 4% of those who completed the study converted to diabetes, compared with expected rates of as much as 16%.
This is a “fantastic success,” co-lead investigator and physiologist, Ian Macdonald, PhD, of the University of Nottingham (England), said in a presentation of the PREVIEW study at the annual scientific sessions of the American Diabetes Association.
The randomized, controlled, multicenter trial recruited 2,223 participants with prediabetes in several European countries and Australia and New Zealand. The participants, of whom about two-thirds were women, were aged 25-70 years (average, 52 years) and had an average body mass index of 35 kg/m2.
They were assigned to a 2-month, rapid weight-loss program in which they were limited to no more than 800 calories per day. “The participants were fully briefed on the risks to health associated with prediabetes and on the problems of diabetes itself, and they were highly motivated to take part in the study,” Dr. Macdonald said in an interview after the presentation.
A total of 1,857 participants achieved the required weight loss of at least 8% and were then assigned to one of four interventions: a high-protein, low-glycemic diet (either with moderate- or high-intensity physical activity) or a moderate-protein, moderate-glycemic diet (either with moderate- or high-intensity physical activity).
A total of 962 participants remained in the study for another 34 months until completion, with roughly the same number (235-244) in each of the four intervention groups.
The researchers expected that 16% of those in the moderate-diet group would convert to type 2 diabetes, as would 11% of those in the high-protein, low-glycemic group, Dr. Macdonald said in the presentation.
The researchers, who offered limited statistical detail about the study, did not disclose how many participants in each group actually developed diabetes by 36 months (January 2019). Dr. Macdonald said in the interview that those numbers would not be available until the study has been accepted for publication. He noted, however, that the numbers in the two groups were nearly identical, and the researchers disclosed that the overall number was just 4% (n = 62).
That number is “substantially less than would be predicted,” Dr. Macdonald noted in the presentation, adding that “there is no difference” between the interventions.
He said protein consumption in the high-protein diet was not sustained, probably because of lack of adherence. In contrast, the physical activity in the groups increased significantly at the beginning of the study, he said, and “it did not fall off too badly.”
According to Dr. Macdonald, the prevention of progression to diabetes “was almost certainly because of this large, initial weight loss, which was at least partially and impressively sustained. A high-protein, low-glycemic diet was not superior to a moderate-protein, moderate-glycemic diet in relation to prevention of type 2 diabetes.”
The study was funded by the European Union and various other sources, including national funds, in the participating countries. Dr. Macdonald reported advisory board service with Nestlé Research, European Juice Manufacturers, and Mars.
SAN FRANCISCO – And to the surprise of researchers, the results were the same regardless of dietary and exercise interventions more than 3 years after the initial weight loss.
There’s a big limitation, though: About half of the participants who initially lost weight dropped out during the 3-year study, and data about them are not yet available. Still, only 4% of those who completed the study converted to diabetes, compared with expected rates of as much as 16%.
This is a “fantastic success,” co-lead investigator and physiologist, Ian Macdonald, PhD, of the University of Nottingham (England), said in a presentation of the PREVIEW study at the annual scientific sessions of the American Diabetes Association.
The randomized, controlled, multicenter trial recruited 2,223 participants with prediabetes in several European countries and Australia and New Zealand. The participants, of whom about two-thirds were women, were aged 25-70 years (average, 52 years) and had an average body mass index of 35 kg/m2.
They were assigned to a 2-month, rapid weight-loss program in which they were limited to no more than 800 calories per day. “The participants were fully briefed on the risks to health associated with prediabetes and on the problems of diabetes itself, and they were highly motivated to take part in the study,” Dr. Macdonald said in an interview after the presentation.
A total of 1,857 participants achieved the required weight loss of at least 8% and were then assigned to one of four interventions: a high-protein, low-glycemic diet (either with moderate- or high-intensity physical activity) or a moderate-protein, moderate-glycemic diet (either with moderate- or high-intensity physical activity).
A total of 962 participants remained in the study for another 34 months until completion, with roughly the same number (235-244) in each of the four intervention groups.
The researchers expected that 16% of those in the moderate-diet group would convert to type 2 diabetes, as would 11% of those in the high-protein, low-glycemic group, Dr. Macdonald said in the presentation.
The researchers, who offered limited statistical detail about the study, did not disclose how many participants in each group actually developed diabetes by 36 months (January 2019). Dr. Macdonald said in the interview that those numbers would not be available until the study has been accepted for publication. He noted, however, that the numbers in the two groups were nearly identical, and the researchers disclosed that the overall number was just 4% (n = 62).
That number is “substantially less than would be predicted,” Dr. Macdonald noted in the presentation, adding that “there is no difference” between the interventions.
He said protein consumption in the high-protein diet was not sustained, probably because of lack of adherence. In contrast, the physical activity in the groups increased significantly at the beginning of the study, he said, and “it did not fall off too badly.”
According to Dr. Macdonald, the prevention of progression to diabetes “was almost certainly because of this large, initial weight loss, which was at least partially and impressively sustained. A high-protein, low-glycemic diet was not superior to a moderate-protein, moderate-glycemic diet in relation to prevention of type 2 diabetes.”
The study was funded by the European Union and various other sources, including national funds, in the participating countries. Dr. Macdonald reported advisory board service with Nestlé Research, European Juice Manufacturers, and Mars.
SAN FRANCISCO – And to the surprise of researchers, the results were the same regardless of dietary and exercise interventions more than 3 years after the initial weight loss.
There’s a big limitation, though: About half of the participants who initially lost weight dropped out during the 3-year study, and data about them are not yet available. Still, only 4% of those who completed the study converted to diabetes, compared with expected rates of as much as 16%.
This is a “fantastic success,” co-lead investigator and physiologist, Ian Macdonald, PhD, of the University of Nottingham (England), said in a presentation of the PREVIEW study at the annual scientific sessions of the American Diabetes Association.
The randomized, controlled, multicenter trial recruited 2,223 participants with prediabetes in several European countries and Australia and New Zealand. The participants, of whom about two-thirds were women, were aged 25-70 years (average, 52 years) and had an average body mass index of 35 kg/m2.
They were assigned to a 2-month, rapid weight-loss program in which they were limited to no more than 800 calories per day. “The participants were fully briefed on the risks to health associated with prediabetes and on the problems of diabetes itself, and they were highly motivated to take part in the study,” Dr. Macdonald said in an interview after the presentation.
A total of 1,857 participants achieved the required weight loss of at least 8% and were then assigned to one of four interventions: a high-protein, low-glycemic diet (either with moderate- or high-intensity physical activity) or a moderate-protein, moderate-glycemic diet (either with moderate- or high-intensity physical activity).
A total of 962 participants remained in the study for another 34 months until completion, with roughly the same number (235-244) in each of the four intervention groups.
The researchers expected that 16% of those in the moderate-diet group would convert to type 2 diabetes, as would 11% of those in the high-protein, low-glycemic group, Dr. Macdonald said in the presentation.
The researchers, who offered limited statistical detail about the study, did not disclose how many participants in each group actually developed diabetes by 36 months (January 2019). Dr. Macdonald said in the interview that those numbers would not be available until the study has been accepted for publication. He noted, however, that the numbers in the two groups were nearly identical, and the researchers disclosed that the overall number was just 4% (n = 62).
That number is “substantially less than would be predicted,” Dr. Macdonald noted in the presentation, adding that “there is no difference” between the interventions.
He said protein consumption in the high-protein diet was not sustained, probably because of lack of adherence. In contrast, the physical activity in the groups increased significantly at the beginning of the study, he said, and “it did not fall off too badly.”
According to Dr. Macdonald, the prevention of progression to diabetes “was almost certainly because of this large, initial weight loss, which was at least partially and impressively sustained. A high-protein, low-glycemic diet was not superior to a moderate-protein, moderate-glycemic diet in relation to prevention of type 2 diabetes.”
The study was funded by the European Union and various other sources, including national funds, in the participating countries. Dr. Macdonald reported advisory board service with Nestlé Research, European Juice Manufacturers, and Mars.
REPORTING FROM ADA 2019
Darwin’s diet of species, umbrellas’ searing SPF, and trypophobia terror
Forks out for science
True scientists should have no limits to what they’ll do for their research. Charles Darwin proved that greatly during his life – he spent years discovering and cataloging new species.
But did you know he also chowed down on nearly every animal he found?
His taste for unusual fare began at Cambridge as a member of the “Glutton Club.” He and his fellow gluttons were dedicated to sampling “birds and beasts which were before unknown to human palate,” as reported in an article on NPR. His eating adventures only grew while on the famed Beagle voyage, where he tried puma, iguanas, armadillos, giant tortoises, and even a 20-pound rodent that he declared “the very best meat I ever tasted.”
The noble tradition of tasting your test subjects continues today. The author of the article referenced above asked scientists on social media for stories of eating what they are supposed to be studying, and the answers came pouring in.
From tasting tadpoles to nibbling on 30,000-year-old bison meat, scientists all over the world have found they can’t resist the call to just have a tiny taste.
The umbrella’s just not cutting it
Bad news for everyone who hates melanoma but also hates sunscreen: That Tommy Bahama beach umbrella isn’t doing much to shield your skin.
A team lead by researcher Hao Ou-Yang conducted a study comparing the effects of harmful UV rays on subjects who used sunscreen with subjects who only used the shade of an umbrella.
In the battle of Sun vs. Umbrella, the humble parasol had no chance. While neither sun protection method completely prevented sunburn, 78% of the umbrella-only group experienced sunburn, compared with 25% of the sunscreen wearers.
The researchers determined that umbrella shade alone is not sufficient to protect against sunburn during extended exposure to the sun (in the case of this experiment, exposure was 3.5 hours). Sunscreen, despite being smelly and sticky and gloopy, is definitely needed to protect skin from those UV rays. So, suck it up and pile on that Coppertone this summer.
Oh no, there goes Tokyo (again)
Godzilla. The king of the monsters. For 65 years, the big green guy has been the scourge (mostly) of Japan and the entire world. He arrives, he destroys, and there is very nearly nothing we can do about him.
If you’re an astute fan of the Godzilla series (and we love a good Godzilla movie at MDedge headquarters), you’ll have noticed that Godzilla is a lot bigger than he used to be. In the first movie, he stood at a relatively meager 50 meters. Nowadays, he’s scraping 120 meters, more than double his original size.
What’s going on?
In an actual study published in Science, a team at Dartmouth College in Hanover, N.H., determined that Godzilla is evolving 30 times faster than any other organism on Earth. It’s enough to make even the influenza virus jealous.
So, what is going on? Why is Godzilla evolving so quickly? The scientists assumed that Godzilla is a ceratosaurid dinosaur and ran through the usual suspects. No other dinosaur of that family got so big. Genetic drift and natural selection can’t explain it either.
The truth may be more unsettling: Our own anxiety is fueling his growth. Godzilla was born because of nuclear testing and the fear stemming from it. And the Dartmouth team even found a correlation between Godzilla’s size and American military spending from 1954 to 2019, a neat barometer of the world’s collective anxiety.
Or, you know, people just want to see a 400-foot-tall lizard destroying things. But that’s hardly worthy of a study in an elite research journal.
Hole lotta trypophobia goin’ on
We didn’t know this was even a thing, but Twitter doesn’t like pictures of woodpeckers … digging little holes in tree trunks … and then stuffing the holes with acorns.
A recent tweet of such a photo caused a minor pandemic of virality when users reacted with revulsion and panic caused by trypophobia, which is a fear of irregular patterns of small holes or bumps. You won’t find trypophobia in the DSM-5 – the term was first used in an Internet forum in 2005 – but it is a source of some debate among academics, according to Live Science.
One group says the patterns look like some poisonous animals, and that people are programmed by evolution to fear such creatures. Others suggest that the reaction is not fear but disgust, because the patterns of holes look like the lesions and pustules caused by infectious diseases such as smallpox.
We’re not scientists, so we’ll stay out of the debate on causality. But we do think we’ve uncovered the first documented case, and it goes back to the 1960s TV series “Batman.” The hero’s trusted sidekick, Robin (coincidentally, another type of bird), must have been the first person with trypophobia:
“Holy tintinnabulation!”
“Holy uncanny photographic mental processes!”
“Holy priceless collection of Etruscan snoods!”
Holy patterns of woodpecker acorns! There can be no diagnostic doubt: For Robin, it was all about the holes.
Forks out for science
True scientists should have no limits to what they’ll do for their research. Charles Darwin proved that greatly during his life – he spent years discovering and cataloging new species.
But did you know he also chowed down on nearly every animal he found?
His taste for unusual fare began at Cambridge as a member of the “Glutton Club.” He and his fellow gluttons were dedicated to sampling “birds and beasts which were before unknown to human palate,” as reported in an article on NPR. His eating adventures only grew while on the famed Beagle voyage, where he tried puma, iguanas, armadillos, giant tortoises, and even a 20-pound rodent that he declared “the very best meat I ever tasted.”
The noble tradition of tasting your test subjects continues today. The author of the article referenced above asked scientists on social media for stories of eating what they are supposed to be studying, and the answers came pouring in.
From tasting tadpoles to nibbling on 30,000-year-old bison meat, scientists all over the world have found they can’t resist the call to just have a tiny taste.
The umbrella’s just not cutting it
Bad news for everyone who hates melanoma but also hates sunscreen: That Tommy Bahama beach umbrella isn’t doing much to shield your skin.
A team lead by researcher Hao Ou-Yang conducted a study comparing the effects of harmful UV rays on subjects who used sunscreen with subjects who only used the shade of an umbrella.
In the battle of Sun vs. Umbrella, the humble parasol had no chance. While neither sun protection method completely prevented sunburn, 78% of the umbrella-only group experienced sunburn, compared with 25% of the sunscreen wearers.
The researchers determined that umbrella shade alone is not sufficient to protect against sunburn during extended exposure to the sun (in the case of this experiment, exposure was 3.5 hours). Sunscreen, despite being smelly and sticky and gloopy, is definitely needed to protect skin from those UV rays. So, suck it up and pile on that Coppertone this summer.
Oh no, there goes Tokyo (again)
Godzilla. The king of the monsters. For 65 years, the big green guy has been the scourge (mostly) of Japan and the entire world. He arrives, he destroys, and there is very nearly nothing we can do about him.
If you’re an astute fan of the Godzilla series (and we love a good Godzilla movie at MDedge headquarters), you’ll have noticed that Godzilla is a lot bigger than he used to be. In the first movie, he stood at a relatively meager 50 meters. Nowadays, he’s scraping 120 meters, more than double his original size.
What’s going on?
In an actual study published in Science, a team at Dartmouth College in Hanover, N.H., determined that Godzilla is evolving 30 times faster than any other organism on Earth. It’s enough to make even the influenza virus jealous.
So, what is going on? Why is Godzilla evolving so quickly? The scientists assumed that Godzilla is a ceratosaurid dinosaur and ran through the usual suspects. No other dinosaur of that family got so big. Genetic drift and natural selection can’t explain it either.
The truth may be more unsettling: Our own anxiety is fueling his growth. Godzilla was born because of nuclear testing and the fear stemming from it. And the Dartmouth team even found a correlation between Godzilla’s size and American military spending from 1954 to 2019, a neat barometer of the world’s collective anxiety.
Or, you know, people just want to see a 400-foot-tall lizard destroying things. But that’s hardly worthy of a study in an elite research journal.
Hole lotta trypophobia goin’ on
We didn’t know this was even a thing, but Twitter doesn’t like pictures of woodpeckers … digging little holes in tree trunks … and then stuffing the holes with acorns.
A recent tweet of such a photo caused a minor pandemic of virality when users reacted with revulsion and panic caused by trypophobia, which is a fear of irregular patterns of small holes or bumps. You won’t find trypophobia in the DSM-5 – the term was first used in an Internet forum in 2005 – but it is a source of some debate among academics, according to Live Science.
One group says the patterns look like some poisonous animals, and that people are programmed by evolution to fear such creatures. Others suggest that the reaction is not fear but disgust, because the patterns of holes look like the lesions and pustules caused by infectious diseases such as smallpox.
We’re not scientists, so we’ll stay out of the debate on causality. But we do think we’ve uncovered the first documented case, and it goes back to the 1960s TV series “Batman.” The hero’s trusted sidekick, Robin (coincidentally, another type of bird), must have been the first person with trypophobia:
“Holy tintinnabulation!”
“Holy uncanny photographic mental processes!”
“Holy priceless collection of Etruscan snoods!”
Holy patterns of woodpecker acorns! There can be no diagnostic doubt: For Robin, it was all about the holes.
Forks out for science
True scientists should have no limits to what they’ll do for their research. Charles Darwin proved that greatly during his life – he spent years discovering and cataloging new species.
But did you know he also chowed down on nearly every animal he found?
His taste for unusual fare began at Cambridge as a member of the “Glutton Club.” He and his fellow gluttons were dedicated to sampling “birds and beasts which were before unknown to human palate,” as reported in an article on NPR. His eating adventures only grew while on the famed Beagle voyage, where he tried puma, iguanas, armadillos, giant tortoises, and even a 20-pound rodent that he declared “the very best meat I ever tasted.”
The noble tradition of tasting your test subjects continues today. The author of the article referenced above asked scientists on social media for stories of eating what they are supposed to be studying, and the answers came pouring in.
From tasting tadpoles to nibbling on 30,000-year-old bison meat, scientists all over the world have found they can’t resist the call to just have a tiny taste.
The umbrella’s just not cutting it
Bad news for everyone who hates melanoma but also hates sunscreen: That Tommy Bahama beach umbrella isn’t doing much to shield your skin.
A team lead by researcher Hao Ou-Yang conducted a study comparing the effects of harmful UV rays on subjects who used sunscreen with subjects who only used the shade of an umbrella.
In the battle of Sun vs. Umbrella, the humble parasol had no chance. While neither sun protection method completely prevented sunburn, 78% of the umbrella-only group experienced sunburn, compared with 25% of the sunscreen wearers.
The researchers determined that umbrella shade alone is not sufficient to protect against sunburn during extended exposure to the sun (in the case of this experiment, exposure was 3.5 hours). Sunscreen, despite being smelly and sticky and gloopy, is definitely needed to protect skin from those UV rays. So, suck it up and pile on that Coppertone this summer.
Oh no, there goes Tokyo (again)
Godzilla. The king of the monsters. For 65 years, the big green guy has been the scourge (mostly) of Japan and the entire world. He arrives, he destroys, and there is very nearly nothing we can do about him.
If you’re an astute fan of the Godzilla series (and we love a good Godzilla movie at MDedge headquarters), you’ll have noticed that Godzilla is a lot bigger than he used to be. In the first movie, he stood at a relatively meager 50 meters. Nowadays, he’s scraping 120 meters, more than double his original size.
What’s going on?
In an actual study published in Science, a team at Dartmouth College in Hanover, N.H., determined that Godzilla is evolving 30 times faster than any other organism on Earth. It’s enough to make even the influenza virus jealous.
So, what is going on? Why is Godzilla evolving so quickly? The scientists assumed that Godzilla is a ceratosaurid dinosaur and ran through the usual suspects. No other dinosaur of that family got so big. Genetic drift and natural selection can’t explain it either.
The truth may be more unsettling: Our own anxiety is fueling his growth. Godzilla was born because of nuclear testing and the fear stemming from it. And the Dartmouth team even found a correlation between Godzilla’s size and American military spending from 1954 to 2019, a neat barometer of the world’s collective anxiety.
Or, you know, people just want to see a 400-foot-tall lizard destroying things. But that’s hardly worthy of a study in an elite research journal.
Hole lotta trypophobia goin’ on
We didn’t know this was even a thing, but Twitter doesn’t like pictures of woodpeckers … digging little holes in tree trunks … and then stuffing the holes with acorns.
A recent tweet of such a photo caused a minor pandemic of virality when users reacted with revulsion and panic caused by trypophobia, which is a fear of irregular patterns of small holes or bumps. You won’t find trypophobia in the DSM-5 – the term was first used in an Internet forum in 2005 – but it is a source of some debate among academics, according to Live Science.
One group says the patterns look like some poisonous animals, and that people are programmed by evolution to fear such creatures. Others suggest that the reaction is not fear but disgust, because the patterns of holes look like the lesions and pustules caused by infectious diseases such as smallpox.
We’re not scientists, so we’ll stay out of the debate on causality. But we do think we’ve uncovered the first documented case, and it goes back to the 1960s TV series “Batman.” The hero’s trusted sidekick, Robin (coincidentally, another type of bird), must have been the first person with trypophobia:
“Holy tintinnabulation!”
“Holy uncanny photographic mental processes!”
“Holy priceless collection of Etruscan snoods!”
Holy patterns of woodpecker acorns! There can be no diagnostic doubt: For Robin, it was all about the holes.
Psychiatrists discuss work on climate change
SAN FRANCISCO –
“We can find reasons to hope even in dark times,” Dr. Van Susteren said. “We understand science. We have all the tools ... this is what we do for a living. We warn about behaviors that are going hurt us now and are going to be even worse down the road.”
In a video discussion, Dr. Van Susteren spoke with David A. Pollack, MD, about the accomplishments of the Climate Psychiatry Alliance, an organization they helped launch more than 2 years ago that warns the medical profession and the public about risks of climate change and the impact of climate disruption on mental health. One victory, for example, was getting the APA to vote to divest from fossil fuels.
Dr. Van Susteren and Dr. Pollack also discuss steps psychiatrists can take as individuals to provide care for patients suffering from the effects of climate change – such as prescribing “park therapy.” In their offices, physicians can look toward emerging solutions such as My Green Doctor and Health Care Without Harm, Dr. Pollack said.
Dr. Van Susteren has a private psychiatry private practice in Washington and has no disclosures. Dr. Pollack is affiliated with Oregon Health & Science University in Portland. He has no disclosures.
SAN FRANCISCO –
“We can find reasons to hope even in dark times,” Dr. Van Susteren said. “We understand science. We have all the tools ... this is what we do for a living. We warn about behaviors that are going hurt us now and are going to be even worse down the road.”
In a video discussion, Dr. Van Susteren spoke with David A. Pollack, MD, about the accomplishments of the Climate Psychiatry Alliance, an organization they helped launch more than 2 years ago that warns the medical profession and the public about risks of climate change and the impact of climate disruption on mental health. One victory, for example, was getting the APA to vote to divest from fossil fuels.
Dr. Van Susteren and Dr. Pollack also discuss steps psychiatrists can take as individuals to provide care for patients suffering from the effects of climate change – such as prescribing “park therapy.” In their offices, physicians can look toward emerging solutions such as My Green Doctor and Health Care Without Harm, Dr. Pollack said.
Dr. Van Susteren has a private psychiatry private practice in Washington and has no disclosures. Dr. Pollack is affiliated with Oregon Health & Science University in Portland. He has no disclosures.
SAN FRANCISCO –
“We can find reasons to hope even in dark times,” Dr. Van Susteren said. “We understand science. We have all the tools ... this is what we do for a living. We warn about behaviors that are going hurt us now and are going to be even worse down the road.”
In a video discussion, Dr. Van Susteren spoke with David A. Pollack, MD, about the accomplishments of the Climate Psychiatry Alliance, an organization they helped launch more than 2 years ago that warns the medical profession and the public about risks of climate change and the impact of climate disruption on mental health. One victory, for example, was getting the APA to vote to divest from fossil fuels.
Dr. Van Susteren and Dr. Pollack also discuss steps psychiatrists can take as individuals to provide care for patients suffering from the effects of climate change – such as prescribing “park therapy.” In their offices, physicians can look toward emerging solutions such as My Green Doctor and Health Care Without Harm, Dr. Pollack said.
Dr. Van Susteren has a private psychiatry private practice in Washington and has no disclosures. Dr. Pollack is affiliated with Oregon Health & Science University in Portland. He has no disclosures.
REPORTING FROM APA 2019
Combined exercise training shows benefit in hemophilia A
Combined aerobic and resistance exercise training was found to be the most effective training technique to reduce proinflammatory markers in overweight patients with moderate hemophilia A.
“Combined training has been established as the most effective type of exercise in terms of modification of cardiovascular disease risk factors,” wrote Behrouz Parhampour, of Iran University of Medical Sciences in Tehran, and colleagues. The findings of the study were published in Haemophilia.
The researchers conducted a randomized clinical study of 48 patients with moderate hemophilia A. Study patients had a body mass index of 25-30 kg/m2 and were aged 35-55 years.
Study participants were randomly allocated to aerobic training (n = 12), resistance training (n = 12), combined training (n = 12), and control (n = 12) arms. The training regimens consisted of 45‐minute sessions three times per week for a total of 6 weeks.
Interleukin‐10, adiponectin, tumor necrosis factor–alpha, IL‐6, and high-sensitive C‐reactive protein were measured before and after training. Weight-related measures, including waist‐to‐hip ratio and waist circumference, were also evaluated.
The researchers found there was a significant reduction in weight, waist‐to‐hip ratio, waist circumference, and body mass index in the combined, resistance, and aerobic training arms, compared with the control arm.
Additionally, they reported a significant reduction in high-sensitive C‐reactive protein, IL‐6, and tumor necrosis factor–alpha levels in the combined training group versus the control group (P equal to or less than .02 for all three).
There were no episodes of bleeding among patients in any of the intervention groups.
“The possible mechanism for the effect of exercise training on weight loss is to increase metabolic consumption which may subsequently reduce the low‐grade inflammation commonly noted among overweight patients,” the researchers wrote.
The authors acknowledged that two key limitations of the study were the short duration of training and small sample size.
“Combined training can be used as an effective nonpharmacological strategy to improve joint function and prevent disorders associated with sedentary lifestyle like cardiovascular complications in [hemophilia patients],” they concluded.
The study was funded by the Iran University of Medical Sciences. The authors reported having no conflicts of interest.
SOURCE: Parhampour B et al. Haemophilia. 2019 May 26. doi: 10.1111/hae.13764.
Combined aerobic and resistance exercise training was found to be the most effective training technique to reduce proinflammatory markers in overweight patients with moderate hemophilia A.
“Combined training has been established as the most effective type of exercise in terms of modification of cardiovascular disease risk factors,” wrote Behrouz Parhampour, of Iran University of Medical Sciences in Tehran, and colleagues. The findings of the study were published in Haemophilia.
The researchers conducted a randomized clinical study of 48 patients with moderate hemophilia A. Study patients had a body mass index of 25-30 kg/m2 and were aged 35-55 years.
Study participants were randomly allocated to aerobic training (n = 12), resistance training (n = 12), combined training (n = 12), and control (n = 12) arms. The training regimens consisted of 45‐minute sessions three times per week for a total of 6 weeks.
Interleukin‐10, adiponectin, tumor necrosis factor–alpha, IL‐6, and high-sensitive C‐reactive protein were measured before and after training. Weight-related measures, including waist‐to‐hip ratio and waist circumference, were also evaluated.
The researchers found there was a significant reduction in weight, waist‐to‐hip ratio, waist circumference, and body mass index in the combined, resistance, and aerobic training arms, compared with the control arm.
Additionally, they reported a significant reduction in high-sensitive C‐reactive protein, IL‐6, and tumor necrosis factor–alpha levels in the combined training group versus the control group (P equal to or less than .02 for all three).
There were no episodes of bleeding among patients in any of the intervention groups.
“The possible mechanism for the effect of exercise training on weight loss is to increase metabolic consumption which may subsequently reduce the low‐grade inflammation commonly noted among overweight patients,” the researchers wrote.
The authors acknowledged that two key limitations of the study were the short duration of training and small sample size.
“Combined training can be used as an effective nonpharmacological strategy to improve joint function and prevent disorders associated with sedentary lifestyle like cardiovascular complications in [hemophilia patients],” they concluded.
The study was funded by the Iran University of Medical Sciences. The authors reported having no conflicts of interest.
SOURCE: Parhampour B et al. Haemophilia. 2019 May 26. doi: 10.1111/hae.13764.
Combined aerobic and resistance exercise training was found to be the most effective training technique to reduce proinflammatory markers in overweight patients with moderate hemophilia A.
“Combined training has been established as the most effective type of exercise in terms of modification of cardiovascular disease risk factors,” wrote Behrouz Parhampour, of Iran University of Medical Sciences in Tehran, and colleagues. The findings of the study were published in Haemophilia.
The researchers conducted a randomized clinical study of 48 patients with moderate hemophilia A. Study patients had a body mass index of 25-30 kg/m2 and were aged 35-55 years.
Study participants were randomly allocated to aerobic training (n = 12), resistance training (n = 12), combined training (n = 12), and control (n = 12) arms. The training regimens consisted of 45‐minute sessions three times per week for a total of 6 weeks.
Interleukin‐10, adiponectin, tumor necrosis factor–alpha, IL‐6, and high-sensitive C‐reactive protein were measured before and after training. Weight-related measures, including waist‐to‐hip ratio and waist circumference, were also evaluated.
The researchers found there was a significant reduction in weight, waist‐to‐hip ratio, waist circumference, and body mass index in the combined, resistance, and aerobic training arms, compared with the control arm.
Additionally, they reported a significant reduction in high-sensitive C‐reactive protein, IL‐6, and tumor necrosis factor–alpha levels in the combined training group versus the control group (P equal to or less than .02 for all three).
There were no episodes of bleeding among patients in any of the intervention groups.
“The possible mechanism for the effect of exercise training on weight loss is to increase metabolic consumption which may subsequently reduce the low‐grade inflammation commonly noted among overweight patients,” the researchers wrote.
The authors acknowledged that two key limitations of the study were the short duration of training and small sample size.
“Combined training can be used as an effective nonpharmacological strategy to improve joint function and prevent disorders associated with sedentary lifestyle like cardiovascular complications in [hemophilia patients],” they concluded.
The study was funded by the Iran University of Medical Sciences. The authors reported having no conflicts of interest.
SOURCE: Parhampour B et al. Haemophilia. 2019 May 26. doi: 10.1111/hae.13764.
FROM HAEMOPHILIA
Four-drug combo bests triplet in newly diagnosed myeloma
CHICAGO – Daratumumab plus bortezomib, thalidomide, and dexamethasone (D-VTd) provided a “robust clinical benefit” over bortezomib, thalidomide, and dexamethasone alone (VTd) in a phase 3 trial of patients with newly diagnosed multiple myeloma, according to the trial’s principal investigator.
D-VTd produced significantly higher rates of stringent complete response (sCR) and progression-free survival (PFS) than did VTd, said Philippe Moreau, MD, of the University Hospital of Nantes (France).
Dr. Moreau presented these results, from the CASSIOPEIA trial, at the annual meeting of the American Society of Clinical Oncology. The findings were simultaneously published in the Lancet (2019 Jun 3. doi: 10.1016/S0140-6736[19]31240-1).
CASSIOPEIA enrolled 1,085 patients with newly diagnosed multiple myeloma who were eligible for high-dose chemotherapy and hematopoietic stem cell transplant (HSCT). This is a two-part trial, and Dr. Moreau presented final results from part 1.
In part 1, patients were randomized to induction with D-VTd or VTd, followed by autologous HSCT and consolidation with D-VTd or VTd. In part 2, which is ongoing, patients who achieve a partial response or better are randomized to observation or maintenance with daratumumab for up to 2 years.
Baseline characteristics were well balanced between the D-VTd and VTd arms. The median age was 59 years (range, 22-65) and 58 years (range, 26-65), respectively. Most patients had an Eastern Cooperative Oncology Group performance status of 0 or 1, and most had an International Staging System stage of I or II.
The median follow-up was 18.8 months. Most patients completed induction – 85% in the D-VTd arm and 81% in the VTd arm – and went on to HSCT – 90% and 89%, respectively. The most common reasons for treatment discontinuation in both arms were adverse events and progression.
Response and survival
The primary endpoint for part 1 was the rate of sCR at 100 days after HSCT. The sCR rate was significantly higher in the D-VTd arm than it was in the VTd arm – 29% and 20%, respectively (odds ratio, 1.60; P less than .0010).
The overall response rate was significantly higher in the D-VTd arm than in the VTd arm – 93% and 90%, respectively (P less than .0001) – as was the rate of minimal residual disease (MRD) negativity – 64% and 44%, respectively (P less than .0001).
Dr. Moreau noted that sCR and MRD negativity rates were superior with D-VTd across all subgroups except among patients with high-risk cytogenetics and International Staging System stage III disease.
“Dara-VTd resulted in a robust clinical benefit with a higher rate of response, including stringent CR, including MRD negativity,” Dr. Moreau said. “And this translated into a better progression-free survival, with a 53% reduction in the risk of progression or death.”
The 18-month PFS was 93% in the D-VTd arm and 85% in the VTd arm (hazard ratio, 0.47; P less than .0001). D-VTd reduced the risk of progression or death across all subgroups.
The median overall survival (OS) was not reached in either treatment arm. The 18-month OS rate was 98% in the D-VTd arm and 95% in the VTd arm. The 24-month OS rate was 97% and 93%, respectively.
“These results are the best ever reported in the setting of stem cell transplantation,” Dr. Moreau said.
Safety
The most common grade 3/4 treatment-emergent adverse events (in the D-VTd and VTd arms, respectively) were neutropenia (28% and 15%), lymphopenia (17% and 10%), stomatitis (13% and 16%), and thrombocytopenia (11% and 7%).
The rate of infusion-related reactions was 35% in the D-VTd arm and 0% in the VTd arm. The rate of infections was 66% and 57%, respectively. The most common serious infection was pneumonia, which occurred in 4% and 2% of patients, respectively. The rate of second primary malignancies was 2% in both arms.
Based on the safety and efficacy results, Dr. Moreau concluded that D-VTd “should be considered a valid treatment option” for newly diagnosed multiple myeloma patients who are eligible for HSCT.
Dr. Moreau reported relationships with Amgen, Celgene, Janssen-Cilag, Novartis, and Takeda. The study is sponsored by the French Intergroupe Francophone du Myelome in collaboration with the Dutch-Belgian Cooperative Trial Group for Hematology Oncology and Janssen Research & Development.
SOURCE: Moreau P et al. ASCO 2019, Abstract 8003.
CHICAGO – Daratumumab plus bortezomib, thalidomide, and dexamethasone (D-VTd) provided a “robust clinical benefit” over bortezomib, thalidomide, and dexamethasone alone (VTd) in a phase 3 trial of patients with newly diagnosed multiple myeloma, according to the trial’s principal investigator.
D-VTd produced significantly higher rates of stringent complete response (sCR) and progression-free survival (PFS) than did VTd, said Philippe Moreau, MD, of the University Hospital of Nantes (France).
Dr. Moreau presented these results, from the CASSIOPEIA trial, at the annual meeting of the American Society of Clinical Oncology. The findings were simultaneously published in the Lancet (2019 Jun 3. doi: 10.1016/S0140-6736[19]31240-1).
CASSIOPEIA enrolled 1,085 patients with newly diagnosed multiple myeloma who were eligible for high-dose chemotherapy and hematopoietic stem cell transplant (HSCT). This is a two-part trial, and Dr. Moreau presented final results from part 1.
In part 1, patients were randomized to induction with D-VTd or VTd, followed by autologous HSCT and consolidation with D-VTd or VTd. In part 2, which is ongoing, patients who achieve a partial response or better are randomized to observation or maintenance with daratumumab for up to 2 years.
Baseline characteristics were well balanced between the D-VTd and VTd arms. The median age was 59 years (range, 22-65) and 58 years (range, 26-65), respectively. Most patients had an Eastern Cooperative Oncology Group performance status of 0 or 1, and most had an International Staging System stage of I or II.
The median follow-up was 18.8 months. Most patients completed induction – 85% in the D-VTd arm and 81% in the VTd arm – and went on to HSCT – 90% and 89%, respectively. The most common reasons for treatment discontinuation in both arms were adverse events and progression.
Response and survival
The primary endpoint for part 1 was the rate of sCR at 100 days after HSCT. The sCR rate was significantly higher in the D-VTd arm than it was in the VTd arm – 29% and 20%, respectively (odds ratio, 1.60; P less than .0010).
The overall response rate was significantly higher in the D-VTd arm than in the VTd arm – 93% and 90%, respectively (P less than .0001) – as was the rate of minimal residual disease (MRD) negativity – 64% and 44%, respectively (P less than .0001).
Dr. Moreau noted that sCR and MRD negativity rates were superior with D-VTd across all subgroups except among patients with high-risk cytogenetics and International Staging System stage III disease.
“Dara-VTd resulted in a robust clinical benefit with a higher rate of response, including stringent CR, including MRD negativity,” Dr. Moreau said. “And this translated into a better progression-free survival, with a 53% reduction in the risk of progression or death.”
The 18-month PFS was 93% in the D-VTd arm and 85% in the VTd arm (hazard ratio, 0.47; P less than .0001). D-VTd reduced the risk of progression or death across all subgroups.
The median overall survival (OS) was not reached in either treatment arm. The 18-month OS rate was 98% in the D-VTd arm and 95% in the VTd arm. The 24-month OS rate was 97% and 93%, respectively.
“These results are the best ever reported in the setting of stem cell transplantation,” Dr. Moreau said.
Safety
The most common grade 3/4 treatment-emergent adverse events (in the D-VTd and VTd arms, respectively) were neutropenia (28% and 15%), lymphopenia (17% and 10%), stomatitis (13% and 16%), and thrombocytopenia (11% and 7%).
The rate of infusion-related reactions was 35% in the D-VTd arm and 0% in the VTd arm. The rate of infections was 66% and 57%, respectively. The most common serious infection was pneumonia, which occurred in 4% and 2% of patients, respectively. The rate of second primary malignancies was 2% in both arms.
Based on the safety and efficacy results, Dr. Moreau concluded that D-VTd “should be considered a valid treatment option” for newly diagnosed multiple myeloma patients who are eligible for HSCT.
Dr. Moreau reported relationships with Amgen, Celgene, Janssen-Cilag, Novartis, and Takeda. The study is sponsored by the French Intergroupe Francophone du Myelome in collaboration with the Dutch-Belgian Cooperative Trial Group for Hematology Oncology and Janssen Research & Development.
SOURCE: Moreau P et al. ASCO 2019, Abstract 8003.
CHICAGO – Daratumumab plus bortezomib, thalidomide, and dexamethasone (D-VTd) provided a “robust clinical benefit” over bortezomib, thalidomide, and dexamethasone alone (VTd) in a phase 3 trial of patients with newly diagnosed multiple myeloma, according to the trial’s principal investigator.
D-VTd produced significantly higher rates of stringent complete response (sCR) and progression-free survival (PFS) than did VTd, said Philippe Moreau, MD, of the University Hospital of Nantes (France).
Dr. Moreau presented these results, from the CASSIOPEIA trial, at the annual meeting of the American Society of Clinical Oncology. The findings were simultaneously published in the Lancet (2019 Jun 3. doi: 10.1016/S0140-6736[19]31240-1).
CASSIOPEIA enrolled 1,085 patients with newly diagnosed multiple myeloma who were eligible for high-dose chemotherapy and hematopoietic stem cell transplant (HSCT). This is a two-part trial, and Dr. Moreau presented final results from part 1.
In part 1, patients were randomized to induction with D-VTd or VTd, followed by autologous HSCT and consolidation with D-VTd or VTd. In part 2, which is ongoing, patients who achieve a partial response or better are randomized to observation or maintenance with daratumumab for up to 2 years.
Baseline characteristics were well balanced between the D-VTd and VTd arms. The median age was 59 years (range, 22-65) and 58 years (range, 26-65), respectively. Most patients had an Eastern Cooperative Oncology Group performance status of 0 or 1, and most had an International Staging System stage of I or II.
The median follow-up was 18.8 months. Most patients completed induction – 85% in the D-VTd arm and 81% in the VTd arm – and went on to HSCT – 90% and 89%, respectively. The most common reasons for treatment discontinuation in both arms were adverse events and progression.
Response and survival
The primary endpoint for part 1 was the rate of sCR at 100 days after HSCT. The sCR rate was significantly higher in the D-VTd arm than it was in the VTd arm – 29% and 20%, respectively (odds ratio, 1.60; P less than .0010).
The overall response rate was significantly higher in the D-VTd arm than in the VTd arm – 93% and 90%, respectively (P less than .0001) – as was the rate of minimal residual disease (MRD) negativity – 64% and 44%, respectively (P less than .0001).
Dr. Moreau noted that sCR and MRD negativity rates were superior with D-VTd across all subgroups except among patients with high-risk cytogenetics and International Staging System stage III disease.
“Dara-VTd resulted in a robust clinical benefit with a higher rate of response, including stringent CR, including MRD negativity,” Dr. Moreau said. “And this translated into a better progression-free survival, with a 53% reduction in the risk of progression or death.”
The 18-month PFS was 93% in the D-VTd arm and 85% in the VTd arm (hazard ratio, 0.47; P less than .0001). D-VTd reduced the risk of progression or death across all subgroups.
The median overall survival (OS) was not reached in either treatment arm. The 18-month OS rate was 98% in the D-VTd arm and 95% in the VTd arm. The 24-month OS rate was 97% and 93%, respectively.
“These results are the best ever reported in the setting of stem cell transplantation,” Dr. Moreau said.
Safety
The most common grade 3/4 treatment-emergent adverse events (in the D-VTd and VTd arms, respectively) were neutropenia (28% and 15%), lymphopenia (17% and 10%), stomatitis (13% and 16%), and thrombocytopenia (11% and 7%).
The rate of infusion-related reactions was 35% in the D-VTd arm and 0% in the VTd arm. The rate of infections was 66% and 57%, respectively. The most common serious infection was pneumonia, which occurred in 4% and 2% of patients, respectively. The rate of second primary malignancies was 2% in both arms.
Based on the safety and efficacy results, Dr. Moreau concluded that D-VTd “should be considered a valid treatment option” for newly diagnosed multiple myeloma patients who are eligible for HSCT.
Dr. Moreau reported relationships with Amgen, Celgene, Janssen-Cilag, Novartis, and Takeda. The study is sponsored by the French Intergroupe Francophone du Myelome in collaboration with the Dutch-Belgian Cooperative Trial Group for Hematology Oncology and Janssen Research & Development.
SOURCE: Moreau P et al. ASCO 2019, Abstract 8003.
REPORTING FROM ASCO 2019
GLP-1 RA dulaglutide yields cardiac gains, even in non–at-risk patients
SAN FRANCISCO – A large, long-term study is linking yet another glucagon-like peptide–1 receptor agonist diabetes drug to positive cardiovascular outcomes: Patients with type 2 diabetes and heart disease risk factors who took dulaglutide for about 5 years during the REWIND study had a 12% lower risk of major adverse cardiovascular events, compared with those who took placebo.
These new findings on cardiac risk are unusual compared with other newer-generation diabetes drugs, because a high percentage of the participants did not have existing cardiovascular disease. In addition, the study population had a higher percentage of women, compared with previous studies.
“We feel very strongly that the participants were similar to the ... ambulatory patients with type 2 diabetes with cardiovascular risk who are routinely seen in clinical practice,” study coauthor Jeffrey L. Probstfield, MD, of the University of Washington, Seattle, saidin a presentation at the annual scientific sessions of the American Diabetes Association. The findings were published simultaneously in The Lancet (2019 Jun 10. doi: 10.1016/S0140-6736(19)31149-3.
Dulaglutide’s serious adverse-effect profile was similar to that of placebo, the study authors noted, and the drug also showed benefits in renal outcomes, as reported in a separate study (Gerstein HC et al. Lancet. 2019 Jun 10. doi: 10.1016/S0140-6736(19)31150-3.
The Food and Drug Administration has mandated that six glucagon-like peptide–1 receptor agonists (GLP-1 RAs) – albiglutide (Tanzeum), exenatide (Byetta), liraglutide (Victoza), lixisenatide (Adlyxin), semaglutide (Ozempic) and dulaglutide (Trulicity) – undergo testing of cardiovascular outcomes. Dulaglutide is the fourth, following albiglutide, liraglutide, and semaglutide, to show consistent, statistically significant reduction in major adverse cardiovascular events (MACE).
For the double-blind, randomized, placebo-controlled REWIND study, researchers recruited 9,901 participants who were at least 50 years old with type 2 diabetes, a hemoglobin A1c (HbA1c) level of 9.5% or less, and a body mass index of more than 23 kg/m2. The participants came from 371 sites in 24 countries, including the United States and Canada. More than 80% were taking an angiotensin-converting enzyme inhibitor or angiotensin II receptor blocker, and other blood pressure drugs were also common.
The average mean age was 66 years; 46% of the participants were women, three-quarters were white, and 31% had previous cardiovascular disease. Previous GLP-1 RA studies of this type had markedly lower percentages of women – the other studies comprised 30%-39% women – and included higher percentages of participants with previous cardiovascular disease (73%-100%).
Of the participants in the current study, 4,949 were assigned to receive dulaglutide and 4,952 to receive placebo. They were followed for a median 5.4 years. About 57% never stopped using the drug, and 11% of those in the drug group and 7.5% in the placebo group stopped use because of adverse effects.
In regard to diabetes outcomes, HbA1c levels fell in the drug group by a mean –0.61% (95% confidence interval, –0.65 to –0.58; P less than .0001), compared with placebo. Their weight decreased by a mean –1.5 kg (95% CI, -1.7 to -1.3; P less than .0001) Systolic blood pressure and LDL cholesterol levels were slightly lower in the drug group, but heart rate was higher.
On the heart front, MACE fell by 12% in the drug group, compared with placebo (hazard ratio, 0.88; 95% CI, 0.79-0.99; P = .026). “The effect of the intervention begins [within] the first year and continued in a progressive, proportional fashion throughout the follow-up period,” said study lead author Hertzel C. Gerstein, MD, of McMaster University and Hamilton Health Sciences, Hamilton, Ont.
There was an especially large decline in the number of nonfatal stroke cases in the drug group, compared with placebo (135 vs. 175, respectively; HR, 0.76; 95% CI, 0.61-0.95; P = .017). The drug did not have a statistically significant effect on cardiovascular death.
The researchers found no difference in the drug’s effects on MACE in subgroups including age, gender, ethnicity, duration of diabetes, and history of cardiovascular disease.
They also reported a decline in a renal composite outcome (first macroalbuminuria, sustained decline in estimated glomerular filtration rate of 30% or more, chronic renal replacement) in the drug group (HR, 0.85; 95% CI, 0.77-0.93; P = .0004).
Rates of serious adverse effects were similar in the drug and placebo groups. Gastrointestinal adverse effects – including nausea, constipation, and diarrhea – were as expected, Dr. Gerstein said.
“The addition of dulaglutide could be considered for both primary and secondary cardiovascular prevention in middle-aged patients with type 2 diabetes and cardiovascular risk factors,” Dr. Gerstein said.
In an independent commentary at the meeting presentation, Sophia Zoungas, MBBS (Hons), FRCP, PhD, of Monash University, Melbourne, praised the study and applauded the findings.
However, she called attention to the results that pinpointed higher levels of microvascular-related eye outcomes (HR, 1.24; 95% CI, 0.92-1.68) and fatal myocardial infarction (HR, 1.29; 95% CI, 0.72-2.30) in the dulaglutide group. Both of those outcomes were rare – 171 eye outcomes and 46 fatal myocardial infarctions overall. She also questioned whether the adherence rates would be as high in a real-world setting.
Eli Lilly funded the study. Three of the authors were employees of Eli Lilly, eight reported financial relationships with the company, five reported financial relationships with other firms, and the remaining authors reported no competing interests.
SOURCE: Gerstein HC et al. Lancet. 2019 Jun 10. doi: 10.1016/S0140-6736(19)31149-3.
SAN FRANCISCO – A large, long-term study is linking yet another glucagon-like peptide–1 receptor agonist diabetes drug to positive cardiovascular outcomes: Patients with type 2 diabetes and heart disease risk factors who took dulaglutide for about 5 years during the REWIND study had a 12% lower risk of major adverse cardiovascular events, compared with those who took placebo.
These new findings on cardiac risk are unusual compared with other newer-generation diabetes drugs, because a high percentage of the participants did not have existing cardiovascular disease. In addition, the study population had a higher percentage of women, compared with previous studies.
“We feel very strongly that the participants were similar to the ... ambulatory patients with type 2 diabetes with cardiovascular risk who are routinely seen in clinical practice,” study coauthor Jeffrey L. Probstfield, MD, of the University of Washington, Seattle, saidin a presentation at the annual scientific sessions of the American Diabetes Association. The findings were published simultaneously in The Lancet (2019 Jun 10. doi: 10.1016/S0140-6736(19)31149-3.
Dulaglutide’s serious adverse-effect profile was similar to that of placebo, the study authors noted, and the drug also showed benefits in renal outcomes, as reported in a separate study (Gerstein HC et al. Lancet. 2019 Jun 10. doi: 10.1016/S0140-6736(19)31150-3.
The Food and Drug Administration has mandated that six glucagon-like peptide–1 receptor agonists (GLP-1 RAs) – albiglutide (Tanzeum), exenatide (Byetta), liraglutide (Victoza), lixisenatide (Adlyxin), semaglutide (Ozempic) and dulaglutide (Trulicity) – undergo testing of cardiovascular outcomes. Dulaglutide is the fourth, following albiglutide, liraglutide, and semaglutide, to show consistent, statistically significant reduction in major adverse cardiovascular events (MACE).
For the double-blind, randomized, placebo-controlled REWIND study, researchers recruited 9,901 participants who were at least 50 years old with type 2 diabetes, a hemoglobin A1c (HbA1c) level of 9.5% or less, and a body mass index of more than 23 kg/m2. The participants came from 371 sites in 24 countries, including the United States and Canada. More than 80% were taking an angiotensin-converting enzyme inhibitor or angiotensin II receptor blocker, and other blood pressure drugs were also common.
The average mean age was 66 years; 46% of the participants were women, three-quarters were white, and 31% had previous cardiovascular disease. Previous GLP-1 RA studies of this type had markedly lower percentages of women – the other studies comprised 30%-39% women – and included higher percentages of participants with previous cardiovascular disease (73%-100%).
Of the participants in the current study, 4,949 were assigned to receive dulaglutide and 4,952 to receive placebo. They were followed for a median 5.4 years. About 57% never stopped using the drug, and 11% of those in the drug group and 7.5% in the placebo group stopped use because of adverse effects.
In regard to diabetes outcomes, HbA1c levels fell in the drug group by a mean –0.61% (95% confidence interval, –0.65 to –0.58; P less than .0001), compared with placebo. Their weight decreased by a mean –1.5 kg (95% CI, -1.7 to -1.3; P less than .0001) Systolic blood pressure and LDL cholesterol levels were slightly lower in the drug group, but heart rate was higher.
On the heart front, MACE fell by 12% in the drug group, compared with placebo (hazard ratio, 0.88; 95% CI, 0.79-0.99; P = .026). “The effect of the intervention begins [within] the first year and continued in a progressive, proportional fashion throughout the follow-up period,” said study lead author Hertzel C. Gerstein, MD, of McMaster University and Hamilton Health Sciences, Hamilton, Ont.
There was an especially large decline in the number of nonfatal stroke cases in the drug group, compared with placebo (135 vs. 175, respectively; HR, 0.76; 95% CI, 0.61-0.95; P = .017). The drug did not have a statistically significant effect on cardiovascular death.
The researchers found no difference in the drug’s effects on MACE in subgroups including age, gender, ethnicity, duration of diabetes, and history of cardiovascular disease.
They also reported a decline in a renal composite outcome (first macroalbuminuria, sustained decline in estimated glomerular filtration rate of 30% or more, chronic renal replacement) in the drug group (HR, 0.85; 95% CI, 0.77-0.93; P = .0004).
Rates of serious adverse effects were similar in the drug and placebo groups. Gastrointestinal adverse effects – including nausea, constipation, and diarrhea – were as expected, Dr. Gerstein said.
“The addition of dulaglutide could be considered for both primary and secondary cardiovascular prevention in middle-aged patients with type 2 diabetes and cardiovascular risk factors,” Dr. Gerstein said.
In an independent commentary at the meeting presentation, Sophia Zoungas, MBBS (Hons), FRCP, PhD, of Monash University, Melbourne, praised the study and applauded the findings.
However, she called attention to the results that pinpointed higher levels of microvascular-related eye outcomes (HR, 1.24; 95% CI, 0.92-1.68) and fatal myocardial infarction (HR, 1.29; 95% CI, 0.72-2.30) in the dulaglutide group. Both of those outcomes were rare – 171 eye outcomes and 46 fatal myocardial infarctions overall. She also questioned whether the adherence rates would be as high in a real-world setting.
Eli Lilly funded the study. Three of the authors were employees of Eli Lilly, eight reported financial relationships with the company, five reported financial relationships with other firms, and the remaining authors reported no competing interests.
SOURCE: Gerstein HC et al. Lancet. 2019 Jun 10. doi: 10.1016/S0140-6736(19)31149-3.
SAN FRANCISCO – A large, long-term study is linking yet another glucagon-like peptide–1 receptor agonist diabetes drug to positive cardiovascular outcomes: Patients with type 2 diabetes and heart disease risk factors who took dulaglutide for about 5 years during the REWIND study had a 12% lower risk of major adverse cardiovascular events, compared with those who took placebo.
These new findings on cardiac risk are unusual compared with other newer-generation diabetes drugs, because a high percentage of the participants did not have existing cardiovascular disease. In addition, the study population had a higher percentage of women, compared with previous studies.
“We feel very strongly that the participants were similar to the ... ambulatory patients with type 2 diabetes with cardiovascular risk who are routinely seen in clinical practice,” study coauthor Jeffrey L. Probstfield, MD, of the University of Washington, Seattle, saidin a presentation at the annual scientific sessions of the American Diabetes Association. The findings were published simultaneously in The Lancet (2019 Jun 10. doi: 10.1016/S0140-6736(19)31149-3.
Dulaglutide’s serious adverse-effect profile was similar to that of placebo, the study authors noted, and the drug also showed benefits in renal outcomes, as reported in a separate study (Gerstein HC et al. Lancet. 2019 Jun 10. doi: 10.1016/S0140-6736(19)31150-3.
The Food and Drug Administration has mandated that six glucagon-like peptide–1 receptor agonists (GLP-1 RAs) – albiglutide (Tanzeum), exenatide (Byetta), liraglutide (Victoza), lixisenatide (Adlyxin), semaglutide (Ozempic) and dulaglutide (Trulicity) – undergo testing of cardiovascular outcomes. Dulaglutide is the fourth, following albiglutide, liraglutide, and semaglutide, to show consistent, statistically significant reduction in major adverse cardiovascular events (MACE).
For the double-blind, randomized, placebo-controlled REWIND study, researchers recruited 9,901 participants who were at least 50 years old with type 2 diabetes, a hemoglobin A1c (HbA1c) level of 9.5% or less, and a body mass index of more than 23 kg/m2. The participants came from 371 sites in 24 countries, including the United States and Canada. More than 80% were taking an angiotensin-converting enzyme inhibitor or angiotensin II receptor blocker, and other blood pressure drugs were also common.
The average mean age was 66 years; 46% of the participants were women, three-quarters were white, and 31% had previous cardiovascular disease. Previous GLP-1 RA studies of this type had markedly lower percentages of women – the other studies comprised 30%-39% women – and included higher percentages of participants with previous cardiovascular disease (73%-100%).
Of the participants in the current study, 4,949 were assigned to receive dulaglutide and 4,952 to receive placebo. They were followed for a median 5.4 years. About 57% never stopped using the drug, and 11% of those in the drug group and 7.5% in the placebo group stopped use because of adverse effects.
In regard to diabetes outcomes, HbA1c levels fell in the drug group by a mean –0.61% (95% confidence interval, –0.65 to –0.58; P less than .0001), compared with placebo. Their weight decreased by a mean –1.5 kg (95% CI, -1.7 to -1.3; P less than .0001) Systolic blood pressure and LDL cholesterol levels were slightly lower in the drug group, but heart rate was higher.
On the heart front, MACE fell by 12% in the drug group, compared with placebo (hazard ratio, 0.88; 95% CI, 0.79-0.99; P = .026). “The effect of the intervention begins [within] the first year and continued in a progressive, proportional fashion throughout the follow-up period,” said study lead author Hertzel C. Gerstein, MD, of McMaster University and Hamilton Health Sciences, Hamilton, Ont.
There was an especially large decline in the number of nonfatal stroke cases in the drug group, compared with placebo (135 vs. 175, respectively; HR, 0.76; 95% CI, 0.61-0.95; P = .017). The drug did not have a statistically significant effect on cardiovascular death.
The researchers found no difference in the drug’s effects on MACE in subgroups including age, gender, ethnicity, duration of diabetes, and history of cardiovascular disease.
They also reported a decline in a renal composite outcome (first macroalbuminuria, sustained decline in estimated glomerular filtration rate of 30% or more, chronic renal replacement) in the drug group (HR, 0.85; 95% CI, 0.77-0.93; P = .0004).
Rates of serious adverse effects were similar in the drug and placebo groups. Gastrointestinal adverse effects – including nausea, constipation, and diarrhea – were as expected, Dr. Gerstein said.
“The addition of dulaglutide could be considered for both primary and secondary cardiovascular prevention in middle-aged patients with type 2 diabetes and cardiovascular risk factors,” Dr. Gerstein said.
In an independent commentary at the meeting presentation, Sophia Zoungas, MBBS (Hons), FRCP, PhD, of Monash University, Melbourne, praised the study and applauded the findings.
However, she called attention to the results that pinpointed higher levels of microvascular-related eye outcomes (HR, 1.24; 95% CI, 0.92-1.68) and fatal myocardial infarction (HR, 1.29; 95% CI, 0.72-2.30) in the dulaglutide group. Both of those outcomes were rare – 171 eye outcomes and 46 fatal myocardial infarctions overall. She also questioned whether the adherence rates would be as high in a real-world setting.
Eli Lilly funded the study. Three of the authors were employees of Eli Lilly, eight reported financial relationships with the company, five reported financial relationships with other firms, and the remaining authors reported no competing interests.
SOURCE: Gerstein HC et al. Lancet. 2019 Jun 10. doi: 10.1016/S0140-6736(19)31149-3.
REPORTING FROM ADA 2019
Bullous Systemic Lupus Erythematosus Successfully Treated With Rituximab
Bullous systemic lupus erythematosus (BSLE) is a rare cutaneous presentation of systemic lupus erythematosus (SLE).1 Although 59% to 85% of SLE patients develop skin-related symptoms, fewer than 5% of SLE patients develop BSLE.1-3 This acquired autoimmune bullous disease, characterized by subepidermal bullae with a neutrophilic infiltrate on histopathology, is precipitated by autoantibodies to type VII collagen. Bullae can appear on both cutaneous and mucosal surfaces but tend to favor the trunk, upper extremities, neck, face, and vermilion border.3
Our case of an 18-year-old black woman with BSLE was originally reported in 2011.4 We update the case to illustrate the heterogeneous presentation of BSLE in a single patient and to expand on the role of rituximab in this disease.
Case Report
An 18-year-old black woman presented with a vesicular eruption of 3 weeks’ duration that started on the trunk and buttocks and progressed to involve the face, oral mucosa, and posterior auricular area. The vesicular eruption was accompanied by fatigue, arthralgia, and myalgia.
Physical examination revealed multiple tense, fluid-filled vesicles, measuring roughly 2 to 3 mm in diameter, over the cheeks, chin, postauricular area, vermilion border, oral mucosa, and left side of the neck and shoulder. Resolved lesions on the trunk and buttocks were marked by superficial crust and postinflammatory hyperpigmentation. Scarring was absent.
Laboratory analysis demonstrated hemolytic anemia with a positive direct antiglobulin test, hypocomplementemia, and an elevated erythrocyte sedimentation rate. Antinuclear antibody testing was positive (titer, 1:640).
Biopsies were taken from the left cheek for hematoxylin and eosin (H&E) staining and direct immunofluorescence (DIF), which revealed subepidermal clefting, few neutrophils, and notable mucin deposition. Direct immunofluorescence showed a broad deposition of IgG, IgA, and IgM, as well as C3 in a ribbonlike pattern at the dermoepidermal junction.
A diagnosis of SLE with BSLE was made. The patient initially was treated with prednisone, hydroxychloroquine, mycophenolate mofetil, and intravenous immunoglobulin, but the cutaneous disease persisted. The bullous eruption resolved with 2 infusions of rituximab (1000 mg) spaced 2 weeks apart.
The patient was in remission on 5 mg of prednisone for 2 years following the initial course of rituximab. However, she developed a flare of SLE, with fatigue, arthralgia, hypocomplementemia, and recurrence of BSLE with tense bullae on the face and lips. The flare resolved with prednisone and a single infusion of rituximab (1000 mg). She was then maintained on hydroxychloroquine (200 mg/d).
Three years later (5 years after the initial presentation), the patient presented with pruritic erythematous papulovesicles on the bilateral extensor elbows and right knee (Figure 1). The clinical appearance suggested dermatitis herpetiformis (DH).
Punch biopsies were obtained from the right elbow for H&E and DIF testing; the H&E-stained specimen showed lichenoid dermatitis with prominent dermal mucin, consistent with cutaneous lupus erythematosus. Direct immunofluorescence showed prominent linear IgG, linear IgA, and granular IgM along the basement membrane, which were identical to DIF findings of the original eruption.
Further laboratory testing revealed hypocomplementemia, anemia of chronic disease (hemoglobin, 8.4 g/dL [reference range, 14.0–17.5 g/dL]), and an elevated erythrocyte sedimentation rate. Given the clinical appearance of the vesicles, DIF findings, and the corresponding SLE flare, a diagnosis of BSLE was made. Because of the systemic symptoms, skin findings, and laboratory results, azathioprine was started. The cutaneous symptoms were treated and resolved with the addition of triamcinolone ointment 0.1% twice daily.
Six months later, the patient presented to our facility with fatigue, arthralgia, and numerous erythematous papules coalescing into a large plaque on the left upper arm (Figure 2). Biopsy showed interface dermatitis with numerous neutrophils and early vesiculation, consistent with BSLE (Figure 3). She underwent another course of 2 infusions of rituximab (1000 mg) administered 2 weeks apart, with resolution of cutaneous and systemic disease.
Comment
Diagnosis of BSLE
Bullous systemic lupus erythematosus is a rare cutaneous complication of SLE. It typically affects young black women in the second to fourth decades of life.1 It is a heterogeneous disorder with several clinical variants reported in the literature, and it can be mistaken for bullous pemphigoid, epidermolysis bullosa acquisita (EBA), linear IgA bullous dermatosis, and DH.1-3 Despite its varying clinical phenotypes, BSLE is associated with autoantibodies to the EBA antigen, type VII collagen.1
Current diagnostic criteria for BSLE, revised in 1995,5 include the following: (1) a diagnosis of SLE, based on criteria outlined by the American College of Rheumatology6; (2) vesicles or bullae, or both, involving but not limited to sun-exposed skin; (3) histopathologic features similar to DH; (4) DIF with IgG or IgM, or both, and IgA at the basement membrane zone; and (5) indirect immunofluorescence testing for circulating autoantibodies against the basement membrane zone, using the salt-split skin technique.
Clinical Presentation of BSLE
The classic phenotype associated with BSLE is similar to our patient’s original eruption, with tense bullae favoring the upper trunk and healing without scarring. The extensor surfaces typically are spared. Another presentation of BSLE is an EBA-like phenotype, with bullae on acral and extensor surfaces that heal with scarring. The EBA-like phenotype usually is more difficult to control. Lesions appearing clinically similar to DH have been reported, either as DH associated with SLE (later postulated to have been BSLE) or as herpetiform BSLE.1,4,7-10
Histopathology of BSLE
The typical histologic appearance of BSLE is similar to DH or linear IgA bullous dermatosis, with a predominantly neutrophilic inflammatory infiltrate in the upper dermis and a subepidermal split. Direct immunofluorescence shows broad deposition of IgG along the basement membrane zone (93% of cases; 60% of which are linear and 40% are granular), with approximately 70% of cases showing positive IgA or IgM, or both, at the basement membrane zone. Indirect immunofluorescence performed on 1 M NaCl salt-split skin showed staining on the dermal side of the split, similar to EBA.11
Treatment Options
Rapid clinical response has been reported with dapsone, usually in combination with other immunosuppresants.1,2 A subset of patients does not respond to dapsone, however, as was the case in our patient who tried dapsone early in the disease course but was not effective. Other therapies including azathioprine, cyclophosphamide, mycophenolate mofetil, and antimalarials have been used with some success.3
Rituximab, an anti-CD20 monoclonal antibody, has been used off label to treat BSLE cases that are resistant to dapsone, corticosteroids, and other immunosuppressants.12 Rituximab functions by depleting CD20+ B cells, thus altering the production of autoantibodies and, in the case of BSLE, reducing the concentration of circulating anti–type VII collagen antibodies. Rituximab was approved by the US Food and Drug Administration in 1997 for the treatment of non–Hodgkin lymphoma and later for chronic lymphocytic leukemia, rheumatoid arthritis, granulomatosis with polyangiitis (Wegener granulomatosis), and microscopic polyangiitis.12 Off-label administration of rituximab to treat autoimmune bullous dermatoses has been increasing, and the drug is now approved by the US Food and Drug Administration to treat pemphigus vulgaris (as of June 2018).13
In 2011, Alsanafi et al12 reported successful treatment of BSLE with rituximab in a 61-year-old black woman who had rapid clearance of skin lesions. Our patient had rapid resolution of cutaneous disease with rituximab after the second infusion in a 2-infusion regimen. Interestingly, rituximab is the only agent that has reliably resulted in resolution of our patient’s cutaneous and systemic disease during multiple episodes.
There is little information in the literature regarding the duration of response to rituximab in BSLE or its use in subsequent flares. Our patient relapsed at 2 years and again 3 years later (5 years after the initial presentation). The original cutaneous outbreak and subsequent relapse had classic clinical and histological findings for BSLE; however, the third cutaneous relapse was more similar to DH, given its distribution and appearance. However, the histopathologic findings were the same at the third relapse as they were at the initial presentation and not reflective of DH. We propose that our patient’s prior treatment with rituximab and ongoing immunosuppression at presentation contributed to the more atypical cutaneous findings observed late in the disease course.
Conclusion
We report this case to highlight the heterogeneity of BSLE, even in a single patient, and to report the time course of treatment with rituximab. Although BSLE is considered a rare cutaneous complication of SLE, it is important to note that BSLE also can present as the initial manifestation of SLE.7 As such, BSLE should always be included in the differential diagnosis for a patient presenting with a bullous eruption and symptoms that suggest SLE.
This case also illustrates the repeated use of rituximab for the treatment of BSLE over a 5-year period and justifies the need for larger population-based studies to demonstrate the efficacy of rituximab in BSLE.
- Contestable JJ, Edhegard KD, Meyerle JH. Bullous systemic lupus erythematosus: a review and update to diagnosis and treatment. Am J Clin Dermatol. 2014;15:517-524.
- Camisa C. Vesiculobullous systemic lupus erythematosus. a report of four cases. J Am Acad Dermatol. 1988;18(1, pt 1):93-100.
- Tincopa M, Puttgen KB, Sule S, et al. Bullous lupus: an unusual initial presentation of systemic lupus erythematosus in an adolescent girl. Pediatr Dermatol. 2010;27:373-376.
- Burke KR, Green BP, Meyerle J. Bullous lupus in an 18-year-old. Pediatr Dermatol. 2011;28:483.
- Yell JA, Allen J, Wojnarowska F, et al. Bullous systemic lupus erythematosus: revised criteria for diagnosis. Br J Dermatol. 1995;132:921-928.
- Hochberg MC. Updating the American College of Rheumatology revised criteria for the classification of systemic lupus erythematosus. Arthritis Rheumat. 1997;40:1725.
- Fujimoto W, Hamada T, Yamada J, et al. Bullous systemic lupus erythematosus as an initial manifestation of SLE. J Dermatol. 2005;32:1021-1027.
- Moncada B. Dermatitis herpetiformis in association with systemic lupus erythematosus. Arch Dermatol. 1974;109:723-725.
- Davies MG, Marks R, Waddington E. Simultaneous systemic lupus erythematosus and dermatitis herpetiformis. Arch Dermatol. 1976;112:1292-1294.
- Burrows N, Bhogal BS, Black MM, et al. Bullous eruption of systemic lupus erythematosus: a clinicopathological study of four cases. Br J Dermatol. 1993;128:332-338.
- Sebaratnam DF, Murrell DF. Bullous systemic lupus erythematosus. Dermatol Clin. 2011;29:649-653.
- Alsanafi S, Kovarik C, Mermelstein AL, et al. Rituximab in the treatment of bullous systemic lupus erythematosus. J Clin Rheumatol. 2011;17:142-144.
- Durable remission of pemphigus with a fixed-dose rituximab protocol. JAMA Dermatol. 2014;150:703-708.
Bullous systemic lupus erythematosus (BSLE) is a rare cutaneous presentation of systemic lupus erythematosus (SLE).1 Although 59% to 85% of SLE patients develop skin-related symptoms, fewer than 5% of SLE patients develop BSLE.1-3 This acquired autoimmune bullous disease, characterized by subepidermal bullae with a neutrophilic infiltrate on histopathology, is precipitated by autoantibodies to type VII collagen. Bullae can appear on both cutaneous and mucosal surfaces but tend to favor the trunk, upper extremities, neck, face, and vermilion border.3
Our case of an 18-year-old black woman with BSLE was originally reported in 2011.4 We update the case to illustrate the heterogeneous presentation of BSLE in a single patient and to expand on the role of rituximab in this disease.
Case Report
An 18-year-old black woman presented with a vesicular eruption of 3 weeks’ duration that started on the trunk and buttocks and progressed to involve the face, oral mucosa, and posterior auricular area. The vesicular eruption was accompanied by fatigue, arthralgia, and myalgia.
Physical examination revealed multiple tense, fluid-filled vesicles, measuring roughly 2 to 3 mm in diameter, over the cheeks, chin, postauricular area, vermilion border, oral mucosa, and left side of the neck and shoulder. Resolved lesions on the trunk and buttocks were marked by superficial crust and postinflammatory hyperpigmentation. Scarring was absent.
Laboratory analysis demonstrated hemolytic anemia with a positive direct antiglobulin test, hypocomplementemia, and an elevated erythrocyte sedimentation rate. Antinuclear antibody testing was positive (titer, 1:640).
Biopsies were taken from the left cheek for hematoxylin and eosin (H&E) staining and direct immunofluorescence (DIF), which revealed subepidermal clefting, few neutrophils, and notable mucin deposition. Direct immunofluorescence showed a broad deposition of IgG, IgA, and IgM, as well as C3 in a ribbonlike pattern at the dermoepidermal junction.
A diagnosis of SLE with BSLE was made. The patient initially was treated with prednisone, hydroxychloroquine, mycophenolate mofetil, and intravenous immunoglobulin, but the cutaneous disease persisted. The bullous eruption resolved with 2 infusions of rituximab (1000 mg) spaced 2 weeks apart.
The patient was in remission on 5 mg of prednisone for 2 years following the initial course of rituximab. However, she developed a flare of SLE, with fatigue, arthralgia, hypocomplementemia, and recurrence of BSLE with tense bullae on the face and lips. The flare resolved with prednisone and a single infusion of rituximab (1000 mg). She was then maintained on hydroxychloroquine (200 mg/d).
Three years later (5 years after the initial presentation), the patient presented with pruritic erythematous papulovesicles on the bilateral extensor elbows and right knee (Figure 1). The clinical appearance suggested dermatitis herpetiformis (DH).
Punch biopsies were obtained from the right elbow for H&E and DIF testing; the H&E-stained specimen showed lichenoid dermatitis with prominent dermal mucin, consistent with cutaneous lupus erythematosus. Direct immunofluorescence showed prominent linear IgG, linear IgA, and granular IgM along the basement membrane, which were identical to DIF findings of the original eruption.
Further laboratory testing revealed hypocomplementemia, anemia of chronic disease (hemoglobin, 8.4 g/dL [reference range, 14.0–17.5 g/dL]), and an elevated erythrocyte sedimentation rate. Given the clinical appearance of the vesicles, DIF findings, and the corresponding SLE flare, a diagnosis of BSLE was made. Because of the systemic symptoms, skin findings, and laboratory results, azathioprine was started. The cutaneous symptoms were treated and resolved with the addition of triamcinolone ointment 0.1% twice daily.
Six months later, the patient presented to our facility with fatigue, arthralgia, and numerous erythematous papules coalescing into a large plaque on the left upper arm (Figure 2). Biopsy showed interface dermatitis with numerous neutrophils and early vesiculation, consistent with BSLE (Figure 3). She underwent another course of 2 infusions of rituximab (1000 mg) administered 2 weeks apart, with resolution of cutaneous and systemic disease.
Comment
Diagnosis of BSLE
Bullous systemic lupus erythematosus is a rare cutaneous complication of SLE. It typically affects young black women in the second to fourth decades of life.1 It is a heterogeneous disorder with several clinical variants reported in the literature, and it can be mistaken for bullous pemphigoid, epidermolysis bullosa acquisita (EBA), linear IgA bullous dermatosis, and DH.1-3 Despite its varying clinical phenotypes, BSLE is associated with autoantibodies to the EBA antigen, type VII collagen.1
Current diagnostic criteria for BSLE, revised in 1995,5 include the following: (1) a diagnosis of SLE, based on criteria outlined by the American College of Rheumatology6; (2) vesicles or bullae, or both, involving but not limited to sun-exposed skin; (3) histopathologic features similar to DH; (4) DIF with IgG or IgM, or both, and IgA at the basement membrane zone; and (5) indirect immunofluorescence testing for circulating autoantibodies against the basement membrane zone, using the salt-split skin technique.
Clinical Presentation of BSLE
The classic phenotype associated with BSLE is similar to our patient’s original eruption, with tense bullae favoring the upper trunk and healing without scarring. The extensor surfaces typically are spared. Another presentation of BSLE is an EBA-like phenotype, with bullae on acral and extensor surfaces that heal with scarring. The EBA-like phenotype usually is more difficult to control. Lesions appearing clinically similar to DH have been reported, either as DH associated with SLE (later postulated to have been BSLE) or as herpetiform BSLE.1,4,7-10
Histopathology of BSLE
The typical histologic appearance of BSLE is similar to DH or linear IgA bullous dermatosis, with a predominantly neutrophilic inflammatory infiltrate in the upper dermis and a subepidermal split. Direct immunofluorescence shows broad deposition of IgG along the basement membrane zone (93% of cases; 60% of which are linear and 40% are granular), with approximately 70% of cases showing positive IgA or IgM, or both, at the basement membrane zone. Indirect immunofluorescence performed on 1 M NaCl salt-split skin showed staining on the dermal side of the split, similar to EBA.11
Treatment Options
Rapid clinical response has been reported with dapsone, usually in combination with other immunosuppresants.1,2 A subset of patients does not respond to dapsone, however, as was the case in our patient who tried dapsone early in the disease course but was not effective. Other therapies including azathioprine, cyclophosphamide, mycophenolate mofetil, and antimalarials have been used with some success.3
Rituximab, an anti-CD20 monoclonal antibody, has been used off label to treat BSLE cases that are resistant to dapsone, corticosteroids, and other immunosuppressants.12 Rituximab functions by depleting CD20+ B cells, thus altering the production of autoantibodies and, in the case of BSLE, reducing the concentration of circulating anti–type VII collagen antibodies. Rituximab was approved by the US Food and Drug Administration in 1997 for the treatment of non–Hodgkin lymphoma and later for chronic lymphocytic leukemia, rheumatoid arthritis, granulomatosis with polyangiitis (Wegener granulomatosis), and microscopic polyangiitis.12 Off-label administration of rituximab to treat autoimmune bullous dermatoses has been increasing, and the drug is now approved by the US Food and Drug Administration to treat pemphigus vulgaris (as of June 2018).13
In 2011, Alsanafi et al12 reported successful treatment of BSLE with rituximab in a 61-year-old black woman who had rapid clearance of skin lesions. Our patient had rapid resolution of cutaneous disease with rituximab after the second infusion in a 2-infusion regimen. Interestingly, rituximab is the only agent that has reliably resulted in resolution of our patient’s cutaneous and systemic disease during multiple episodes.
There is little information in the literature regarding the duration of response to rituximab in BSLE or its use in subsequent flares. Our patient relapsed at 2 years and again 3 years later (5 years after the initial presentation). The original cutaneous outbreak and subsequent relapse had classic clinical and histological findings for BSLE; however, the third cutaneous relapse was more similar to DH, given its distribution and appearance. However, the histopathologic findings were the same at the third relapse as they were at the initial presentation and not reflective of DH. We propose that our patient’s prior treatment with rituximab and ongoing immunosuppression at presentation contributed to the more atypical cutaneous findings observed late in the disease course.
Conclusion
We report this case to highlight the heterogeneity of BSLE, even in a single patient, and to report the time course of treatment with rituximab. Although BSLE is considered a rare cutaneous complication of SLE, it is important to note that BSLE also can present as the initial manifestation of SLE.7 As such, BSLE should always be included in the differential diagnosis for a patient presenting with a bullous eruption and symptoms that suggest SLE.
This case also illustrates the repeated use of rituximab for the treatment of BSLE over a 5-year period and justifies the need for larger population-based studies to demonstrate the efficacy of rituximab in BSLE.
Bullous systemic lupus erythematosus (BSLE) is a rare cutaneous presentation of systemic lupus erythematosus (SLE).1 Although 59% to 85% of SLE patients develop skin-related symptoms, fewer than 5% of SLE patients develop BSLE.1-3 This acquired autoimmune bullous disease, characterized by subepidermal bullae with a neutrophilic infiltrate on histopathology, is precipitated by autoantibodies to type VII collagen. Bullae can appear on both cutaneous and mucosal surfaces but tend to favor the trunk, upper extremities, neck, face, and vermilion border.3
Our case of an 18-year-old black woman with BSLE was originally reported in 2011.4 We update the case to illustrate the heterogeneous presentation of BSLE in a single patient and to expand on the role of rituximab in this disease.
Case Report
An 18-year-old black woman presented with a vesicular eruption of 3 weeks’ duration that started on the trunk and buttocks and progressed to involve the face, oral mucosa, and posterior auricular area. The vesicular eruption was accompanied by fatigue, arthralgia, and myalgia.
Physical examination revealed multiple tense, fluid-filled vesicles, measuring roughly 2 to 3 mm in diameter, over the cheeks, chin, postauricular area, vermilion border, oral mucosa, and left side of the neck and shoulder. Resolved lesions on the trunk and buttocks were marked by superficial crust and postinflammatory hyperpigmentation. Scarring was absent.
Laboratory analysis demonstrated hemolytic anemia with a positive direct antiglobulin test, hypocomplementemia, and an elevated erythrocyte sedimentation rate. Antinuclear antibody testing was positive (titer, 1:640).
Biopsies were taken from the left cheek for hematoxylin and eosin (H&E) staining and direct immunofluorescence (DIF), which revealed subepidermal clefting, few neutrophils, and notable mucin deposition. Direct immunofluorescence showed a broad deposition of IgG, IgA, and IgM, as well as C3 in a ribbonlike pattern at the dermoepidermal junction.
A diagnosis of SLE with BSLE was made. The patient initially was treated with prednisone, hydroxychloroquine, mycophenolate mofetil, and intravenous immunoglobulin, but the cutaneous disease persisted. The bullous eruption resolved with 2 infusions of rituximab (1000 mg) spaced 2 weeks apart.
The patient was in remission on 5 mg of prednisone for 2 years following the initial course of rituximab. However, she developed a flare of SLE, with fatigue, arthralgia, hypocomplementemia, and recurrence of BSLE with tense bullae on the face and lips. The flare resolved with prednisone and a single infusion of rituximab (1000 mg). She was then maintained on hydroxychloroquine (200 mg/d).
Three years later (5 years after the initial presentation), the patient presented with pruritic erythematous papulovesicles on the bilateral extensor elbows and right knee (Figure 1). The clinical appearance suggested dermatitis herpetiformis (DH).
Punch biopsies were obtained from the right elbow for H&E and DIF testing; the H&E-stained specimen showed lichenoid dermatitis with prominent dermal mucin, consistent with cutaneous lupus erythematosus. Direct immunofluorescence showed prominent linear IgG, linear IgA, and granular IgM along the basement membrane, which were identical to DIF findings of the original eruption.
Further laboratory testing revealed hypocomplementemia, anemia of chronic disease (hemoglobin, 8.4 g/dL [reference range, 14.0–17.5 g/dL]), and an elevated erythrocyte sedimentation rate. Given the clinical appearance of the vesicles, DIF findings, and the corresponding SLE flare, a diagnosis of BSLE was made. Because of the systemic symptoms, skin findings, and laboratory results, azathioprine was started. The cutaneous symptoms were treated and resolved with the addition of triamcinolone ointment 0.1% twice daily.
Six months later, the patient presented to our facility with fatigue, arthralgia, and numerous erythematous papules coalescing into a large plaque on the left upper arm (Figure 2). Biopsy showed interface dermatitis with numerous neutrophils and early vesiculation, consistent with BSLE (Figure 3). She underwent another course of 2 infusions of rituximab (1000 mg) administered 2 weeks apart, with resolution of cutaneous and systemic disease.
Comment
Diagnosis of BSLE
Bullous systemic lupus erythematosus is a rare cutaneous complication of SLE. It typically affects young black women in the second to fourth decades of life.1 It is a heterogeneous disorder with several clinical variants reported in the literature, and it can be mistaken for bullous pemphigoid, epidermolysis bullosa acquisita (EBA), linear IgA bullous dermatosis, and DH.1-3 Despite its varying clinical phenotypes, BSLE is associated with autoantibodies to the EBA antigen, type VII collagen.1
Current diagnostic criteria for BSLE, revised in 1995,5 include the following: (1) a diagnosis of SLE, based on criteria outlined by the American College of Rheumatology6; (2) vesicles or bullae, or both, involving but not limited to sun-exposed skin; (3) histopathologic features similar to DH; (4) DIF with IgG or IgM, or both, and IgA at the basement membrane zone; and (5) indirect immunofluorescence testing for circulating autoantibodies against the basement membrane zone, using the salt-split skin technique.
Clinical Presentation of BSLE
The classic phenotype associated with BSLE is similar to our patient’s original eruption, with tense bullae favoring the upper trunk and healing without scarring. The extensor surfaces typically are spared. Another presentation of BSLE is an EBA-like phenotype, with bullae on acral and extensor surfaces that heal with scarring. The EBA-like phenotype usually is more difficult to control. Lesions appearing clinically similar to DH have been reported, either as DH associated with SLE (later postulated to have been BSLE) or as herpetiform BSLE.1,4,7-10
Histopathology of BSLE
The typical histologic appearance of BSLE is similar to DH or linear IgA bullous dermatosis, with a predominantly neutrophilic inflammatory infiltrate in the upper dermis and a subepidermal split. Direct immunofluorescence shows broad deposition of IgG along the basement membrane zone (93% of cases; 60% of which are linear and 40% are granular), with approximately 70% of cases showing positive IgA or IgM, or both, at the basement membrane zone. Indirect immunofluorescence performed on 1 M NaCl salt-split skin showed staining on the dermal side of the split, similar to EBA.11
Treatment Options
Rapid clinical response has been reported with dapsone, usually in combination with other immunosuppresants.1,2 A subset of patients does not respond to dapsone, however, as was the case in our patient who tried dapsone early in the disease course but was not effective. Other therapies including azathioprine, cyclophosphamide, mycophenolate mofetil, and antimalarials have been used with some success.3
Rituximab, an anti-CD20 monoclonal antibody, has been used off label to treat BSLE cases that are resistant to dapsone, corticosteroids, and other immunosuppressants.12 Rituximab functions by depleting CD20+ B cells, thus altering the production of autoantibodies and, in the case of BSLE, reducing the concentration of circulating anti–type VII collagen antibodies. Rituximab was approved by the US Food and Drug Administration in 1997 for the treatment of non–Hodgkin lymphoma and later for chronic lymphocytic leukemia, rheumatoid arthritis, granulomatosis with polyangiitis (Wegener granulomatosis), and microscopic polyangiitis.12 Off-label administration of rituximab to treat autoimmune bullous dermatoses has been increasing, and the drug is now approved by the US Food and Drug Administration to treat pemphigus vulgaris (as of June 2018).13
In 2011, Alsanafi et al12 reported successful treatment of BSLE with rituximab in a 61-year-old black woman who had rapid clearance of skin lesions. Our patient had rapid resolution of cutaneous disease with rituximab after the second infusion in a 2-infusion regimen. Interestingly, rituximab is the only agent that has reliably resulted in resolution of our patient’s cutaneous and systemic disease during multiple episodes.
There is little information in the literature regarding the duration of response to rituximab in BSLE or its use in subsequent flares. Our patient relapsed at 2 years and again 3 years later (5 years after the initial presentation). The original cutaneous outbreak and subsequent relapse had classic clinical and histological findings for BSLE; however, the third cutaneous relapse was more similar to DH, given its distribution and appearance. However, the histopathologic findings were the same at the third relapse as they were at the initial presentation and not reflective of DH. We propose that our patient’s prior treatment with rituximab and ongoing immunosuppression at presentation contributed to the more atypical cutaneous findings observed late in the disease course.
Conclusion
We report this case to highlight the heterogeneity of BSLE, even in a single patient, and to report the time course of treatment with rituximab. Although BSLE is considered a rare cutaneous complication of SLE, it is important to note that BSLE also can present as the initial manifestation of SLE.7 As such, BSLE should always be included in the differential diagnosis for a patient presenting with a bullous eruption and symptoms that suggest SLE.
This case also illustrates the repeated use of rituximab for the treatment of BSLE over a 5-year period and justifies the need for larger population-based studies to demonstrate the efficacy of rituximab in BSLE.
- Contestable JJ, Edhegard KD, Meyerle JH. Bullous systemic lupus erythematosus: a review and update to diagnosis and treatment. Am J Clin Dermatol. 2014;15:517-524.
- Camisa C. Vesiculobullous systemic lupus erythematosus. a report of four cases. J Am Acad Dermatol. 1988;18(1, pt 1):93-100.
- Tincopa M, Puttgen KB, Sule S, et al. Bullous lupus: an unusual initial presentation of systemic lupus erythematosus in an adolescent girl. Pediatr Dermatol. 2010;27:373-376.
- Burke KR, Green BP, Meyerle J. Bullous lupus in an 18-year-old. Pediatr Dermatol. 2011;28:483.
- Yell JA, Allen J, Wojnarowska F, et al. Bullous systemic lupus erythematosus: revised criteria for diagnosis. Br J Dermatol. 1995;132:921-928.
- Hochberg MC. Updating the American College of Rheumatology revised criteria for the classification of systemic lupus erythematosus. Arthritis Rheumat. 1997;40:1725.
- Fujimoto W, Hamada T, Yamada J, et al. Bullous systemic lupus erythematosus as an initial manifestation of SLE. J Dermatol. 2005;32:1021-1027.
- Moncada B. Dermatitis herpetiformis in association with systemic lupus erythematosus. Arch Dermatol. 1974;109:723-725.
- Davies MG, Marks R, Waddington E. Simultaneous systemic lupus erythematosus and dermatitis herpetiformis. Arch Dermatol. 1976;112:1292-1294.
- Burrows N, Bhogal BS, Black MM, et al. Bullous eruption of systemic lupus erythematosus: a clinicopathological study of four cases. Br J Dermatol. 1993;128:332-338.
- Sebaratnam DF, Murrell DF. Bullous systemic lupus erythematosus. Dermatol Clin. 2011;29:649-653.
- Alsanafi S, Kovarik C, Mermelstein AL, et al. Rituximab in the treatment of bullous systemic lupus erythematosus. J Clin Rheumatol. 2011;17:142-144.
- Durable remission of pemphigus with a fixed-dose rituximab protocol. JAMA Dermatol. 2014;150:703-708.
- Contestable JJ, Edhegard KD, Meyerle JH. Bullous systemic lupus erythematosus: a review and update to diagnosis and treatment. Am J Clin Dermatol. 2014;15:517-524.
- Camisa C. Vesiculobullous systemic lupus erythematosus. a report of four cases. J Am Acad Dermatol. 1988;18(1, pt 1):93-100.
- Tincopa M, Puttgen KB, Sule S, et al. Bullous lupus: an unusual initial presentation of systemic lupus erythematosus in an adolescent girl. Pediatr Dermatol. 2010;27:373-376.
- Burke KR, Green BP, Meyerle J. Bullous lupus in an 18-year-old. Pediatr Dermatol. 2011;28:483.
- Yell JA, Allen J, Wojnarowska F, et al. Bullous systemic lupus erythematosus: revised criteria for diagnosis. Br J Dermatol. 1995;132:921-928.
- Hochberg MC. Updating the American College of Rheumatology revised criteria for the classification of systemic lupus erythematosus. Arthritis Rheumat. 1997;40:1725.
- Fujimoto W, Hamada T, Yamada J, et al. Bullous systemic lupus erythematosus as an initial manifestation of SLE. J Dermatol. 2005;32:1021-1027.
- Moncada B. Dermatitis herpetiformis in association with systemic lupus erythematosus. Arch Dermatol. 1974;109:723-725.
- Davies MG, Marks R, Waddington E. Simultaneous systemic lupus erythematosus and dermatitis herpetiformis. Arch Dermatol. 1976;112:1292-1294.
- Burrows N, Bhogal BS, Black MM, et al. Bullous eruption of systemic lupus erythematosus: a clinicopathological study of four cases. Br J Dermatol. 1993;128:332-338.
- Sebaratnam DF, Murrell DF. Bullous systemic lupus erythematosus. Dermatol Clin. 2011;29:649-653.
- Alsanafi S, Kovarik C, Mermelstein AL, et al. Rituximab in the treatment of bullous systemic lupus erythematosus. J Clin Rheumatol. 2011;17:142-144.
- Durable remission of pemphigus with a fixed-dose rituximab protocol. JAMA Dermatol. 2014;150:703-708.
Practice Points
- Bullous systemic lupus erythematosus (BSLE) can present with a waxing and waning course punctuated by flares.
- Different clinical presentations can occur over the disease course.
- Rituximab is a viable treatment option in BSLE.
