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Ethnicity seems to affect predisposition to components of metabolic syndrome
SAN DIEGO – .
“It appears that not all components of metabolic syndrome directly correlate with visceral fat,” lead study author Patrick Chen, DO, said at the annual Digestive Disease Week.
According to Dr. Chen, a gastroenterology fellow at Wright State University, Dayton, Ohio, the prevalence of obesity in the United States increased from 30.5% in 2000 to 39.6% in 2015, a condition that costs the U.S. medical system $150 billion each year and is associated with 19% of all deaths. “We also know that abdominal visceral fat is more associated with mortality and cardiac events than overall adiposity, while visceral fat contributes to nonalcoholic fatty liver disease and metabolic syndrome,” he said.
For Asian populations, the World Health Organization has set body mass indexes of 23 kg/m2 for overweight and 27.5 kg/m2 for obesity. “This has led to an ongoing debate as to whether we should be adopting regional anthropometric criteria based on race-unique risk factors,” Dr. Chen said. “Despite all of these association studies, the mechanisms are still undergoing research and still unknown to this day.”
For the current analysis, he and his colleagues assessed the prevalence of type 2 diabetes, hypertension, and hyperlipidemia and the impact of increasing BMI among racial groups in the United States. They drew from the National Ambulatory Medical Care Survey from 2011 to 2015 to collect and compare data on patient race, BMI, and the prevalence of type 2 diabetes, hypertension, and dyslipidemia, and used SPSS software for chi-square analysis. They excluded patients under the age of 18, those with type 1 diabetes, those with no listed race, and Native American populations, “since there were too few patients for meaningful analysis,” he said.
The 69,949 patients in the analysis included 57,448 whites, 9,281 African Americans, and 2,142 Asians. The majority (64,091) were listed as non-Hispanic, while 5,858 were listed as Hispanic. The mean age of the study population ranged from 49 to 55 years. African Americans had the highest mean BMI (31 kg/m2), followed by whites (29 kg/m2) and Asians (25 kg/m2). Meanwhile, both Hispanics and non-Hispanics had a mean BMI of 29 kg/m2.
Dr. Chen reported that African Americans (19.3%) and Asians (18.5%) had a higher prevalence of type 2 diabetes compared with whites (13.4%; P less than .001), while Hispanics had a higher prevalence of type 2 diabetes compared with non-Hispanics (18.9% vs. 13.9%; P less than .001). At the same time, African Americans had a higher prevalence of hypertension (49.6%) compared with whites (38.2%) and Asians (37.9%; P less than .001 for both associations), while non-Hispanics had a higher prevalence of hypertension compared with Hispanics (40.4% vs. 33.1%; P less than .001). Asians had a higher prevalence of hyperlipidemia (28.4%) compared with whites (25.6%; P = .004); both groups had a higher prevalence compared with African Americans (21.9%, P less than .001). Hispanics had a lower prevalence of hyperlipidemia compared with non-Hispanics (23.6% vs. 25.1%; P = .005).
“Diabetes, hypertension, and hyperlipidemia likely have different mechanisms that lead to different race’s predisposition to these diseases,” Dr. Chen concluded. “This study supports that regional anthropometric criteria should be done based on ethnicity-specific risk factors. Some food for thought is whether we need to change our screening guidelines for conditions like diabetes for Asian patients and hypertension in African American patients. We should also consider ethnicity when we look for NAFLD. Overall, continued research is needed to explain these correlations.”
The researchers reported having no financial disclosures.
SOURCE: Chen P et al. DDW 2019, Abstract 447.
SAN DIEGO – .
“It appears that not all components of metabolic syndrome directly correlate with visceral fat,” lead study author Patrick Chen, DO, said at the annual Digestive Disease Week.
According to Dr. Chen, a gastroenterology fellow at Wright State University, Dayton, Ohio, the prevalence of obesity in the United States increased from 30.5% in 2000 to 39.6% in 2015, a condition that costs the U.S. medical system $150 billion each year and is associated with 19% of all deaths. “We also know that abdominal visceral fat is more associated with mortality and cardiac events than overall adiposity, while visceral fat contributes to nonalcoholic fatty liver disease and metabolic syndrome,” he said.
For Asian populations, the World Health Organization has set body mass indexes of 23 kg/m2 for overweight and 27.5 kg/m2 for obesity. “This has led to an ongoing debate as to whether we should be adopting regional anthropometric criteria based on race-unique risk factors,” Dr. Chen said. “Despite all of these association studies, the mechanisms are still undergoing research and still unknown to this day.”
For the current analysis, he and his colleagues assessed the prevalence of type 2 diabetes, hypertension, and hyperlipidemia and the impact of increasing BMI among racial groups in the United States. They drew from the National Ambulatory Medical Care Survey from 2011 to 2015 to collect and compare data on patient race, BMI, and the prevalence of type 2 diabetes, hypertension, and dyslipidemia, and used SPSS software for chi-square analysis. They excluded patients under the age of 18, those with type 1 diabetes, those with no listed race, and Native American populations, “since there were too few patients for meaningful analysis,” he said.
The 69,949 patients in the analysis included 57,448 whites, 9,281 African Americans, and 2,142 Asians. The majority (64,091) were listed as non-Hispanic, while 5,858 were listed as Hispanic. The mean age of the study population ranged from 49 to 55 years. African Americans had the highest mean BMI (31 kg/m2), followed by whites (29 kg/m2) and Asians (25 kg/m2). Meanwhile, both Hispanics and non-Hispanics had a mean BMI of 29 kg/m2.
Dr. Chen reported that African Americans (19.3%) and Asians (18.5%) had a higher prevalence of type 2 diabetes compared with whites (13.4%; P less than .001), while Hispanics had a higher prevalence of type 2 diabetes compared with non-Hispanics (18.9% vs. 13.9%; P less than .001). At the same time, African Americans had a higher prevalence of hypertension (49.6%) compared with whites (38.2%) and Asians (37.9%; P less than .001 for both associations), while non-Hispanics had a higher prevalence of hypertension compared with Hispanics (40.4% vs. 33.1%; P less than .001). Asians had a higher prevalence of hyperlipidemia (28.4%) compared with whites (25.6%; P = .004); both groups had a higher prevalence compared with African Americans (21.9%, P less than .001). Hispanics had a lower prevalence of hyperlipidemia compared with non-Hispanics (23.6% vs. 25.1%; P = .005).
“Diabetes, hypertension, and hyperlipidemia likely have different mechanisms that lead to different race’s predisposition to these diseases,” Dr. Chen concluded. “This study supports that regional anthropometric criteria should be done based on ethnicity-specific risk factors. Some food for thought is whether we need to change our screening guidelines for conditions like diabetes for Asian patients and hypertension in African American patients. We should also consider ethnicity when we look for NAFLD. Overall, continued research is needed to explain these correlations.”
The researchers reported having no financial disclosures.
SOURCE: Chen P et al. DDW 2019, Abstract 447.
SAN DIEGO – .
“It appears that not all components of metabolic syndrome directly correlate with visceral fat,” lead study author Patrick Chen, DO, said at the annual Digestive Disease Week.
According to Dr. Chen, a gastroenterology fellow at Wright State University, Dayton, Ohio, the prevalence of obesity in the United States increased from 30.5% in 2000 to 39.6% in 2015, a condition that costs the U.S. medical system $150 billion each year and is associated with 19% of all deaths. “We also know that abdominal visceral fat is more associated with mortality and cardiac events than overall adiposity, while visceral fat contributes to nonalcoholic fatty liver disease and metabolic syndrome,” he said.
For Asian populations, the World Health Organization has set body mass indexes of 23 kg/m2 for overweight and 27.5 kg/m2 for obesity. “This has led to an ongoing debate as to whether we should be adopting regional anthropometric criteria based on race-unique risk factors,” Dr. Chen said. “Despite all of these association studies, the mechanisms are still undergoing research and still unknown to this day.”
For the current analysis, he and his colleagues assessed the prevalence of type 2 diabetes, hypertension, and hyperlipidemia and the impact of increasing BMI among racial groups in the United States. They drew from the National Ambulatory Medical Care Survey from 2011 to 2015 to collect and compare data on patient race, BMI, and the prevalence of type 2 diabetes, hypertension, and dyslipidemia, and used SPSS software for chi-square analysis. They excluded patients under the age of 18, those with type 1 diabetes, those with no listed race, and Native American populations, “since there were too few patients for meaningful analysis,” he said.
The 69,949 patients in the analysis included 57,448 whites, 9,281 African Americans, and 2,142 Asians. The majority (64,091) were listed as non-Hispanic, while 5,858 were listed as Hispanic. The mean age of the study population ranged from 49 to 55 years. African Americans had the highest mean BMI (31 kg/m2), followed by whites (29 kg/m2) and Asians (25 kg/m2). Meanwhile, both Hispanics and non-Hispanics had a mean BMI of 29 kg/m2.
Dr. Chen reported that African Americans (19.3%) and Asians (18.5%) had a higher prevalence of type 2 diabetes compared with whites (13.4%; P less than .001), while Hispanics had a higher prevalence of type 2 diabetes compared with non-Hispanics (18.9% vs. 13.9%; P less than .001). At the same time, African Americans had a higher prevalence of hypertension (49.6%) compared with whites (38.2%) and Asians (37.9%; P less than .001 for both associations), while non-Hispanics had a higher prevalence of hypertension compared with Hispanics (40.4% vs. 33.1%; P less than .001). Asians had a higher prevalence of hyperlipidemia (28.4%) compared with whites (25.6%; P = .004); both groups had a higher prevalence compared with African Americans (21.9%, P less than .001). Hispanics had a lower prevalence of hyperlipidemia compared with non-Hispanics (23.6% vs. 25.1%; P = .005).
“Diabetes, hypertension, and hyperlipidemia likely have different mechanisms that lead to different race’s predisposition to these diseases,” Dr. Chen concluded. “This study supports that regional anthropometric criteria should be done based on ethnicity-specific risk factors. Some food for thought is whether we need to change our screening guidelines for conditions like diabetes for Asian patients and hypertension in African American patients. We should also consider ethnicity when we look for NAFLD. Overall, continued research is needed to explain these correlations.”
The researchers reported having no financial disclosures.
SOURCE: Chen P et al. DDW 2019, Abstract 447.
REPORTING FROM DDW 2019
FVIII/W ratio may help predict relapse in hemophilia A
, according to a retrospective analysis.
Marc Trossaert, MD, PhD, of the CHU de Nantes, France, and colleagues conducted a retrospective analysis of 64 consecutive patients diagnosed with acquired hemophilia A over a period of 15 years (2000-2015). Data were obtained from institutional databases at the Toulouse and Nantes university hospitals in France.
Data collected included patient demographics, comorbidities, biological factors, and information related to immunosuppressive therapy. The findings of the study were published in Haemophilia.
To ascertain normal parameters and uses of the FVIII/W ratio, the team assessed FVIII:C and VWF:Ag levels of 40 healthy individuals and normal parameters of the ratio were defined using these levels.
Among the 64 patients with acquired hemophilia A who were enrolled in the study, 55 patients achieved complete remission. Of that group, 44 patients did not relapse. Researchers had follow-up data of at least 1 year for 22 of these patients. They found that the FVIII/W ratio remained within normal parameters for all 22 patients.
Researchers had follow-up data on 5 of the 11 patients who relapsed during the study period. For 4 of the patients, a decrease of FVIII/W ratio was the first indicator of relapse. In the fifth patient, an abnormal activated partial thromboplastin time (aPTT) displayed before the changes were observed in the FVIII/W ratio.
Dr. Trossaert and his colleagues acknowledged that a key limitation of the study was the retrospective design.
“We cannot eliminate the fact that in these patients less frequent testing may have influenced the chance of seeing a low FVIII/W ratio,” they wrote.
The biomarker now needs to be studied in larger cohorts, the researchers suggested.
No funding sources were reported. The authors reported having no conflicts of interest.
SOURCE: Trossaert M et al. Haemophilia. 2019 May 2. doi: 10.1111/hae.13752.
, according to a retrospective analysis.
Marc Trossaert, MD, PhD, of the CHU de Nantes, France, and colleagues conducted a retrospective analysis of 64 consecutive patients diagnosed with acquired hemophilia A over a period of 15 years (2000-2015). Data were obtained from institutional databases at the Toulouse and Nantes university hospitals in France.
Data collected included patient demographics, comorbidities, biological factors, and information related to immunosuppressive therapy. The findings of the study were published in Haemophilia.
To ascertain normal parameters and uses of the FVIII/W ratio, the team assessed FVIII:C and VWF:Ag levels of 40 healthy individuals and normal parameters of the ratio were defined using these levels.
Among the 64 patients with acquired hemophilia A who were enrolled in the study, 55 patients achieved complete remission. Of that group, 44 patients did not relapse. Researchers had follow-up data of at least 1 year for 22 of these patients. They found that the FVIII/W ratio remained within normal parameters for all 22 patients.
Researchers had follow-up data on 5 of the 11 patients who relapsed during the study period. For 4 of the patients, a decrease of FVIII/W ratio was the first indicator of relapse. In the fifth patient, an abnormal activated partial thromboplastin time (aPTT) displayed before the changes were observed in the FVIII/W ratio.
Dr. Trossaert and his colleagues acknowledged that a key limitation of the study was the retrospective design.
“We cannot eliminate the fact that in these patients less frequent testing may have influenced the chance of seeing a low FVIII/W ratio,” they wrote.
The biomarker now needs to be studied in larger cohorts, the researchers suggested.
No funding sources were reported. The authors reported having no conflicts of interest.
SOURCE: Trossaert M et al. Haemophilia. 2019 May 2. doi: 10.1111/hae.13752.
, according to a retrospective analysis.
Marc Trossaert, MD, PhD, of the CHU de Nantes, France, and colleagues conducted a retrospective analysis of 64 consecutive patients diagnosed with acquired hemophilia A over a period of 15 years (2000-2015). Data were obtained from institutional databases at the Toulouse and Nantes university hospitals in France.
Data collected included patient demographics, comorbidities, biological factors, and information related to immunosuppressive therapy. The findings of the study were published in Haemophilia.
To ascertain normal parameters and uses of the FVIII/W ratio, the team assessed FVIII:C and VWF:Ag levels of 40 healthy individuals and normal parameters of the ratio were defined using these levels.
Among the 64 patients with acquired hemophilia A who were enrolled in the study, 55 patients achieved complete remission. Of that group, 44 patients did not relapse. Researchers had follow-up data of at least 1 year for 22 of these patients. They found that the FVIII/W ratio remained within normal parameters for all 22 patients.
Researchers had follow-up data on 5 of the 11 patients who relapsed during the study period. For 4 of the patients, a decrease of FVIII/W ratio was the first indicator of relapse. In the fifth patient, an abnormal activated partial thromboplastin time (aPTT) displayed before the changes were observed in the FVIII/W ratio.
Dr. Trossaert and his colleagues acknowledged that a key limitation of the study was the retrospective design.
“We cannot eliminate the fact that in these patients less frequent testing may have influenced the chance of seeing a low FVIII/W ratio,” they wrote.
The biomarker now needs to be studied in larger cohorts, the researchers suggested.
No funding sources were reported. The authors reported having no conflicts of interest.
SOURCE: Trossaert M et al. Haemophilia. 2019 May 2. doi: 10.1111/hae.13752.
FROM HAEMOPHILIA
Targeted sequencing panel IDs Lynch syndrome in women with/at risk for endometrial cancer
NASHVILLE, TENN. – , according to findings in a prospective patient cohort.
The findings, which also suggest that the incidence of Lynch syndrome among endometrial cancer patients is higher than previously recognized, have “immediate and major implications for the individual patient with endometrial cancer ... and implications for related family members,” Maria Mercedes M. Padron, MD, reported during an e-poster session at the annual clinical and scientific meeting of the American College of Obstetricians and Gynecologists.
Of 71 patients included in the study, 67 were undergoing endometrial cancer treatment and 7 (3 among those undergoing endometrial cancer treatment and 4 who did not have endometrial cancer) were known to have Lynch syndrome.
Of the 67 undergoing treatment, 22 (33%) were identified by the direct sequencing panel as having Lynch syndrome mutations, and of those, 7 (10%) had mutations classified as high confidence inactivating mutations in either MLH1, MSH6, PMS2, or MSH2 genes, said Dr. Padron, a research scholar at Icahn School of Medicine at Mount Sinai, New York. The remaining 15 patients had rare mutations and met previously defined phenotypic criteria for Lynch syndrome pathogenicity, she reported.
The sequencing panel–based results were compared with commercially available gene tests, including immunohistochemistry (IHC) and microsatellite instability testing (MSI); 10 patients were identified by IHC to have loss of nuclear mismatch repair (MMR) protein expression, and 8 of those were Lynch syndrome mutation positive. In addition, two patients were MSI-high, and both of those were Lynch syndrome mutation positive.
Thus, two Lynch syndrome patients were missed by direct sequencing, noted Dr. Padron.
However, an additional 10 patients who were not identified as having Lynch syndrome by IHC and MSI testing were potentially identified as such using the sequencing panel, Dr. Padron said, noting that “the pathogenicity of these additional variants needs to be defined.”
Lynch syndrome is a hereditary cancer syndrome caused by germline mutations in DNA MMR genes; it is the third most common malignancy in women and it confers an increased risk of several types of cancer, including colorectal, ovarian, gastric, and endometrial cancer, among others.
“It is estimated that 3% to 5% of endometrial cancers will arise from Lynch syndrome,” Dr. Padron explained during the poster session.
Because the presence of Lynch syndrome directly affects immediate clinical management and future risk-reducing and surveillance strategies for patients and at-risk family members, screening is recommended in all women with endometrial cancer, she added, noting, however, that “the optimum screening method has yet to be established.”
The sequencing panel evaluated in this study – Swift’s Accel-Amplicon Plus Lynch Syndrome Panel – requires only low input amounts of DNA, and in an earlier test using 10 control samples, it exhibited greater than 90% on-target and coverage uniformity. The work flow allowed for data analysis within 2 days, Dr. Padron noted.
The panel then was tested in the current cohort of patients who were referred to a gynecology oncology clinic for either treatment of endometrial cancer or for evaluation of risk for endometrial cancer.
Germline/tumor DNA was isolated and 10 ng DNA was used for targeted exon-level hotspot coverage of MLH1, MSH2, MSH6, and PMS2.
The findings suggest that the prevalence of Lynch syndrome may be six to seven times greater than previously estimated, Dr. Padron said during the poster presentation.
“If confirmed, this would have huge implications for our patients and health care system,” she said, adding that the ability to perform and analyze the sequencing within 48 hours of sample collection using a very low DNA input also was of note.
Taken together, “the findings of this study support future larger studies that can be performed concurrently with current standard of care technologies,” she and her colleagues concluded, noting that such studies would better determine more robust estimates of the prevalence of Lynch syndrome in women with endometrial cancer, help define improved standard-of-care guidelines, and provide future guidance for possible universal/targeted screening programs – all with the goal of improving the clinical care of women.
Dr. Padron reported having no relevant financial disclosures.
NASHVILLE, TENN. – , according to findings in a prospective patient cohort.
The findings, which also suggest that the incidence of Lynch syndrome among endometrial cancer patients is higher than previously recognized, have “immediate and major implications for the individual patient with endometrial cancer ... and implications for related family members,” Maria Mercedes M. Padron, MD, reported during an e-poster session at the annual clinical and scientific meeting of the American College of Obstetricians and Gynecologists.
Of 71 patients included in the study, 67 were undergoing endometrial cancer treatment and 7 (3 among those undergoing endometrial cancer treatment and 4 who did not have endometrial cancer) were known to have Lynch syndrome.
Of the 67 undergoing treatment, 22 (33%) were identified by the direct sequencing panel as having Lynch syndrome mutations, and of those, 7 (10%) had mutations classified as high confidence inactivating mutations in either MLH1, MSH6, PMS2, or MSH2 genes, said Dr. Padron, a research scholar at Icahn School of Medicine at Mount Sinai, New York. The remaining 15 patients had rare mutations and met previously defined phenotypic criteria for Lynch syndrome pathogenicity, she reported.
The sequencing panel–based results were compared with commercially available gene tests, including immunohistochemistry (IHC) and microsatellite instability testing (MSI); 10 patients were identified by IHC to have loss of nuclear mismatch repair (MMR) protein expression, and 8 of those were Lynch syndrome mutation positive. In addition, two patients were MSI-high, and both of those were Lynch syndrome mutation positive.
Thus, two Lynch syndrome patients were missed by direct sequencing, noted Dr. Padron.
However, an additional 10 patients who were not identified as having Lynch syndrome by IHC and MSI testing were potentially identified as such using the sequencing panel, Dr. Padron said, noting that “the pathogenicity of these additional variants needs to be defined.”
Lynch syndrome is a hereditary cancer syndrome caused by germline mutations in DNA MMR genes; it is the third most common malignancy in women and it confers an increased risk of several types of cancer, including colorectal, ovarian, gastric, and endometrial cancer, among others.
“It is estimated that 3% to 5% of endometrial cancers will arise from Lynch syndrome,” Dr. Padron explained during the poster session.
Because the presence of Lynch syndrome directly affects immediate clinical management and future risk-reducing and surveillance strategies for patients and at-risk family members, screening is recommended in all women with endometrial cancer, she added, noting, however, that “the optimum screening method has yet to be established.”
The sequencing panel evaluated in this study – Swift’s Accel-Amplicon Plus Lynch Syndrome Panel – requires only low input amounts of DNA, and in an earlier test using 10 control samples, it exhibited greater than 90% on-target and coverage uniformity. The work flow allowed for data analysis within 2 days, Dr. Padron noted.
The panel then was tested in the current cohort of patients who were referred to a gynecology oncology clinic for either treatment of endometrial cancer or for evaluation of risk for endometrial cancer.
Germline/tumor DNA was isolated and 10 ng DNA was used for targeted exon-level hotspot coverage of MLH1, MSH2, MSH6, and PMS2.
The findings suggest that the prevalence of Lynch syndrome may be six to seven times greater than previously estimated, Dr. Padron said during the poster presentation.
“If confirmed, this would have huge implications for our patients and health care system,” she said, adding that the ability to perform and analyze the sequencing within 48 hours of sample collection using a very low DNA input also was of note.
Taken together, “the findings of this study support future larger studies that can be performed concurrently with current standard of care technologies,” she and her colleagues concluded, noting that such studies would better determine more robust estimates of the prevalence of Lynch syndrome in women with endometrial cancer, help define improved standard-of-care guidelines, and provide future guidance for possible universal/targeted screening programs – all with the goal of improving the clinical care of women.
Dr. Padron reported having no relevant financial disclosures.
NASHVILLE, TENN. – , according to findings in a prospective patient cohort.
The findings, which also suggest that the incidence of Lynch syndrome among endometrial cancer patients is higher than previously recognized, have “immediate and major implications for the individual patient with endometrial cancer ... and implications for related family members,” Maria Mercedes M. Padron, MD, reported during an e-poster session at the annual clinical and scientific meeting of the American College of Obstetricians and Gynecologists.
Of 71 patients included in the study, 67 were undergoing endometrial cancer treatment and 7 (3 among those undergoing endometrial cancer treatment and 4 who did not have endometrial cancer) were known to have Lynch syndrome.
Of the 67 undergoing treatment, 22 (33%) were identified by the direct sequencing panel as having Lynch syndrome mutations, and of those, 7 (10%) had mutations classified as high confidence inactivating mutations in either MLH1, MSH6, PMS2, or MSH2 genes, said Dr. Padron, a research scholar at Icahn School of Medicine at Mount Sinai, New York. The remaining 15 patients had rare mutations and met previously defined phenotypic criteria for Lynch syndrome pathogenicity, she reported.
The sequencing panel–based results were compared with commercially available gene tests, including immunohistochemistry (IHC) and microsatellite instability testing (MSI); 10 patients were identified by IHC to have loss of nuclear mismatch repair (MMR) protein expression, and 8 of those were Lynch syndrome mutation positive. In addition, two patients were MSI-high, and both of those were Lynch syndrome mutation positive.
Thus, two Lynch syndrome patients were missed by direct sequencing, noted Dr. Padron.
However, an additional 10 patients who were not identified as having Lynch syndrome by IHC and MSI testing were potentially identified as such using the sequencing panel, Dr. Padron said, noting that “the pathogenicity of these additional variants needs to be defined.”
Lynch syndrome is a hereditary cancer syndrome caused by germline mutations in DNA MMR genes; it is the third most common malignancy in women and it confers an increased risk of several types of cancer, including colorectal, ovarian, gastric, and endometrial cancer, among others.
“It is estimated that 3% to 5% of endometrial cancers will arise from Lynch syndrome,” Dr. Padron explained during the poster session.
Because the presence of Lynch syndrome directly affects immediate clinical management and future risk-reducing and surveillance strategies for patients and at-risk family members, screening is recommended in all women with endometrial cancer, she added, noting, however, that “the optimum screening method has yet to be established.”
The sequencing panel evaluated in this study – Swift’s Accel-Amplicon Plus Lynch Syndrome Panel – requires only low input amounts of DNA, and in an earlier test using 10 control samples, it exhibited greater than 90% on-target and coverage uniformity. The work flow allowed for data analysis within 2 days, Dr. Padron noted.
The panel then was tested in the current cohort of patients who were referred to a gynecology oncology clinic for either treatment of endometrial cancer or for evaluation of risk for endometrial cancer.
Germline/tumor DNA was isolated and 10 ng DNA was used for targeted exon-level hotspot coverage of MLH1, MSH2, MSH6, and PMS2.
The findings suggest that the prevalence of Lynch syndrome may be six to seven times greater than previously estimated, Dr. Padron said during the poster presentation.
“If confirmed, this would have huge implications for our patients and health care system,” she said, adding that the ability to perform and analyze the sequencing within 48 hours of sample collection using a very low DNA input also was of note.
Taken together, “the findings of this study support future larger studies that can be performed concurrently with current standard of care technologies,” she and her colleagues concluded, noting that such studies would better determine more robust estimates of the prevalence of Lynch syndrome in women with endometrial cancer, help define improved standard-of-care guidelines, and provide future guidance for possible universal/targeted screening programs – all with the goal of improving the clinical care of women.
Dr. Padron reported having no relevant financial disclosures.
REPORTING FROM ACOG 2019
Diabetes, hypertension remission more prevalent in adolescents than adults after gastric bypass
according to two related studies of 5-year outcomes after Roux-en-Y gastric bypass.
However, despite adolescents’ better outcomes for diabetes and hypertension, their rate of abdominal reoperations was significantly higher during the 5-year follow-up period, and at 2 years post surgery, they were found to have low ferritin levels. The rates of death were similar in the two groups at 5 years.
“We have documented similar and durable weight loss after gastric bypass in adolescents and adults, but important differences between these cohorts were observed in specific health outcomes,” wrote Thomas H. Inge, MD, PhD, of the University of Colorado at Denver, Aurora, and his coauthors. The study was published in the New England Journal of Medicine.
To evaluate and compare outcomes after bariatric surgery, the researchers undertook the Teen–Longitudinal Assessment of Bariatric Surgery (Teen-LABS) study and the LABS study. The two were related but independent observational studies of postsurgery patient cohorts. The Teen-LABS study included 161 adolescents with severe obesity, and the LABS study included 396 adults who reported becoming obese during adolescence.
At 5-year follow-up, there was no significant difference in mean percentage weight change between adolescents (−26%; 95% confidence interval, −29 to −23) and adults (−29%; 95% CI, −31 to −27; P = .08). Adolescents were more likely than were adults to have remission of type 2 diabetes (86% vs. 53%, respectively; risk ratio, 1.27; 95% CI, 1.03 to 1.57; P = .03) as well as hypertension (68% vs. 41%; risk ratio, 1.51; 95% CI, 1.21 to 1.88; P less than .001).
In addition, 20% of adolescents and 16% of adults underwent intra-abdominal procedures within 5 years of surgery, with cholecystectomy being the most common, followed by surgery for bowel obstruction or hernia repair, and gastrostomy. At 2 years, ferritin levels were lower in adolescents than in adults (48% of patients vs. 29%, respectively). Five-year ferritin levels were not assessed.
In all, three adolescents (1.9%) and seven adults (1.8%) died over the 5-year period. Among the adolescents, one patient with type 1 diabetes died 3 years after surgery from complications after a hypoglycemic episode, and the other two deaths, both 4 years after surgery, were consistent with overdose. Among the adults, three of the deaths occurred within 3 weeks of surgery and were related to gastric bypass, two were of indeterminate cause (at 11 months and 5 years after surgery), one was by suicide at 3 years, and one was from colon cancer at 4 years.
The authors acknowledged the limitations of their study, including its observational design, low counts for some of the outcomes, and a lack of nonsurgical controls. They also noted potential unmeasured biases in the adult cohort, including the effects of weight cycling and inaccuracies in recalling adolescent weight issues.
The study and several of its authors were supported by grants from the National Institute of Diabetes and Digestive and Kidney Diseases. Several authors reported receiving grants, honoraria, and consulting fees from medical technology and pharmaceutical companies.
SOURCE: Inge TH et al. N Engl J Med. 2019 May 16. doi: 10.1056/NEJMoa1813909.
For obese adolescents, making a decision with lifelong consequences, as is the case with bariatric surgery, should still be handled on a case-by-case basis, according to Ted D. Adams, PhD, of the University of Utah, Salt Lake City.
In general, treatment approaches for children and adults differ because of their physiological and psychological differences, but that does not apply in the case of obesity, wrote Dr. Adams, who noted the similarities in obesity across age groups. In addition, he said, most adolescents who are obese remain obese into adulthood, and obese adults who were obese when they were younger face worse outcomes than do those who become obese in adulthood.
As such, this study from Dr. Inge and his colleagues is clinically important given the prevalence of obesity in the United States and a step in the right direction. However, Dr. Adams acknowledged concerns over certain elements, including the higher rate of abdominal reoperations in adolescents during the 5-year postsurgery period.
For now, a case-by-case basis remains his recommendation. “More complete data will be required to fully inform clinicians, parents, and adolescents whether to embark on surgical intervention or to postpone it,” he wrote, adding that “the 5-year data look promising but ... the lifetime outcome is unknown.”
These comments are adapted from an editorial (N Engl J Med. 2019 May 16. doi: 10.1056/NEJMe1905778 ). Dr. Adams reported receiving grants from the National Institute of Diabetes and Digestive and Kidney Diseases as well as the Intermountain Research Foundation and Ethicon Endo-Surgery, a subsidiary of Johnson & Johnson.
For obese adolescents, making a decision with lifelong consequences, as is the case with bariatric surgery, should still be handled on a case-by-case basis, according to Ted D. Adams, PhD, of the University of Utah, Salt Lake City.
In general, treatment approaches for children and adults differ because of their physiological and psychological differences, but that does not apply in the case of obesity, wrote Dr. Adams, who noted the similarities in obesity across age groups. In addition, he said, most adolescents who are obese remain obese into adulthood, and obese adults who were obese when they were younger face worse outcomes than do those who become obese in adulthood.
As such, this study from Dr. Inge and his colleagues is clinically important given the prevalence of obesity in the United States and a step in the right direction. However, Dr. Adams acknowledged concerns over certain elements, including the higher rate of abdominal reoperations in adolescents during the 5-year postsurgery period.
For now, a case-by-case basis remains his recommendation. “More complete data will be required to fully inform clinicians, parents, and adolescents whether to embark on surgical intervention or to postpone it,” he wrote, adding that “the 5-year data look promising but ... the lifetime outcome is unknown.”
These comments are adapted from an editorial (N Engl J Med. 2019 May 16. doi: 10.1056/NEJMe1905778 ). Dr. Adams reported receiving grants from the National Institute of Diabetes and Digestive and Kidney Diseases as well as the Intermountain Research Foundation and Ethicon Endo-Surgery, a subsidiary of Johnson & Johnson.
For obese adolescents, making a decision with lifelong consequences, as is the case with bariatric surgery, should still be handled on a case-by-case basis, according to Ted D. Adams, PhD, of the University of Utah, Salt Lake City.
In general, treatment approaches for children and adults differ because of their physiological and psychological differences, but that does not apply in the case of obesity, wrote Dr. Adams, who noted the similarities in obesity across age groups. In addition, he said, most adolescents who are obese remain obese into adulthood, and obese adults who were obese when they were younger face worse outcomes than do those who become obese in adulthood.
As such, this study from Dr. Inge and his colleagues is clinically important given the prevalence of obesity in the United States and a step in the right direction. However, Dr. Adams acknowledged concerns over certain elements, including the higher rate of abdominal reoperations in adolescents during the 5-year postsurgery period.
For now, a case-by-case basis remains his recommendation. “More complete data will be required to fully inform clinicians, parents, and adolescents whether to embark on surgical intervention or to postpone it,” he wrote, adding that “the 5-year data look promising but ... the lifetime outcome is unknown.”
These comments are adapted from an editorial (N Engl J Med. 2019 May 16. doi: 10.1056/NEJMe1905778 ). Dr. Adams reported receiving grants from the National Institute of Diabetes and Digestive and Kidney Diseases as well as the Intermountain Research Foundation and Ethicon Endo-Surgery, a subsidiary of Johnson & Johnson.
according to two related studies of 5-year outcomes after Roux-en-Y gastric bypass.
However, despite adolescents’ better outcomes for diabetes and hypertension, their rate of abdominal reoperations was significantly higher during the 5-year follow-up period, and at 2 years post surgery, they were found to have low ferritin levels. The rates of death were similar in the two groups at 5 years.
“We have documented similar and durable weight loss after gastric bypass in adolescents and adults, but important differences between these cohorts were observed in specific health outcomes,” wrote Thomas H. Inge, MD, PhD, of the University of Colorado at Denver, Aurora, and his coauthors. The study was published in the New England Journal of Medicine.
To evaluate and compare outcomes after bariatric surgery, the researchers undertook the Teen–Longitudinal Assessment of Bariatric Surgery (Teen-LABS) study and the LABS study. The two were related but independent observational studies of postsurgery patient cohorts. The Teen-LABS study included 161 adolescents with severe obesity, and the LABS study included 396 adults who reported becoming obese during adolescence.
At 5-year follow-up, there was no significant difference in mean percentage weight change between adolescents (−26%; 95% confidence interval, −29 to −23) and adults (−29%; 95% CI, −31 to −27; P = .08). Adolescents were more likely than were adults to have remission of type 2 diabetes (86% vs. 53%, respectively; risk ratio, 1.27; 95% CI, 1.03 to 1.57; P = .03) as well as hypertension (68% vs. 41%; risk ratio, 1.51; 95% CI, 1.21 to 1.88; P less than .001).
In addition, 20% of adolescents and 16% of adults underwent intra-abdominal procedures within 5 years of surgery, with cholecystectomy being the most common, followed by surgery for bowel obstruction or hernia repair, and gastrostomy. At 2 years, ferritin levels were lower in adolescents than in adults (48% of patients vs. 29%, respectively). Five-year ferritin levels were not assessed.
In all, three adolescents (1.9%) and seven adults (1.8%) died over the 5-year period. Among the adolescents, one patient with type 1 diabetes died 3 years after surgery from complications after a hypoglycemic episode, and the other two deaths, both 4 years after surgery, were consistent with overdose. Among the adults, three of the deaths occurred within 3 weeks of surgery and were related to gastric bypass, two were of indeterminate cause (at 11 months and 5 years after surgery), one was by suicide at 3 years, and one was from colon cancer at 4 years.
The authors acknowledged the limitations of their study, including its observational design, low counts for some of the outcomes, and a lack of nonsurgical controls. They also noted potential unmeasured biases in the adult cohort, including the effects of weight cycling and inaccuracies in recalling adolescent weight issues.
The study and several of its authors were supported by grants from the National Institute of Diabetes and Digestive and Kidney Diseases. Several authors reported receiving grants, honoraria, and consulting fees from medical technology and pharmaceutical companies.
SOURCE: Inge TH et al. N Engl J Med. 2019 May 16. doi: 10.1056/NEJMoa1813909.
according to two related studies of 5-year outcomes after Roux-en-Y gastric bypass.
However, despite adolescents’ better outcomes for diabetes and hypertension, their rate of abdominal reoperations was significantly higher during the 5-year follow-up period, and at 2 years post surgery, they were found to have low ferritin levels. The rates of death were similar in the two groups at 5 years.
“We have documented similar and durable weight loss after gastric bypass in adolescents and adults, but important differences between these cohorts were observed in specific health outcomes,” wrote Thomas H. Inge, MD, PhD, of the University of Colorado at Denver, Aurora, and his coauthors. The study was published in the New England Journal of Medicine.
To evaluate and compare outcomes after bariatric surgery, the researchers undertook the Teen–Longitudinal Assessment of Bariatric Surgery (Teen-LABS) study and the LABS study. The two were related but independent observational studies of postsurgery patient cohorts. The Teen-LABS study included 161 adolescents with severe obesity, and the LABS study included 396 adults who reported becoming obese during adolescence.
At 5-year follow-up, there was no significant difference in mean percentage weight change between adolescents (−26%; 95% confidence interval, −29 to −23) and adults (−29%; 95% CI, −31 to −27; P = .08). Adolescents were more likely than were adults to have remission of type 2 diabetes (86% vs. 53%, respectively; risk ratio, 1.27; 95% CI, 1.03 to 1.57; P = .03) as well as hypertension (68% vs. 41%; risk ratio, 1.51; 95% CI, 1.21 to 1.88; P less than .001).
In addition, 20% of adolescents and 16% of adults underwent intra-abdominal procedures within 5 years of surgery, with cholecystectomy being the most common, followed by surgery for bowel obstruction or hernia repair, and gastrostomy. At 2 years, ferritin levels were lower in adolescents than in adults (48% of patients vs. 29%, respectively). Five-year ferritin levels were not assessed.
In all, three adolescents (1.9%) and seven adults (1.8%) died over the 5-year period. Among the adolescents, one patient with type 1 diabetes died 3 years after surgery from complications after a hypoglycemic episode, and the other two deaths, both 4 years after surgery, were consistent with overdose. Among the adults, three of the deaths occurred within 3 weeks of surgery and were related to gastric bypass, two were of indeterminate cause (at 11 months and 5 years after surgery), one was by suicide at 3 years, and one was from colon cancer at 4 years.
The authors acknowledged the limitations of their study, including its observational design, low counts for some of the outcomes, and a lack of nonsurgical controls. They also noted potential unmeasured biases in the adult cohort, including the effects of weight cycling and inaccuracies in recalling adolescent weight issues.
The study and several of its authors were supported by grants from the National Institute of Diabetes and Digestive and Kidney Diseases. Several authors reported receiving grants, honoraria, and consulting fees from medical technology and pharmaceutical companies.
SOURCE: Inge TH et al. N Engl J Med. 2019 May 16. doi: 10.1056/NEJMoa1813909.
FROM THE NEW ENGLAND JOURNAL OF MEDICINE
Patients with intellectual disability require nuanced care
SAN FRANCISCO – Some physicians are uncomfortable providing mental health care to patients with intellectual disability (ID) because many of the patients’ communications skills are limited. But many resources are available that can help.
In this video, Nita V. Bhatt, MD, MPH, interviews Julie P. Gentile, MD, about some of those resources and discusses how to approach psychiatric treatment interventions for patients with ID.
In addition to the DSM-5, Dr. Gentile said the National Association for the Dually Diagnosed has published the Diagnostic Manual – Intellectual Disability. Another resource is a practical reference manual originally proposed by one of Dr. Gentile’s residents.
“He came into my office for supervision one day and said, ‘You know, there’s all these nuances for psychiatric treatment in this patient population. So we should write a practice, quick reference manual to help clinicians who aren’t able to spend as much time concentrate on this patient population.’ ”
As a result, several residents and faculty members formed a team to produce an 18-chapter book published this year by Springer called the Guide to Intellectual Disabilities: A Clinical Handbook.
Dr. Bhatt is a staff psychiatrist at Twin Valley Behavioral Healthcare, the state psychiatric hospital in Columbus, Ohio. Dr. Gentile is professor and chair of the department of psychiatry at Wright State in Dayton. She is also serves as project director of Ohio’s Telepsychiatry Project for Intellectual Disability and has been awarded more than $7 million in grant funding to support her projects in the field of ID.
Dr. Gentile’s work has been funded by the Ohio Department of Developmental Disabilities and the Ohio Department of Mental Health and Addiction Services.
SAN FRANCISCO – Some physicians are uncomfortable providing mental health care to patients with intellectual disability (ID) because many of the patients’ communications skills are limited. But many resources are available that can help.
In this video, Nita V. Bhatt, MD, MPH, interviews Julie P. Gentile, MD, about some of those resources and discusses how to approach psychiatric treatment interventions for patients with ID.
In addition to the DSM-5, Dr. Gentile said the National Association for the Dually Diagnosed has published the Diagnostic Manual – Intellectual Disability. Another resource is a practical reference manual originally proposed by one of Dr. Gentile’s residents.
“He came into my office for supervision one day and said, ‘You know, there’s all these nuances for psychiatric treatment in this patient population. So we should write a practice, quick reference manual to help clinicians who aren’t able to spend as much time concentrate on this patient population.’ ”
As a result, several residents and faculty members formed a team to produce an 18-chapter book published this year by Springer called the Guide to Intellectual Disabilities: A Clinical Handbook.
Dr. Bhatt is a staff psychiatrist at Twin Valley Behavioral Healthcare, the state psychiatric hospital in Columbus, Ohio. Dr. Gentile is professor and chair of the department of psychiatry at Wright State in Dayton. She is also serves as project director of Ohio’s Telepsychiatry Project for Intellectual Disability and has been awarded more than $7 million in grant funding to support her projects in the field of ID.
Dr. Gentile’s work has been funded by the Ohio Department of Developmental Disabilities and the Ohio Department of Mental Health and Addiction Services.
SAN FRANCISCO – Some physicians are uncomfortable providing mental health care to patients with intellectual disability (ID) because many of the patients’ communications skills are limited. But many resources are available that can help.
In this video, Nita V. Bhatt, MD, MPH, interviews Julie P. Gentile, MD, about some of those resources and discusses how to approach psychiatric treatment interventions for patients with ID.
In addition to the DSM-5, Dr. Gentile said the National Association for the Dually Diagnosed has published the Diagnostic Manual – Intellectual Disability. Another resource is a practical reference manual originally proposed by one of Dr. Gentile’s residents.
“He came into my office for supervision one day and said, ‘You know, there’s all these nuances for psychiatric treatment in this patient population. So we should write a practice, quick reference manual to help clinicians who aren’t able to spend as much time concentrate on this patient population.’ ”
As a result, several residents and faculty members formed a team to produce an 18-chapter book published this year by Springer called the Guide to Intellectual Disabilities: A Clinical Handbook.
Dr. Bhatt is a staff psychiatrist at Twin Valley Behavioral Healthcare, the state psychiatric hospital in Columbus, Ohio. Dr. Gentile is professor and chair of the department of psychiatry at Wright State in Dayton. She is also serves as project director of Ohio’s Telepsychiatry Project for Intellectual Disability and has been awarded more than $7 million in grant funding to support her projects in the field of ID.
Dr. Gentile’s work has been funded by the Ohio Department of Developmental Disabilities and the Ohio Department of Mental Health and Addiction Services.
REPORTING FROM APA 2019
The great sunscreen ingredient debate
In a commentary issued on May 6, the Food and Drug Administration stated that “with sunscreens now being used with greater frequency, in larger amounts, and by broader populations, it is more important than ever to ensure that sunscreens are safe and effective for daily, lifelong use.” The statement coincided with the publication of the randomized study, “Effect of sunscreen application under maximal use conditions on plasma concentrations of sunscreen active ingredients,” by Matta et al. of the FDA and others in JAMA (2019 May 6. doi: 10.1001/jama.2019.5586). A maximal usage trial examines the systemic absorption of a topical drug when used according to the guidelines given for the product’s maximum usage. In this study, adult participants were randomized to one of four commercially available sunscreen products: spray 1 (n = 6), spray 2 (n = 6), a lotion (n = 6), and a cream (n = 6). Two mg of sunscreen per 1 cm2 was applied to 75% of body surface area four times per day for 4 days, and blood samples were collected from each individual over 7 days.
The FDA’s guidance for industry and proposed rule on OTC sunscreens state that active ingredients with systemic absorption at 0.5 ng/mL or higher or with possible safety concerns need to undergo further nonclinical toxicology assessment to evaluate risk of systemic carcinogenicity, developmental/reproductive abnormalities, or other adverse effects.
Absorption of some sunscreen ingredients has been detected in other studies. Despite systemic absorption, two active ingredients – zinc oxide and titanium dioxide – have been found by the FDA to be generally recognized as safe and effective. But for 12 other active ingredients (cinoxate, dioxybenzone, ensulizole, homosalate, meradimate, octinoxate, octisalate, octocrylene, padimate O, sulisobenzone, oxybenzone, and avobenzone), there are insufficient data to make a “generally recognized as safe and effective” determination; thus, more data have been requested from the manufacturers. While physical blocking sunscreens have improved in their UV-blocking ability without compromising cosmesis over the past several years, some sunscreens containing chemical blockers are able to achieve higher SPFs with good cosmesis when applied to the skin.
Our skin acts as the ultimate barrier between ourselves and the environment, and it is not uncommon for substances to be blocked, absorbed, or excreted from the skin. Absorption of an ingredient through the skin and into the body does not indicate that the ingredient is unsafe. Rather, findings such as these call for further testing and research to determine the safety of that ingredient with repeated use. Per the FDA, such testing is part of the standard premarket safety evaluation of most chronically administered drugs with appreciable systemic absorption.
In February 2019, the FDA’s proposed rule was issued to “update regulatory requirements for most sunscreen products in the United States,” with the goal of bringing OTC sunscreens “up to date with the latest scientific standards,” according to the FDA May 6 commentary. “As part of this rule, the FDA is asking industry and other interested parties for additional safety data on the 12 active sunscreen ingredients currently available in marketed products” mentioned previously. These rules are being put into place to address the “key data gap” for these 12 ingredients, which is “understanding whether, and to what extent the ingredient is absorbed into the body after topical application.”
In other previously published studies, oxybenzone, along with some other sunscreen active ingredients including octocrylene, have been found in human breast milk. In addition, oxybenzone has been detected in amniotic fluid, urine, and blood. Whether these findings have any clinical implications needs to be further assessed. Some studies in the literature have raised questions about the potential for oxybenzone to affect endocrine activity.
Another issue that has been raised is the potential impact of sunscreen on the environment, specifically, coral reefs. In July 2018, Hawaii Governor David Ige (D) signed a bill (SB 2571) that bans the sale of sunscreens containing oxybenzone and octinoxate beginning in 2021, making Hawaii the first state to ban the sale of sunscreens containing these two chemicals. Shortly afterward, the Republic of Palau and city of Key West, Fla., also took action to ban sunscreens containing chemicals potentially harmful to marine life. In Hawaii, what’s know as “reef safe” sunscreen is sold.
More research in this area is needed, but studies have linked these ingredients to harming coral by bleaching, disease, and damage to DNA, and also to decreasing fertility in fish, impairing algae growth, inducing defects in mussel and sea urchin young, and accumulating in the tissues of dolphins. According to NASA, as much as 27% of monitored reef formation have already been lost and over the following 32 years, 32% more are at risk. Reefs cover a mere 0.2% of the ocean’s floor, but it is estimated that reefs are home to and protect nearly 1 million species of fish, invertebrates, and algae.
In early May, Rep. Tulsi Gabbard (D-Hawaii) and Sen. Tim Ryan (D-Ohio) introduced legislation known as the Oxybenzone and Octinoxate Impact Study Act of 2019 (H.R. 2588) to require the Environmental Protection Agency to study the impact of those two chemicals on human health and the environment and to provide findings to Congress and the public within 18 months.
The importance of sun protection and prevention of sunburns is paramount. We know that multiple sunburn events during childhood double a child’s risk of developing skin cancer later in life, and skin cancer is the most common cancer diagnosed in the United States, with 5 million cases treated every year. One in five Americans will develop skin cancer by age 70 years.
As a Mohs and a cosmetic dermatologic surgeon, I appreciate the unquestionable protective effects of sunscreen products with regards to skin cancer, dyspigmentation, solar elastosis, and rhytids associated with photoaging. We can applaud the FDA for improving testing and regulation of OTC ingredients, including those in sunscreen. These types of studies are important and monumental in ensuring that we are utilizing the right type of ingredients to protect our patients, our oceans, and our reefs.
Dr. Wesley and Dr. Talakoub are co-contributors to this column. Dr. Wesley practices dermatology in Beverly Hills, Calif. Dr. Talakoub is in private practice in McLean, Va. This month’s column is by Dr. Wesley. Write to them at [email protected]. They had no relevant disclosures.
References
- Matta MK et al. JAMA. 2019 May 6. doi: 10.1001/jama.2019.5586.
- Shedding new light on sunscreen absorption, by Janet Woodcock, MD, director, Center for Drug Evaluation and Research, and Theresa M. Michele, MD, director, CDER’s Division of Nonprescription Drug Products, Office of New Drugs
- Food and Drug Administration. Sunscreen drug products for over-the-counter human use: Proposed rule. Fed Regist. 2019;84(38):6204-75.
- Schlumpf M et al. Chemosphere. 2010 Nov;81(10):1171-83.
- Krause M et al. Int J Androl. 2012 Jun;35(3):424-36.
In a commentary issued on May 6, the Food and Drug Administration stated that “with sunscreens now being used with greater frequency, in larger amounts, and by broader populations, it is more important than ever to ensure that sunscreens are safe and effective for daily, lifelong use.” The statement coincided with the publication of the randomized study, “Effect of sunscreen application under maximal use conditions on plasma concentrations of sunscreen active ingredients,” by Matta et al. of the FDA and others in JAMA (2019 May 6. doi: 10.1001/jama.2019.5586). A maximal usage trial examines the systemic absorption of a topical drug when used according to the guidelines given for the product’s maximum usage. In this study, adult participants were randomized to one of four commercially available sunscreen products: spray 1 (n = 6), spray 2 (n = 6), a lotion (n = 6), and a cream (n = 6). Two mg of sunscreen per 1 cm2 was applied to 75% of body surface area four times per day for 4 days, and blood samples were collected from each individual over 7 days.
The FDA’s guidance for industry and proposed rule on OTC sunscreens state that active ingredients with systemic absorption at 0.5 ng/mL or higher or with possible safety concerns need to undergo further nonclinical toxicology assessment to evaluate risk of systemic carcinogenicity, developmental/reproductive abnormalities, or other adverse effects.
Absorption of some sunscreen ingredients has been detected in other studies. Despite systemic absorption, two active ingredients – zinc oxide and titanium dioxide – have been found by the FDA to be generally recognized as safe and effective. But for 12 other active ingredients (cinoxate, dioxybenzone, ensulizole, homosalate, meradimate, octinoxate, octisalate, octocrylene, padimate O, sulisobenzone, oxybenzone, and avobenzone), there are insufficient data to make a “generally recognized as safe and effective” determination; thus, more data have been requested from the manufacturers. While physical blocking sunscreens have improved in their UV-blocking ability without compromising cosmesis over the past several years, some sunscreens containing chemical blockers are able to achieve higher SPFs with good cosmesis when applied to the skin.
Our skin acts as the ultimate barrier between ourselves and the environment, and it is not uncommon for substances to be blocked, absorbed, or excreted from the skin. Absorption of an ingredient through the skin and into the body does not indicate that the ingredient is unsafe. Rather, findings such as these call for further testing and research to determine the safety of that ingredient with repeated use. Per the FDA, such testing is part of the standard premarket safety evaluation of most chronically administered drugs with appreciable systemic absorption.
In February 2019, the FDA’s proposed rule was issued to “update regulatory requirements for most sunscreen products in the United States,” with the goal of bringing OTC sunscreens “up to date with the latest scientific standards,” according to the FDA May 6 commentary. “As part of this rule, the FDA is asking industry and other interested parties for additional safety data on the 12 active sunscreen ingredients currently available in marketed products” mentioned previously. These rules are being put into place to address the “key data gap” for these 12 ingredients, which is “understanding whether, and to what extent the ingredient is absorbed into the body after topical application.”
In other previously published studies, oxybenzone, along with some other sunscreen active ingredients including octocrylene, have been found in human breast milk. In addition, oxybenzone has been detected in amniotic fluid, urine, and blood. Whether these findings have any clinical implications needs to be further assessed. Some studies in the literature have raised questions about the potential for oxybenzone to affect endocrine activity.
Another issue that has been raised is the potential impact of sunscreen on the environment, specifically, coral reefs. In July 2018, Hawaii Governor David Ige (D) signed a bill (SB 2571) that bans the sale of sunscreens containing oxybenzone and octinoxate beginning in 2021, making Hawaii the first state to ban the sale of sunscreens containing these two chemicals. Shortly afterward, the Republic of Palau and city of Key West, Fla., also took action to ban sunscreens containing chemicals potentially harmful to marine life. In Hawaii, what’s know as “reef safe” sunscreen is sold.
More research in this area is needed, but studies have linked these ingredients to harming coral by bleaching, disease, and damage to DNA, and also to decreasing fertility in fish, impairing algae growth, inducing defects in mussel and sea urchin young, and accumulating in the tissues of dolphins. According to NASA, as much as 27% of monitored reef formation have already been lost and over the following 32 years, 32% more are at risk. Reefs cover a mere 0.2% of the ocean’s floor, but it is estimated that reefs are home to and protect nearly 1 million species of fish, invertebrates, and algae.
In early May, Rep. Tulsi Gabbard (D-Hawaii) and Sen. Tim Ryan (D-Ohio) introduced legislation known as the Oxybenzone and Octinoxate Impact Study Act of 2019 (H.R. 2588) to require the Environmental Protection Agency to study the impact of those two chemicals on human health and the environment and to provide findings to Congress and the public within 18 months.
The importance of sun protection and prevention of sunburns is paramount. We know that multiple sunburn events during childhood double a child’s risk of developing skin cancer later in life, and skin cancer is the most common cancer diagnosed in the United States, with 5 million cases treated every year. One in five Americans will develop skin cancer by age 70 years.
As a Mohs and a cosmetic dermatologic surgeon, I appreciate the unquestionable protective effects of sunscreen products with regards to skin cancer, dyspigmentation, solar elastosis, and rhytids associated with photoaging. We can applaud the FDA for improving testing and regulation of OTC ingredients, including those in sunscreen. These types of studies are important and monumental in ensuring that we are utilizing the right type of ingredients to protect our patients, our oceans, and our reefs.
Dr. Wesley and Dr. Talakoub are co-contributors to this column. Dr. Wesley practices dermatology in Beverly Hills, Calif. Dr. Talakoub is in private practice in McLean, Va. This month’s column is by Dr. Wesley. Write to them at [email protected]. They had no relevant disclosures.
References
- Matta MK et al. JAMA. 2019 May 6. doi: 10.1001/jama.2019.5586.
- Shedding new light on sunscreen absorption, by Janet Woodcock, MD, director, Center for Drug Evaluation and Research, and Theresa M. Michele, MD, director, CDER’s Division of Nonprescription Drug Products, Office of New Drugs
- Food and Drug Administration. Sunscreen drug products for over-the-counter human use: Proposed rule. Fed Regist. 2019;84(38):6204-75.
- Schlumpf M et al. Chemosphere. 2010 Nov;81(10):1171-83.
- Krause M et al. Int J Androl. 2012 Jun;35(3):424-36.
In a commentary issued on May 6, the Food and Drug Administration stated that “with sunscreens now being used with greater frequency, in larger amounts, and by broader populations, it is more important than ever to ensure that sunscreens are safe and effective for daily, lifelong use.” The statement coincided with the publication of the randomized study, “Effect of sunscreen application under maximal use conditions on plasma concentrations of sunscreen active ingredients,” by Matta et al. of the FDA and others in JAMA (2019 May 6. doi: 10.1001/jama.2019.5586). A maximal usage trial examines the systemic absorption of a topical drug when used according to the guidelines given for the product’s maximum usage. In this study, adult participants were randomized to one of four commercially available sunscreen products: spray 1 (n = 6), spray 2 (n = 6), a lotion (n = 6), and a cream (n = 6). Two mg of sunscreen per 1 cm2 was applied to 75% of body surface area four times per day for 4 days, and blood samples were collected from each individual over 7 days.
The FDA’s guidance for industry and proposed rule on OTC sunscreens state that active ingredients with systemic absorption at 0.5 ng/mL or higher or with possible safety concerns need to undergo further nonclinical toxicology assessment to evaluate risk of systemic carcinogenicity, developmental/reproductive abnormalities, or other adverse effects.
Absorption of some sunscreen ingredients has been detected in other studies. Despite systemic absorption, two active ingredients – zinc oxide and titanium dioxide – have been found by the FDA to be generally recognized as safe and effective. But for 12 other active ingredients (cinoxate, dioxybenzone, ensulizole, homosalate, meradimate, octinoxate, octisalate, octocrylene, padimate O, sulisobenzone, oxybenzone, and avobenzone), there are insufficient data to make a “generally recognized as safe and effective” determination; thus, more data have been requested from the manufacturers. While physical blocking sunscreens have improved in their UV-blocking ability without compromising cosmesis over the past several years, some sunscreens containing chemical blockers are able to achieve higher SPFs with good cosmesis when applied to the skin.
Our skin acts as the ultimate barrier between ourselves and the environment, and it is not uncommon for substances to be blocked, absorbed, or excreted from the skin. Absorption of an ingredient through the skin and into the body does not indicate that the ingredient is unsafe. Rather, findings such as these call for further testing and research to determine the safety of that ingredient with repeated use. Per the FDA, such testing is part of the standard premarket safety evaluation of most chronically administered drugs with appreciable systemic absorption.
In February 2019, the FDA’s proposed rule was issued to “update regulatory requirements for most sunscreen products in the United States,” with the goal of bringing OTC sunscreens “up to date with the latest scientific standards,” according to the FDA May 6 commentary. “As part of this rule, the FDA is asking industry and other interested parties for additional safety data on the 12 active sunscreen ingredients currently available in marketed products” mentioned previously. These rules are being put into place to address the “key data gap” for these 12 ingredients, which is “understanding whether, and to what extent the ingredient is absorbed into the body after topical application.”
In other previously published studies, oxybenzone, along with some other sunscreen active ingredients including octocrylene, have been found in human breast milk. In addition, oxybenzone has been detected in amniotic fluid, urine, and blood. Whether these findings have any clinical implications needs to be further assessed. Some studies in the literature have raised questions about the potential for oxybenzone to affect endocrine activity.
Another issue that has been raised is the potential impact of sunscreen on the environment, specifically, coral reefs. In July 2018, Hawaii Governor David Ige (D) signed a bill (SB 2571) that bans the sale of sunscreens containing oxybenzone and octinoxate beginning in 2021, making Hawaii the first state to ban the sale of sunscreens containing these two chemicals. Shortly afterward, the Republic of Palau and city of Key West, Fla., also took action to ban sunscreens containing chemicals potentially harmful to marine life. In Hawaii, what’s know as “reef safe” sunscreen is sold.
More research in this area is needed, but studies have linked these ingredients to harming coral by bleaching, disease, and damage to DNA, and also to decreasing fertility in fish, impairing algae growth, inducing defects in mussel and sea urchin young, and accumulating in the tissues of dolphins. According to NASA, as much as 27% of monitored reef formation have already been lost and over the following 32 years, 32% more are at risk. Reefs cover a mere 0.2% of the ocean’s floor, but it is estimated that reefs are home to and protect nearly 1 million species of fish, invertebrates, and algae.
In early May, Rep. Tulsi Gabbard (D-Hawaii) and Sen. Tim Ryan (D-Ohio) introduced legislation known as the Oxybenzone and Octinoxate Impact Study Act of 2019 (H.R. 2588) to require the Environmental Protection Agency to study the impact of those two chemicals on human health and the environment and to provide findings to Congress and the public within 18 months.
The importance of sun protection and prevention of sunburns is paramount. We know that multiple sunburn events during childhood double a child’s risk of developing skin cancer later in life, and skin cancer is the most common cancer diagnosed in the United States, with 5 million cases treated every year. One in five Americans will develop skin cancer by age 70 years.
As a Mohs and a cosmetic dermatologic surgeon, I appreciate the unquestionable protective effects of sunscreen products with regards to skin cancer, dyspigmentation, solar elastosis, and rhytids associated with photoaging. We can applaud the FDA for improving testing and regulation of OTC ingredients, including those in sunscreen. These types of studies are important and monumental in ensuring that we are utilizing the right type of ingredients to protect our patients, our oceans, and our reefs.
Dr. Wesley and Dr. Talakoub are co-contributors to this column. Dr. Wesley practices dermatology in Beverly Hills, Calif. Dr. Talakoub is in private practice in McLean, Va. This month’s column is by Dr. Wesley. Write to them at [email protected]. They had no relevant disclosures.
References
- Matta MK et al. JAMA. 2019 May 6. doi: 10.1001/jama.2019.5586.
- Shedding new light on sunscreen absorption, by Janet Woodcock, MD, director, Center for Drug Evaluation and Research, and Theresa M. Michele, MD, director, CDER’s Division of Nonprescription Drug Products, Office of New Drugs
- Food and Drug Administration. Sunscreen drug products for over-the-counter human use: Proposed rule. Fed Regist. 2019;84(38):6204-75.
- Schlumpf M et al. Chemosphere. 2010 Nov;81(10):1171-83.
- Krause M et al. Int J Androl. 2012 Jun;35(3):424-36.
p-TIPS improves outcomes for high-risk variceal bleeding
Background: Acute variceal bleeding remains the most severe and life-threatening complication of portal hypertension in cirrhotic patients. Several small studies have shown improved outcomes with p-TIPS without worsening of hepatic encephalopathy or other adverse events.
Study design: Multicenter, international, observational study.
Setting: One Canadian and 33 European referral centers.
Synopsis: 2,138 patients were registered for analysis, of which 671 were identified as high risk based on Child-Pugh score (either Child class C of less than 14 or Child class B with active bleeding seen on endoscopy). Multiple exclusion criteria were used including Child-Pugh score of 14 or more, renal failure, occlusive portal vein thrombosis, sepsis, heart failure, or hepatocellular carcinoma outside Milan criteria. Each patient underwent initial management with vasoactive medications, antibiotics, and endoscopy with subsequent intervention (p-TIPS vs. standard care) based on provider decision. p-TIPS was defined as TIPS within 72 hours of initial bleed. 31.4% of the cohort was lost to follow-up at 1 year. p-TIPS improved 1-year mortality significantly (78% vs. 62%; P = .014) and did not confer an increased risk of hepatic encephalopathy or other complication. Additionally, the authors found that the effect was significantly greater in the Child-Pugh Class C group (1-year mortality rate of 78% vs. 53%; P = .002). The authors then compared observed mortality with MELD-predicted mortality and found that with standard care, MELD scores matched with predicted mortality, but with p-TIPS, MELD scores predicted a greater mortality than the observed mortality. The authors calculated that the number needed to treat to save one life for 1 year with p-TIPS is 4.2. The major limitation of this study is the observational design and the inherent risk of selection bias. Additionally, almost one-third of patients were lost to follow-up.
Bottom line: Significant improvements in mortality are observed when high-risk patients undergo p-TIPS procedures as opposed to usual care with medications and endoscopy.
Citation: Hernández Gea V et al. Preemptive TIPS improves outcome in high risk variceal bleeding: An observational study. Hepatology. 2018 Jul 16. doi: 10.1002/hep.30182.
Dr. Imber is an assistant professor in the division of hospital medicine, University of New Mexico.
Background: Acute variceal bleeding remains the most severe and life-threatening complication of portal hypertension in cirrhotic patients. Several small studies have shown improved outcomes with p-TIPS without worsening of hepatic encephalopathy or other adverse events.
Study design: Multicenter, international, observational study.
Setting: One Canadian and 33 European referral centers.
Synopsis: 2,138 patients were registered for analysis, of which 671 were identified as high risk based on Child-Pugh score (either Child class C of less than 14 or Child class B with active bleeding seen on endoscopy). Multiple exclusion criteria were used including Child-Pugh score of 14 or more, renal failure, occlusive portal vein thrombosis, sepsis, heart failure, or hepatocellular carcinoma outside Milan criteria. Each patient underwent initial management with vasoactive medications, antibiotics, and endoscopy with subsequent intervention (p-TIPS vs. standard care) based on provider decision. p-TIPS was defined as TIPS within 72 hours of initial bleed. 31.4% of the cohort was lost to follow-up at 1 year. p-TIPS improved 1-year mortality significantly (78% vs. 62%; P = .014) and did not confer an increased risk of hepatic encephalopathy or other complication. Additionally, the authors found that the effect was significantly greater in the Child-Pugh Class C group (1-year mortality rate of 78% vs. 53%; P = .002). The authors then compared observed mortality with MELD-predicted mortality and found that with standard care, MELD scores matched with predicted mortality, but with p-TIPS, MELD scores predicted a greater mortality than the observed mortality. The authors calculated that the number needed to treat to save one life for 1 year with p-TIPS is 4.2. The major limitation of this study is the observational design and the inherent risk of selection bias. Additionally, almost one-third of patients were lost to follow-up.
Bottom line: Significant improvements in mortality are observed when high-risk patients undergo p-TIPS procedures as opposed to usual care with medications and endoscopy.
Citation: Hernández Gea V et al. Preemptive TIPS improves outcome in high risk variceal bleeding: An observational study. Hepatology. 2018 Jul 16. doi: 10.1002/hep.30182.
Dr. Imber is an assistant professor in the division of hospital medicine, University of New Mexico.
Background: Acute variceal bleeding remains the most severe and life-threatening complication of portal hypertension in cirrhotic patients. Several small studies have shown improved outcomes with p-TIPS without worsening of hepatic encephalopathy or other adverse events.
Study design: Multicenter, international, observational study.
Setting: One Canadian and 33 European referral centers.
Synopsis: 2,138 patients were registered for analysis, of which 671 were identified as high risk based on Child-Pugh score (either Child class C of less than 14 or Child class B with active bleeding seen on endoscopy). Multiple exclusion criteria were used including Child-Pugh score of 14 or more, renal failure, occlusive portal vein thrombosis, sepsis, heart failure, or hepatocellular carcinoma outside Milan criteria. Each patient underwent initial management with vasoactive medications, antibiotics, and endoscopy with subsequent intervention (p-TIPS vs. standard care) based on provider decision. p-TIPS was defined as TIPS within 72 hours of initial bleed. 31.4% of the cohort was lost to follow-up at 1 year. p-TIPS improved 1-year mortality significantly (78% vs. 62%; P = .014) and did not confer an increased risk of hepatic encephalopathy or other complication. Additionally, the authors found that the effect was significantly greater in the Child-Pugh Class C group (1-year mortality rate of 78% vs. 53%; P = .002). The authors then compared observed mortality with MELD-predicted mortality and found that with standard care, MELD scores matched with predicted mortality, but with p-TIPS, MELD scores predicted a greater mortality than the observed mortality. The authors calculated that the number needed to treat to save one life for 1 year with p-TIPS is 4.2. The major limitation of this study is the observational design and the inherent risk of selection bias. Additionally, almost one-third of patients were lost to follow-up.
Bottom line: Significant improvements in mortality are observed when high-risk patients undergo p-TIPS procedures as opposed to usual care with medications and endoscopy.
Citation: Hernández Gea V et al. Preemptive TIPS improves outcome in high risk variceal bleeding: An observational study. Hepatology. 2018 Jul 16. doi: 10.1002/hep.30182.
Dr. Imber is an assistant professor in the division of hospital medicine, University of New Mexico.
Novel chromogenic assay looks accurate in hemophilia A diagnosis
, according to recent study findings.
“The original one‐stage clotting assay is still the most widely used method for measuring FVIII activity in these patients, although the chromogenic assay is recognized to be less prone to the variability related to the use of different reagents and to the presence of interferences,” Cristina Novembrino, MD, of the Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, in Milan, and colleagues wrote in Haemophilia. “The choice of the proper assay is a crucial point in the frame of diagnosis, particularly in moderate or mild [hemophilia A] patients.”
The BIOPHEN FVIII:C assay, used on the Sysmex CS‐2400 analyzer, is a novel chromogenic diagnostic tool used to analyze FVIII clotting activity in patients with hemophilia A of all severity levels. The researchers evaluated the diagnostic and clinical capabilities of the assay in 60 patients with hemophilia A and 120 healthy controls.
Dr. Novembrino and colleagues used samples of FVIII deficient plasma and Actin FS to compare the novel tool to a one-stage assay and another chromogenic assay.
After analysis, the researchers found that the inter‐assay and intra‐assay coefficient of variation were less than 6%. The mean recovery and limit of detection were 91.7% (range, 79.8%-98.6%) and 0.2%, respectively.
The linearity test revealed positive results of up to 1/128 dilution (r = 0.99).
“The K coefficient was 0.91 when BIOPHEN FVIII:C was compared with the historical classification of the patients, demonstrating an optimal diagnostic accuracy in hemophilia A,” the researchers wrote.
The novel assay may be an appropriate laboratory tool for the diagnosis and therapeutic monitoring of patients with hemophilia A, they added.
Sysmex Corporation and Hyphen BioMed provided the instrument and reagents for the study. One of the authors is an employee of Sysmex Corporation. The authors reported having no other conflicts of interest.
SOURCE: Novembrino C et al. Haemophilia. 2019 May 2. doi: 10.1111/hae.13746.
, according to recent study findings.
“The original one‐stage clotting assay is still the most widely used method for measuring FVIII activity in these patients, although the chromogenic assay is recognized to be less prone to the variability related to the use of different reagents and to the presence of interferences,” Cristina Novembrino, MD, of the Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, in Milan, and colleagues wrote in Haemophilia. “The choice of the proper assay is a crucial point in the frame of diagnosis, particularly in moderate or mild [hemophilia A] patients.”
The BIOPHEN FVIII:C assay, used on the Sysmex CS‐2400 analyzer, is a novel chromogenic diagnostic tool used to analyze FVIII clotting activity in patients with hemophilia A of all severity levels. The researchers evaluated the diagnostic and clinical capabilities of the assay in 60 patients with hemophilia A and 120 healthy controls.
Dr. Novembrino and colleagues used samples of FVIII deficient plasma and Actin FS to compare the novel tool to a one-stage assay and another chromogenic assay.
After analysis, the researchers found that the inter‐assay and intra‐assay coefficient of variation were less than 6%. The mean recovery and limit of detection were 91.7% (range, 79.8%-98.6%) and 0.2%, respectively.
The linearity test revealed positive results of up to 1/128 dilution (r = 0.99).
“The K coefficient was 0.91 when BIOPHEN FVIII:C was compared with the historical classification of the patients, demonstrating an optimal diagnostic accuracy in hemophilia A,” the researchers wrote.
The novel assay may be an appropriate laboratory tool for the diagnosis and therapeutic monitoring of patients with hemophilia A, they added.
Sysmex Corporation and Hyphen BioMed provided the instrument and reagents for the study. One of the authors is an employee of Sysmex Corporation. The authors reported having no other conflicts of interest.
SOURCE: Novembrino C et al. Haemophilia. 2019 May 2. doi: 10.1111/hae.13746.
, according to recent study findings.
“The original one‐stage clotting assay is still the most widely used method for measuring FVIII activity in these patients, although the chromogenic assay is recognized to be less prone to the variability related to the use of different reagents and to the presence of interferences,” Cristina Novembrino, MD, of the Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, in Milan, and colleagues wrote in Haemophilia. “The choice of the proper assay is a crucial point in the frame of diagnosis, particularly in moderate or mild [hemophilia A] patients.”
The BIOPHEN FVIII:C assay, used on the Sysmex CS‐2400 analyzer, is a novel chromogenic diagnostic tool used to analyze FVIII clotting activity in patients with hemophilia A of all severity levels. The researchers evaluated the diagnostic and clinical capabilities of the assay in 60 patients with hemophilia A and 120 healthy controls.
Dr. Novembrino and colleagues used samples of FVIII deficient plasma and Actin FS to compare the novel tool to a one-stage assay and another chromogenic assay.
After analysis, the researchers found that the inter‐assay and intra‐assay coefficient of variation were less than 6%. The mean recovery and limit of detection were 91.7% (range, 79.8%-98.6%) and 0.2%, respectively.
The linearity test revealed positive results of up to 1/128 dilution (r = 0.99).
“The K coefficient was 0.91 when BIOPHEN FVIII:C was compared with the historical classification of the patients, demonstrating an optimal diagnostic accuracy in hemophilia A,” the researchers wrote.
The novel assay may be an appropriate laboratory tool for the diagnosis and therapeutic monitoring of patients with hemophilia A, they added.
Sysmex Corporation and Hyphen BioMed provided the instrument and reagents for the study. One of the authors is an employee of Sysmex Corporation. The authors reported having no other conflicts of interest.
SOURCE: Novembrino C et al. Haemophilia. 2019 May 2. doi: 10.1111/hae.13746.
FROM HAEMOPHILIA
Zoster vaccination is underused but looks effective in IBD
For men with inflammatory bowel disease, herpes zoster vaccination was associated with about a 46% decrease in risk of associated infection, according to the results of a retrospective study from the national Veterans Affairs Healthcare System.
Crude rates of herpes zoster infection were 4.09 cases per 1,000 person-years among vaccinated patients versus 6.97 cases per 1,000 person-years among unvaccinated patients, for an adjusted hazard ratio of 0.54 (95% confidence interval, 0.44-0.68), reported Nabeel Khan, MD, of the University of Pennsylvania, Philadelphia, and associates. “This vaccine is therefore effective in patients with IBD, but underused,” they wrote in Clinical Gastroenterology and Hepatology.
Studies have linked IBD with a 1.2- to 1.8-fold increased risk of herpes zoster infection, the researchers noted. Relevant risk factors include older age, disease flare, recent use or high cumulative use of prednisone, and use of thiopurines, either alone or in combination with a tumor necrosis factor (TNF) inhibitor. Although the American College of Gastroenterology recommends that all patients with IBD receive the herpes zoster vaccine by age 50 years, the efficacy of the vaccine in these patients remains unclear.
For their study, Dr. Khan and associates analyzed International Classification of Diseases (ICD) codes and other medical record data from 39,983 veterans with IBD who had not received the herpes zoster vaccine by age 60 years. In all, 97% of patients were male, and 94% were white. Most patients had high rates of health care utilization: Approximately half visited VA clinics or hospitals at least 13 times per year, and another third made 6-12 annual visits.
Despite their many contacts with VA health care systems, only 7,170 (17.9%) patients received the herpes zoster vaccine during 2000-2016, the researchers found. Vaccination rates varied substantially by region – they were highest in the Midwest (35%) and North Atlantic states (29%) but reached only 9% in Montana, Utah, Wyoming, Colorado, Oklahoma, Texas, Arkansas, and Louisiana, collectively.
The crude rate of herpes zoster infection among unvaccinated patients with IBD resembled the incidence reported in prior studies, the researchers said. After researchers accounted for differences in geography, demographics, and health care utilization between vaccinated and unvaccinated veterans with IBD, they found that vaccination was associated with an approximately 46% decrease in the risk of herpes zoster infection.
Very few patients were vaccinated for herpes zoster while on a TNF inhibitor, precluding the ability to study this subgroup. However, the vaccine showed a protective effect (adjusted HR, 0.63) among patients who received thiopurines without a TNF inhibitor. This effect did not reach statistical significance, perhaps because of lack of power, the researchers noted. “Among the 315 patients who were [vaccinated while] on thiopurines, none developed a documented painful or painless vesicular rash within 42 days of herpes zoster vaccination,” they added. One patient developed a painful blister 20 days post vaccination without vesicles or long-term sequelae.
Pfizer provided funding. Dr. Khan disclosed research funding from Pfizer, Luitpold, and Takeda Pharmaceuticals. One coinvestigator disclosed ties to Pfizer, Gilead, Merck, AbbVie, Lilly, Janssen, Johnson & Johnson, UCB, and Nestle Health Science. The remaining researchers disclosed no conflicts.
SOURCE: Khan N et al. Clin Gastroenterol Hepatol. 2018 Oct 13. doi: 10.1016/j.cgh.2018.10.016.
Preventive care is an underemphasized component of IBD management because the primary focus tends to be control of active symptoms. However, as patients are treated with immunosuppression, particularly combinations of therapies and newer mechanisms of action such as the Janus kinase inhibitors, the risk of infections increases, including those that are vaccine preventable including shingles and its related complications.
This study by Khan et al. highlights several important messages for patients and providers. First, in this large older IBD cohort, the vaccination rates were very low at 18% even though more than 80% of patients had more than six annual visits to the VA Health Systems during the study period. These represent multiple missed opportunities to discuss and administer vaccinations. Second, the authors highlighted the vaccine’s efficacy: Persons receiving herpes zoster vaccination had a clearly decreased risk of subsequent infection. While the number of vaccinated patients on immunosuppression was too small to draw conclusions about efficacy, the live attenuated vaccination is contraindicated for immunosuppressed patients. However, the newer recombinant shingles vaccine offers the opportunity to extend the reach of shingles vaccination to include those on immunosuppression. As utilization of the newer vaccine series increases, we will be able to evaluate the efficacy for immunosuppressed IBD patients, although studies from other disease states suggest efficacy. However, vaccinations will never work if they aren’t administered. Counseling patients and providers regarding the importance of vaccinations is a low-risk, efficacious means to decrease infection and associated morbidity.
Christina Ha, MD, AGAF, associate professor of medicine, Inflammatory Bowel Disease Center, division of digestive diseases, Cedars-Sinai Medical Center, Los Angeles. She is a speaker, consultant, or on the advisory board for AbbVie, Janssen, Genentech, Samsung Bioepis, and Takeda. She received grant funding from Pfizer.
Preventive care is an underemphasized component of IBD management because the primary focus tends to be control of active symptoms. However, as patients are treated with immunosuppression, particularly combinations of therapies and newer mechanisms of action such as the Janus kinase inhibitors, the risk of infections increases, including those that are vaccine preventable including shingles and its related complications.
This study by Khan et al. highlights several important messages for patients and providers. First, in this large older IBD cohort, the vaccination rates were very low at 18% even though more than 80% of patients had more than six annual visits to the VA Health Systems during the study period. These represent multiple missed opportunities to discuss and administer vaccinations. Second, the authors highlighted the vaccine’s efficacy: Persons receiving herpes zoster vaccination had a clearly decreased risk of subsequent infection. While the number of vaccinated patients on immunosuppression was too small to draw conclusions about efficacy, the live attenuated vaccination is contraindicated for immunosuppressed patients. However, the newer recombinant shingles vaccine offers the opportunity to extend the reach of shingles vaccination to include those on immunosuppression. As utilization of the newer vaccine series increases, we will be able to evaluate the efficacy for immunosuppressed IBD patients, although studies from other disease states suggest efficacy. However, vaccinations will never work if they aren’t administered. Counseling patients and providers regarding the importance of vaccinations is a low-risk, efficacious means to decrease infection and associated morbidity.
Christina Ha, MD, AGAF, associate professor of medicine, Inflammatory Bowel Disease Center, division of digestive diseases, Cedars-Sinai Medical Center, Los Angeles. She is a speaker, consultant, or on the advisory board for AbbVie, Janssen, Genentech, Samsung Bioepis, and Takeda. She received grant funding from Pfizer.
Preventive care is an underemphasized component of IBD management because the primary focus tends to be control of active symptoms. However, as patients are treated with immunosuppression, particularly combinations of therapies and newer mechanisms of action such as the Janus kinase inhibitors, the risk of infections increases, including those that are vaccine preventable including shingles and its related complications.
This study by Khan et al. highlights several important messages for patients and providers. First, in this large older IBD cohort, the vaccination rates were very low at 18% even though more than 80% of patients had more than six annual visits to the VA Health Systems during the study period. These represent multiple missed opportunities to discuss and administer vaccinations. Second, the authors highlighted the vaccine’s efficacy: Persons receiving herpes zoster vaccination had a clearly decreased risk of subsequent infection. While the number of vaccinated patients on immunosuppression was too small to draw conclusions about efficacy, the live attenuated vaccination is contraindicated for immunosuppressed patients. However, the newer recombinant shingles vaccine offers the opportunity to extend the reach of shingles vaccination to include those on immunosuppression. As utilization of the newer vaccine series increases, we will be able to evaluate the efficacy for immunosuppressed IBD patients, although studies from other disease states suggest efficacy. However, vaccinations will never work if they aren’t administered. Counseling patients and providers regarding the importance of vaccinations is a low-risk, efficacious means to decrease infection and associated morbidity.
Christina Ha, MD, AGAF, associate professor of medicine, Inflammatory Bowel Disease Center, division of digestive diseases, Cedars-Sinai Medical Center, Los Angeles. She is a speaker, consultant, or on the advisory board for AbbVie, Janssen, Genentech, Samsung Bioepis, and Takeda. She received grant funding from Pfizer.
For men with inflammatory bowel disease, herpes zoster vaccination was associated with about a 46% decrease in risk of associated infection, according to the results of a retrospective study from the national Veterans Affairs Healthcare System.
Crude rates of herpes zoster infection were 4.09 cases per 1,000 person-years among vaccinated patients versus 6.97 cases per 1,000 person-years among unvaccinated patients, for an adjusted hazard ratio of 0.54 (95% confidence interval, 0.44-0.68), reported Nabeel Khan, MD, of the University of Pennsylvania, Philadelphia, and associates. “This vaccine is therefore effective in patients with IBD, but underused,” they wrote in Clinical Gastroenterology and Hepatology.
Studies have linked IBD with a 1.2- to 1.8-fold increased risk of herpes zoster infection, the researchers noted. Relevant risk factors include older age, disease flare, recent use or high cumulative use of prednisone, and use of thiopurines, either alone or in combination with a tumor necrosis factor (TNF) inhibitor. Although the American College of Gastroenterology recommends that all patients with IBD receive the herpes zoster vaccine by age 50 years, the efficacy of the vaccine in these patients remains unclear.
For their study, Dr. Khan and associates analyzed International Classification of Diseases (ICD) codes and other medical record data from 39,983 veterans with IBD who had not received the herpes zoster vaccine by age 60 years. In all, 97% of patients were male, and 94% were white. Most patients had high rates of health care utilization: Approximately half visited VA clinics or hospitals at least 13 times per year, and another third made 6-12 annual visits.
Despite their many contacts with VA health care systems, only 7,170 (17.9%) patients received the herpes zoster vaccine during 2000-2016, the researchers found. Vaccination rates varied substantially by region – they were highest in the Midwest (35%) and North Atlantic states (29%) but reached only 9% in Montana, Utah, Wyoming, Colorado, Oklahoma, Texas, Arkansas, and Louisiana, collectively.
The crude rate of herpes zoster infection among unvaccinated patients with IBD resembled the incidence reported in prior studies, the researchers said. After researchers accounted for differences in geography, demographics, and health care utilization between vaccinated and unvaccinated veterans with IBD, they found that vaccination was associated with an approximately 46% decrease in the risk of herpes zoster infection.
Very few patients were vaccinated for herpes zoster while on a TNF inhibitor, precluding the ability to study this subgroup. However, the vaccine showed a protective effect (adjusted HR, 0.63) among patients who received thiopurines without a TNF inhibitor. This effect did not reach statistical significance, perhaps because of lack of power, the researchers noted. “Among the 315 patients who were [vaccinated while] on thiopurines, none developed a documented painful or painless vesicular rash within 42 days of herpes zoster vaccination,” they added. One patient developed a painful blister 20 days post vaccination without vesicles or long-term sequelae.
Pfizer provided funding. Dr. Khan disclosed research funding from Pfizer, Luitpold, and Takeda Pharmaceuticals. One coinvestigator disclosed ties to Pfizer, Gilead, Merck, AbbVie, Lilly, Janssen, Johnson & Johnson, UCB, and Nestle Health Science. The remaining researchers disclosed no conflicts.
SOURCE: Khan N et al. Clin Gastroenterol Hepatol. 2018 Oct 13. doi: 10.1016/j.cgh.2018.10.016.
For men with inflammatory bowel disease, herpes zoster vaccination was associated with about a 46% decrease in risk of associated infection, according to the results of a retrospective study from the national Veterans Affairs Healthcare System.
Crude rates of herpes zoster infection were 4.09 cases per 1,000 person-years among vaccinated patients versus 6.97 cases per 1,000 person-years among unvaccinated patients, for an adjusted hazard ratio of 0.54 (95% confidence interval, 0.44-0.68), reported Nabeel Khan, MD, of the University of Pennsylvania, Philadelphia, and associates. “This vaccine is therefore effective in patients with IBD, but underused,” they wrote in Clinical Gastroenterology and Hepatology.
Studies have linked IBD with a 1.2- to 1.8-fold increased risk of herpes zoster infection, the researchers noted. Relevant risk factors include older age, disease flare, recent use or high cumulative use of prednisone, and use of thiopurines, either alone or in combination with a tumor necrosis factor (TNF) inhibitor. Although the American College of Gastroenterology recommends that all patients with IBD receive the herpes zoster vaccine by age 50 years, the efficacy of the vaccine in these patients remains unclear.
For their study, Dr. Khan and associates analyzed International Classification of Diseases (ICD) codes and other medical record data from 39,983 veterans with IBD who had not received the herpes zoster vaccine by age 60 years. In all, 97% of patients were male, and 94% were white. Most patients had high rates of health care utilization: Approximately half visited VA clinics or hospitals at least 13 times per year, and another third made 6-12 annual visits.
Despite their many contacts with VA health care systems, only 7,170 (17.9%) patients received the herpes zoster vaccine during 2000-2016, the researchers found. Vaccination rates varied substantially by region – they were highest in the Midwest (35%) and North Atlantic states (29%) but reached only 9% in Montana, Utah, Wyoming, Colorado, Oklahoma, Texas, Arkansas, and Louisiana, collectively.
The crude rate of herpes zoster infection among unvaccinated patients with IBD resembled the incidence reported in prior studies, the researchers said. After researchers accounted for differences in geography, demographics, and health care utilization between vaccinated and unvaccinated veterans with IBD, they found that vaccination was associated with an approximately 46% decrease in the risk of herpes zoster infection.
Very few patients were vaccinated for herpes zoster while on a TNF inhibitor, precluding the ability to study this subgroup. However, the vaccine showed a protective effect (adjusted HR, 0.63) among patients who received thiopurines without a TNF inhibitor. This effect did not reach statistical significance, perhaps because of lack of power, the researchers noted. “Among the 315 patients who were [vaccinated while] on thiopurines, none developed a documented painful or painless vesicular rash within 42 days of herpes zoster vaccination,” they added. One patient developed a painful blister 20 days post vaccination without vesicles or long-term sequelae.
Pfizer provided funding. Dr. Khan disclosed research funding from Pfizer, Luitpold, and Takeda Pharmaceuticals. One coinvestigator disclosed ties to Pfizer, Gilead, Merck, AbbVie, Lilly, Janssen, Johnson & Johnson, UCB, and Nestle Health Science. The remaining researchers disclosed no conflicts.
SOURCE: Khan N et al. Clin Gastroenterol Hepatol. 2018 Oct 13. doi: 10.1016/j.cgh.2018.10.016.
FROM CLINICAL GASTROENTEROLOGY AND HEPATOLOGY
Prepare for deluge of JAK inhibitors for RA
MAUI, HAWAII – As it grows increasingly likely that oral Janus kinase inhibitors will constitute a major development in the treatment of rheumatoid arthritis, with a bevy of these agents becoming available for that indication, rheumatologists are asking questions about the coming revolution. Like, when should these agents be used? What are the major safety and efficacy differences, if any, within the class? How clinically relevant is JAK selectivity? And which JAK inhibitor is the best choice?
on these and other related questions at the 2019 Rheumatology Winter Clinical Symposium.
These issues take on growing relevance for clinicians and their RA patients because two oral small molecule JAK inhibitors – tofacitinib (Xeljanz) and baricitinib (Olumiant) – are already approved for RA, and three more – upadacitinib, filgotinib, and peficitinib – are on the horizon. Indeed, AbbVie has already filed for marketing approval of once-daily upadacitinib for RA on the basis of an impressive development program featuring six phase 3 trials, with a priority review decision from the Food and Drug Administration anticipated this fall. Filgotinib is the focus of three phase 3 studies, one of which is viewed as a home run, with the other two yet to report results. Peficitinib is backed by two positive phase 3 trials, although its manufacturer will at least initially seek marketing approval only in Japan and South Korea. And numerous other JAK inhibitors are in development for a variety of indications.
When should a JAK inhibitor be used?
That’s easy, according to Roy M. Fleischmann, MD: If the cost proves comparable, it makes sense to turn to a JAK inhibitor ahead of a tumor necrosis factor inhibitor or other biologic.
He noted that in the double-blind, phase 3 SELECT-COMPARE head-to-head comparison of upadacitinib at 15 mg/day, adalimumab (Humira) at 40 mg every other week, versus placebo, all on top of background methotrexate, upadacitinib proved superior to the market-leading tumor necrosis factor inhibitor in terms of both the American College of Rheumatology–defined 20% level of response (ACR 20) and 28-joint Disease Activity Score based on C-reactive protein (DAS28-CRP).
“The results were very dramatic,” noted Dr. Fleischmann, who presented the SELECT-COMPARE findings at the 2018 annual meeting of the American College of Rheumatology.
Moreover, other major trials have shown that baricitinib at 4 mg/day was superior in efficacy to adalimumab, and tofacitinib and peficitinib were “at least equal” to anti-TNF therapy, he added.
“These numbers are clinically meaningful – not so much for the difference in ACR 20, but in the depth of response: the ACR 50 and 70, the CDAI. I think these drugs are better than adalimumab,” declared Dr. Fleischmann, codirector of the division of rheumatology at Texas Health Presbyterian Medical Center, Dallas.
Mark Genovese, MD, concurred.
“I think that for most patients who don’t have a lot of other comorbidities, they would certainly prefer to take a pill over a shot. And if you have a drug that’s more effective than the standard of care and it comes at a reasonable price point – and ‘reasonable’ is in the eye of the beholder – but if I can get access to it on the formulary, I’d have no qualms about putting them on a JAK inhibitor before I’d move to a TNF inhibitor,” said Dr. Genovese, professor of medicine and director of the rheumatology clinic at Stanford (Calif.) University.
Upadacitinib elicited a better response at 30 mg than at 15 mg once daily in the phase 3 program; however, both speakers indicated they’d be happy with access to the 15-mg dose, should the FDA go that route, since it has a better safety profile.
Dr. Genovese was principal investigator in the previously reported multicenter FINCH2 trial of filgotinib at 100 or 200 mg/day in RA patients with a prior inadequate response to one or more biologic disease-modifying antirheumatic drugs.
“Impressive results in a refractory population,” he said. “I don’t see a big difference in safety between 100 and 200 mg, so I’d opt for the 200 because it worked really well in patients who had refractory disease.”
Other advantages of JAK inhibitors
Speed of onset is another advantage in addition to oral administration and efficacy greater than or equivalent to anti-TNF therapy, according to Dr. Genovese.
“As a class, JAK inhibitors have a faster onset than methotrexate in terms of improvement in disease activity and pain. So in a few weeks you can have a sense of whether folks are going to be responders,” the rheumatologist said.
Does JAK isoform selectivity really make a difference in terms of efficacy and safety?
It’s doubtful, the rheumatologists agreed. All of these oral small molecules target JAK1, and that’s what’s key.
Tofacitinib is relatively selective for JAK1 and JAK3, baricitinib for JAK1 and JAK2, upadacitinib and fibotinib for JAK1, and peficitinib is a pan-JAK inhibitor.
What are the safety concerns with this class of medications?
The risk of herpes zoster is higher than with TNF inhibitors, reinforcing the importance of varicella vaccination in JAK inhibitor candidates. Anemia occurs in a small percentage of patients. As for the risk of venous thromboembolism as a potential side effect of JAK inhibitors, a topic of great concern to the FDA, Dr. Fleischmann dismissed it as vastly overblown.
“I think VTEs are an RA effect. You see it with all the drugs, including methotrexate,” he said.
Idiosyncratic self-limited increases in creatine kinase have been seen in 2%-4% of patients on JAK inhibitors in pretty much all of the clinical trials. “I’m not aware of any cases of myositis, though,” Dr. Fleischmann noted.
As for the teratogenicity potential of JAK inhibitors, Dr. Genovese said that, as is true for most medications, it hasn’t been well studied.
“We don’t know. But I would not choose to use a JAK inhibitor in a woman who is going to conceive, has conceived, or is breastfeeding. I just don’t think that would be a good decision,” according to the rheumatologist.
Which JAK inhibitor is the best choice for treatment of RA?
It’s impossible to say because of the hazards in trying to draw meaningful conclusions from cross-study comparisons, the experts agreed.
“It’s a challenge. I think at the end of the day there will probably be one agent that looks like it might be best in class predicated on having the most number of indications, and that will probably become a preferred agent. The question is, does that happen before tofacitinib goes generic? And I don’t know the answer to that,” Dr. Genovese said.
Notably, upadacitinib is the subject of a plethora of ongoing phase 3 trials in atopic dermatitis, psoriatic arthritis, Crohn’s disease, and ulcerative colitis. It is also in earlier-phase investigation for the treatment of ankylosing spondylitis.
Do we really need all these JAK inhibitors?
“How many TNF inhibitors do you need?” Dr. Genovese retorted. “I think the reality is there’s probably a finite number and additional members add to the class, but there probably will always be one or two that are going to be best in class.”
Both rheumatologists indicated they serve as consultants to more than a dozen pharmaceutical companies and receive research grants from numerous firms.
MAUI, HAWAII – As it grows increasingly likely that oral Janus kinase inhibitors will constitute a major development in the treatment of rheumatoid arthritis, with a bevy of these agents becoming available for that indication, rheumatologists are asking questions about the coming revolution. Like, when should these agents be used? What are the major safety and efficacy differences, if any, within the class? How clinically relevant is JAK selectivity? And which JAK inhibitor is the best choice?
on these and other related questions at the 2019 Rheumatology Winter Clinical Symposium.
These issues take on growing relevance for clinicians and their RA patients because two oral small molecule JAK inhibitors – tofacitinib (Xeljanz) and baricitinib (Olumiant) – are already approved for RA, and three more – upadacitinib, filgotinib, and peficitinib – are on the horizon. Indeed, AbbVie has already filed for marketing approval of once-daily upadacitinib for RA on the basis of an impressive development program featuring six phase 3 trials, with a priority review decision from the Food and Drug Administration anticipated this fall. Filgotinib is the focus of three phase 3 studies, one of which is viewed as a home run, with the other two yet to report results. Peficitinib is backed by two positive phase 3 trials, although its manufacturer will at least initially seek marketing approval only in Japan and South Korea. And numerous other JAK inhibitors are in development for a variety of indications.
When should a JAK inhibitor be used?
That’s easy, according to Roy M. Fleischmann, MD: If the cost proves comparable, it makes sense to turn to a JAK inhibitor ahead of a tumor necrosis factor inhibitor or other biologic.
He noted that in the double-blind, phase 3 SELECT-COMPARE head-to-head comparison of upadacitinib at 15 mg/day, adalimumab (Humira) at 40 mg every other week, versus placebo, all on top of background methotrexate, upadacitinib proved superior to the market-leading tumor necrosis factor inhibitor in terms of both the American College of Rheumatology–defined 20% level of response (ACR 20) and 28-joint Disease Activity Score based on C-reactive protein (DAS28-CRP).
“The results were very dramatic,” noted Dr. Fleischmann, who presented the SELECT-COMPARE findings at the 2018 annual meeting of the American College of Rheumatology.
Moreover, other major trials have shown that baricitinib at 4 mg/day was superior in efficacy to adalimumab, and tofacitinib and peficitinib were “at least equal” to anti-TNF therapy, he added.
“These numbers are clinically meaningful – not so much for the difference in ACR 20, but in the depth of response: the ACR 50 and 70, the CDAI. I think these drugs are better than adalimumab,” declared Dr. Fleischmann, codirector of the division of rheumatology at Texas Health Presbyterian Medical Center, Dallas.
Mark Genovese, MD, concurred.
“I think that for most patients who don’t have a lot of other comorbidities, they would certainly prefer to take a pill over a shot. And if you have a drug that’s more effective than the standard of care and it comes at a reasonable price point – and ‘reasonable’ is in the eye of the beholder – but if I can get access to it on the formulary, I’d have no qualms about putting them on a JAK inhibitor before I’d move to a TNF inhibitor,” said Dr. Genovese, professor of medicine and director of the rheumatology clinic at Stanford (Calif.) University.
Upadacitinib elicited a better response at 30 mg than at 15 mg once daily in the phase 3 program; however, both speakers indicated they’d be happy with access to the 15-mg dose, should the FDA go that route, since it has a better safety profile.
Dr. Genovese was principal investigator in the previously reported multicenter FINCH2 trial of filgotinib at 100 or 200 mg/day in RA patients with a prior inadequate response to one or more biologic disease-modifying antirheumatic drugs.
“Impressive results in a refractory population,” he said. “I don’t see a big difference in safety between 100 and 200 mg, so I’d opt for the 200 because it worked really well in patients who had refractory disease.”
Other advantages of JAK inhibitors
Speed of onset is another advantage in addition to oral administration and efficacy greater than or equivalent to anti-TNF therapy, according to Dr. Genovese.
“As a class, JAK inhibitors have a faster onset than methotrexate in terms of improvement in disease activity and pain. So in a few weeks you can have a sense of whether folks are going to be responders,” the rheumatologist said.
Does JAK isoform selectivity really make a difference in terms of efficacy and safety?
It’s doubtful, the rheumatologists agreed. All of these oral small molecules target JAK1, and that’s what’s key.
Tofacitinib is relatively selective for JAK1 and JAK3, baricitinib for JAK1 and JAK2, upadacitinib and fibotinib for JAK1, and peficitinib is a pan-JAK inhibitor.
What are the safety concerns with this class of medications?
The risk of herpes zoster is higher than with TNF inhibitors, reinforcing the importance of varicella vaccination in JAK inhibitor candidates. Anemia occurs in a small percentage of patients. As for the risk of venous thromboembolism as a potential side effect of JAK inhibitors, a topic of great concern to the FDA, Dr. Fleischmann dismissed it as vastly overblown.
“I think VTEs are an RA effect. You see it with all the drugs, including methotrexate,” he said.
Idiosyncratic self-limited increases in creatine kinase have been seen in 2%-4% of patients on JAK inhibitors in pretty much all of the clinical trials. “I’m not aware of any cases of myositis, though,” Dr. Fleischmann noted.
As for the teratogenicity potential of JAK inhibitors, Dr. Genovese said that, as is true for most medications, it hasn’t been well studied.
“We don’t know. But I would not choose to use a JAK inhibitor in a woman who is going to conceive, has conceived, or is breastfeeding. I just don’t think that would be a good decision,” according to the rheumatologist.
Which JAK inhibitor is the best choice for treatment of RA?
It’s impossible to say because of the hazards in trying to draw meaningful conclusions from cross-study comparisons, the experts agreed.
“It’s a challenge. I think at the end of the day there will probably be one agent that looks like it might be best in class predicated on having the most number of indications, and that will probably become a preferred agent. The question is, does that happen before tofacitinib goes generic? And I don’t know the answer to that,” Dr. Genovese said.
Notably, upadacitinib is the subject of a plethora of ongoing phase 3 trials in atopic dermatitis, psoriatic arthritis, Crohn’s disease, and ulcerative colitis. It is also in earlier-phase investigation for the treatment of ankylosing spondylitis.
Do we really need all these JAK inhibitors?
“How many TNF inhibitors do you need?” Dr. Genovese retorted. “I think the reality is there’s probably a finite number and additional members add to the class, but there probably will always be one or two that are going to be best in class.”
Both rheumatologists indicated they serve as consultants to more than a dozen pharmaceutical companies and receive research grants from numerous firms.
MAUI, HAWAII – As it grows increasingly likely that oral Janus kinase inhibitors will constitute a major development in the treatment of rheumatoid arthritis, with a bevy of these agents becoming available for that indication, rheumatologists are asking questions about the coming revolution. Like, when should these agents be used? What are the major safety and efficacy differences, if any, within the class? How clinically relevant is JAK selectivity? And which JAK inhibitor is the best choice?
on these and other related questions at the 2019 Rheumatology Winter Clinical Symposium.
These issues take on growing relevance for clinicians and their RA patients because two oral small molecule JAK inhibitors – tofacitinib (Xeljanz) and baricitinib (Olumiant) – are already approved for RA, and three more – upadacitinib, filgotinib, and peficitinib – are on the horizon. Indeed, AbbVie has already filed for marketing approval of once-daily upadacitinib for RA on the basis of an impressive development program featuring six phase 3 trials, with a priority review decision from the Food and Drug Administration anticipated this fall. Filgotinib is the focus of three phase 3 studies, one of which is viewed as a home run, with the other two yet to report results. Peficitinib is backed by two positive phase 3 trials, although its manufacturer will at least initially seek marketing approval only in Japan and South Korea. And numerous other JAK inhibitors are in development for a variety of indications.
When should a JAK inhibitor be used?
That’s easy, according to Roy M. Fleischmann, MD: If the cost proves comparable, it makes sense to turn to a JAK inhibitor ahead of a tumor necrosis factor inhibitor or other biologic.
He noted that in the double-blind, phase 3 SELECT-COMPARE head-to-head comparison of upadacitinib at 15 mg/day, adalimumab (Humira) at 40 mg every other week, versus placebo, all on top of background methotrexate, upadacitinib proved superior to the market-leading tumor necrosis factor inhibitor in terms of both the American College of Rheumatology–defined 20% level of response (ACR 20) and 28-joint Disease Activity Score based on C-reactive protein (DAS28-CRP).
“The results were very dramatic,” noted Dr. Fleischmann, who presented the SELECT-COMPARE findings at the 2018 annual meeting of the American College of Rheumatology.
Moreover, other major trials have shown that baricitinib at 4 mg/day was superior in efficacy to adalimumab, and tofacitinib and peficitinib were “at least equal” to anti-TNF therapy, he added.
“These numbers are clinically meaningful – not so much for the difference in ACR 20, but in the depth of response: the ACR 50 and 70, the CDAI. I think these drugs are better than adalimumab,” declared Dr. Fleischmann, codirector of the division of rheumatology at Texas Health Presbyterian Medical Center, Dallas.
Mark Genovese, MD, concurred.
“I think that for most patients who don’t have a lot of other comorbidities, they would certainly prefer to take a pill over a shot. And if you have a drug that’s more effective than the standard of care and it comes at a reasonable price point – and ‘reasonable’ is in the eye of the beholder – but if I can get access to it on the formulary, I’d have no qualms about putting them on a JAK inhibitor before I’d move to a TNF inhibitor,” said Dr. Genovese, professor of medicine and director of the rheumatology clinic at Stanford (Calif.) University.
Upadacitinib elicited a better response at 30 mg than at 15 mg once daily in the phase 3 program; however, both speakers indicated they’d be happy with access to the 15-mg dose, should the FDA go that route, since it has a better safety profile.
Dr. Genovese was principal investigator in the previously reported multicenter FINCH2 trial of filgotinib at 100 or 200 mg/day in RA patients with a prior inadequate response to one or more biologic disease-modifying antirheumatic drugs.
“Impressive results in a refractory population,” he said. “I don’t see a big difference in safety between 100 and 200 mg, so I’d opt for the 200 because it worked really well in patients who had refractory disease.”
Other advantages of JAK inhibitors
Speed of onset is another advantage in addition to oral administration and efficacy greater than or equivalent to anti-TNF therapy, according to Dr. Genovese.
“As a class, JAK inhibitors have a faster onset than methotrexate in terms of improvement in disease activity and pain. So in a few weeks you can have a sense of whether folks are going to be responders,” the rheumatologist said.
Does JAK isoform selectivity really make a difference in terms of efficacy and safety?
It’s doubtful, the rheumatologists agreed. All of these oral small molecules target JAK1, and that’s what’s key.
Tofacitinib is relatively selective for JAK1 and JAK3, baricitinib for JAK1 and JAK2, upadacitinib and fibotinib for JAK1, and peficitinib is a pan-JAK inhibitor.
What are the safety concerns with this class of medications?
The risk of herpes zoster is higher than with TNF inhibitors, reinforcing the importance of varicella vaccination in JAK inhibitor candidates. Anemia occurs in a small percentage of patients. As for the risk of venous thromboembolism as a potential side effect of JAK inhibitors, a topic of great concern to the FDA, Dr. Fleischmann dismissed it as vastly overblown.
“I think VTEs are an RA effect. You see it with all the drugs, including methotrexate,” he said.
Idiosyncratic self-limited increases in creatine kinase have been seen in 2%-4% of patients on JAK inhibitors in pretty much all of the clinical trials. “I’m not aware of any cases of myositis, though,” Dr. Fleischmann noted.
As for the teratogenicity potential of JAK inhibitors, Dr. Genovese said that, as is true for most medications, it hasn’t been well studied.
“We don’t know. But I would not choose to use a JAK inhibitor in a woman who is going to conceive, has conceived, or is breastfeeding. I just don’t think that would be a good decision,” according to the rheumatologist.
Which JAK inhibitor is the best choice for treatment of RA?
It’s impossible to say because of the hazards in trying to draw meaningful conclusions from cross-study comparisons, the experts agreed.
“It’s a challenge. I think at the end of the day there will probably be one agent that looks like it might be best in class predicated on having the most number of indications, and that will probably become a preferred agent. The question is, does that happen before tofacitinib goes generic? And I don’t know the answer to that,” Dr. Genovese said.
Notably, upadacitinib is the subject of a plethora of ongoing phase 3 trials in atopic dermatitis, psoriatic arthritis, Crohn’s disease, and ulcerative colitis. It is also in earlier-phase investigation for the treatment of ankylosing spondylitis.
Do we really need all these JAK inhibitors?
“How many TNF inhibitors do you need?” Dr. Genovese retorted. “I think the reality is there’s probably a finite number and additional members add to the class, but there probably will always be one or two that are going to be best in class.”
Both rheumatologists indicated they serve as consultants to more than a dozen pharmaceutical companies and receive research grants from numerous firms.
REPORTING FROM RWCS 2019
