The estimated prevalence of multiple sclerosis (MS) as of 2010 is the highest to date, according to an analysis of administrative health claims (AHC) datasets and 2010 U.S. Census data.

“Our findings suggest that there has been a steady rise in the prevalence of MS over the past 5 decades, that the prevalence of MS remains higher for women than men, and that a north-south geographic gradient still persists,” wrote lead author Mitchell T. Wallin, MD, of Georgetown University, Washington, and his coauthors. The study was published in Neurology.

To determine adult cases of MS, Dr. Wallin and colleagues applied a validated algorithm to private, military, and public AHC datasets. Data from the 2010 U.S. Census were also used to standardize age and sex. In total, 125 million people over 18 years of age were captured in the study, nearly 45% of the U.S. population.

After adjustment, the 2010 prevalence for MS cumulated over 10 years was 309.2 per 100,000 adults (95% confidence interval, 308.1-310.1). This represented a total of 727,344 people with MS. The female to male ratio was 2.8, with a prevalence of 450.1 per 100,000 (95% CI, 448.1-451.6) for women versus a prevalence of 159.7 (95% CI, 158.7-160.6) for men. The age group with the highest estimated prevalence was 55-64 years old, and the prevalence in northern regions of the United States was statistically significantly higher than in southern regions.

The limitations of this study included not including children, the Indian Health Service, the U.S. prison system, or undocumented U.S. residents in the prevalence estimates. However, the authors did note that “these segments of the population are relatively small or, in the case of children, would contribute few cases.” In addition, they were unable to acquire more than 3 years of data for all insurance pools because of high costs.

The study was funded by a grant from the National Multiple Sclerosis Society. The authors reported numerous disclosures, including receiving consulting fees, researching funding, and grant support from various government agencies, foundations, and pharmaceutical companies.

SOURCE: Wallin MT et al. Neurology. 2019 Feb 15. doi: 10.1212/WNL.0000000000007035.

The estimated prevalence of multiple sclerosis (MS) as of 2010 is the highest to date, according to an analysis of administrative health claims (AHC) datasets and 2010 U.S. Census data.

“Our findings suggest that there has been a steady rise in the prevalence of MS over the past 5 decades, that the prevalence of MS remains higher for women than men, and that a north-south geographic gradient still persists,” wrote lead author Mitchell T. Wallin, MD, of Georgetown University, Washington, and his coauthors. The study was published in Neurology.

To determine adult cases of MS, Dr. Wallin and colleagues applied a validated algorithm to private, military, and public AHC datasets. Data from the 2010 U.S. Census were also used to standardize age and sex. In total, 125 million people over 18 years of age were captured in the study, nearly 45% of the U.S. population.

After adjustment, the 2010 prevalence for MS cumulated over 10 years was 309.2 per 100,000 adults (95% confidence interval, 308.1-310.1). This represented a total of 727,344 people with MS. The female to male ratio was 2.8, with a prevalence of 450.1 per 100,000 (95% CI, 448.1-451.6) for women versus a prevalence of 159.7 (95% CI, 158.7-160.6) for men. The age group with the highest estimated prevalence was 55-64 years old, and the prevalence in northern regions of the United States was statistically significantly higher than in southern regions.

The limitations of this study included not including children, the Indian Health Service, the U.S. prison system, or undocumented U.S. residents in the prevalence estimates. However, the authors did note that “these segments of the population are relatively small or, in the case of children, would contribute few cases.” In addition, they were unable to acquire more than 3 years of data for all insurance pools because of high costs.

The study was funded by a grant from the National Multiple Sclerosis Society. The authors reported numerous disclosures, including receiving consulting fees, researching funding, and grant support from various government agencies, foundations, and pharmaceutical companies.

SOURCE: Wallin MT et al. Neurology. 2019 Feb 15. doi: 10.1212/WNL.0000000000007035.

The estimated prevalence of multiple sclerosis (MS) as of 2010 is the highest to date, according to an analysis of administrative health claims (AHC) datasets and 2010 U.S. Census data.

“Our findings suggest that there has been a steady rise in the prevalence of MS over the past 5 decades, that the prevalence of MS remains higher for women than men, and that a north-south geographic gradient still persists,” wrote lead author Mitchell T. Wallin, MD, of Georgetown University, Washington, and his coauthors. The study was published in Neurology.

To determine adult cases of MS, Dr. Wallin and colleagues applied a validated algorithm to private, military, and public AHC datasets. Data from the 2010 U.S. Census were also used to standardize age and sex. In total, 125 million people over 18 years of age were captured in the study, nearly 45% of the U.S. population.

After adjustment, the 2010 prevalence for MS cumulated over 10 years was 309.2 per 100,000 adults (95% confidence interval, 308.1-310.1). This represented a total of 727,344 people with MS. The female to male ratio was 2.8, with a prevalence of 450.1 per 100,000 (95% CI, 448.1-451.6) for women versus a prevalence of 159.7 (95% CI, 158.7-160.6) for men. The age group with the highest estimated prevalence was 55-64 years old, and the prevalence in northern regions of the United States was statistically significantly higher than in southern regions.

The limitations of this study included not including children, the Indian Health Service, the U.S. prison system, or undocumented U.S. residents in the prevalence estimates. However, the authors did note that “these segments of the population are relatively small or, in the case of children, would contribute few cases.” In addition, they were unable to acquire more than 3 years of data for all insurance pools because of high costs.

The study was funded by a grant from the National Multiple Sclerosis Society. The authors reported numerous disclosures, including receiving consulting fees, researching funding, and grant support from various government agencies, foundations, and pharmaceutical companies.

SOURCE: Wallin MT et al. Neurology. 2019 Feb 15. doi: 10.1212/WNL.0000000000007035.

SAN DIEGO – A simplified version of the Sequential Organ Failure Assessment (SOFA) criteria, known as eSOFA, has the potential to make it easier for hospitals to benchmark sepsis outcomes and quality of care, and could propel new sepsis research. The new method replaces some of SOFA’s more subjective criteria with objective measures.

eSOFA relies on electronic health records to reduce reliance on administrative records, which suffer from cross-hospital variability in diagnosis and coding practices, as well as changes in these practices over time. The diagnosis of sepsis itself is also highly subjective. Instead, eSOFA determines dysfunction in six organ systems, indicated by use of vasopressors and mechanical ventilation, and the presence of abnormal laboratory values.

“The SOFA score includes measures like the Glasgow Coma Scale, which undoubtedly at the bedside is a very important clinical sign, but when trying to implement something that is objective for purposes of retrospective case counting and standardization, it can be problematic. The measures we chose [for eSOFA] are concrete, important maneuvers that were initiated by clinicians,” Chanu Rhee, MD, said in an interview.

Dr. Rhee is assistant professor of population medicine at Harvard Medical School and Brigham and Women’s Hospital, Boston. He presented the results of the study at the Critical Care Congress sponsored by the Society of Critical Care Medicine, and the work was simultaneously published online in Critical Care Medicine.

Key elements of SOFA that pose challenges for administrative data include: PaO₂/FiO₂, which are not routinely measured, and can be difficult to assign to arterial or venous samples; inconsistency in blood pressure and transient increases in vasopressor dose; the subjectivity of the Glasgow Coma Scale, which is also difficult to assess in sedated patients; and inconsistent urine output.

eSOFA introduced new measures for various organ functions, including cardiovascular (vasopressor initiation), pulmonary (mechanical ventilation initiation), renal (doubling of creatinine levels or a 50% or greater decrease in estimated glomerular filtration rate, compared with baseline), hepatic (bilirubin levels greater than or equal to 2.0 mg/dL and at least doubled from baseline), coagulation (platelet count less than 100 cells/mcL and at least a 50% decrease from a baseline of at least 100 cells/mcL), and neurological (lactate greater than or equal to 2.0 mmol/L).

“[eSOFA] opens a window into inter-facility comparisons that has not been possible to do. It’s really critical to ask, ‘How am I doing compared to my peer institutions?’ If you’re doing worse, you can look at the whole spectrum of things to try to drive improvements in care,” said Dr. Rhee.

The new tool isn’t just limited to quality improvement research. Shaeesta Khan, MD, assistant professor of critical care medicine at Geisinger Medical Center,Danville, Pa., has found eSOFA to be useful in her research into how genetic polymorphisms play a role in sepsis outcomes. Geisinger has a large population of patients with completed whole genome sequencing, and Dr. Khan began by trying to glean sepsis outcomes from administrative data.

“I explained SOFA scores to our data broker, and he pulled up 3,000 patients and gave everybody a SOFA score based on the algorithm he created, and it was all over the chart. Once I started doing chart review and phenotype verification, it was just a nightmare,” Dr. Khan said in an interview.

After struggling with the project, one of her mentors put her in touch with one of Dr. Rhee’s colleagues, and she asked the data broker to modify the eSOFA algorithm to fit her specific criteria. “It was a blessing,” she said.

Now, she has data from 5,000 patients with sepsis and sequenced DNA, and can begin comparing outcomes and genetic variants. About 20 candidate genes for sepsis outcomes have been identified to date, but she has a particular interest in PCSK9, which is an innate immune system regulator. She hopes to present results at CCC49 in 2020.
 

Validating mortality prediction

The researchers compared eSOFA and SOFA in a sample from 111 U.S. acute care hospitals to see if eSOFA had a comparable predictive validity for mortality. The analysis included 942,360 adults seen between 2013 and 2015. A total of 11.1% (104,903) had a presumed serious infection based on a blood culture order and at least 4 consecutive days of antibiotic use.

The analysis showed that 6.1% of those with infections had a sepsis event based on at least a 2-point increase in SOFA score from baseline (Sepsis-3 criteria), compared with 4.4% identified by at least a 1-point increase in eSOFA score. A total of 34,174 patients (3.6%) overlapped between SOFA and eSOFA, which represented good agreement (Cronbach’s alpha, 0.81). Compared with SOFA/Sepsis-3, eSOFA had a sensitivity of 60%, and a positive predictive value of 82%.

Patients identified by eSOFA were slightly more ill, with more requiring ICU admission (41% vs. 35%), and a greater frequency of in-hospital mortality (17% vs. 14%). Those patients who were identified by SOFA/Sepsis-3, but missed by eSOFA, had an overall lower mortality (6%).

There was a similar risk of mortality across deciles between SOFA- and eSOFA-identified sepsis patients. In an independent analysis of four hospitals from the Emory system, the area under the receiver operating characteristics was 0.77 for eSOFA and 0.76 for SOFA (P less than .001).

The Centers for Disease Control and Prevention and the Agency for Healthcare Research and Quality funded the study. Dr. Rhee and Dr. Khan have no relevant financial conflicts.
 

SOURCE: Rhee C et al. Crit Care Med. 2019;47(3):307-14.

SAN DIEGO – A simplified version of the Sequential Organ Failure Assessment (SOFA) criteria, known as eSOFA, has the potential to make it easier for hospitals to benchmark sepsis outcomes and quality of care, and could propel new sepsis research. The new method replaces some of SOFA’s more subjective criteria with objective measures.

eSOFA relies on electronic health records to reduce reliance on administrative records, which suffer from cross-hospital variability in diagnosis and coding practices, as well as changes in these practices over time. The diagnosis of sepsis itself is also highly subjective. Instead, eSOFA determines dysfunction in six organ systems, indicated by use of vasopressors and mechanical ventilation, and the presence of abnormal laboratory values.

“The SOFA score includes measures like the Glasgow Coma Scale, which undoubtedly at the bedside is a very important clinical sign, but when trying to implement something that is objective for purposes of retrospective case counting and standardization, it can be problematic. The measures we chose [for eSOFA] are concrete, important maneuvers that were initiated by clinicians,” Chanu Rhee, MD, said in an interview.

Dr. Rhee is assistant professor of population medicine at Harvard Medical School and Brigham and Women’s Hospital, Boston. He presented the results of the study at the Critical Care Congress sponsored by the Society of Critical Care Medicine, and the work was simultaneously published online in Critical Care Medicine.

Key elements of SOFA that pose challenges for administrative data include: PaO₂/FiO₂, which are not routinely measured, and can be difficult to assign to arterial or venous samples; inconsistency in blood pressure and transient increases in vasopressor dose; the subjectivity of the Glasgow Coma Scale, which is also difficult to assess in sedated patients; and inconsistent urine output.

eSOFA introduced new measures for various organ functions, including cardiovascular (vasopressor initiation), pulmonary (mechanical ventilation initiation), renal (doubling of creatinine levels or a 50% or greater decrease in estimated glomerular filtration rate, compared with baseline), hepatic (bilirubin levels greater than or equal to 2.0 mg/dL and at least doubled from baseline), coagulation (platelet count less than 100 cells/mcL and at least a 50% decrease from a baseline of at least 100 cells/mcL), and neurological (lactate greater than or equal to 2.0 mmol/L).

“[eSOFA] opens a window into inter-facility comparisons that has not been possible to do. It’s really critical to ask, ‘How am I doing compared to my peer institutions?’ If you’re doing worse, you can look at the whole spectrum of things to try to drive improvements in care,” said Dr. Rhee.

The new tool isn’t just limited to quality improvement research. Shaeesta Khan, MD, assistant professor of critical care medicine at Geisinger Medical Center,Danville, Pa., has found eSOFA to be useful in her research into how genetic polymorphisms play a role in sepsis outcomes. Geisinger has a large population of patients with completed whole genome sequencing, and Dr. Khan began by trying to glean sepsis outcomes from administrative data.

“I explained SOFA scores to our data broker, and he pulled up 3,000 patients and gave everybody a SOFA score based on the algorithm he created, and it was all over the chart. Once I started doing chart review and phenotype verification, it was just a nightmare,” Dr. Khan said in an interview.

After struggling with the project, one of her mentors put her in touch with one of Dr. Rhee’s colleagues, and she asked the data broker to modify the eSOFA algorithm to fit her specific criteria. “It was a blessing,” she said.

Now, she has data from 5,000 patients with sepsis and sequenced DNA, and can begin comparing outcomes and genetic variants. About 20 candidate genes for sepsis outcomes have been identified to date, but she has a particular interest in PCSK9, which is an innate immune system regulator. She hopes to present results at CCC49 in 2020.
 

Validating mortality prediction

The researchers compared eSOFA and SOFA in a sample from 111 U.S. acute care hospitals to see if eSOFA had a comparable predictive validity for mortality. The analysis included 942,360 adults seen between 2013 and 2015. A total of 11.1% (104,903) had a presumed serious infection based on a blood culture order and at least 4 consecutive days of antibiotic use.

The analysis showed that 6.1% of those with infections had a sepsis event based on at least a 2-point increase in SOFA score from baseline (Sepsis-3 criteria), compared with 4.4% identified by at least a 1-point increase in eSOFA score. A total of 34,174 patients (3.6%) overlapped between SOFA and eSOFA, which represented good agreement (Cronbach’s alpha, 0.81). Compared with SOFA/Sepsis-3, eSOFA had a sensitivity of 60%, and a positive predictive value of 82%.

Patients identified by eSOFA were slightly more ill, with more requiring ICU admission (41% vs. 35%), and a greater frequency of in-hospital mortality (17% vs. 14%). Those patients who were identified by SOFA/Sepsis-3, but missed by eSOFA, had an overall lower mortality (6%).

There was a similar risk of mortality across deciles between SOFA- and eSOFA-identified sepsis patients. In an independent analysis of four hospitals from the Emory system, the area under the receiver operating characteristics was 0.77 for eSOFA and 0.76 for SOFA (P less than .001).

The Centers for Disease Control and Prevention and the Agency for Healthcare Research and Quality funded the study. Dr. Rhee and Dr. Khan have no relevant financial conflicts.
 

SOURCE: Rhee C et al. Crit Care Med. 2019;47(3):307-14.

SAN DIEGO – A simplified version of the Sequential Organ Failure Assessment (SOFA) criteria, known as eSOFA, has the potential to make it easier for hospitals to benchmark sepsis outcomes and quality of care, and could propel new sepsis research. The new method replaces some of SOFA’s more subjective criteria with objective measures.

eSOFA relies on electronic health records to reduce reliance on administrative records, which suffer from cross-hospital variability in diagnosis and coding practices, as well as changes in these practices over time. The diagnosis of sepsis itself is also highly subjective. Instead, eSOFA determines dysfunction in six organ systems, indicated by use of vasopressors and mechanical ventilation, and the presence of abnormal laboratory values.

“The SOFA score includes measures like the Glasgow Coma Scale, which undoubtedly at the bedside is a very important clinical sign, but when trying to implement something that is objective for purposes of retrospective case counting and standardization, it can be problematic. The measures we chose [for eSOFA] are concrete, important maneuvers that were initiated by clinicians,” Chanu Rhee, MD, said in an interview.

Dr. Rhee is assistant professor of population medicine at Harvard Medical School and Brigham and Women’s Hospital, Boston. He presented the results of the study at the Critical Care Congress sponsored by the Society of Critical Care Medicine, and the work was simultaneously published online in Critical Care Medicine.

Key elements of SOFA that pose challenges for administrative data include: PaO₂/FiO₂, which are not routinely measured, and can be difficult to assign to arterial or venous samples; inconsistency in blood pressure and transient increases in vasopressor dose; the subjectivity of the Glasgow Coma Scale, which is also difficult to assess in sedated patients; and inconsistent urine output.

eSOFA introduced new measures for various organ functions, including cardiovascular (vasopressor initiation), pulmonary (mechanical ventilation initiation), renal (doubling of creatinine levels or a 50% or greater decrease in estimated glomerular filtration rate, compared with baseline), hepatic (bilirubin levels greater than or equal to 2.0 mg/dL and at least doubled from baseline), coagulation (platelet count less than 100 cells/mcL and at least a 50% decrease from a baseline of at least 100 cells/mcL), and neurological (lactate greater than or equal to 2.0 mmol/L).

“[eSOFA] opens a window into inter-facility comparisons that has not been possible to do. It’s really critical to ask, ‘How am I doing compared to my peer institutions?’ If you’re doing worse, you can look at the whole spectrum of things to try to drive improvements in care,” said Dr. Rhee.

The new tool isn’t just limited to quality improvement research. Shaeesta Khan, MD, assistant professor of critical care medicine at Geisinger Medical Center,Danville, Pa., has found eSOFA to be useful in her research into how genetic polymorphisms play a role in sepsis outcomes. Geisinger has a large population of patients with completed whole genome sequencing, and Dr. Khan began by trying to glean sepsis outcomes from administrative data.

“I explained SOFA scores to our data broker, and he pulled up 3,000 patients and gave everybody a SOFA score based on the algorithm he created, and it was all over the chart. Once I started doing chart review and phenotype verification, it was just a nightmare,” Dr. Khan said in an interview.

After struggling with the project, one of her mentors put her in touch with one of Dr. Rhee’s colleagues, and she asked the data broker to modify the eSOFA algorithm to fit her specific criteria. “It was a blessing,” she said.

Now, she has data from 5,000 patients with sepsis and sequenced DNA, and can begin comparing outcomes and genetic variants. About 20 candidate genes for sepsis outcomes have been identified to date, but she has a particular interest in PCSK9, which is an innate immune system regulator. She hopes to present results at CCC49 in 2020.
 

Validating mortality prediction

The researchers compared eSOFA and SOFA in a sample from 111 U.S. acute care hospitals to see if eSOFA had a comparable predictive validity for mortality. The analysis included 942,360 adults seen between 2013 and 2015. A total of 11.1% (104,903) had a presumed serious infection based on a blood culture order and at least 4 consecutive days of antibiotic use.

The analysis showed that 6.1% of those with infections had a sepsis event based on at least a 2-point increase in SOFA score from baseline (Sepsis-3 criteria), compared with 4.4% identified by at least a 1-point increase in eSOFA score. A total of 34,174 patients (3.6%) overlapped between SOFA and eSOFA, which represented good agreement (Cronbach’s alpha, 0.81). Compared with SOFA/Sepsis-3, eSOFA had a sensitivity of 60%, and a positive predictive value of 82%.

Patients identified by eSOFA were slightly more ill, with more requiring ICU admission (41% vs. 35%), and a greater frequency of in-hospital mortality (17% vs. 14%). Those patients who were identified by SOFA/Sepsis-3, but missed by eSOFA, had an overall lower mortality (6%).

There was a similar risk of mortality across deciles between SOFA- and eSOFA-identified sepsis patients. In an independent analysis of four hospitals from the Emory system, the area under the receiver operating characteristics was 0.77 for eSOFA and 0.76 for SOFA (P less than .001).

The Centers for Disease Control and Prevention and the Agency for Healthcare Research and Quality funded the study. Dr. Rhee and Dr. Khan have no relevant financial conflicts.
 

SOURCE: Rhee C et al. Crit Care Med. 2019;47(3):307-14.

It appears to be safe to hold the anthracycline in patients with HER2-negative early breast cancer who are at intermediate-to-high genomic risk, results of a large randomized trial suggest.

Among both pre- and postmenopausal women with pathologic stage T1 to T4c with positive nodes or node-negative but high-risk early breast cancer, there were no significant differences in 5-year outcomes for patients treated with six cycles of docetaxel and cyclophosphamide (TC) or four cycles of epirubicin and cyclophosphamide followed by four cycles of docetaxel (EC-T), reported Ulrike Nitz, MD, from the West German Study Group in Mönchengladbach, Germany, and her colleagues in the West German Study PlanB Trial.

Disease-free survival (DFS, the primary endpoint), distant recurrence-free interval (dRFI), and overall survival (OS) “were excellent and virtually identical in patients who received the anthracycline-containing or the anthracycline-free regimen. Subgroups that benefited from the anthracycline-containing regimen were not identified by interaction analysis, although a potentially clinically relevant benefit in particular (e.g., high-risk) subgroups cannot be ruled out,” they wrote. The report is in Journal of Clinical Oncology.

The investigators noted that anthracyclines are associated with increased risk for cardiac disease and hematologic malignancies, prompting investigators in other trials to consider anthracycline-free regimens.

“As the number of long-term survivors, elderly patients, and patients with preexisting cardiac risk factors increases, the toxicity profile becomes a more important discriminator in adjuvant treatment selection,” they wrote.

The investigators enrolled and randomized 2,449 women (median age 55, range 25-77 years) who had histologically confirmed, unilateral primary invasive breast cancer, adequate surgical treatment, and no evidence of metastatic disease. The patients all had HER2-negative disease, pT1 to pT4c, known hormone receptor status, and either pN+ or pN0 with one or more risk factors.

The intention-to-treat analysis included 1,227 patients assigned to EC-T and 1,222 assigned to TC in the efficacy population, and 1,167 and 1,178 patients, respectively, in the safety population.

After a median follow-up of 60 months, the 5-year DFS rate in the TC-treated group was 89.6%, compared with 89.9% in the EC-T–treated group. The estimated 5-year dRFI rates were 94.1% vs. 93.4%, and the estimated 5-year OS rates were 94.7% vs. 94.5%, respectively. None of the comparisons were statistically significant.

There were five treatment-related deaths in the TC arm, (one each from urosepsis, Streptococcus septicemia, peritonitis/diverticulitis, Staphylococcus epidermidis septicemia, and pulmonary embolism), and one in the EC-T arm (from septicemia).

In an interim safety analysis, the rate of febrile neutropenia was 6.1% in the TC arm and 3.9% in the EC-T arm, leading to a recommendation for “generous” prophylaxis with granulocyte-colony stimulating factor, and ciprofloxacine for patients with a history of diverticulitis or chronic infectious GI disease, or expected duration of neutropenia greater than 1 week.

Rates of grade 3 or 4 leukopenia, neutropenia, nausea, vomiting, peripheral polyneuropathy, hand-foot syndrome, mucositis/stomatitis, arthralgia, myalgia, and fatigue were significantly higher among patients treated with EC-T. There were numerically more grade 3-4 infections and febrile neutropenia within the TC arm, but this trend did not reach statistical significance.

The investigators noted that the results of their trial provide the strongest evidence for patients with pathologic NO or N1 disease, and that the trial did not examine the question of dose-dense chemotherapy in patients with high-risk early breast cancer.

Genomic Health, Sanofi, and Amgen supported the study. Dr. Nitz and multiple coauthors disclosed financial relationships with these companies and others.

SOURCE: Nitz U et al. J Clin Oncol. 2019 Feb 20. doi: 10.1200/JCO.18.00028.

It appears to be safe to hold the anthracycline in patients with HER2-negative early breast cancer who are at intermediate-to-high genomic risk, results of a large randomized trial suggest.

Among both pre- and postmenopausal women with pathologic stage T1 to T4c with positive nodes or node-negative but high-risk early breast cancer, there were no significant differences in 5-year outcomes for patients treated with six cycles of docetaxel and cyclophosphamide (TC) or four cycles of epirubicin and cyclophosphamide followed by four cycles of docetaxel (EC-T), reported Ulrike Nitz, MD, from the West German Study Group in Mönchengladbach, Germany, and her colleagues in the West German Study PlanB Trial.

Disease-free survival (DFS, the primary endpoint), distant recurrence-free interval (dRFI), and overall survival (OS) “were excellent and virtually identical in patients who received the anthracycline-containing or the anthracycline-free regimen. Subgroups that benefited from the anthracycline-containing regimen were not identified by interaction analysis, although a potentially clinically relevant benefit in particular (e.g., high-risk) subgroups cannot be ruled out,” they wrote. The report is in Journal of Clinical Oncology.

The investigators noted that anthracyclines are associated with increased risk for cardiac disease and hematologic malignancies, prompting investigators in other trials to consider anthracycline-free regimens.

“As the number of long-term survivors, elderly patients, and patients with preexisting cardiac risk factors increases, the toxicity profile becomes a more important discriminator in adjuvant treatment selection,” they wrote.

The investigators enrolled and randomized 2,449 women (median age 55, range 25-77 years) who had histologically confirmed, unilateral primary invasive breast cancer, adequate surgical treatment, and no evidence of metastatic disease. The patients all had HER2-negative disease, pT1 to pT4c, known hormone receptor status, and either pN+ or pN0 with one or more risk factors.

The intention-to-treat analysis included 1,227 patients assigned to EC-T and 1,222 assigned to TC in the efficacy population, and 1,167 and 1,178 patients, respectively, in the safety population.

After a median follow-up of 60 months, the 5-year DFS rate in the TC-treated group was 89.6%, compared with 89.9% in the EC-T–treated group. The estimated 5-year dRFI rates were 94.1% vs. 93.4%, and the estimated 5-year OS rates were 94.7% vs. 94.5%, respectively. None of the comparisons were statistically significant.

There were five treatment-related deaths in the TC arm, (one each from urosepsis, Streptococcus septicemia, peritonitis/diverticulitis, Staphylococcus epidermidis septicemia, and pulmonary embolism), and one in the EC-T arm (from septicemia).

In an interim safety analysis, the rate of febrile neutropenia was 6.1% in the TC arm and 3.9% in the EC-T arm, leading to a recommendation for “generous” prophylaxis with granulocyte-colony stimulating factor, and ciprofloxacine for patients with a history of diverticulitis or chronic infectious GI disease, or expected duration of neutropenia greater than 1 week.

Rates of grade 3 or 4 leukopenia, neutropenia, nausea, vomiting, peripheral polyneuropathy, hand-foot syndrome, mucositis/stomatitis, arthralgia, myalgia, and fatigue were significantly higher among patients treated with EC-T. There were numerically more grade 3-4 infections and febrile neutropenia within the TC arm, but this trend did not reach statistical significance.

The investigators noted that the results of their trial provide the strongest evidence for patients with pathologic NO or N1 disease, and that the trial did not examine the question of dose-dense chemotherapy in patients with high-risk early breast cancer.

Genomic Health, Sanofi, and Amgen supported the study. Dr. Nitz and multiple coauthors disclosed financial relationships with these companies and others.

SOURCE: Nitz U et al. J Clin Oncol. 2019 Feb 20. doi: 10.1200/JCO.18.00028.

It appears to be safe to hold the anthracycline in patients with HER2-negative early breast cancer who are at intermediate-to-high genomic risk, results of a large randomized trial suggest.

Among both pre- and postmenopausal women with pathologic stage T1 to T4c with positive nodes or node-negative but high-risk early breast cancer, there were no significant differences in 5-year outcomes for patients treated with six cycles of docetaxel and cyclophosphamide (TC) or four cycles of epirubicin and cyclophosphamide followed by four cycles of docetaxel (EC-T), reported Ulrike Nitz, MD, from the West German Study Group in Mönchengladbach, Germany, and her colleagues in the West German Study PlanB Trial.

Disease-free survival (DFS, the primary endpoint), distant recurrence-free interval (dRFI), and overall survival (OS) “were excellent and virtually identical in patients who received the anthracycline-containing or the anthracycline-free regimen. Subgroups that benefited from the anthracycline-containing regimen were not identified by interaction analysis, although a potentially clinically relevant benefit in particular (e.g., high-risk) subgroups cannot be ruled out,” they wrote. The report is in Journal of Clinical Oncology.

The investigators noted that anthracyclines are associated with increased risk for cardiac disease and hematologic malignancies, prompting investigators in other trials to consider anthracycline-free regimens.

“As the number of long-term survivors, elderly patients, and patients with preexisting cardiac risk factors increases, the toxicity profile becomes a more important discriminator in adjuvant treatment selection,” they wrote.

The investigators enrolled and randomized 2,449 women (median age 55, range 25-77 years) who had histologically confirmed, unilateral primary invasive breast cancer, adequate surgical treatment, and no evidence of metastatic disease. The patients all had HER2-negative disease, pT1 to pT4c, known hormone receptor status, and either pN+ or pN0 with one or more risk factors.

The intention-to-treat analysis included 1,227 patients assigned to EC-T and 1,222 assigned to TC in the efficacy population, and 1,167 and 1,178 patients, respectively, in the safety population.

After a median follow-up of 60 months, the 5-year DFS rate in the TC-treated group was 89.6%, compared with 89.9% in the EC-T–treated group. The estimated 5-year dRFI rates were 94.1% vs. 93.4%, and the estimated 5-year OS rates were 94.7% vs. 94.5%, respectively. None of the comparisons were statistically significant.

There were five treatment-related deaths in the TC arm, (one each from urosepsis, Streptococcus septicemia, peritonitis/diverticulitis, Staphylococcus epidermidis septicemia, and pulmonary embolism), and one in the EC-T arm (from septicemia).

In an interim safety analysis, the rate of febrile neutropenia was 6.1% in the TC arm and 3.9% in the EC-T arm, leading to a recommendation for “generous” prophylaxis with granulocyte-colony stimulating factor, and ciprofloxacine for patients with a history of diverticulitis or chronic infectious GI disease, or expected duration of neutropenia greater than 1 week.

Rates of grade 3 or 4 leukopenia, neutropenia, nausea, vomiting, peripheral polyneuropathy, hand-foot syndrome, mucositis/stomatitis, arthralgia, myalgia, and fatigue were significantly higher among patients treated with EC-T. There were numerically more grade 3-4 infections and febrile neutropenia within the TC arm, but this trend did not reach statistical significance.

The investigators noted that the results of their trial provide the strongest evidence for patients with pathologic NO or N1 disease, and that the trial did not examine the question of dose-dense chemotherapy in patients with high-risk early breast cancer.

Genomic Health, Sanofi, and Amgen supported the study. Dr. Nitz and multiple coauthors disclosed financial relationships with these companies and others.

SOURCE: Nitz U et al. J Clin Oncol. 2019 Feb 20. doi: 10.1200/JCO.18.00028.

The American Society of Clinical Oncology has issued a new guideline on the early detection and management of colorectal cancer in people at average risk for colorectal cancer, which was written by Gilberto Lopes, MD, of the University of Miami and his associates on an ASCO expert panel.

The panel assembled by ASCO to write the guideline consisted of medical oncology, surgical oncology, surgery, gastroenterology, health technology assessment, cancer epidemiology, pathology, radiology, radiation oncology, and patient advocacy experts. Guidelines from eight different developers were examined, and recommendations from those guidelines were adapted to form the new ASCO guideline. The guideline was published in the Journal of Global Oncology.

In people who are asymptomatic, are aged 50-75 years, have no family history of colorectal cancer, are at average risk, and are in settings with high incidences of colorectal cancer, the expert panel recommends guaiac fecal occult blood test or fecal immunochemical testing every 1-2 years, flexible sigmoidoscopy every 5 years, a combination of flexible sigmoidoscopy every 10 years and annual stool-based testing, or colonoscopy every 10 years, depending on available resources. The testing strategy for those with positive stool-based testing or flexible sigmoidoscopy is colonoscopy or a double-contrast barium enema if colonoscopy is unavailable.

For patients who have polyps, polypectomy at the time of colonoscopy is recommended, with the option of referral for surgical resection if not suitable for endoscopic resection. When symptoms (iron-deficiency anemia, bleeding, abdominal pain, and/or change in bowel habits) are present, a colonoscopy should be performed if available. If colonoscopy is contraindicated, a double-contrast barium enema can be performed; if endoscopy is contraindicated, CT colonography can be performed.

More information, including a data supplement with additional evidence tables, a methodology supplement with information about evidence quality and strength of recommendations, slide sets, and clinical tools and resources is available at www.asco.org/resource-stratified-guidelines, the guideline noted.

Several members of the expert panel reported conflicts of interest.

lfranki@mdedge.com

SOURCE: Lopes G et al. J Glob Oncol. 2019 Feb 25. doi: 10.1200/JGO.18.00213.

This story was updated on March 4, 2019.

The American Society of Clinical Oncology has issued a new guideline on the early detection and management of colorectal cancer in people at average risk for colorectal cancer, which was written by Gilberto Lopes, MD, of the University of Miami and his associates on an ASCO expert panel.

The panel assembled by ASCO to write the guideline consisted of medical oncology, surgical oncology, surgery, gastroenterology, health technology assessment, cancer epidemiology, pathology, radiology, radiation oncology, and patient advocacy experts. Guidelines from eight different developers were examined, and recommendations from those guidelines were adapted to form the new ASCO guideline. The guideline was published in the Journal of Global Oncology.

In people who are asymptomatic, are aged 50-75 years, have no family history of colorectal cancer, are at average risk, and are in settings with high incidences of colorectal cancer, the expert panel recommends guaiac fecal occult blood test or fecal immunochemical testing every 1-2 years, flexible sigmoidoscopy every 5 years, a combination of flexible sigmoidoscopy every 10 years and annual stool-based testing, or colonoscopy every 10 years, depending on available resources. The testing strategy for those with positive stool-based testing or flexible sigmoidoscopy is colonoscopy or a double-contrast barium enema if colonoscopy is unavailable.

For patients who have polyps, polypectomy at the time of colonoscopy is recommended, with the option of referral for surgical resection if not suitable for endoscopic resection. When symptoms (iron-deficiency anemia, bleeding, abdominal pain, and/or change in bowel habits) are present, a colonoscopy should be performed if available. If colonoscopy is contraindicated, a double-contrast barium enema can be performed; if endoscopy is contraindicated, CT colonography can be performed.

More information, including a data supplement with additional evidence tables, a methodology supplement with information about evidence quality and strength of recommendations, slide sets, and clinical tools and resources is available at www.asco.org/resource-stratified-guidelines, the guideline noted.

Several members of the expert panel reported conflicts of interest.

lfranki@mdedge.com

SOURCE: Lopes G et al. J Glob Oncol. 2019 Feb 25. doi: 10.1200/JGO.18.00213.

This story was updated on March 4, 2019.

The American Society of Clinical Oncology has issued a new guideline on the early detection and management of colorectal cancer in people at average risk for colorectal cancer, which was written by Gilberto Lopes, MD, of the University of Miami and his associates on an ASCO expert panel.

The panel assembled by ASCO to write the guideline consisted of medical oncology, surgical oncology, surgery, gastroenterology, health technology assessment, cancer epidemiology, pathology, radiology, radiation oncology, and patient advocacy experts. Guidelines from eight different developers were examined, and recommendations from those guidelines were adapted to form the new ASCO guideline. The guideline was published in the Journal of Global Oncology.

In people who are asymptomatic, are aged 50-75 years, have no family history of colorectal cancer, are at average risk, and are in settings with high incidences of colorectal cancer, the expert panel recommends guaiac fecal occult blood test or fecal immunochemical testing every 1-2 years, flexible sigmoidoscopy every 5 years, a combination of flexible sigmoidoscopy every 10 years and annual stool-based testing, or colonoscopy every 10 years, depending on available resources. The testing strategy for those with positive stool-based testing or flexible sigmoidoscopy is colonoscopy or a double-contrast barium enema if colonoscopy is unavailable.

For patients who have polyps, polypectomy at the time of colonoscopy is recommended, with the option of referral for surgical resection if not suitable for endoscopic resection. When symptoms (iron-deficiency anemia, bleeding, abdominal pain, and/or change in bowel habits) are present, a colonoscopy should be performed if available. If colonoscopy is contraindicated, a double-contrast barium enema can be performed; if endoscopy is contraindicated, CT colonography can be performed.

More information, including a data supplement with additional evidence tables, a methodology supplement with information about evidence quality and strength of recommendations, slide sets, and clinical tools and resources is available at www.asco.org/resource-stratified-guidelines, the guideline noted.

Several members of the expert panel reported conflicts of interest.

lfranki@mdedge.com

SOURCE: Lopes G et al. J Glob Oncol. 2019 Feb 25. doi: 10.1200/JGO.18.00213.

This story was updated on March 4, 2019.

SAN FRANCISCO – A peanut or egg allergy diagnosed when infants were 1 year of age often resolved by the time they turned 6, in a longitudinal, population-based study of more than 5,000 Australian children.

Mitchel L. Zoler/MDedge News

Among 131 infants diagnosed with a peanut allergy when they were 1 year old and then followed with repeat testing 5 years later, 41 (31%) had complete resolution of their peanut allergy, while the allergy persisted in the other 90 children, Rachel L. Peters, PhD, said at the annual meeting of the American Academy of Allergy, Asthma, and Immunology. The study also followed 404 infants diagnosed with an egg allergy at 1 year of age and found that by age 6 the allergy had resolved in 368 (91%), while persisting in 36 children, said Dr. Peters, an epidemiologist at Murdoch Children’s Research Institute in Parkville, Australia.


The analysis also identified risk factors that linked with an increased rate of allergy persistence. For peanut allergy persistence beyond the first year, the correlating factors were early-onset eczema, tree nut allergy, and a stronger peanut allergy identified by a greater than 4-mm reaction to a peanut skin-prick test. Factors that linked with an increased rate of persistent egg allergy were eczema, peanut allergy, gastrointestinal or respiratory reaction symptoms to milk, and reaction on an oral food challenge elicited by a low dose (less than 0.5 mL) of milk.

A consequence of the frequent resolution of these food allergies was that a positive skin-prick test reaction to either peanut or egg at 1 year old was poorly predictive of allergy status at age 6, while skin-prick tests at age 6 worked well for identifying a persistent food allergy at that age.

The analyses that Dr. Peters and her associates ran used data collected in the HealthNuts study, a comprehensive, prospective, population-based study of food allergies in children that enrolled 5,276 infants at 1 year old. The HealthNuts researchers enrolled infants at immunization clinics in the Melbourne area, with enrollment stratified to represent the people who live in that region (Clin Exp Allergy. 2010 Oct;40[10]:1516-22).

mzoler@mdedge.com

On Twitter @mitchelzoler

SOURCE: Peters R et al. J Allergy Clin Immunol. 2019 Feb;143[2]:AB421.

SAN FRANCISCO – A peanut or egg allergy diagnosed when infants were 1 year of age often resolved by the time they turned 6, in a longitudinal, population-based study of more than 5,000 Australian children.

Mitchel L. Zoler/MDedge News

Among 131 infants diagnosed with a peanut allergy when they were 1 year old and then followed with repeat testing 5 years later, 41 (31%) had complete resolution of their peanut allergy, while the allergy persisted in the other 90 children, Rachel L. Peters, PhD, said at the annual meeting of the American Academy of Allergy, Asthma, and Immunology. The study also followed 404 infants diagnosed with an egg allergy at 1 year of age and found that by age 6 the allergy had resolved in 368 (91%), while persisting in 36 children, said Dr. Peters, an epidemiologist at Murdoch Children’s Research Institute in Parkville, Australia.


The analysis also identified risk factors that linked with an increased rate of allergy persistence. For peanut allergy persistence beyond the first year, the correlating factors were early-onset eczema, tree nut allergy, and a stronger peanut allergy identified by a greater than 4-mm reaction to a peanut skin-prick test. Factors that linked with an increased rate of persistent egg allergy were eczema, peanut allergy, gastrointestinal or respiratory reaction symptoms to milk, and reaction on an oral food challenge elicited by a low dose (less than 0.5 mL) of milk.

A consequence of the frequent resolution of these food allergies was that a positive skin-prick test reaction to either peanut or egg at 1 year old was poorly predictive of allergy status at age 6, while skin-prick tests at age 6 worked well for identifying a persistent food allergy at that age.

The analyses that Dr. Peters and her associates ran used data collected in the HealthNuts study, a comprehensive, prospective, population-based study of food allergies in children that enrolled 5,276 infants at 1 year old. The HealthNuts researchers enrolled infants at immunization clinics in the Melbourne area, with enrollment stratified to represent the people who live in that region (Clin Exp Allergy. 2010 Oct;40[10]:1516-22).

mzoler@mdedge.com

On Twitter @mitchelzoler

SOURCE: Peters R et al. J Allergy Clin Immunol. 2019 Feb;143[2]:AB421.

SAN FRANCISCO – A peanut or egg allergy diagnosed when infants were 1 year of age often resolved by the time they turned 6, in a longitudinal, population-based study of more than 5,000 Australian children.

Mitchel L. Zoler/MDedge News

Among 131 infants diagnosed with a peanut allergy when they were 1 year old and then followed with repeat testing 5 years later, 41 (31%) had complete resolution of their peanut allergy, while the allergy persisted in the other 90 children, Rachel L. Peters, PhD, said at the annual meeting of the American Academy of Allergy, Asthma, and Immunology. The study also followed 404 infants diagnosed with an egg allergy at 1 year of age and found that by age 6 the allergy had resolved in 368 (91%), while persisting in 36 children, said Dr. Peters, an epidemiologist at Murdoch Children’s Research Institute in Parkville, Australia.


The analysis also identified risk factors that linked with an increased rate of allergy persistence. For peanut allergy persistence beyond the first year, the correlating factors were early-onset eczema, tree nut allergy, and a stronger peanut allergy identified by a greater than 4-mm reaction to a peanut skin-prick test. Factors that linked with an increased rate of persistent egg allergy were eczema, peanut allergy, gastrointestinal or respiratory reaction symptoms to milk, and reaction on an oral food challenge elicited by a low dose (less than 0.5 mL) of milk.

A consequence of the frequent resolution of these food allergies was that a positive skin-prick test reaction to either peanut or egg at 1 year old was poorly predictive of allergy status at age 6, while skin-prick tests at age 6 worked well for identifying a persistent food allergy at that age.

The analyses that Dr. Peters and her associates ran used data collected in the HealthNuts study, a comprehensive, prospective, population-based study of food allergies in children that enrolled 5,276 infants at 1 year old. The HealthNuts researchers enrolled infants at immunization clinics in the Melbourne area, with enrollment stratified to represent the people who live in that region (Clin Exp Allergy. 2010 Oct;40[10]:1516-22).

mzoler@mdedge.com

On Twitter @mitchelzoler

SOURCE: Peters R et al. J Allergy Clin Immunol. 2019 Feb;143[2]:AB421.

Single-patient use (SPU) of investigational therapies via the Food and Drug Administration’s Expanded Access program is an option worth considering for heavily pretreated cancer patients, according to a retrospective analysis of SPUs at Memorial Sloan Kettering Cancer Center.

Although approximately 2% of cancer cases at Kettering are pediatric, 34.1% of SPUs were for children, reported lead author Noah Z. Feit of Cornell University, New York, and his colleagues.

Therefore, “SPUs may provide an important means of pediatric drug access,” the investigators wrote in a JAMA Oncology letter.

The analysis involved 179 patients with 43 cancer types; these were more often solid tumors than hematologic malignancies (57.9% vs. 42.1%). The most common solid tumor type was neuroblastoma (15.3%), followed by lung (7.9%), primary brain (7.9%), and breast (5.9%). Sixty-six investigational products were given; the top three types were kinase inhibitors (28.8%), naked antibodies (12.5%), and allogeneic cell therapy (12.0%). Therapies were in various stages of development, including phase 3 (39.4%), phase 2 (36.1%), and phase 1 (18.8%). SPU approval was most often based on previous clinical experience (61.5%), although genomic data (38.0%) and preclinical evidence (30.8%) were also cited. The median number of prior treatments was four, suggesting a heavily pretreated patient population.

Analysis showed that the overall response rate to SPU agents was 20.1%, and patients with hematologic cancers responded more often than did those with solid tumors (30.4% vs. 12.2%). Median progression-free survival and overall survival were 3.9 months and 11.4 months, respectively. About one-third of patients (29.7%) had at least one serious treatment-related adverse event, with adults more often affected than children (35.3% vs. 19.1%). No treatment-related deaths occurred.

“In summary, our data provide an initial evidence basis to evaluate the FDA Expanded Access mechanism. We find its use is broad, involving a wide variety of patients and products, and clinical benefit was observed,” the investigators concluded. “Routine prospective collection of key safety and efficacy metrics should be considered moving forward.”

The study was funded by National Institutes of Health, the St. Baldrick’s Foundation, and the Nonna’s Garden Foundation Initiative in Precision Oncology. The investigators reported financial relationships with Mylan, Atara Biotherapeutics, Chugai Pharma, Boehringer Ingelheim, and others.

SOURCE: Feit et al. JAMA Onc. 2019 Feb 28. doi: 10.1001/jamaoncol.2018.7002.

Single-patient use (SPU) of investigational therapies via the Food and Drug Administration’s Expanded Access program is an option worth considering for heavily pretreated cancer patients, according to a retrospective analysis of SPUs at Memorial Sloan Kettering Cancer Center.

Although approximately 2% of cancer cases at Kettering are pediatric, 34.1% of SPUs were for children, reported lead author Noah Z. Feit of Cornell University, New York, and his colleagues.

Therefore, “SPUs may provide an important means of pediatric drug access,” the investigators wrote in a JAMA Oncology letter.

The analysis involved 179 patients with 43 cancer types; these were more often solid tumors than hematologic malignancies (57.9% vs. 42.1%). The most common solid tumor type was neuroblastoma (15.3%), followed by lung (7.9%), primary brain (7.9%), and breast (5.9%). Sixty-six investigational products were given; the top three types were kinase inhibitors (28.8%), naked antibodies (12.5%), and allogeneic cell therapy (12.0%). Therapies were in various stages of development, including phase 3 (39.4%), phase 2 (36.1%), and phase 1 (18.8%). SPU approval was most often based on previous clinical experience (61.5%), although genomic data (38.0%) and preclinical evidence (30.8%) were also cited. The median number of prior treatments was four, suggesting a heavily pretreated patient population.

Analysis showed that the overall response rate to SPU agents was 20.1%, and patients with hematologic cancers responded more often than did those with solid tumors (30.4% vs. 12.2%). Median progression-free survival and overall survival were 3.9 months and 11.4 months, respectively. About one-third of patients (29.7%) had at least one serious treatment-related adverse event, with adults more often affected than children (35.3% vs. 19.1%). No treatment-related deaths occurred.

“In summary, our data provide an initial evidence basis to evaluate the FDA Expanded Access mechanism. We find its use is broad, involving a wide variety of patients and products, and clinical benefit was observed,” the investigators concluded. “Routine prospective collection of key safety and efficacy metrics should be considered moving forward.”

The study was funded by National Institutes of Health, the St. Baldrick’s Foundation, and the Nonna’s Garden Foundation Initiative in Precision Oncology. The investigators reported financial relationships with Mylan, Atara Biotherapeutics, Chugai Pharma, Boehringer Ingelheim, and others.

SOURCE: Feit et al. JAMA Onc. 2019 Feb 28. doi: 10.1001/jamaoncol.2018.7002.

Single-patient use (SPU) of investigational therapies via the Food and Drug Administration’s Expanded Access program is an option worth considering for heavily pretreated cancer patients, according to a retrospective analysis of SPUs at Memorial Sloan Kettering Cancer Center.

Although approximately 2% of cancer cases at Kettering are pediatric, 34.1% of SPUs were for children, reported lead author Noah Z. Feit of Cornell University, New York, and his colleagues.

Therefore, “SPUs may provide an important means of pediatric drug access,” the investigators wrote in a JAMA Oncology letter.

The analysis involved 179 patients with 43 cancer types; these were more often solid tumors than hematologic malignancies (57.9% vs. 42.1%). The most common solid tumor type was neuroblastoma (15.3%), followed by lung (7.9%), primary brain (7.9%), and breast (5.9%). Sixty-six investigational products were given; the top three types were kinase inhibitors (28.8%), naked antibodies (12.5%), and allogeneic cell therapy (12.0%). Therapies were in various stages of development, including phase 3 (39.4%), phase 2 (36.1%), and phase 1 (18.8%). SPU approval was most often based on previous clinical experience (61.5%), although genomic data (38.0%) and preclinical evidence (30.8%) were also cited. The median number of prior treatments was four, suggesting a heavily pretreated patient population.

Analysis showed that the overall response rate to SPU agents was 20.1%, and patients with hematologic cancers responded more often than did those with solid tumors (30.4% vs. 12.2%). Median progression-free survival and overall survival were 3.9 months and 11.4 months, respectively. About one-third of patients (29.7%) had at least one serious treatment-related adverse event, with adults more often affected than children (35.3% vs. 19.1%). No treatment-related deaths occurred.

“In summary, our data provide an initial evidence basis to evaluate the FDA Expanded Access mechanism. We find its use is broad, involving a wide variety of patients and products, and clinical benefit was observed,” the investigators concluded. “Routine prospective collection of key safety and efficacy metrics should be considered moving forward.”

The study was funded by National Institutes of Health, the St. Baldrick’s Foundation, and the Nonna’s Garden Foundation Initiative in Precision Oncology. The investigators reported financial relationships with Mylan, Atara Biotherapeutics, Chugai Pharma, Boehringer Ingelheim, and others.

SOURCE: Feit et al. JAMA Onc. 2019 Feb 28. doi: 10.1001/jamaoncol.2018.7002.

Evidence-based research and guidelines regarding contraception are continually changing. Health care providers often have difficulty memorizing and staying up-to-date on all the important developments around family planning. Those who provide contraceptive counseling may not all use guidelines to inform their choices, and some may have misperceptions about patient eligibility for certain methods.^1,2 Mobile health applications (apps) that present this information in an easily accessible fashion have the potential to improve family planning services.

In a search for contraception apps, Dr. Rachel Perry and colleagues identified two contraception apps that were evaluated highly: 1) the Centers for Disease Control and Prevention (CDC) US Medical Eligibility Criteria for Contraceptive Use (MEC) app and 2) the iContraception app.³

Two free contraception apps for clinician use. Both the CDC Contraception and iContraception apps are based on CDC MEC information and provide guidance on contraceptive initiation and maintenance.⁴ Notably, the American College of Obstetricians and Gynecologists (ACOG) endorses the use of the CDC MEC.⁵

These two apps can aid physicians in prescribing appropriate and safe contraceptive methods and can help them tailor the extensive CDC MEC guidelines for an individual patient. Additionally, the iContraception app allows a user to input multiple clinical and demographic characteristics to determine an individual patient’s eligibility for a specific contraceptive method (that is, it incorporates a clinical decision tree).

The recommended contraception apps are listed in the TABLE and are detailed with a shortened version of the APPLICATIONS scoring system, APPLI (app comprehensiveness, price, platform, literature used, and important special features).⁶ I hope that the apps described here will assist you in managing patients who need contraception counseling.

Evidence-based research and guidelines regarding contraception are continually changing. Health care providers often have difficulty memorizing and staying up-to-date on all the important developments around family planning. Those who provide contraceptive counseling may not all use guidelines to inform their choices, and some may have misperceptions about patient eligibility for certain methods.^1,2 Mobile health applications (apps) that present this information in an easily accessible fashion have the potential to improve family planning services.

In a search for contraception apps, Dr. Rachel Perry and colleagues identified two contraception apps that were evaluated highly: 1) the Centers for Disease Control and Prevention (CDC) US Medical Eligibility Criteria for Contraceptive Use (MEC) app and 2) the iContraception app.³

Two free contraception apps for clinician use. Both the CDC Contraception and iContraception apps are based on CDC MEC information and provide guidance on contraceptive initiation and maintenance.⁴ Notably, the American College of Obstetricians and Gynecologists (ACOG) endorses the use of the CDC MEC.⁵

These two apps can aid physicians in prescribing appropriate and safe contraceptive methods and can help them tailor the extensive CDC MEC guidelines for an individual patient. Additionally, the iContraception app allows a user to input multiple clinical and demographic characteristics to determine an individual patient’s eligibility for a specific contraceptive method (that is, it incorporates a clinical decision tree).

The recommended contraception apps are listed in the TABLE and are detailed with a shortened version of the APPLICATIONS scoring system, APPLI (app comprehensiveness, price, platform, literature used, and important special features).⁶ I hope that the apps described here will assist you in managing patients who need contraception counseling.

Evidence-based research and guidelines regarding contraception are continually changing. Health care providers often have difficulty memorizing and staying up-to-date on all the important developments around family planning. Those who provide contraceptive counseling may not all use guidelines to inform their choices, and some may have misperceptions about patient eligibility for certain methods.^1,2 Mobile health applications (apps) that present this information in an easily accessible fashion have the potential to improve family planning services.

In a search for contraception apps, Dr. Rachel Perry and colleagues identified two contraception apps that were evaluated highly: 1) the Centers for Disease Control and Prevention (CDC) US Medical Eligibility Criteria for Contraceptive Use (MEC) app and 2) the iContraception app.³

Two free contraception apps for clinician use. Both the CDC Contraception and iContraception apps are based on CDC MEC information and provide guidance on contraceptive initiation and maintenance.⁴ Notably, the American College of Obstetricians and Gynecologists (ACOG) endorses the use of the CDC MEC.⁵

These two apps can aid physicians in prescribing appropriate and safe contraceptive methods and can help them tailor the extensive CDC MEC guidelines for an individual patient. Additionally, the iContraception app allows a user to input multiple clinical and demographic characteristics to determine an individual patient’s eligibility for a specific contraceptive method (that is, it incorporates a clinical decision tree).

The recommended contraception apps are listed in the TABLE and are detailed with a shortened version of the APPLICATIONS scoring system, APPLI (app comprehensiveness, price, platform, literature used, and important special features).⁶ I hope that the apps described here will assist you in managing patients who need contraception counseling.

Psoriasis is a chronic skin condition affecting approximately 2% to 3% of the population.^1,2 Beyond cutaneous manifestations, psoriasis is a systemic inflammatory state that is associated with an increased risk for cardiovascular disease, including obesity,^3,4 type 2 diabetes mellitus,^5,6 hypertension,⁵ dyslipidemia,^3,7 metabolic syndrome,⁷ atherosclerosis,⁸ peripheral vascular disease,⁹ coronary artery calcification,¹⁰ myocardial infarction,^11-13 stroke,^9,14 and cardiac death.^15,16

Psoriasis also has been associated with inflammatory bowel disease (IBD), possibly because of similar autoimmune mechanisms in the pathogenesis of both diseases.^17,18 However, there is no literature regarding the risk for acute gastrointestinal pathologies such as appendicitis, cholecystitis, or diverticulitis in patients with psoriasis.

The primary objective of this study was to examine if patients with psoriasis are at increased risk for appendicitis, cholecystitis, or diverticulitis compared to the general population. The secondary objective was to determine if patients with severe psoriasis (ie, patients treated with phototherapy or systemic therapy) are at a higher risk for these conditions compared to patients with mild psoriasis.

Methods

Patients and Tools
A descriptive, population-based cohort study design with controls from a matched cohort was used to ascertain the effect of psoriasis status on patients’ risk for appendicitis, cholecystitis, or diverticulitis. Our cohort was selected using administrative data from Kaiser Permanente Southern California (KPSC) during the study period (January 1, 2004, through December 31, 2016).

Kaiser Permanente Southern California is a large integrated health maintenance organization that includes approximately 4 million patients as of December 31, 2016, and includes roughly 20% of the region’s population. The geographic area served extends from Bakersfield in the lower California Central Valley to San Diego on the border with Mexico. Membership demographics, socioeconomic status, and ethnicity composition are representative of California.

Patients were included if they had a diagnosis of psoriasis (International Classification of Diseases, Ninth Revision, Clinical Modification [ICD-9-CM] code 696.1; International Classification of Diseases, Tenth Revision, Clinical Modification [ICD-10-CM] codes L40.0, L40.4, L40.8, or L40.9) for at least 3 visits between January 1, 2004, and December 31, 2016. Patients were not excluded if they also had a diagnosis of psoriatic arthritis (ICD-9-CM code 696.0; ICD-10-CM code L40.5x). Patients also must have been continuously enrolled for at least 1 year before and 1 year after the index date, which was defined as the date of the third psoriasis diagnosis.

Each patient with psoriasis was assigned to 1 of 2 cohorts: (1) severe psoriasis: patients who received UVB phototherapy, psoralen plus UVA phototherapy, methotrexate, acitretin, cyclosporine, apremilast, etanercept, adalimumab, infliximab, ustekinumab, efalizumab, alefacept, secukinumab, or ixekizumab during the study period; and (2) mild psoriasis: patients who had a diagnosis of psoriasis who did not receive one of these therapies during the study period.

Patients were excluded if they had a history of appendicitis, cholecystitis, or diverticulitis at any time before the index date. Only patients older than 18 years were included.

Patients with psoriasis were frequency matched (1:5) with healthy patients, also from the KPSC network. Individuals were matched by age, sex, and ethnicity.

Statistical Analysis
Baseline characteristics were described with means and SD for continuous variables as well as percentages for categorical variables. Chi-square tests for categorical variables and the Mann-Whitney U Test for continuous variables were used to compare the patients’ characteristics by psoriasis status. Cox proportional hazards regression models were used to examine the risk for appendicitis, cholecystitis, or diverticulitis among patients with and without psoriasis and among patients with mild and severe psoriasis. Proportionality assumption was validated using Pearson product moment correlation between the scaled Schoenfeld residuals and log transformed time for each covariate.

Results were presented as crude (unadjusted) hazard ratios (HRs) and adjusted HRs, where confounding factors (ie, age, sex, ethnicity, body mass index [BMI], alcohol use, smoking status, income, education, and membership length) were adjusted. All tests were performed with SAS EG 5.1 and R software. P<.05 was considered statistically significant. Results are reported with the 95% confidence interval (CI), when appropriate.

Results

A total of 1,690,214 KPSC patients were eligible for the study; 10,307 (0.6%) met diagnostic and inclusion criteria for the psoriasis cohort. Patients with psoriasis had a significantly higher mean BMI (29.9 vs 28.7; P<.0001) as well as higher mean rates of alcohol use (56% vs 53%; P<.0001) and smoking (47% vs 38%; P<.01) compared to controls. Psoriasis patients had a shorter average duration of membership within the Kaiser network (P=.0001) compared to controls.

A total of 7416 patients met criteria for mild psoriasis and 2891 patients met criteria for severe psoriasis (eTable). Patients with severe psoriasis were significantly younger and had significantly higher mean BMI compared to patients with mild psoriasis (P<.0001 and P=.0001, respectively). No significant difference in rates of alcohol or tobacco use was detected among patients with mild and severe psoriasis.

Diverticulitis
Patients with psoriasis had a significantly greater prevalence of diverticulitis compared to the control cohort (5.1% vs 4.2%; P<.0001). There was no difference in prevalence between the severe psoriasis group and the mild psoriasis group (P=.96), but the time to diagnosis of diverticulitis was shorter in the severe psoriasis group than in the mild psoriasis group (7.2 years vs 7.9 years; P<.0001). Psoriasis patients had an incidence rate of diverticulitis of 6.61 per 1000 patient-years compared to 5.38 per 1000 patient-years in the control group. Psoriasis conferred a higher risk for diverticulitis in both the crude and adjusted models (HR, 1.23; 95% CI, 1.11-1.35 [P<.001] and HR, 1.16; 95% CI, 1.05-1.29; [P<.01], respectively)(Table 3); however, when stratified by disease severity, only patients with severe psoriasis were found to be at higher risk (HR, 1.26; 95% CI, 1.15-1.61; P<.001 for the adjusted model).

Comment

The objective of this study was to examine the background risks for specific gastrointestinal pathologies in a large cohort of patients with psoriasis compared to the general population. After adjusting for measured confounders, patients with severe psoriasis had a significantly higher risk of diverticulitis compared to the general population. Although more patients with severe psoriasis developed appendicitis or cholecystitis, the difference was not significant.

The pathogenesis of diverticulosis and diverticulitis has been thought to be related to increased intracolonic pressure and decreased dietary fiber intake, leading to formation of diverticula in the colon.¹⁹ Our study did not correct for differences in diet between the 2 groups, making it a possible confounding variable. Studies evaluating dietary habits of psoriatic patients have found that adult males with psoriasis might consume less fiber compared to healthy patients,²⁰ and psoriasis patients also might consume less whole-grain fiber.²¹ Furthermore, fiber deficiency also might affect gut flora, causing low-grade chronic inflammation,¹⁸ which also has been supported by response to anti-inflammatory medications such as mesalazine.²² Given the autoimmune association between psoriasis and IBD, it is possible that psoriasis also might create an environment of chronic inflammation in the gut, predisposing patients with psoriasis to diverticulitis. However, further research is needed to better evaluate this possibility.

Our study also does not address any potential effects on outcomes of specific treatments for psoriasis. Brandl et al²³ found that patients on immunosuppressive therapy for autoimmune diseases had longer hospital and intensive care unit stays, higher rates of emergency operations, and higher mortality while hospitalized. Because our results suggest that patients with severe psoriasis, who are therefore more likely to require treatment with an immunomodulator, are at higher risk for diverticulitis, these patients also might be at risk for poorer outcomes.

There is no literature evaluating the relationship between psoriasis and appendicitis. Our study found a slightly lower incidence rate compared to the national trend (9.38 per 10,000 patient-years in the United States in 2008) in both healthy patients and psoriasis patients.²⁴ Of note, this statistic includes children, whereas our study did not, which might in part account for the lower rate. However, Cheluvappa et al²⁵ hypothesized a relationship between appendicitis and subsequent appendectomy at a young age and protection against IBD. They also found that the mechanism for protection involves downregulation of the helper T cell (T_H17) pathway,²⁵ which also has been found to play a role in psoriasis pathogenesis.^26,27 Although our results suggest that the risk for appendicitis is not increased for patients with psoriasis, further research might be able to determine if appendicitis and subsequent appendectomy also can offer protection against development of psoriasis.

We found that patients with severe psoriasis had a higher incidence rate of cholecystitis compared to patients with mild psoriasis. Egeberg et al²⁸ found an increased risk for cholelithiasis among patients with psoriasis, which may contribute to a higher rate of cholecystitis. Although both acute and chronic cholecystitis were incorporated in this study, a Russian study found that chronic cholecystitis may be a predictor of progression of psoriasis.²⁹ Moreover, patients with severe psoriasis had a shorter duration to diagnosis of cholecystitis than patients with mild psoriasis. It is possible that patients with severe psoriasis are in a state of greater chronic inflammation than those with mild psoriasis, and therefore, when combined with other risk factors for cholecystitis, may progress to disease more quickly. Alternatively, this finding could be treatment related, as there have been reported cases of cholecystitis related to etanercept use in patients treated for psoriasis and juvenile polyarticular rheumatoid arthritis.^30,31 The relationship is not yet well defined, however, and further research is necessary to evaluate this association.

Study Strengths
Key strengths of this study include the large sample size and diversity of the patient population. Kaiser Permanente Southern California membership generally is representative of the broader community, making our results fairly generalizable to populations with health insurance. Use of a matched control cohort allows the results to be more specific to the disease of interest, and the population-based design minimizes bias.

Study Limitations
This study has several limitations. Although the cohorts were categorized based on type of treatment received, exact therapies were not specified. As a retrospective study, it is difficult to control for potential confounding variables that are not included in the electronic medical record. The results of this study also demonstrated significantly shorter durations to diagnosis of all 3 conditions, indicating that surveillance bias may be present.

Conclusion

Patients with psoriasis may be at an increased risk for diverticulitis compared to patients without psoriasis, which could be due to the chronic inflammatory state induced by psoriasis. Therefore, it may be beneficial for clinicians to evaluate psoriasis patients for other risk factors for diverticulitis and subsequently provide counseling to these patients to minimize their risk for diverticulitis. Psoriasis patients do not appear to be at an increased risk for appendicitis or cholecystitis compared to controls; however, further research is needed for confirmation.

Psoriasis is a chronic skin condition affecting approximately 2% to 3% of the population.^1,2 Beyond cutaneous manifestations, psoriasis is a systemic inflammatory state that is associated with an increased risk for cardiovascular disease, including obesity,^3,4 type 2 diabetes mellitus,^5,6 hypertension,⁵ dyslipidemia,^3,7 metabolic syndrome,⁷ atherosclerosis,⁸ peripheral vascular disease,⁹ coronary artery calcification,¹⁰ myocardial infarction,^11-13 stroke,^9,14 and cardiac death.^15,16

Psoriasis also has been associated with inflammatory bowel disease (IBD), possibly because of similar autoimmune mechanisms in the pathogenesis of both diseases.^17,18 However, there is no literature regarding the risk for acute gastrointestinal pathologies such as appendicitis, cholecystitis, or diverticulitis in patients with psoriasis.

The primary objective of this study was to examine if patients with psoriasis are at increased risk for appendicitis, cholecystitis, or diverticulitis compared to the general population. The secondary objective was to determine if patients with severe psoriasis (ie, patients treated with phototherapy or systemic therapy) are at a higher risk for these conditions compared to patients with mild psoriasis.

Methods

Patients and Tools
A descriptive, population-based cohort study design with controls from a matched cohort was used to ascertain the effect of psoriasis status on patients’ risk for appendicitis, cholecystitis, or diverticulitis. Our cohort was selected using administrative data from Kaiser Permanente Southern California (KPSC) during the study period (January 1, 2004, through December 31, 2016).

Kaiser Permanente Southern California is a large integrated health maintenance organization that includes approximately 4 million patients as of December 31, 2016, and includes roughly 20% of the region’s population. The geographic area served extends from Bakersfield in the lower California Central Valley to San Diego on the border with Mexico. Membership demographics, socioeconomic status, and ethnicity composition are representative of California.

Patients were included if they had a diagnosis of psoriasis (International Classification of Diseases, Ninth Revision, Clinical Modification [ICD-9-CM] code 696.1; International Classification of Diseases, Tenth Revision, Clinical Modification [ICD-10-CM] codes L40.0, L40.4, L40.8, or L40.9) for at least 3 visits between January 1, 2004, and December 31, 2016. Patients were not excluded if they also had a diagnosis of psoriatic arthritis (ICD-9-CM code 696.0; ICD-10-CM code L40.5x). Patients also must have been continuously enrolled for at least 1 year before and 1 year after the index date, which was defined as the date of the third psoriasis diagnosis.

Each patient with psoriasis was assigned to 1 of 2 cohorts: (1) severe psoriasis: patients who received UVB phototherapy, psoralen plus UVA phototherapy, methotrexate, acitretin, cyclosporine, apremilast, etanercept, adalimumab, infliximab, ustekinumab, efalizumab, alefacept, secukinumab, or ixekizumab during the study period; and (2) mild psoriasis: patients who had a diagnosis of psoriasis who did not receive one of these therapies during the study period.

Patients were excluded if they had a history of appendicitis, cholecystitis, or diverticulitis at any time before the index date. Only patients older than 18 years were included.

Patients with psoriasis were frequency matched (1:5) with healthy patients, also from the KPSC network. Individuals were matched by age, sex, and ethnicity.

Statistical Analysis
Baseline characteristics were described with means and SD for continuous variables as well as percentages for categorical variables. Chi-square tests for categorical variables and the Mann-Whitney U Test for continuous variables were used to compare the patients’ characteristics by psoriasis status. Cox proportional hazards regression models were used to examine the risk for appendicitis, cholecystitis, or diverticulitis among patients with and without psoriasis and among patients with mild and severe psoriasis. Proportionality assumption was validated using Pearson product moment correlation between the scaled Schoenfeld residuals and log transformed time for each covariate.

Results were presented as crude (unadjusted) hazard ratios (HRs) and adjusted HRs, where confounding factors (ie, age, sex, ethnicity, body mass index [BMI], alcohol use, smoking status, income, education, and membership length) were adjusted. All tests were performed with SAS EG 5.1 and R software. P<.05 was considered statistically significant. Results are reported with the 95% confidence interval (CI), when appropriate.

Results

A total of 1,690,214 KPSC patients were eligible for the study; 10,307 (0.6%) met diagnostic and inclusion criteria for the psoriasis cohort. Patients with psoriasis had a significantly higher mean BMI (29.9 vs 28.7; P<.0001) as well as higher mean rates of alcohol use (56% vs 53%; P<.0001) and smoking (47% vs 38%; P<.01) compared to controls. Psoriasis patients had a shorter average duration of membership within the Kaiser network (P=.0001) compared to controls.

A total of 7416 patients met criteria for mild psoriasis and 2891 patients met criteria for severe psoriasis (eTable). Patients with severe psoriasis were significantly younger and had significantly higher mean BMI compared to patients with mild psoriasis (P<.0001 and P=.0001, respectively). No significant difference in rates of alcohol or tobacco use was detected among patients with mild and severe psoriasis.

Diverticulitis
Patients with psoriasis had a significantly greater prevalence of diverticulitis compared to the control cohort (5.1% vs 4.2%; P<.0001). There was no difference in prevalence between the severe psoriasis group and the mild psoriasis group (P=.96), but the time to diagnosis of diverticulitis was shorter in the severe psoriasis group than in the mild psoriasis group (7.2 years vs 7.9 years; P<.0001). Psoriasis patients had an incidence rate of diverticulitis of 6.61 per 1000 patient-years compared to 5.38 per 1000 patient-years in the control group. Psoriasis conferred a higher risk for diverticulitis in both the crude and adjusted models (HR, 1.23; 95% CI, 1.11-1.35 [P<.001] and HR, 1.16; 95% CI, 1.05-1.29; [P<.01], respectively)(Table 3); however, when stratified by disease severity, only patients with severe psoriasis were found to be at higher risk (HR, 1.26; 95% CI, 1.15-1.61; P<.001 for the adjusted model).

Comment

The objective of this study was to examine the background risks for specific gastrointestinal pathologies in a large cohort of patients with psoriasis compared to the general population. After adjusting for measured confounders, patients with severe psoriasis had a significantly higher risk of diverticulitis compared to the general population. Although more patients with severe psoriasis developed appendicitis or cholecystitis, the difference was not significant.

The pathogenesis of diverticulosis and diverticulitis has been thought to be related to increased intracolonic pressure and decreased dietary fiber intake, leading to formation of diverticula in the colon.¹⁹ Our study did not correct for differences in diet between the 2 groups, making it a possible confounding variable. Studies evaluating dietary habits of psoriatic patients have found that adult males with psoriasis might consume less fiber compared to healthy patients,²⁰ and psoriasis patients also might consume less whole-grain fiber.²¹ Furthermore, fiber deficiency also might affect gut flora, causing low-grade chronic inflammation,¹⁸ which also has been supported by response to anti-inflammatory medications such as mesalazine.²² Given the autoimmune association between psoriasis and IBD, it is possible that psoriasis also might create an environment of chronic inflammation in the gut, predisposing patients with psoriasis to diverticulitis. However, further research is needed to better evaluate this possibility.

Our study also does not address any potential effects on outcomes of specific treatments for psoriasis. Brandl et al²³ found that patients on immunosuppressive therapy for autoimmune diseases had longer hospital and intensive care unit stays, higher rates of emergency operations, and higher mortality while hospitalized. Because our results suggest that patients with severe psoriasis, who are therefore more likely to require treatment with an immunomodulator, are at higher risk for diverticulitis, these patients also might be at risk for poorer outcomes.

There is no literature evaluating the relationship between psoriasis and appendicitis. Our study found a slightly lower incidence rate compared to the national trend (9.38 per 10,000 patient-years in the United States in 2008) in both healthy patients and psoriasis patients.²⁴ Of note, this statistic includes children, whereas our study did not, which might in part account for the lower rate. However, Cheluvappa et al²⁵ hypothesized a relationship between appendicitis and subsequent appendectomy at a young age and protection against IBD. They also found that the mechanism for protection involves downregulation of the helper T cell (T_H17) pathway,²⁵ which also has been found to play a role in psoriasis pathogenesis.^26,27 Although our results suggest that the risk for appendicitis is not increased for patients with psoriasis, further research might be able to determine if appendicitis and subsequent appendectomy also can offer protection against development of psoriasis.

We found that patients with severe psoriasis had a higher incidence rate of cholecystitis compared to patients with mild psoriasis. Egeberg et al²⁸ found an increased risk for cholelithiasis among patients with psoriasis, which may contribute to a higher rate of cholecystitis. Although both acute and chronic cholecystitis were incorporated in this study, a Russian study found that chronic cholecystitis may be a predictor of progression of psoriasis.²⁹ Moreover, patients with severe psoriasis had a shorter duration to diagnosis of cholecystitis than patients with mild psoriasis. It is possible that patients with severe psoriasis are in a state of greater chronic inflammation than those with mild psoriasis, and therefore, when combined with other risk factors for cholecystitis, may progress to disease more quickly. Alternatively, this finding could be treatment related, as there have been reported cases of cholecystitis related to etanercept use in patients treated for psoriasis and juvenile polyarticular rheumatoid arthritis.^30,31 The relationship is not yet well defined, however, and further research is necessary to evaluate this association.

Study Strengths
Key strengths of this study include the large sample size and diversity of the patient population. Kaiser Permanente Southern California membership generally is representative of the broader community, making our results fairly generalizable to populations with health insurance. Use of a matched control cohort allows the results to be more specific to the disease of interest, and the population-based design minimizes bias.

Study Limitations
This study has several limitations. Although the cohorts were categorized based on type of treatment received, exact therapies were not specified. As a retrospective study, it is difficult to control for potential confounding variables that are not included in the electronic medical record. The results of this study also demonstrated significantly shorter durations to diagnosis of all 3 conditions, indicating that surveillance bias may be present.

Conclusion

Patients with psoriasis may be at an increased risk for diverticulitis compared to patients without psoriasis, which could be due to the chronic inflammatory state induced by psoriasis. Therefore, it may be beneficial for clinicians to evaluate psoriasis patients for other risk factors for diverticulitis and subsequently provide counseling to these patients to minimize their risk for diverticulitis. Psoriasis patients do not appear to be at an increased risk for appendicitis or cholecystitis compared to controls; however, further research is needed for confirmation.

Psoriasis is a chronic skin condition affecting approximately 2% to 3% of the population.^1,2 Beyond cutaneous manifestations, psoriasis is a systemic inflammatory state that is associated with an increased risk for cardiovascular disease, including obesity,^3,4 type 2 diabetes mellitus,^5,6 hypertension,⁵ dyslipidemia,^3,7 metabolic syndrome,⁷ atherosclerosis,⁸ peripheral vascular disease,⁹ coronary artery calcification,¹⁰ myocardial infarction,^11-13 stroke,^9,14 and cardiac death.^15,16

Psoriasis also has been associated with inflammatory bowel disease (IBD), possibly because of similar autoimmune mechanisms in the pathogenesis of both diseases.^17,18 However, there is no literature regarding the risk for acute gastrointestinal pathologies such as appendicitis, cholecystitis, or diverticulitis in patients with psoriasis.

The primary objective of this study was to examine if patients with psoriasis are at increased risk for appendicitis, cholecystitis, or diverticulitis compared to the general population. The secondary objective was to determine if patients with severe psoriasis (ie, patients treated with phototherapy or systemic therapy) are at a higher risk for these conditions compared to patients with mild psoriasis.

Methods

Patients and Tools
A descriptive, population-based cohort study design with controls from a matched cohort was used to ascertain the effect of psoriasis status on patients’ risk for appendicitis, cholecystitis, or diverticulitis. Our cohort was selected using administrative data from Kaiser Permanente Southern California (KPSC) during the study period (January 1, 2004, through December 31, 2016).

Kaiser Permanente Southern California is a large integrated health maintenance organization that includes approximately 4 million patients as of December 31, 2016, and includes roughly 20% of the region’s population. The geographic area served extends from Bakersfield in the lower California Central Valley to San Diego on the border with Mexico. Membership demographics, socioeconomic status, and ethnicity composition are representative of California.

Patients were included if they had a diagnosis of psoriasis (International Classification of Diseases, Ninth Revision, Clinical Modification [ICD-9-CM] code 696.1; International Classification of Diseases, Tenth Revision, Clinical Modification [ICD-10-CM] codes L40.0, L40.4, L40.8, or L40.9) for at least 3 visits between January 1, 2004, and December 31, 2016. Patients were not excluded if they also had a diagnosis of psoriatic arthritis (ICD-9-CM code 696.0; ICD-10-CM code L40.5x). Patients also must have been continuously enrolled for at least 1 year before and 1 year after the index date, which was defined as the date of the third psoriasis diagnosis.

Each patient with psoriasis was assigned to 1 of 2 cohorts: (1) severe psoriasis: patients who received UVB phototherapy, psoralen plus UVA phototherapy, methotrexate, acitretin, cyclosporine, apremilast, etanercept, adalimumab, infliximab, ustekinumab, efalizumab, alefacept, secukinumab, or ixekizumab during the study period; and (2) mild psoriasis: patients who had a diagnosis of psoriasis who did not receive one of these therapies during the study period.

Patients were excluded if they had a history of appendicitis, cholecystitis, or diverticulitis at any time before the index date. Only patients older than 18 years were included.

Patients with psoriasis were frequency matched (1:5) with healthy patients, also from the KPSC network. Individuals were matched by age, sex, and ethnicity.

Statistical Analysis
Baseline characteristics were described with means and SD for continuous variables as well as percentages for categorical variables. Chi-square tests for categorical variables and the Mann-Whitney U Test for continuous variables were used to compare the patients’ characteristics by psoriasis status. Cox proportional hazards regression models were used to examine the risk for appendicitis, cholecystitis, or diverticulitis among patients with and without psoriasis and among patients with mild and severe psoriasis. Proportionality assumption was validated using Pearson product moment correlation between the scaled Schoenfeld residuals and log transformed time for each covariate.

Results were presented as crude (unadjusted) hazard ratios (HRs) and adjusted HRs, where confounding factors (ie, age, sex, ethnicity, body mass index [BMI], alcohol use, smoking status, income, education, and membership length) were adjusted. All tests were performed with SAS EG 5.1 and R software. P<.05 was considered statistically significant. Results are reported with the 95% confidence interval (CI), when appropriate.

Results

A total of 1,690,214 KPSC patients were eligible for the study; 10,307 (0.6%) met diagnostic and inclusion criteria for the psoriasis cohort. Patients with psoriasis had a significantly higher mean BMI (29.9 vs 28.7; P<.0001) as well as higher mean rates of alcohol use (56% vs 53%; P<.0001) and smoking (47% vs 38%; P<.01) compared to controls. Psoriasis patients had a shorter average duration of membership within the Kaiser network (P=.0001) compared to controls.

A total of 7416 patients met criteria for mild psoriasis and 2891 patients met criteria for severe psoriasis (eTable). Patients with severe psoriasis were significantly younger and had significantly higher mean BMI compared to patients with mild psoriasis (P<.0001 and P=.0001, respectively). No significant difference in rates of alcohol or tobacco use was detected among patients with mild and severe psoriasis.

Diverticulitis
Patients with psoriasis had a significantly greater prevalence of diverticulitis compared to the control cohort (5.1% vs 4.2%; P<.0001). There was no difference in prevalence between the severe psoriasis group and the mild psoriasis group (P=.96), but the time to diagnosis of diverticulitis was shorter in the severe psoriasis group than in the mild psoriasis group (7.2 years vs 7.9 years; P<.0001). Psoriasis patients had an incidence rate of diverticulitis of 6.61 per 1000 patient-years compared to 5.38 per 1000 patient-years in the control group. Psoriasis conferred a higher risk for diverticulitis in both the crude and adjusted models (HR, 1.23; 95% CI, 1.11-1.35 [P<.001] and HR, 1.16; 95% CI, 1.05-1.29; [P<.01], respectively)(Table 3); however, when stratified by disease severity, only patients with severe psoriasis were found to be at higher risk (HR, 1.26; 95% CI, 1.15-1.61; P<.001 for the adjusted model).

Comment

The objective of this study was to examine the background risks for specific gastrointestinal pathologies in a large cohort of patients with psoriasis compared to the general population. After adjusting for measured confounders, patients with severe psoriasis had a significantly higher risk of diverticulitis compared to the general population. Although more patients with severe psoriasis developed appendicitis or cholecystitis, the difference was not significant.

The pathogenesis of diverticulosis and diverticulitis has been thought to be related to increased intracolonic pressure and decreased dietary fiber intake, leading to formation of diverticula in the colon.¹⁹ Our study did not correct for differences in diet between the 2 groups, making it a possible confounding variable. Studies evaluating dietary habits of psoriatic patients have found that adult males with psoriasis might consume less fiber compared to healthy patients,²⁰ and psoriasis patients also might consume less whole-grain fiber.²¹ Furthermore, fiber deficiency also might affect gut flora, causing low-grade chronic inflammation,¹⁸ which also has been supported by response to anti-inflammatory medications such as mesalazine.²² Given the autoimmune association between psoriasis and IBD, it is possible that psoriasis also might create an environment of chronic inflammation in the gut, predisposing patients with psoriasis to diverticulitis. However, further research is needed to better evaluate this possibility.

Our study also does not address any potential effects on outcomes of specific treatments for psoriasis. Brandl et al²³ found that patients on immunosuppressive therapy for autoimmune diseases had longer hospital and intensive care unit stays, higher rates of emergency operations, and higher mortality while hospitalized. Because our results suggest that patients with severe psoriasis, who are therefore more likely to require treatment with an immunomodulator, are at higher risk for diverticulitis, these patients also might be at risk for poorer outcomes.

There is no literature evaluating the relationship between psoriasis and appendicitis. Our study found a slightly lower incidence rate compared to the national trend (9.38 per 10,000 patient-years in the United States in 2008) in both healthy patients and psoriasis patients.²⁴ Of note, this statistic includes children, whereas our study did not, which might in part account for the lower rate. However, Cheluvappa et al²⁵ hypothesized a relationship between appendicitis and subsequent appendectomy at a young age and protection against IBD. They also found that the mechanism for protection involves downregulation of the helper T cell (T_H17) pathway,²⁵ which also has been found to play a role in psoriasis pathogenesis.^26,27 Although our results suggest that the risk for appendicitis is not increased for patients with psoriasis, further research might be able to determine if appendicitis and subsequent appendectomy also can offer protection against development of psoriasis.

We found that patients with severe psoriasis had a higher incidence rate of cholecystitis compared to patients with mild psoriasis. Egeberg et al²⁸ found an increased risk for cholelithiasis among patients with psoriasis, which may contribute to a higher rate of cholecystitis. Although both acute and chronic cholecystitis were incorporated in this study, a Russian study found that chronic cholecystitis may be a predictor of progression of psoriasis.²⁹ Moreover, patients with severe psoriasis had a shorter duration to diagnosis of cholecystitis than patients with mild psoriasis. It is possible that patients with severe psoriasis are in a state of greater chronic inflammation than those with mild psoriasis, and therefore, when combined with other risk factors for cholecystitis, may progress to disease more quickly. Alternatively, this finding could be treatment related, as there have been reported cases of cholecystitis related to etanercept use in patients treated for psoriasis and juvenile polyarticular rheumatoid arthritis.^30,31 The relationship is not yet well defined, however, and further research is necessary to evaluate this association.

Study Strengths
Key strengths of this study include the large sample size and diversity of the patient population. Kaiser Permanente Southern California membership generally is representative of the broader community, making our results fairly generalizable to populations with health insurance. Use of a matched control cohort allows the results to be more specific to the disease of interest, and the population-based design minimizes bias.

Study Limitations
This study has several limitations. Although the cohorts were categorized based on type of treatment received, exact therapies were not specified. As a retrospective study, it is difficult to control for potential confounding variables that are not included in the electronic medical record. The results of this study also demonstrated significantly shorter durations to diagnosis of all 3 conditions, indicating that surveillance bias may be present.

Conclusion

Patients with psoriasis may be at an increased risk for diverticulitis compared to patients without psoriasis, which could be due to the chronic inflammatory state induced by psoriasis. Therefore, it may be beneficial for clinicians to evaluate psoriasis patients for other risk factors for diverticulitis and subsequently provide counseling to these patients to minimize their risk for diverticulitis. Psoriasis patients do not appear to be at an increased risk for appendicitis or cholecystitis compared to controls; however, further research is needed for confirmation.

Case Report

A 31-year-old black woman presented with a slow-spreading pruritic rash on the right thigh of 1 year’s duration. She had previously seen a dermatologist and was prescribed triamcinolone acetonide cream 0.1% and mupirocin ointment 2% but declined a biopsy. Review of symptoms was negative for any constitutional symptoms. Family history included hypertension and eczema with a personal history of anxiety. Clinical examination revealed grouped flesh-colored to light pink papules and plaques within a hyperpigmented patch on the right medial thigh (Figure 1).

Histopathology
A punch biopsy was negative for fungal, bacterial, or acid-fast bacilli culture. Histopathologic evaluation demonstrated a dense dermal infiltrate of large histiocytes admixed with inflammatory cells composed predominantly of lymphocytes and plasma cells. The histiocytes within the inflammatory infiltrate had vesicular nuclei and abundant eosinophilic cytoplasm (Figure 2A). Areas of emperipolesis were noted (Figure 2B). The large histiocytes stained positive for S-100 protein (Figure 2C) and negative for CD1a.

Comment

Rosai-Dorfman disease (also known as sinus histiocytosis with massive lymphadenopathy) is a non–Langerhans cell histiocytosis.¹ There are 2 main forms of RDD: one form that affects the lymph nodes and in certain cases the extranodal organs, and the other is purely CRDD. Cutaneous RDD is extremely rare and the etiology is unknown, though a number of viral and immune causes have been postulated. Cutaneous RDD presents as solitary or numerous papules, nodules, and/or plaques. Treatment options include steroids, methotrexate, dapsone, thalidomide, and isotretinoin, with varying efficacy reported.¹

Extranodal forms occur in 43% of RDD cases, with the skin being the most common site.¹ Other extranodal sites include the soft tissue, upper and lower respiratory tract, bones, genitourinary tract, oral cavity, gastrointestinal tract, orbits, testes, and rarely central nervous system involvement.²

Cutaneous RDD and RDD may be distinct clinical entities. Cutaneous RDD has a later age of onset than RDD (median age, 43.5 years vs 20.6 years) and a female predominance (2:1 vs 1.4:1). It most commonly affects Asian and white individuals while the majority of patients with RDD are of African descent with rare reports in Asians.¹

The etiology of CRDD remains unknown with hypotheses of viral and immune causes such as human herpesvirus 6, Epstein-Barr virus, and parvovirus B19. The polyclonal nature of the cell infiltrate and the clinical progression of RDD suggest a reactive process rather than a neoplastic disorder.¹ Rosai-Dorfman disease has been hypothesized to be closely related to autoimmune lymphoproliferative syndrome, an inherited disorder associated with defects in Fas-mediated apoptosis.⁵

Histologic findings in CRDD are similar to those in RDD, with a superficial and deep perivascular infiltrate of lymphocytes and plasma cells. A diffuse and nodular dermal infiltrate of foamy histiocytes exists in a background infiltrate of lymphocytes and plasma cells. Foamy histiocytes may be seen in dermal lymphatics, and lymphoid follicles with reactive germinal centers also may be present. Emperipolesis, the presence of intact inflammatory cells within histiocytes, is common in CRDD. Less often, histiocytes may contain plasma cells, neutrophils, and red blood cells. Mitoses and nuclear atypia are rare. Cutaneous RDD histiocytes stain positive for S-100 protein, CD4, factor XIIIa, and CD68, and negative for CD1a. Birbeck granules are absent on electronic microscopy of CRDD tissue, eliminating Langerhans cell histiocytosis.^1,3,5

The clinical diagnosis of CRDD is hard to confirm in the absence of lymphadenopathy. The lesions in CRDD may be solitary or numerous, usually presenting as papules, nodules, and/or plaques. More rarely, the lesions may present as pustules, acneform lesions, mimickers of vasculitis and panniculitis, macular erythema, large annular lesions resembling granuloma annulare, or even a breast mass.^1,3 One case report with involvement of deep subcutaneous fat presented with flank swelling beneath papules and nodules.⁶

The most common site of lesions in CRDD is the face, with the eyelids and malar regions frequently involved, followed by the back, chest, thighs, flanks, and shoulders.^1,5 Rarely, CRDD may be associated with other disorders, including bilateral uveitis, antinuclear antibody–positive lupus erythematosus, rheumatoid arthritis, hypothyroidism, lymphoma, and human immunodeficiency virus.¹

Numerous treatments have been attempted, yet the response often is poor. Because RDD is a benign and self-limiting disease, less aggressive therapeutic approaches should be used, if possible. Surgical excision of the lesions has been helpful in certain cases.⁶ Cryotherapy and local radiation, topical steroids, or laser treatment also have been found to improve the condition.^1,7 For refractory cases, dapsone and thalidomide have been effective. Mixed results have been observed with isotretinoin and imatinib; some patients improved whereas others did not. Utikal et al⁸ described a patient with complete remission of CRDD after receiving imatinib therapy; however, a different study reported a patient with CRDD who was completely resistant to this treatment.⁹ One case presenting on the breast did not respond to topical steroids, acitretin, and thalidomide but later responded to methotrexate.¹⁰

Conclusion

Cutaneous RDD is an unusual clinical entity with varied lesions. Generally, CRDD follows a benign clinical course, with a possibility of spontaneous remission. Further studies are required to confidently classify the etiology and variance between both RDD and CRDD.

Case Report

A 31-year-old black woman presented with a slow-spreading pruritic rash on the right thigh of 1 year’s duration. She had previously seen a dermatologist and was prescribed triamcinolone acetonide cream 0.1% and mupirocin ointment 2% but declined a biopsy. Review of symptoms was negative for any constitutional symptoms. Family history included hypertension and eczema with a personal history of anxiety. Clinical examination revealed grouped flesh-colored to light pink papules and plaques within a hyperpigmented patch on the right medial thigh (Figure 1).

Histopathology
A punch biopsy was negative for fungal, bacterial, or acid-fast bacilli culture. Histopathologic evaluation demonstrated a dense dermal infiltrate of large histiocytes admixed with inflammatory cells composed predominantly of lymphocytes and plasma cells. The histiocytes within the inflammatory infiltrate had vesicular nuclei and abundant eosinophilic cytoplasm (Figure 2A). Areas of emperipolesis were noted (Figure 2B). The large histiocytes stained positive for S-100 protein (Figure 2C) and negative for CD1a.

Comment

Rosai-Dorfman disease (also known as sinus histiocytosis with massive lymphadenopathy) is a non–Langerhans cell histiocytosis.¹ There are 2 main forms of RDD: one form that affects the lymph nodes and in certain cases the extranodal organs, and the other is purely CRDD. Cutaneous RDD is extremely rare and the etiology is unknown, though a number of viral and immune causes have been postulated. Cutaneous RDD presents as solitary or numerous papules, nodules, and/or plaques. Treatment options include steroids, methotrexate, dapsone, thalidomide, and isotretinoin, with varying efficacy reported.¹

Extranodal forms occur in 43% of RDD cases, with the skin being the most common site.¹ Other extranodal sites include the soft tissue, upper and lower respiratory tract, bones, genitourinary tract, oral cavity, gastrointestinal tract, orbits, testes, and rarely central nervous system involvement.²

Cutaneous RDD and RDD may be distinct clinical entities. Cutaneous RDD has a later age of onset than RDD (median age, 43.5 years vs 20.6 years) and a female predominance (2:1 vs 1.4:1). It most commonly affects Asian and white individuals while the majority of patients with RDD are of African descent with rare reports in Asians.¹

The etiology of CRDD remains unknown with hypotheses of viral and immune causes such as human herpesvirus 6, Epstein-Barr virus, and parvovirus B19. The polyclonal nature of the cell infiltrate and the clinical progression of RDD suggest a reactive process rather than a neoplastic disorder.¹ Rosai-Dorfman disease has been hypothesized to be closely related to autoimmune lymphoproliferative syndrome, an inherited disorder associated with defects in Fas-mediated apoptosis.⁵

Histologic findings in CRDD are similar to those in RDD, with a superficial and deep perivascular infiltrate of lymphocytes and plasma cells. A diffuse and nodular dermal infiltrate of foamy histiocytes exists in a background infiltrate of lymphocytes and plasma cells. Foamy histiocytes may be seen in dermal lymphatics, and lymphoid follicles with reactive germinal centers also may be present. Emperipolesis, the presence of intact inflammatory cells within histiocytes, is common in CRDD. Less often, histiocytes may contain plasma cells, neutrophils, and red blood cells. Mitoses and nuclear atypia are rare. Cutaneous RDD histiocytes stain positive for S-100 protein, CD4, factor XIIIa, and CD68, and negative for CD1a. Birbeck granules are absent on electronic microscopy of CRDD tissue, eliminating Langerhans cell histiocytosis.^1,3,5

The clinical diagnosis of CRDD is hard to confirm in the absence of lymphadenopathy. The lesions in CRDD may be solitary or numerous, usually presenting as papules, nodules, and/or plaques. More rarely, the lesions may present as pustules, acneform lesions, mimickers of vasculitis and panniculitis, macular erythema, large annular lesions resembling granuloma annulare, or even a breast mass.^1,3 One case report with involvement of deep subcutaneous fat presented with flank swelling beneath papules and nodules.⁶

The most common site of lesions in CRDD is the face, with the eyelids and malar regions frequently involved, followed by the back, chest, thighs, flanks, and shoulders.^1,5 Rarely, CRDD may be associated with other disorders, including bilateral uveitis, antinuclear antibody–positive lupus erythematosus, rheumatoid arthritis, hypothyroidism, lymphoma, and human immunodeficiency virus.¹

Numerous treatments have been attempted, yet the response often is poor. Because RDD is a benign and self-limiting disease, less aggressive therapeutic approaches should be used, if possible. Surgical excision of the lesions has been helpful in certain cases.⁶ Cryotherapy and local radiation, topical steroids, or laser treatment also have been found to improve the condition.^1,7 For refractory cases, dapsone and thalidomide have been effective. Mixed results have been observed with isotretinoin and imatinib; some patients improved whereas others did not. Utikal et al⁸ described a patient with complete remission of CRDD after receiving imatinib therapy; however, a different study reported a patient with CRDD who was completely resistant to this treatment.⁹ One case presenting on the breast did not respond to topical steroids, acitretin, and thalidomide but later responded to methotrexate.¹⁰

Conclusion

Cutaneous RDD is an unusual clinical entity with varied lesions. Generally, CRDD follows a benign clinical course, with a possibility of spontaneous remission. Further studies are required to confidently classify the etiology and variance between both RDD and CRDD.

Case Report

A 31-year-old black woman presented with a slow-spreading pruritic rash on the right thigh of 1 year’s duration. She had previously seen a dermatologist and was prescribed triamcinolone acetonide cream 0.1% and mupirocin ointment 2% but declined a biopsy. Review of symptoms was negative for any constitutional symptoms. Family history included hypertension and eczema with a personal history of anxiety. Clinical examination revealed grouped flesh-colored to light pink papules and plaques within a hyperpigmented patch on the right medial thigh (Figure 1).

Histopathology
A punch biopsy was negative for fungal, bacterial, or acid-fast bacilli culture. Histopathologic evaluation demonstrated a dense dermal infiltrate of large histiocytes admixed with inflammatory cells composed predominantly of lymphocytes and plasma cells. The histiocytes within the inflammatory infiltrate had vesicular nuclei and abundant eosinophilic cytoplasm (Figure 2A). Areas of emperipolesis were noted (Figure 2B). The large histiocytes stained positive for S-100 protein (Figure 2C) and negative for CD1a.

Comment

Rosai-Dorfman disease (also known as sinus histiocytosis with massive lymphadenopathy) is a non–Langerhans cell histiocytosis.¹ There are 2 main forms of RDD: one form that affects the lymph nodes and in certain cases the extranodal organs, and the other is purely CRDD. Cutaneous RDD is extremely rare and the etiology is unknown, though a number of viral and immune causes have been postulated. Cutaneous RDD presents as solitary or numerous papules, nodules, and/or plaques. Treatment options include steroids, methotrexate, dapsone, thalidomide, and isotretinoin, with varying efficacy reported.¹

Extranodal forms occur in 43% of RDD cases, with the skin being the most common site.¹ Other extranodal sites include the soft tissue, upper and lower respiratory tract, bones, genitourinary tract, oral cavity, gastrointestinal tract, orbits, testes, and rarely central nervous system involvement.²

Cutaneous RDD and RDD may be distinct clinical entities. Cutaneous RDD has a later age of onset than RDD (median age, 43.5 years vs 20.6 years) and a female predominance (2:1 vs 1.4:1). It most commonly affects Asian and white individuals while the majority of patients with RDD are of African descent with rare reports in Asians.¹

The etiology of CRDD remains unknown with hypotheses of viral and immune causes such as human herpesvirus 6, Epstein-Barr virus, and parvovirus B19. The polyclonal nature of the cell infiltrate and the clinical progression of RDD suggest a reactive process rather than a neoplastic disorder.¹ Rosai-Dorfman disease has been hypothesized to be closely related to autoimmune lymphoproliferative syndrome, an inherited disorder associated with defects in Fas-mediated apoptosis.⁵

Histologic findings in CRDD are similar to those in RDD, with a superficial and deep perivascular infiltrate of lymphocytes and plasma cells. A diffuse and nodular dermal infiltrate of foamy histiocytes exists in a background infiltrate of lymphocytes and plasma cells. Foamy histiocytes may be seen in dermal lymphatics, and lymphoid follicles with reactive germinal centers also may be present. Emperipolesis, the presence of intact inflammatory cells within histiocytes, is common in CRDD. Less often, histiocytes may contain plasma cells, neutrophils, and red blood cells. Mitoses and nuclear atypia are rare. Cutaneous RDD histiocytes stain positive for S-100 protein, CD4, factor XIIIa, and CD68, and negative for CD1a. Birbeck granules are absent on electronic microscopy of CRDD tissue, eliminating Langerhans cell histiocytosis.^1,3,5

The clinical diagnosis of CRDD is hard to confirm in the absence of lymphadenopathy. The lesions in CRDD may be solitary or numerous, usually presenting as papules, nodules, and/or plaques. More rarely, the lesions may present as pustules, acneform lesions, mimickers of vasculitis and panniculitis, macular erythema, large annular lesions resembling granuloma annulare, or even a breast mass.^1,3 One case report with involvement of deep subcutaneous fat presented with flank swelling beneath papules and nodules.⁶

The most common site of lesions in CRDD is the face, with the eyelids and malar regions frequently involved, followed by the back, chest, thighs, flanks, and shoulders.^1,5 Rarely, CRDD may be associated with other disorders, including bilateral uveitis, antinuclear antibody–positive lupus erythematosus, rheumatoid arthritis, hypothyroidism, lymphoma, and human immunodeficiency virus.¹

Numerous treatments have been attempted, yet the response often is poor. Because RDD is a benign and self-limiting disease, less aggressive therapeutic approaches should be used, if possible. Surgical excision of the lesions has been helpful in certain cases.⁶ Cryotherapy and local radiation, topical steroids, or laser treatment also have been found to improve the condition.^1,7 For refractory cases, dapsone and thalidomide have been effective. Mixed results have been observed with isotretinoin and imatinib; some patients improved whereas others did not. Utikal et al⁸ described a patient with complete remission of CRDD after receiving imatinib therapy; however, a different study reported a patient with CRDD who was completely resistant to this treatment.⁹ One case presenting on the breast did not respond to topical steroids, acitretin, and thalidomide but later responded to methotrexate.¹⁰

Conclusion

Cutaneous RDD is an unusual clinical entity with varied lesions. Generally, CRDD follows a benign clinical course, with a possibility of spontaneous remission. Further studies are required to confidently classify the etiology and variance between both RDD and CRDD.

To the Editor:

I read with interest the informative Cutis article by Hashim et al,¹ which not only summarized the key features of vaginal rejuvenation but also concisely reviewed noninvasive treatments, including lasers and radiofrequency devices, that can be used to address this important issue. The authors emphasized that these treatments may represent a valuable addition to the cosmetic landscape. In addition, they also asserted that noninvasive vaginal rejuvenation is an expanding focus of cosmetic dermatology.¹

Genital rejuvenation includes rejuvenation of the vagina in women and the scrotum in men. Since the term initially appeared in the literature in 2007,² a PubMed search of articles indexed for MEDLINE yields an increasing number of articles on vaginal rejuvenation. More recently, the concept of scrotal rejuvenation was introduced in 2018.³

Similar to vaginal rejuvenation, scrotal rejuvenation includes procedures to remedy medical or cosmetic conditions of the scrotum. Hashim et al¹ focused on morphology-associated vaginal changes for which rejuvenation techniques have been successful, such as excess clitoral hood; excess labia majora or minora; vaginal laxity; and vulvovaginal atrophy, which is considered to be a component of genitourinary syndrome of menopause. Morphology-associated changes of the scrotum include wrinkling (cutis scrotum gyratum or scrotum rugosum) and laxity (low-hanging or sagging scrotum or scrotomegaly). Potential treatments of noninvasive scrotal rejuvenation include botulinum toxin for wrinkling and the SCROTUM (Sutures Can Raise by Orienting Threads in an Upward Manner) procedure for laxity.^3,4

Intrinsic (aging) and extrinsic (trauma) alterations also can result in other changes that may be amenable to vaginal or scrotal rejuvenation; for example, in addition to changes in morphology, there are hair (eg, alopecia, hypertrichosis) and vascular (eg, angiokeratomas) conditions of the vagina and scrotum that may be suitable for rejuvenation.^3-5 Dermatologists have the opportunity to provide treatment for the genital rejuvenation of their patients.

To the Editor:

I read with interest the informative Cutis article by Hashim et al,¹ which not only summarized the key features of vaginal rejuvenation but also concisely reviewed noninvasive treatments, including lasers and radiofrequency devices, that can be used to address this important issue. The authors emphasized that these treatments may represent a valuable addition to the cosmetic landscape. In addition, they also asserted that noninvasive vaginal rejuvenation is an expanding focus of cosmetic dermatology.¹

Genital rejuvenation includes rejuvenation of the vagina in women and the scrotum in men. Since the term initially appeared in the literature in 2007,² a PubMed search of articles indexed for MEDLINE yields an increasing number of articles on vaginal rejuvenation. More recently, the concept of scrotal rejuvenation was introduced in 2018.³

Similar to vaginal rejuvenation, scrotal rejuvenation includes procedures to remedy medical or cosmetic conditions of the scrotum. Hashim et al¹ focused on morphology-associated vaginal changes for which rejuvenation techniques have been successful, such as excess clitoral hood; excess labia majora or minora; vaginal laxity; and vulvovaginal atrophy, which is considered to be a component of genitourinary syndrome of menopause. Morphology-associated changes of the scrotum include wrinkling (cutis scrotum gyratum or scrotum rugosum) and laxity (low-hanging or sagging scrotum or scrotomegaly). Potential treatments of noninvasive scrotal rejuvenation include botulinum toxin for wrinkling and the SCROTUM (Sutures Can Raise by Orienting Threads in an Upward Manner) procedure for laxity.^3,4

Intrinsic (aging) and extrinsic (trauma) alterations also can result in other changes that may be amenable to vaginal or scrotal rejuvenation; for example, in addition to changes in morphology, there are hair (eg, alopecia, hypertrichosis) and vascular (eg, angiokeratomas) conditions of the vagina and scrotum that may be suitable for rejuvenation.^3-5 Dermatologists have the opportunity to provide treatment for the genital rejuvenation of their patients.

To the Editor:

I read with interest the informative Cutis article by Hashim et al,¹ which not only summarized the key features of vaginal rejuvenation but also concisely reviewed noninvasive treatments, including lasers and radiofrequency devices, that can be used to address this important issue. The authors emphasized that these treatments may represent a valuable addition to the cosmetic landscape. In addition, they also asserted that noninvasive vaginal rejuvenation is an expanding focus of cosmetic dermatology.¹

Genital rejuvenation includes rejuvenation of the vagina in women and the scrotum in men. Since the term initially appeared in the literature in 2007,² a PubMed search of articles indexed for MEDLINE yields an increasing number of articles on vaginal rejuvenation. More recently, the concept of scrotal rejuvenation was introduced in 2018.³

Similar to vaginal rejuvenation, scrotal rejuvenation includes procedures to remedy medical or cosmetic conditions of the scrotum. Hashim et al¹ focused on morphology-associated vaginal changes for which rejuvenation techniques have been successful, such as excess clitoral hood; excess labia majora or minora; vaginal laxity; and vulvovaginal atrophy, which is considered to be a component of genitourinary syndrome of menopause. Morphology-associated changes of the scrotum include wrinkling (cutis scrotum gyratum or scrotum rugosum) and laxity (low-hanging or sagging scrotum or scrotomegaly). Potential treatments of noninvasive scrotal rejuvenation include botulinum toxin for wrinkling and the SCROTUM (Sutures Can Raise by Orienting Threads in an Upward Manner) procedure for laxity.^3,4

Intrinsic (aging) and extrinsic (trauma) alterations also can result in other changes that may be amenable to vaginal or scrotal rejuvenation; for example, in addition to changes in morphology, there are hair (eg, alopecia, hypertrichosis) and vascular (eg, angiokeratomas) conditions of the vagina and scrotum that may be suitable for rejuvenation.^3-5 Dermatologists have the opportunity to provide treatment for the genital rejuvenation of their patients.