Single-nucleotide polymorphisms linked to increased bleeding risk have been identified in patients of African descent taking warfarin, investigators have reported.

Four single-nucleotide polymorphisms (SNPs) were associated with increased major bleeding risk in African Americans at an international normalized ratio (INR) of less than 4, according to results of their preliminary, retrospective study.

The preliminary findings could have implications for patients of African descent, but independent validation of the study results are needed, according to Minoli A. Perera, PharmD, PhD, of Northwestern University, Chicago, and her coauthors.

“Identifying these variants may help physicians make safer choices in anticoagulation therapy for this understudied patient population,” Dr. Perera and her colleagues wrote in JAMA.

Most prior studies looking at warfarin-related bleeding risk have included predominantly white patients and don’t account for differences in warfarin responsiveness between ethnic groups, they wrote.

Moreover, bleeding-associated SNPs have been identified, but in populations of European ancestry, they added.

The report covered results of a discovery cohort based on African American patients from a genome-wide study conducted at the University of Chicago, and a replication cohort based on patients who self-identified as African American and had routinely received care at University of Chicago hospitals.

The discovery cohort included 31 patients with major bleeding that occurred at an INR less than 4 and 184 controls with no documented history of bleeding related to warfarin.

In that cohort, Dr. Perera and her coinvestigators found four SNPs in linkage disequilibrium on chromosome 6 associated with warfarin-related bleeding, including rs115112393, rs16871327, rs78132896, and rs114504854. In particular, the rs78132896 SNP was found in 35.5% of cases (n = 11) and just 4.9% of controls (n = 9), with an odds ratio of 8.31 (95% confidence interval, 3.2-21.5).

The replication cohort, including 40 cases and 148 warfarin-treated controls, was genotyped specifically for rs78132896. That SNP was similarly found in 35.0% of cases (n = 14) and 4.8% of controls (n = 7), with an odds ratio of 8.24 (95% CI, 3.1-25.3).

“Genome-wide significance of this cohort was achieved when the cohorts were combined via meta-analysis,” said the investigators, who reported an odds ratio of 8.27 for that analysis (95% CI, 4.18-16.38).

Compared with wild-type alleles, the rs16871327 and rs78132896 risk alleles increased EPHA7 gene transcription, results of gene assay analyses further showed.

Expression of the EPHA7 gene on vascular endothelial cells and peripheral lymphocytes is increased during inflammation, according to Dr. Perera and her coauthors. Increased EPHA7 expression might lead to bleeding in patients who are taking warfarin.

“This haplotype might also have potential implications for bleeding risk with direct oral anticoagulants,” they said.

Dr. Perera and her coauthors reported no conflicts of interest related to their work on this study, which was funded by grants from the National Heart, Lung, and Blood Institute; the National Institute of General Medicine; the National Institutes of Health; and the American Heart Association Midwest Affiliate; as well as a research award from the University of Illinois at Chicago College of Pharmacy.

SOURCE: Perera MA et al. JAMA. 2018 Oct 23. doi: 10.1001/jama.2018.14955.

Single-nucleotide polymorphisms linked to increased bleeding risk have been identified in patients of African descent taking warfarin, investigators have reported.

Four single-nucleotide polymorphisms (SNPs) were associated with increased major bleeding risk in African Americans at an international normalized ratio (INR) of less than 4, according to results of their preliminary, retrospective study.

The preliminary findings could have implications for patients of African descent, but independent validation of the study results are needed, according to Minoli A. Perera, PharmD, PhD, of Northwestern University, Chicago, and her coauthors.

“Identifying these variants may help physicians make safer choices in anticoagulation therapy for this understudied patient population,” Dr. Perera and her colleagues wrote in JAMA.

Most prior studies looking at warfarin-related bleeding risk have included predominantly white patients and don’t account for differences in warfarin responsiveness between ethnic groups, they wrote.

Moreover, bleeding-associated SNPs have been identified, but in populations of European ancestry, they added.

The report covered results of a discovery cohort based on African American patients from a genome-wide study conducted at the University of Chicago, and a replication cohort based on patients who self-identified as African American and had routinely received care at University of Chicago hospitals.

The discovery cohort included 31 patients with major bleeding that occurred at an INR less than 4 and 184 controls with no documented history of bleeding related to warfarin.

In that cohort, Dr. Perera and her coinvestigators found four SNPs in linkage disequilibrium on chromosome 6 associated with warfarin-related bleeding, including rs115112393, rs16871327, rs78132896, and rs114504854. In particular, the rs78132896 SNP was found in 35.5% of cases (n = 11) and just 4.9% of controls (n = 9), with an odds ratio of 8.31 (95% confidence interval, 3.2-21.5).

The replication cohort, including 40 cases and 148 warfarin-treated controls, was genotyped specifically for rs78132896. That SNP was similarly found in 35.0% of cases (n = 14) and 4.8% of controls (n = 7), with an odds ratio of 8.24 (95% CI, 3.1-25.3).

“Genome-wide significance of this cohort was achieved when the cohorts were combined via meta-analysis,” said the investigators, who reported an odds ratio of 8.27 for that analysis (95% CI, 4.18-16.38).

Compared with wild-type alleles, the rs16871327 and rs78132896 risk alleles increased EPHA7 gene transcription, results of gene assay analyses further showed.

Expression of the EPHA7 gene on vascular endothelial cells and peripheral lymphocytes is increased during inflammation, according to Dr. Perera and her coauthors. Increased EPHA7 expression might lead to bleeding in patients who are taking warfarin.

“This haplotype might also have potential implications for bleeding risk with direct oral anticoagulants,” they said.

Dr. Perera and her coauthors reported no conflicts of interest related to their work on this study, which was funded by grants from the National Heart, Lung, and Blood Institute; the National Institute of General Medicine; the National Institutes of Health; and the American Heart Association Midwest Affiliate; as well as a research award from the University of Illinois at Chicago College of Pharmacy.

SOURCE: Perera MA et al. JAMA. 2018 Oct 23. doi: 10.1001/jama.2018.14955.

Single-nucleotide polymorphisms linked to increased bleeding risk have been identified in patients of African descent taking warfarin, investigators have reported.

Four single-nucleotide polymorphisms (SNPs) were associated with increased major bleeding risk in African Americans at an international normalized ratio (INR) of less than 4, according to results of their preliminary, retrospective study.

The preliminary findings could have implications for patients of African descent, but independent validation of the study results are needed, according to Minoli A. Perera, PharmD, PhD, of Northwestern University, Chicago, and her coauthors.

“Identifying these variants may help physicians make safer choices in anticoagulation therapy for this understudied patient population,” Dr. Perera and her colleagues wrote in JAMA.

Most prior studies looking at warfarin-related bleeding risk have included predominantly white patients and don’t account for differences in warfarin responsiveness between ethnic groups, they wrote.

Moreover, bleeding-associated SNPs have been identified, but in populations of European ancestry, they added.

The report covered results of a discovery cohort based on African American patients from a genome-wide study conducted at the University of Chicago, and a replication cohort based on patients who self-identified as African American and had routinely received care at University of Chicago hospitals.

The discovery cohort included 31 patients with major bleeding that occurred at an INR less than 4 and 184 controls with no documented history of bleeding related to warfarin.

In that cohort, Dr. Perera and her coinvestigators found four SNPs in linkage disequilibrium on chromosome 6 associated with warfarin-related bleeding, including rs115112393, rs16871327, rs78132896, and rs114504854. In particular, the rs78132896 SNP was found in 35.5% of cases (n = 11) and just 4.9% of controls (n = 9), with an odds ratio of 8.31 (95% confidence interval, 3.2-21.5).

The replication cohort, including 40 cases and 148 warfarin-treated controls, was genotyped specifically for rs78132896. That SNP was similarly found in 35.0% of cases (n = 14) and 4.8% of controls (n = 7), with an odds ratio of 8.24 (95% CI, 3.1-25.3).

“Genome-wide significance of this cohort was achieved when the cohorts were combined via meta-analysis,” said the investigators, who reported an odds ratio of 8.27 for that analysis (95% CI, 4.18-16.38).

Compared with wild-type alleles, the rs16871327 and rs78132896 risk alleles increased EPHA7 gene transcription, results of gene assay analyses further showed.

Expression of the EPHA7 gene on vascular endothelial cells and peripheral lymphocytes is increased during inflammation, according to Dr. Perera and her coauthors. Increased EPHA7 expression might lead to bleeding in patients who are taking warfarin.

“This haplotype might also have potential implications for bleeding risk with direct oral anticoagulants,” they said.

Dr. Perera and her coauthors reported no conflicts of interest related to their work on this study, which was funded by grants from the National Heart, Lung, and Blood Institute; the National Institute of General Medicine; the National Institutes of Health; and the American Heart Association Midwest Affiliate; as well as a research award from the University of Illinois at Chicago College of Pharmacy.

SOURCE: Perera MA et al. JAMA. 2018 Oct 23. doi: 10.1001/jama.2018.14955.

TORONTO – Prophylactic cranial irradiation, which is standard-of-care practice in patients with small cell lung cancer, also appears to improve intracranial progression-free survival (iPFS) and overall survival in patients with stage IV non–small cell lung cancer (NSCLC), according to findings from a randomized study.

The cumulative incidence of brain metastases at 2 years was 22% in 41 patients who received prophylactic cranial irradiation (PCI), compared with 52% in 43 patients who received standard care with first- and second-generation tyrosine kinase inhibitors (TKIs) without PCI, Oscar Arrieta, MD, reported at the World Conference on Lung Cancer.

PCI was associated with lower odds of progression to the CNS (odds ratio, 0.16), Dr. Arrieta, of the National Cancer Institute of Mexico, Mexico City, said at the meeting sponsored by the International Association for the Study of Lung Cancer. Further, the relative risk for iPFS in patients with an epithelial growth factor receptor (EGFR) or anaplastic lymphoma kinase mutation (ALK), who comprised 70% of patients in both groups, was 0.29 with PCI.

Median overall survival in the groups was 42.8 months versus 25.9 months (HR, 0.48).

The burden of brain metastases can impact the quality and length of survival in patients with NSCLC, and because of an aging population and advances in detection and treatment of primary cancers, patients are living longer and thus are more likely to experience brain metastases, Dr. Arrieta said, noting that this is particularly true for patients at high risk, such as those with elevated carcinoembryonic antigen levels.

Although PCI is standard in small cell lung cancer, its role in NSCLC remains controversial because of concerns about neurologic morbidity and lack of overall survival benefit, he explained.

“The objective of this study was to determine if the use of PCI reduced the development of brain metastases and improved the survival in this population without impairing quality of life,” he said.

Study participants were patients with confirmed stage IV NSCLC and adenocarcinoma histology at high risk for developing brain metastasis. PCI in the treatment group was delivered at 25 Gy/10 fractions.

The findings suggest that in NSCLC with a high risk of developing brain metastases who are treated with a first- or second-generation TKI – particularly those with EGFR and ALK mutations – PCI increases iPFS, Dr. Arrieta said.

“The findings can be extrapolated to those treated with third-generation TKIs, which have higher CNS penetration,” he said, noting, however, that access to third-generation TKIs is limited in most developing countries and cost barriers are high.

Of note, the relatively low dose of PCI used in this study was not associated with significant differences in Mini-Mental State Examination or quality of life scores in the short-term. Long-term assessments are needed, he said, concluding that, while additional study is needed to confirm the findings, the results, including the overall survival benefit seen with PCI, “highlight the benefits of this approach, particularly among patients with a high risk of developing brain metastases.”

Invited discussant Nasser Hanna, MD, the Tom and Julie Wood Family Foundation Professor of Lung Cancer Clinical Research at Indiana University, Indianapolis, said the findings of this “interesting and important study,” are intriguing, but agreed that additional study is needed.

“The study is far too small ... to definitively make this conclusion [that PCI improves iPFS in this population]; I would not recommend PCI without confirmatory data from larger, randomized trials,” he said.

Dr. Arrieta reported advisory roles or provision of expert testimony for Eli Lilly, AstraZeneca, Boehringer Ingelheim, Roche, Merck, Takeda, and Bristol-Myers Squibb, and receipt of honoraria and/or research funding from AstraZeneca, Boehringer Ingelheim, Merck, Roche, and Bristol-Myers Squibb. Dr. Nasser reported receiving research grants from Bristol-Myers Squibb, AstraZeneca, Genentech, and Merck.

SOURCE: Arrieta O et al. WCLC 2018, Abstract MA08.02.

TORONTO – Prophylactic cranial irradiation, which is standard-of-care practice in patients with small cell lung cancer, also appears to improve intracranial progression-free survival (iPFS) and overall survival in patients with stage IV non–small cell lung cancer (NSCLC), according to findings from a randomized study.

The cumulative incidence of brain metastases at 2 years was 22% in 41 patients who received prophylactic cranial irradiation (PCI), compared with 52% in 43 patients who received standard care with first- and second-generation tyrosine kinase inhibitors (TKIs) without PCI, Oscar Arrieta, MD, reported at the World Conference on Lung Cancer.

PCI was associated with lower odds of progression to the CNS (odds ratio, 0.16), Dr. Arrieta, of the National Cancer Institute of Mexico, Mexico City, said at the meeting sponsored by the International Association for the Study of Lung Cancer. Further, the relative risk for iPFS in patients with an epithelial growth factor receptor (EGFR) or anaplastic lymphoma kinase mutation (ALK), who comprised 70% of patients in both groups, was 0.29 with PCI.

Median overall survival in the groups was 42.8 months versus 25.9 months (HR, 0.48).

The burden of brain metastases can impact the quality and length of survival in patients with NSCLC, and because of an aging population and advances in detection and treatment of primary cancers, patients are living longer and thus are more likely to experience brain metastases, Dr. Arrieta said, noting that this is particularly true for patients at high risk, such as those with elevated carcinoembryonic antigen levels.

Although PCI is standard in small cell lung cancer, its role in NSCLC remains controversial because of concerns about neurologic morbidity and lack of overall survival benefit, he explained.

“The objective of this study was to determine if the use of PCI reduced the development of brain metastases and improved the survival in this population without impairing quality of life,” he said.

Study participants were patients with confirmed stage IV NSCLC and adenocarcinoma histology at high risk for developing brain metastasis. PCI in the treatment group was delivered at 25 Gy/10 fractions.

The findings suggest that in NSCLC with a high risk of developing brain metastases who are treated with a first- or second-generation TKI – particularly those with EGFR and ALK mutations – PCI increases iPFS, Dr. Arrieta said.

“The findings can be extrapolated to those treated with third-generation TKIs, which have higher CNS penetration,” he said, noting, however, that access to third-generation TKIs is limited in most developing countries and cost barriers are high.

Of note, the relatively low dose of PCI used in this study was not associated with significant differences in Mini-Mental State Examination or quality of life scores in the short-term. Long-term assessments are needed, he said, concluding that, while additional study is needed to confirm the findings, the results, including the overall survival benefit seen with PCI, “highlight the benefits of this approach, particularly among patients with a high risk of developing brain metastases.”

Invited discussant Nasser Hanna, MD, the Tom and Julie Wood Family Foundation Professor of Lung Cancer Clinical Research at Indiana University, Indianapolis, said the findings of this “interesting and important study,” are intriguing, but agreed that additional study is needed.

“The study is far too small ... to definitively make this conclusion [that PCI improves iPFS in this population]; I would not recommend PCI without confirmatory data from larger, randomized trials,” he said.

Dr. Arrieta reported advisory roles or provision of expert testimony for Eli Lilly, AstraZeneca, Boehringer Ingelheim, Roche, Merck, Takeda, and Bristol-Myers Squibb, and receipt of honoraria and/or research funding from AstraZeneca, Boehringer Ingelheim, Merck, Roche, and Bristol-Myers Squibb. Dr. Nasser reported receiving research grants from Bristol-Myers Squibb, AstraZeneca, Genentech, and Merck.

SOURCE: Arrieta O et al. WCLC 2018, Abstract MA08.02.

TORONTO – Prophylactic cranial irradiation, which is standard-of-care practice in patients with small cell lung cancer, also appears to improve intracranial progression-free survival (iPFS) and overall survival in patients with stage IV non–small cell lung cancer (NSCLC), according to findings from a randomized study.

The cumulative incidence of brain metastases at 2 years was 22% in 41 patients who received prophylactic cranial irradiation (PCI), compared with 52% in 43 patients who received standard care with first- and second-generation tyrosine kinase inhibitors (TKIs) without PCI, Oscar Arrieta, MD, reported at the World Conference on Lung Cancer.

PCI was associated with lower odds of progression to the CNS (odds ratio, 0.16), Dr. Arrieta, of the National Cancer Institute of Mexico, Mexico City, said at the meeting sponsored by the International Association for the Study of Lung Cancer. Further, the relative risk for iPFS in patients with an epithelial growth factor receptor (EGFR) or anaplastic lymphoma kinase mutation (ALK), who comprised 70% of patients in both groups, was 0.29 with PCI.

Median overall survival in the groups was 42.8 months versus 25.9 months (HR, 0.48).

The burden of brain metastases can impact the quality and length of survival in patients with NSCLC, and because of an aging population and advances in detection and treatment of primary cancers, patients are living longer and thus are more likely to experience brain metastases, Dr. Arrieta said, noting that this is particularly true for patients at high risk, such as those with elevated carcinoembryonic antigen levels.

Although PCI is standard in small cell lung cancer, its role in NSCLC remains controversial because of concerns about neurologic morbidity and lack of overall survival benefit, he explained.

“The objective of this study was to determine if the use of PCI reduced the development of brain metastases and improved the survival in this population without impairing quality of life,” he said.

Study participants were patients with confirmed stage IV NSCLC and adenocarcinoma histology at high risk for developing brain metastasis. PCI in the treatment group was delivered at 25 Gy/10 fractions.

The findings suggest that in NSCLC with a high risk of developing brain metastases who are treated with a first- or second-generation TKI – particularly those with EGFR and ALK mutations – PCI increases iPFS, Dr. Arrieta said.

“The findings can be extrapolated to those treated with third-generation TKIs, which have higher CNS penetration,” he said, noting, however, that access to third-generation TKIs is limited in most developing countries and cost barriers are high.

Of note, the relatively low dose of PCI used in this study was not associated with significant differences in Mini-Mental State Examination or quality of life scores in the short-term. Long-term assessments are needed, he said, concluding that, while additional study is needed to confirm the findings, the results, including the overall survival benefit seen with PCI, “highlight the benefits of this approach, particularly among patients with a high risk of developing brain metastases.”

Invited discussant Nasser Hanna, MD, the Tom and Julie Wood Family Foundation Professor of Lung Cancer Clinical Research at Indiana University, Indianapolis, said the findings of this “interesting and important study,” are intriguing, but agreed that additional study is needed.

“The study is far too small ... to definitively make this conclusion [that PCI improves iPFS in this population]; I would not recommend PCI without confirmatory data from larger, randomized trials,” he said.

Dr. Arrieta reported advisory roles or provision of expert testimony for Eli Lilly, AstraZeneca, Boehringer Ingelheim, Roche, Merck, Takeda, and Bristol-Myers Squibb, and receipt of honoraria and/or research funding from AstraZeneca, Boehringer Ingelheim, Merck, Roche, and Bristol-Myers Squibb. Dr. Nasser reported receiving research grants from Bristol-Myers Squibb, AstraZeneca, Genentech, and Merck.

SOURCE: Arrieta O et al. WCLC 2018, Abstract MA08.02.

CHICAGO – Rheumatoid arthritis–associated interstitial lung disease and idiopathic pulmonary fibrosis without RA share a common genetic underpinning whose hallmark is a gain-of-function MUC5B gene promoter variant that cranks up mucin production in the lungs, Pierre-Antoine Juge, MD, reported at the annual meeting of the American College of Rheumatology.

Bruce Jancin/MDedge News

He presented a seven-country genetic case-control study of 620 patients with RA-associated interstitial lung disease (RA-ILD), 614 with RA but no ILD, and 5,448 unaffected controls. The key finding was that the MUC5B promoter variant rs35705950, already known to be the strongest genetic risk factor for idiopathic pulmonary fibrosis (IPF), also contributes substantially to the risk of RA-ILD.

Indeed, the presence of the MUC5B promoter variant in patients with RA proved to be associated with substantially higher risk of RA-ILD than the previously recognized risk factors for RA-ILD, including cigarette smoking and the human leukocyte antigen locus for RA, according to Dr. Juge, a rheumatologist at Bichat Hospital–Claude Bernard and Paris Diderot University.


MUC5B encodes for mucin production in the lungs. The increased risk of RA-ILD conferred by the presence of the MUC5B promoter variant was confined to the 41% of RA-ILD patients with a pattern of usual interstitial pneumonia (UIP) or possible UIP on high-resolution CT. The presence of the MUC5B promoter variant in RA patients was independently associated with an adjusted 6.1-fold increased risk of ILD with a UIP pattern on imaging – marked by honeycombing, reticular abnormalities, and subpleural involvement – compared with RA patients who didn’t possess the gain-of-function MUC5B variant. The risk of other types of RA-ILD wasn’t affected by the presence or absence of the MUC5B variant.

The MUC5B promoter variant was not a risk factor for development of RA.

These findings have potentially important implications for clinical practice, given that clinically significant ILD is present in about 10% of all RA patients and occult ILD is detectable using high-resolution CT in up to half of individuals with RA, Dr. Juge observed. Detection of the MUC5B promoter variant could be used to screen patients with RA for preclinical ILD. Also, there is now a sound rationale to study drugs known to be effective for IPF as potential treatments for RA-ILD, he said.

Dr. Juge reported having no financial conflicts regarding the study, which was sponsored by the National Institutes of Health, the U.S. Department of Defense, the French Rheumatology Society, the Japanese Society for the Promotion of Science, Fondation Arthritis, and the Nina Ireland Program for Lung Health.

In conjunction with his presentation in Chicago, the study was published online in the New England Journal of Medicine (doi: 10.1056/NEJMoa1801562).

[email protected]

SOURCE: Juge P-A et al. Arthritis Rheumatol. 2018;70(Suppl 10): Abstract 1819.

CHICAGO – Rheumatoid arthritis–associated interstitial lung disease and idiopathic pulmonary fibrosis without RA share a common genetic underpinning whose hallmark is a gain-of-function MUC5B gene promoter variant that cranks up mucin production in the lungs, Pierre-Antoine Juge, MD, reported at the annual meeting of the American College of Rheumatology.

Bruce Jancin/MDedge News

He presented a seven-country genetic case-control study of 620 patients with RA-associated interstitial lung disease (RA-ILD), 614 with RA but no ILD, and 5,448 unaffected controls. The key finding was that the MUC5B promoter variant rs35705950, already known to be the strongest genetic risk factor for idiopathic pulmonary fibrosis (IPF), also contributes substantially to the risk of RA-ILD.

Indeed, the presence of the MUC5B promoter variant in patients with RA proved to be associated with substantially higher risk of RA-ILD than the previously recognized risk factors for RA-ILD, including cigarette smoking and the human leukocyte antigen locus for RA, according to Dr. Juge, a rheumatologist at Bichat Hospital–Claude Bernard and Paris Diderot University.


MUC5B encodes for mucin production in the lungs. The increased risk of RA-ILD conferred by the presence of the MUC5B promoter variant was confined to the 41% of RA-ILD patients with a pattern of usual interstitial pneumonia (UIP) or possible UIP on high-resolution CT. The presence of the MUC5B promoter variant in RA patients was independently associated with an adjusted 6.1-fold increased risk of ILD with a UIP pattern on imaging – marked by honeycombing, reticular abnormalities, and subpleural involvement – compared with RA patients who didn’t possess the gain-of-function MUC5B variant. The risk of other types of RA-ILD wasn’t affected by the presence or absence of the MUC5B variant.

The MUC5B promoter variant was not a risk factor for development of RA.

These findings have potentially important implications for clinical practice, given that clinically significant ILD is present in about 10% of all RA patients and occult ILD is detectable using high-resolution CT in up to half of individuals with RA, Dr. Juge observed. Detection of the MUC5B promoter variant could be used to screen patients with RA for preclinical ILD. Also, there is now a sound rationale to study drugs known to be effective for IPF as potential treatments for RA-ILD, he said.

Dr. Juge reported having no financial conflicts regarding the study, which was sponsored by the National Institutes of Health, the U.S. Department of Defense, the French Rheumatology Society, the Japanese Society for the Promotion of Science, Fondation Arthritis, and the Nina Ireland Program for Lung Health.

In conjunction with his presentation in Chicago, the study was published online in the New England Journal of Medicine (doi: 10.1056/NEJMoa1801562).

[email protected]

SOURCE: Juge P-A et al. Arthritis Rheumatol. 2018;70(Suppl 10): Abstract 1819.

CHICAGO – Rheumatoid arthritis–associated interstitial lung disease and idiopathic pulmonary fibrosis without RA share a common genetic underpinning whose hallmark is a gain-of-function MUC5B gene promoter variant that cranks up mucin production in the lungs, Pierre-Antoine Juge, MD, reported at the annual meeting of the American College of Rheumatology.

Bruce Jancin/MDedge News

He presented a seven-country genetic case-control study of 620 patients with RA-associated interstitial lung disease (RA-ILD), 614 with RA but no ILD, and 5,448 unaffected controls. The key finding was that the MUC5B promoter variant rs35705950, already known to be the strongest genetic risk factor for idiopathic pulmonary fibrosis (IPF), also contributes substantially to the risk of RA-ILD.

Indeed, the presence of the MUC5B promoter variant in patients with RA proved to be associated with substantially higher risk of RA-ILD than the previously recognized risk factors for RA-ILD, including cigarette smoking and the human leukocyte antigen locus for RA, according to Dr. Juge, a rheumatologist at Bichat Hospital–Claude Bernard and Paris Diderot University.


MUC5B encodes for mucin production in the lungs. The increased risk of RA-ILD conferred by the presence of the MUC5B promoter variant was confined to the 41% of RA-ILD patients with a pattern of usual interstitial pneumonia (UIP) or possible UIP on high-resolution CT. The presence of the MUC5B promoter variant in RA patients was independently associated with an adjusted 6.1-fold increased risk of ILD with a UIP pattern on imaging – marked by honeycombing, reticular abnormalities, and subpleural involvement – compared with RA patients who didn’t possess the gain-of-function MUC5B variant. The risk of other types of RA-ILD wasn’t affected by the presence or absence of the MUC5B variant.

The MUC5B promoter variant was not a risk factor for development of RA.

These findings have potentially important implications for clinical practice, given that clinically significant ILD is present in about 10% of all RA patients and occult ILD is detectable using high-resolution CT in up to half of individuals with RA, Dr. Juge observed. Detection of the MUC5B promoter variant could be used to screen patients with RA for preclinical ILD. Also, there is now a sound rationale to study drugs known to be effective for IPF as potential treatments for RA-ILD, he said.

Dr. Juge reported having no financial conflicts regarding the study, which was sponsored by the National Institutes of Health, the U.S. Department of Defense, the French Rheumatology Society, the Japanese Society for the Promotion of Science, Fondation Arthritis, and the Nina Ireland Program for Lung Health.

In conjunction with his presentation in Chicago, the study was published online in the New England Journal of Medicine (doi: 10.1056/NEJMoa1801562).

[email protected]

SOURCE: Juge P-A et al. Arthritis Rheumatol. 2018;70(Suppl 10): Abstract 1819.

Palindromic rheumatism, while often challenging to distinguish from persistent arthritis, has a distinct imaging pattern characterized by extracapsular inflammation, often with no synovitis, results of a recent prospective study show.

Finding the phenotype on ultrasound evaluation may help to separate cases of inflammatory arthritis, which may need early disease-modifying treatment, from palindromic rheumatism, which can be managed conservatively, the study authors reported in Annals of the Rheumatic Diseases.

“These findings may refine diagnosis and improve management of this important condition,” wrote Kulveer Mankia, MD, of the Leeds (England) Institute of Rheumatic and Musculoskeletal Medicine, and his coauthors.

High-resolution imaging studies in palindromic rheumatism have been sparse, in part because of the sporadic nature of flares in these patients, according to Dr. Mankia and his colleagues.

Their report included 79 patients with palindromic rheumatism recruited from two U.K. rheumatology clinics and a national primary care program and compared them with other populations.

The patients underwent ultrasound evaluation by experienced rheumatologists and sonographers, as well as MRI on the most symptomatic region during flares. Those results were compared with clinical and ultrasound assessments in a cohort of patients with new-onset RA, and a second cohort of anticyclic citrullinated peptide (CCP)–positive at-risk individuals.

The investigators were able to assess 31 of the palindromic rheumatism patients during a flare episode. Extracapsular inflammation was frequently found during these episodes, with one or more instances of periarticular inflammation, peritendinous edema, or subcutaneous edema occurring in 19 (61%) of 31 patients.


However, tenosynovitis was detected in just seven of those patients (23%), while peritendinous edema was seen in three (10%).

By contrast, ultrasound abnormalities were infrequent in 27 nonflare evaluations taken in those 31 patients. For example, just four scans (15%) showed extracapsular inflammation.

Overall, extracapsular inflammation was found in 65% of palindromic rheumatism patients, compared with just 29% of new-onset RA cases (P less than .023).

Of particular note, extracapsular inflammation without synovitis was specific for palindromic rheumatism, occurring in 42%, compared with only 4% of RA cases (P = .003) and 6% of anti–CCP-positive at-risk patients (P = .0012).

A total of 13 of the 79 palindromic rheumatism patients (16%) went on to develop persistent inflammatory arthritis over a median follow-up of 42-49 days. Of the 31 patients evaluated during flare, 7 (23%) developed persistent inflammatory arthritis over the follow-up period. Those seven patients all met American College of Rheumatology/European League Against Rheumatism (EULAR) 2010 classification criteria for RA.

The MRI studies concurred with the ultrasound findings and identified some additional abnormalities, the investigators reported.

Altogether, these imaging findings are important to note because of the “variable” progression seen in palindromic rheumatism, Dr. Mankia and his colleagues wrote.

While anti-CCP antibody positivity confers high risk of progression in palindromic rheumatism, presence of this marker does not always mean the patient will develop persistent arthritis on follow-up, they added. In fact, this study showed that, among 47 anti–CCP-positive palindromic rheumatism patients, 35 (74%) did not develop persistent inflammatory arthritis in follow-up.

“In clinical practice, these patients may be inappropriately treated [e.g., with methotrexate] as they often meet ACR/EULAR criteria for rheumatoid arthritis,” the investigators wrote in their report.

Funding for the study came from the National Institute for Health Research Leeds Clinical Research Facility with additional support from an Arthritis Research U.K. grant. The authors reported no competing interests related to their study.

SOURCE: Mankia K et al. Ann Rheum Dis. 2018 Oct 8. doi: 10.1136/annrheumdis-2018-214175.

Palindromic rheumatism, while often challenging to distinguish from persistent arthritis, has a distinct imaging pattern characterized by extracapsular inflammation, often with no synovitis, results of a recent prospective study show.

Finding the phenotype on ultrasound evaluation may help to separate cases of inflammatory arthritis, which may need early disease-modifying treatment, from palindromic rheumatism, which can be managed conservatively, the study authors reported in Annals of the Rheumatic Diseases.

“These findings may refine diagnosis and improve management of this important condition,” wrote Kulveer Mankia, MD, of the Leeds (England) Institute of Rheumatic and Musculoskeletal Medicine, and his coauthors.

High-resolution imaging studies in palindromic rheumatism have been sparse, in part because of the sporadic nature of flares in these patients, according to Dr. Mankia and his colleagues.

Their report included 79 patients with palindromic rheumatism recruited from two U.K. rheumatology clinics and a national primary care program and compared them with other populations.

The patients underwent ultrasound evaluation by experienced rheumatologists and sonographers, as well as MRI on the most symptomatic region during flares. Those results were compared with clinical and ultrasound assessments in a cohort of patients with new-onset RA, and a second cohort of anticyclic citrullinated peptide (CCP)–positive at-risk individuals.

The investigators were able to assess 31 of the palindromic rheumatism patients during a flare episode. Extracapsular inflammation was frequently found during these episodes, with one or more instances of periarticular inflammation, peritendinous edema, or subcutaneous edema occurring in 19 (61%) of 31 patients.


However, tenosynovitis was detected in just seven of those patients (23%), while peritendinous edema was seen in three (10%).

By contrast, ultrasound abnormalities were infrequent in 27 nonflare evaluations taken in those 31 patients. For example, just four scans (15%) showed extracapsular inflammation.

Overall, extracapsular inflammation was found in 65% of palindromic rheumatism patients, compared with just 29% of new-onset RA cases (P less than .023).

Of particular note, extracapsular inflammation without synovitis was specific for palindromic rheumatism, occurring in 42%, compared with only 4% of RA cases (P = .003) and 6% of anti–CCP-positive at-risk patients (P = .0012).

A total of 13 of the 79 palindromic rheumatism patients (16%) went on to develop persistent inflammatory arthritis over a median follow-up of 42-49 days. Of the 31 patients evaluated during flare, 7 (23%) developed persistent inflammatory arthritis over the follow-up period. Those seven patients all met American College of Rheumatology/European League Against Rheumatism (EULAR) 2010 classification criteria for RA.

The MRI studies concurred with the ultrasound findings and identified some additional abnormalities, the investigators reported.

Altogether, these imaging findings are important to note because of the “variable” progression seen in palindromic rheumatism, Dr. Mankia and his colleagues wrote.

While anti-CCP antibody positivity confers high risk of progression in palindromic rheumatism, presence of this marker does not always mean the patient will develop persistent arthritis on follow-up, they added. In fact, this study showed that, among 47 anti–CCP-positive palindromic rheumatism patients, 35 (74%) did not develop persistent inflammatory arthritis in follow-up.

“In clinical practice, these patients may be inappropriately treated [e.g., with methotrexate] as they often meet ACR/EULAR criteria for rheumatoid arthritis,” the investigators wrote in their report.

Funding for the study came from the National Institute for Health Research Leeds Clinical Research Facility with additional support from an Arthritis Research U.K. grant. The authors reported no competing interests related to their study.

SOURCE: Mankia K et al. Ann Rheum Dis. 2018 Oct 8. doi: 10.1136/annrheumdis-2018-214175.

Palindromic rheumatism, while often challenging to distinguish from persistent arthritis, has a distinct imaging pattern characterized by extracapsular inflammation, often with no synovitis, results of a recent prospective study show.

Finding the phenotype on ultrasound evaluation may help to separate cases of inflammatory arthritis, which may need early disease-modifying treatment, from palindromic rheumatism, which can be managed conservatively, the study authors reported in Annals of the Rheumatic Diseases.

“These findings may refine diagnosis and improve management of this important condition,” wrote Kulveer Mankia, MD, of the Leeds (England) Institute of Rheumatic and Musculoskeletal Medicine, and his coauthors.

High-resolution imaging studies in palindromic rheumatism have been sparse, in part because of the sporadic nature of flares in these patients, according to Dr. Mankia and his colleagues.

Their report included 79 patients with palindromic rheumatism recruited from two U.K. rheumatology clinics and a national primary care program and compared them with other populations.

The patients underwent ultrasound evaluation by experienced rheumatologists and sonographers, as well as MRI on the most symptomatic region during flares. Those results were compared with clinical and ultrasound assessments in a cohort of patients with new-onset RA, and a second cohort of anticyclic citrullinated peptide (CCP)–positive at-risk individuals.

The investigators were able to assess 31 of the palindromic rheumatism patients during a flare episode. Extracapsular inflammation was frequently found during these episodes, with one or more instances of periarticular inflammation, peritendinous edema, or subcutaneous edema occurring in 19 (61%) of 31 patients.


However, tenosynovitis was detected in just seven of those patients (23%), while peritendinous edema was seen in three (10%).

By contrast, ultrasound abnormalities were infrequent in 27 nonflare evaluations taken in those 31 patients. For example, just four scans (15%) showed extracapsular inflammation.

Overall, extracapsular inflammation was found in 65% of palindromic rheumatism patients, compared with just 29% of new-onset RA cases (P less than .023).

Of particular note, extracapsular inflammation without synovitis was specific for palindromic rheumatism, occurring in 42%, compared with only 4% of RA cases (P = .003) and 6% of anti–CCP-positive at-risk patients (P = .0012).

A total of 13 of the 79 palindromic rheumatism patients (16%) went on to develop persistent inflammatory arthritis over a median follow-up of 42-49 days. Of the 31 patients evaluated during flare, 7 (23%) developed persistent inflammatory arthritis over the follow-up period. Those seven patients all met American College of Rheumatology/European League Against Rheumatism (EULAR) 2010 classification criteria for RA.

The MRI studies concurred with the ultrasound findings and identified some additional abnormalities, the investigators reported.

Altogether, these imaging findings are important to note because of the “variable” progression seen in palindromic rheumatism, Dr. Mankia and his colleagues wrote.

While anti-CCP antibody positivity confers high risk of progression in palindromic rheumatism, presence of this marker does not always mean the patient will develop persistent arthritis on follow-up, they added. In fact, this study showed that, among 47 anti–CCP-positive palindromic rheumatism patients, 35 (74%) did not develop persistent inflammatory arthritis in follow-up.

“In clinical practice, these patients may be inappropriately treated [e.g., with methotrexate] as they often meet ACR/EULAR criteria for rheumatoid arthritis,” the investigators wrote in their report.

Funding for the study came from the National Institute for Health Research Leeds Clinical Research Facility with additional support from an Arthritis Research U.K. grant. The authors reported no competing interests related to their study.

SOURCE: Mankia K et al. Ann Rheum Dis. 2018 Oct 8. doi: 10.1136/annrheumdis-2018-214175.

Six years ago, there was an outbreak of fungal meningitis from improperly manufactured intrathecal steroid by a criminal pharmacist and pharmacy owner. Physicians, who had nothing to do with the pharmacy, are still struggling with the fallout from this.

In particular, 2 years ago, Ohio became the test state for outrageous restrictions on physician’s use of medications in their offices by a state pharmacy board (see “Beware the state pharmacy board,” Dermatology News, June 3, 2016). These rules degrade patient care by making medications inaccessible and much more expensive, and by eliminating office treatment options – and make the practice of medicine much more difficult.

However, since the original promulgation of these rules in Ohio, organized medicine at the state and national level has resisted and has made some progress.

In its recently published draft guidance for industry, the Food and Drug Administration excluded physician offices from enforcement in its compounding rules. While this is a great victory, the guidance also mentioned that physicians may be subject to rules promulgated by the U.S. Pharmacopeia (USP) and state pharmacy boards, who have adopted USP guidelines to physician offices in the past. Thus, our focus shifts to the USP.

The USP is a private, nongovernmental private organization of mostly pharmacists and national medical society representatives, organized to create a reference of uniform preparations for the most commonly used drugs – with tests to ensure their quality, potency, and purity. This has been a very good thing for American medicine, but the compounding chapter is written by pharmacists, to apply to compounding pharmacies. That is fine. The problem arises when you redefine a physician’s office as a compounding pharmacy. This is what took place in Ohio, and what pharmacy boards want to do nationwide.

Do not be naive. This is a national scope of practice issue that could determine how physicians can use medications in their offices. In Ohio, they were particularly devious in my opinion. The state legislature (in an omnibus spending bill) explicitly expanded the Ohio Board of Pharmacy’s mandate to supervise the “compounding of hazardous medications.” I think the legislature, the state medical society, and everyone else assumed this meant drugs manufactured and sold by compounding pharmacies, such as intrathecal steroids.

The pharmacy board readily recognized an opening here and went on to define hazardous drugs as any prescription drug, and compounding as mixture or even sterile dilution of any prescription drug. The board then proposed a $112 dollar annual licensing fee (since reduced to $55) that would affect, doctors, dentists, and even veterinarians.

When the rules were first published, there was outrage. The board was even going to require a compounding license to reconstitute vaccines. This requirement was quickly withdrawn when it was pointed out that vaccines were advertised for sale at pharmacies, an obvious restraint of trade issue.

So, what’s the big deal with paying $55 a year for a compounding license from the pharmacy board? It involves a 17-page form, and you must agree to unannounced inspections of your office. A northern Ohio physician who obtained his terminal distribution of drugs and compounding license had an almost immediate unannounced inspection, where he was cited for an unlocked sample closet door, expired samples, and for not recording all the lot numbers of each sample dispensed. He also was cited for not having a separate clean drawing room in which he mixed his syringes and for not discarding any reconstitutions or mixtures not used. Think botulinum toxin here. He was required to draft a remediation plan, which includes recording all medications compounded (anything mixed in a syringe!) in separate log books (conventional medical records are not adequate) and recording lot numbers of all samples dispensed. Consider a log entry each time you dilute Kenalog for injection or buffer lidocaine.

Do not think you will fly under the radar here. I expect state pharmacy boards to requisition botulinum toxin and bicarbonate purchase records from supply houses and to investigate purchasers. They can cite you for $3,000 per violation and can also instruct suppliers to no longer sell product to you.

USP Rules

The revised USP rules are a difficult fit for physicians’ offices. Because they have granted a 1-hour exemption, you will have to use buffered lidocaine and reconstituted botulinum toxin in 1 hour or less, then discard it under these rules. This means you cannot draw up all your buffered lidocaine for the day in the morning and use it throughout the day; never mind that there are good data showing redrawn syringes of buffered lidocaine and botulinum toxin are stable for several weeks in a refrigerator (J Clin Neurol. 2013 Jul;9[3]:157-64).

I think these rules eventually will be settled by a restraint of trade lawsuit. After all, none can be shown to improve patient care; in fact, they degrade it and increase the costs to patients and physicians. We may end up being grateful that the U.S. Supreme Court emasculated state professional boards in the famous 2015 North Carolina tooth-whitening ruling.

The USP is accepting comments about the rules until Nov. 30th. The American Academy of Dermatology has a suggested letter to the USP Compounding Expert Committee on its website, which suggests that you ask for at least a 12-hour exemption.

I strongly suggest you write and explain why pharmacy board regulations that interfere with a physician’s ability to administer individualized, customized medication will hurt your patients and will cost more. Physicians have been treating their patients with individualized, customized medications for more than 2,000 years. It seems unreasonable to hand this skillful and essential part of medicine over to pharmacists in the absence of any compelling evidence.

Dr. Coldiron is in private practice but maintains a clinical assistant professorship at the University of Cincinnati. He cares for patients, teaches medical students and residents, and has several active clinical research projects. Dr. Coldiron is the author of more than 80 scientific letters, papers, and several book chapters, and he speaks frequently on a variety of topics. He is a past president of the American Academy of Dermatology. Write to him at [email protected].



 

Six years ago, there was an outbreak of fungal meningitis from improperly manufactured intrathecal steroid by a criminal pharmacist and pharmacy owner. Physicians, who had nothing to do with the pharmacy, are still struggling with the fallout from this.

In particular, 2 years ago, Ohio became the test state for outrageous restrictions on physician’s use of medications in their offices by a state pharmacy board (see “Beware the state pharmacy board,” Dermatology News, June 3, 2016). These rules degrade patient care by making medications inaccessible and much more expensive, and by eliminating office treatment options – and make the practice of medicine much more difficult.

However, since the original promulgation of these rules in Ohio, organized medicine at the state and national level has resisted and has made some progress.

In its recently published draft guidance for industry, the Food and Drug Administration excluded physician offices from enforcement in its compounding rules. While this is a great victory, the guidance also mentioned that physicians may be subject to rules promulgated by the U.S. Pharmacopeia (USP) and state pharmacy boards, who have adopted USP guidelines to physician offices in the past. Thus, our focus shifts to the USP.

The USP is a private, nongovernmental private organization of mostly pharmacists and national medical society representatives, organized to create a reference of uniform preparations for the most commonly used drugs – with tests to ensure their quality, potency, and purity. This has been a very good thing for American medicine, but the compounding chapter is written by pharmacists, to apply to compounding pharmacies. That is fine. The problem arises when you redefine a physician’s office as a compounding pharmacy. This is what took place in Ohio, and what pharmacy boards want to do nationwide.

Do not be naive. This is a national scope of practice issue that could determine how physicians can use medications in their offices. In Ohio, they were particularly devious in my opinion. The state legislature (in an omnibus spending bill) explicitly expanded the Ohio Board of Pharmacy’s mandate to supervise the “compounding of hazardous medications.” I think the legislature, the state medical society, and everyone else assumed this meant drugs manufactured and sold by compounding pharmacies, such as intrathecal steroids.

The pharmacy board readily recognized an opening here and went on to define hazardous drugs as any prescription drug, and compounding as mixture or even sterile dilution of any prescription drug. The board then proposed a $112 dollar annual licensing fee (since reduced to $55) that would affect, doctors, dentists, and even veterinarians.

When the rules were first published, there was outrage. The board was even going to require a compounding license to reconstitute vaccines. This requirement was quickly withdrawn when it was pointed out that vaccines were advertised for sale at pharmacies, an obvious restraint of trade issue.

So, what’s the big deal with paying $55 a year for a compounding license from the pharmacy board? It involves a 17-page form, and you must agree to unannounced inspections of your office. A northern Ohio physician who obtained his terminal distribution of drugs and compounding license had an almost immediate unannounced inspection, where he was cited for an unlocked sample closet door, expired samples, and for not recording all the lot numbers of each sample dispensed. He also was cited for not having a separate clean drawing room in which he mixed his syringes and for not discarding any reconstitutions or mixtures not used. Think botulinum toxin here. He was required to draft a remediation plan, which includes recording all medications compounded (anything mixed in a syringe!) in separate log books (conventional medical records are not adequate) and recording lot numbers of all samples dispensed. Consider a log entry each time you dilute Kenalog for injection or buffer lidocaine.

Do not think you will fly under the radar here. I expect state pharmacy boards to requisition botulinum toxin and bicarbonate purchase records from supply houses and to investigate purchasers. They can cite you for $3,000 per violation and can also instruct suppliers to no longer sell product to you.

USP Rules

The revised USP rules are a difficult fit for physicians’ offices. Because they have granted a 1-hour exemption, you will have to use buffered lidocaine and reconstituted botulinum toxin in 1 hour or less, then discard it under these rules. This means you cannot draw up all your buffered lidocaine for the day in the morning and use it throughout the day; never mind that there are good data showing redrawn syringes of buffered lidocaine and botulinum toxin are stable for several weeks in a refrigerator (J Clin Neurol. 2013 Jul;9[3]:157-64).

I think these rules eventually will be settled by a restraint of trade lawsuit. After all, none can be shown to improve patient care; in fact, they degrade it and increase the costs to patients and physicians. We may end up being grateful that the U.S. Supreme Court emasculated state professional boards in the famous 2015 North Carolina tooth-whitening ruling.

The USP is accepting comments about the rules until Nov. 30th. The American Academy of Dermatology has a suggested letter to the USP Compounding Expert Committee on its website, which suggests that you ask for at least a 12-hour exemption.

I strongly suggest you write and explain why pharmacy board regulations that interfere with a physician’s ability to administer individualized, customized medication will hurt your patients and will cost more. Physicians have been treating their patients with individualized, customized medications for more than 2,000 years. It seems unreasonable to hand this skillful and essential part of medicine over to pharmacists in the absence of any compelling evidence.

Dr. Coldiron is in private practice but maintains a clinical assistant professorship at the University of Cincinnati. He cares for patients, teaches medical students and residents, and has several active clinical research projects. Dr. Coldiron is the author of more than 80 scientific letters, papers, and several book chapters, and he speaks frequently on a variety of topics. He is a past president of the American Academy of Dermatology. Write to him at [email protected].



 

Six years ago, there was an outbreak of fungal meningitis from improperly manufactured intrathecal steroid by a criminal pharmacist and pharmacy owner. Physicians, who had nothing to do with the pharmacy, are still struggling with the fallout from this.

In particular, 2 years ago, Ohio became the test state for outrageous restrictions on physician’s use of medications in their offices by a state pharmacy board (see “Beware the state pharmacy board,” Dermatology News, June 3, 2016). These rules degrade patient care by making medications inaccessible and much more expensive, and by eliminating office treatment options – and make the practice of medicine much more difficult.

However, since the original promulgation of these rules in Ohio, organized medicine at the state and national level has resisted and has made some progress.

In its recently published draft guidance for industry, the Food and Drug Administration excluded physician offices from enforcement in its compounding rules. While this is a great victory, the guidance also mentioned that physicians may be subject to rules promulgated by the U.S. Pharmacopeia (USP) and state pharmacy boards, who have adopted USP guidelines to physician offices in the past. Thus, our focus shifts to the USP.

The USP is a private, nongovernmental private organization of mostly pharmacists and national medical society representatives, organized to create a reference of uniform preparations for the most commonly used drugs – with tests to ensure their quality, potency, and purity. This has been a very good thing for American medicine, but the compounding chapter is written by pharmacists, to apply to compounding pharmacies. That is fine. The problem arises when you redefine a physician’s office as a compounding pharmacy. This is what took place in Ohio, and what pharmacy boards want to do nationwide.

Do not be naive. This is a national scope of practice issue that could determine how physicians can use medications in their offices. In Ohio, they were particularly devious in my opinion. The state legislature (in an omnibus spending bill) explicitly expanded the Ohio Board of Pharmacy’s mandate to supervise the “compounding of hazardous medications.” I think the legislature, the state medical society, and everyone else assumed this meant drugs manufactured and sold by compounding pharmacies, such as intrathecal steroids.

The pharmacy board readily recognized an opening here and went on to define hazardous drugs as any prescription drug, and compounding as mixture or even sterile dilution of any prescription drug. The board then proposed a $112 dollar annual licensing fee (since reduced to $55) that would affect, doctors, dentists, and even veterinarians.

When the rules were first published, there was outrage. The board was even going to require a compounding license to reconstitute vaccines. This requirement was quickly withdrawn when it was pointed out that vaccines were advertised for sale at pharmacies, an obvious restraint of trade issue.

So, what’s the big deal with paying $55 a year for a compounding license from the pharmacy board? It involves a 17-page form, and you must agree to unannounced inspections of your office. A northern Ohio physician who obtained his terminal distribution of drugs and compounding license had an almost immediate unannounced inspection, where he was cited for an unlocked sample closet door, expired samples, and for not recording all the lot numbers of each sample dispensed. He also was cited for not having a separate clean drawing room in which he mixed his syringes and for not discarding any reconstitutions or mixtures not used. Think botulinum toxin here. He was required to draft a remediation plan, which includes recording all medications compounded (anything mixed in a syringe!) in separate log books (conventional medical records are not adequate) and recording lot numbers of all samples dispensed. Consider a log entry each time you dilute Kenalog for injection or buffer lidocaine.

Do not think you will fly under the radar here. I expect state pharmacy boards to requisition botulinum toxin and bicarbonate purchase records from supply houses and to investigate purchasers. They can cite you for $3,000 per violation and can also instruct suppliers to no longer sell product to you.

USP Rules

The revised USP rules are a difficult fit for physicians’ offices. Because they have granted a 1-hour exemption, you will have to use buffered lidocaine and reconstituted botulinum toxin in 1 hour or less, then discard it under these rules. This means you cannot draw up all your buffered lidocaine for the day in the morning and use it throughout the day; never mind that there are good data showing redrawn syringes of buffered lidocaine and botulinum toxin are stable for several weeks in a refrigerator (J Clin Neurol. 2013 Jul;9[3]:157-64).

I think these rules eventually will be settled by a restraint of trade lawsuit. After all, none can be shown to improve patient care; in fact, they degrade it and increase the costs to patients and physicians. We may end up being grateful that the U.S. Supreme Court emasculated state professional boards in the famous 2015 North Carolina tooth-whitening ruling.

The USP is accepting comments about the rules until Nov. 30th. The American Academy of Dermatology has a suggested letter to the USP Compounding Expert Committee on its website, which suggests that you ask for at least a 12-hour exemption.

I strongly suggest you write and explain why pharmacy board regulations that interfere with a physician’s ability to administer individualized, customized medication will hurt your patients and will cost more. Physicians have been treating their patients with individualized, customized medications for more than 2,000 years. It seems unreasonable to hand this skillful and essential part of medicine over to pharmacists in the absence of any compelling evidence.

Dr. Coldiron is in private practice but maintains a clinical assistant professorship at the University of Cincinnati. He cares for patients, teaches medical students and residents, and has several active clinical research projects. Dr. Coldiron is the author of more than 80 scientific letters, papers, and several book chapters, and he speaks frequently on a variety of topics. He is a past president of the American Academy of Dermatology. Write to him at [email protected].



 

BERLIN – Retinal thinning related to ganglion loss may be independent of optic neuritis attacks in patients with neuromyelitis optica spectrum disorders who have anti–aquaporin-4 antibodies.

Michele G. Sullivan/MDedge News

These eyes exhibited an annual retinal volume loss of about 0.6 micrometers – 80 times higher than that of normal controls – even though they did not have a history of optic neuritis (ON), Frederike C. Oertel said at the annual congress of the European Committee for Treatment and Research in Multiple Sclerosis.

“The most likely explanation for this seems to be a disease-related primary retinopathy due to the high density of astrocytic cells in the retina and the afferent visual system,” said Ms. Oertel, a doctoral student at NeuroCure Clinical Research Center, Berlin.

The study appeared in the Journal of Neurology, Neurosurgery & Psychiatry (J Neurol Neurosurg Psychiatry. 2018 Jun 19. doi: 10.1136/jnnp-2018-318382).

A previous cross-sectional study by her group found retinal thinning and an alteration of foveal shape in anti–aquaporin-4 (anti-AQP4) positive patients with neuromyelitis optica spectrum disorders (NMOSD) independent of whether they had experienced a clinical attack of optic neuritis (Neurol Neuroimmunol Neuroinflamm. 2017 May;4[3]:e334). In these patients, the fovea changed shape from a characteristic steeply angled “V” to a broader, flatter “U” shape, she said.

In that 2017 paper, Ms. Oertel and her colleagues theorized that the relationship between the water-channel regulator AQP4 and astrocytes could be the root cause of these microstructural alterations.

“The parafoveal area is characterized by a high density of retinal astrocytic Müller cells, which express AQP4 and may thus serve as retinal targets in NMOSD,” they wrote. “Müller cells regulate the retinal water balance and have a relevant role in neurotransmitter and photopigment recycling, as well as in energy and lipid metabolism. Müller cell dysfunction or degeneration could thus lead to impaired retinal function including changes in water homeostasis. Of interest, both the initial cohort and the confirmatory cohort showed a mild increase of peripapillary retinal nerve fiber layer thickness, which could indicate tissue swelling. These findings are supported by animal studies showing retraction of astrocytic end feet in some and astrocyte death in other cases, suggesting a primary astrocytoma in NMOSD also outside acute lesions.”

The study Ms. Oertel presented at ECTRIMS looked at full retinal thickness using the same imaging tool, optical coherence tomography (OCT). The longitudinal cohort comprised 94 eyes in 51 anti–AQP4-IgG seropositive patients who had NMOSD; 60 of these eyes had experienced an optic neuritis attack and 34 had not. Most of the patients were female; the mean age was 47 years. They were compared against 28 age- and sex-matched healthy controls.


OCT measured combined ganglion cell and inner plexiform layer (GCIP), the peripapillary retinal nerve fiber layer (pRNFL), fovea thickness (FT), inner nuclear layer (INL), and total macular volume (TMV).

At baseline, ON eyes already displayed reduced GCIP, FT, and TMV, compared with healthy controls – but so had eyes that had not had ON. Over the follow-up period, eyes without ON continued to show thinning, even in the absence of a clinical attack. Although visual acuity didn’t change over time, the retinas continued to thin, losing an average of 0.6 micrometers each year, a rate 80 times greater than that seen in the control group.

“We saw this significant loss of the ganglion cell layer volume independent of ON, suggesting that retinal neurodegeneration is not dependent on ON in these patients,” Ms. Oertel said.

The results fit well into the group’s prior theory of astrocytic involvement. However, she added, “We still have to think about an alternative theory of drug-induced neuroaxonal damage and retrograde neuroaxonal degeneration.”

The project was supported with grants from the German Ministry for Education and Research. Ms. Oertel had no financial disclosures relevant to the work, but many coauthors reported financial relationships with industry.

[email protected]

SOURCE: Oertel FC et al. ECTRIMS 2018, Abstract 212.

BERLIN – Retinal thinning related to ganglion loss may be independent of optic neuritis attacks in patients with neuromyelitis optica spectrum disorders who have anti–aquaporin-4 antibodies.

Michele G. Sullivan/MDedge News

These eyes exhibited an annual retinal volume loss of about 0.6 micrometers – 80 times higher than that of normal controls – even though they did not have a history of optic neuritis (ON), Frederike C. Oertel said at the annual congress of the European Committee for Treatment and Research in Multiple Sclerosis.

“The most likely explanation for this seems to be a disease-related primary retinopathy due to the high density of astrocytic cells in the retina and the afferent visual system,” said Ms. Oertel, a doctoral student at NeuroCure Clinical Research Center, Berlin.

The study appeared in the Journal of Neurology, Neurosurgery & Psychiatry (J Neurol Neurosurg Psychiatry. 2018 Jun 19. doi: 10.1136/jnnp-2018-318382).

A previous cross-sectional study by her group found retinal thinning and an alteration of foveal shape in anti–aquaporin-4 (anti-AQP4) positive patients with neuromyelitis optica spectrum disorders (NMOSD) independent of whether they had experienced a clinical attack of optic neuritis (Neurol Neuroimmunol Neuroinflamm. 2017 May;4[3]:e334). In these patients, the fovea changed shape from a characteristic steeply angled “V” to a broader, flatter “U” shape, she said.

In that 2017 paper, Ms. Oertel and her colleagues theorized that the relationship between the water-channel regulator AQP4 and astrocytes could be the root cause of these microstructural alterations.

“The parafoveal area is characterized by a high density of retinal astrocytic Müller cells, which express AQP4 and may thus serve as retinal targets in NMOSD,” they wrote. “Müller cells regulate the retinal water balance and have a relevant role in neurotransmitter and photopigment recycling, as well as in energy and lipid metabolism. Müller cell dysfunction or degeneration could thus lead to impaired retinal function including changes in water homeostasis. Of interest, both the initial cohort and the confirmatory cohort showed a mild increase of peripapillary retinal nerve fiber layer thickness, which could indicate tissue swelling. These findings are supported by animal studies showing retraction of astrocytic end feet in some and astrocyte death in other cases, suggesting a primary astrocytoma in NMOSD also outside acute lesions.”

The study Ms. Oertel presented at ECTRIMS looked at full retinal thickness using the same imaging tool, optical coherence tomography (OCT). The longitudinal cohort comprised 94 eyes in 51 anti–AQP4-IgG seropositive patients who had NMOSD; 60 of these eyes had experienced an optic neuritis attack and 34 had not. Most of the patients were female; the mean age was 47 years. They were compared against 28 age- and sex-matched healthy controls.


OCT measured combined ganglion cell and inner plexiform layer (GCIP), the peripapillary retinal nerve fiber layer (pRNFL), fovea thickness (FT), inner nuclear layer (INL), and total macular volume (TMV).

At baseline, ON eyes already displayed reduced GCIP, FT, and TMV, compared with healthy controls – but so had eyes that had not had ON. Over the follow-up period, eyes without ON continued to show thinning, even in the absence of a clinical attack. Although visual acuity didn’t change over time, the retinas continued to thin, losing an average of 0.6 micrometers each year, a rate 80 times greater than that seen in the control group.

“We saw this significant loss of the ganglion cell layer volume independent of ON, suggesting that retinal neurodegeneration is not dependent on ON in these patients,” Ms. Oertel said.

The results fit well into the group’s prior theory of astrocytic involvement. However, she added, “We still have to think about an alternative theory of drug-induced neuroaxonal damage and retrograde neuroaxonal degeneration.”

The project was supported with grants from the German Ministry for Education and Research. Ms. Oertel had no financial disclosures relevant to the work, but many coauthors reported financial relationships with industry.

[email protected]

SOURCE: Oertel FC et al. ECTRIMS 2018, Abstract 212.

BERLIN – Retinal thinning related to ganglion loss may be independent of optic neuritis attacks in patients with neuromyelitis optica spectrum disorders who have anti–aquaporin-4 antibodies.

Michele G. Sullivan/MDedge News

These eyes exhibited an annual retinal volume loss of about 0.6 micrometers – 80 times higher than that of normal controls – even though they did not have a history of optic neuritis (ON), Frederike C. Oertel said at the annual congress of the European Committee for Treatment and Research in Multiple Sclerosis.

“The most likely explanation for this seems to be a disease-related primary retinopathy due to the high density of astrocytic cells in the retina and the afferent visual system,” said Ms. Oertel, a doctoral student at NeuroCure Clinical Research Center, Berlin.

The study appeared in the Journal of Neurology, Neurosurgery & Psychiatry (J Neurol Neurosurg Psychiatry. 2018 Jun 19. doi: 10.1136/jnnp-2018-318382).

A previous cross-sectional study by her group found retinal thinning and an alteration of foveal shape in anti–aquaporin-4 (anti-AQP4) positive patients with neuromyelitis optica spectrum disorders (NMOSD) independent of whether they had experienced a clinical attack of optic neuritis (Neurol Neuroimmunol Neuroinflamm. 2017 May;4[3]:e334). In these patients, the fovea changed shape from a characteristic steeply angled “V” to a broader, flatter “U” shape, she said.

In that 2017 paper, Ms. Oertel and her colleagues theorized that the relationship between the water-channel regulator AQP4 and astrocytes could be the root cause of these microstructural alterations.

“The parafoveal area is characterized by a high density of retinal astrocytic Müller cells, which express AQP4 and may thus serve as retinal targets in NMOSD,” they wrote. “Müller cells regulate the retinal water balance and have a relevant role in neurotransmitter and photopigment recycling, as well as in energy and lipid metabolism. Müller cell dysfunction or degeneration could thus lead to impaired retinal function including changes in water homeostasis. Of interest, both the initial cohort and the confirmatory cohort showed a mild increase of peripapillary retinal nerve fiber layer thickness, which could indicate tissue swelling. These findings are supported by animal studies showing retraction of astrocytic end feet in some and astrocyte death in other cases, suggesting a primary astrocytoma in NMOSD also outside acute lesions.”

The study Ms. Oertel presented at ECTRIMS looked at full retinal thickness using the same imaging tool, optical coherence tomography (OCT). The longitudinal cohort comprised 94 eyes in 51 anti–AQP4-IgG seropositive patients who had NMOSD; 60 of these eyes had experienced an optic neuritis attack and 34 had not. Most of the patients were female; the mean age was 47 years. They were compared against 28 age- and sex-matched healthy controls.


OCT measured combined ganglion cell and inner plexiform layer (GCIP), the peripapillary retinal nerve fiber layer (pRNFL), fovea thickness (FT), inner nuclear layer (INL), and total macular volume (TMV).

At baseline, ON eyes already displayed reduced GCIP, FT, and TMV, compared with healthy controls – but so had eyes that had not had ON. Over the follow-up period, eyes without ON continued to show thinning, even in the absence of a clinical attack. Although visual acuity didn’t change over time, the retinas continued to thin, losing an average of 0.6 micrometers each year, a rate 80 times greater than that seen in the control group.

“We saw this significant loss of the ganglion cell layer volume independent of ON, suggesting that retinal neurodegeneration is not dependent on ON in these patients,” Ms. Oertel said.

The results fit well into the group’s prior theory of astrocytic involvement. However, she added, “We still have to think about an alternative theory of drug-induced neuroaxonal damage and retrograde neuroaxonal degeneration.”

The project was supported with grants from the German Ministry for Education and Research. Ms. Oertel had no financial disclosures relevant to the work, but many coauthors reported financial relationships with industry.

[email protected]

SOURCE: Oertel FC et al. ECTRIMS 2018, Abstract 212.

CHICAGO – The administration of high-dose vs. standard-dose influenza vaccine provided substantially better immune responses in seropositive rheumatoid arthritis patients in a randomized, active-controlled trial.
 

High-dose trivalent influenza vaccine is known to improve immune responses in the elderly, but the current findings, which were presented at the annual meeting of the American College of Rheumatology, are the first to document a successful intervention to enhance vaccine responses in immunocompromised patients, according to Inés Colmegna, MD, of McGill University, Montreal.

Dr. Colmegna and her colleagues assessed antibody responses to either standard-dose (15 mcg of hemagglutinin per strain) quadrivalent inactivated influenza vaccine (SD-QIV) or high-dose (60 mcg of hemagglutinin per strain) trivalent inactivated influenza vaccine (HD-TIV) in 140 and 139 patients, respectively.

Seroprotection rates prior to vaccination were comparable in the two groups, but the high-dose recipients had consistently higher overall responses to vaccination.

Seroconversion rates were 22.3% vs. 8.6% (odds ratio, 2.93) for the H3N2 strain (A/HongKong/4801/2014), and 44.6% vs. 28.6% (OR, 1.93) for the B Victoria Lin strain (B/Brisbane/60/2008). For the H1N1 strain A/California/7/2009 in 2016-2017 and closely related A/Michigan/45/2015 in 2017-2018, the seroconversion rates were 51.1% vs. 30.0% (OR, 2.91) and 46.4% vs. 24.6% (OR, 2.79), respectively. Seroprotection rates for the H3N2 strain were 48.5% vs. 30.9%, and for the B Victoria Lin strain, 60.0% vs. 50.7%. The seroprotection rates for the H1N1 strains together were and 80.4% vs. 73.5%, Dr. Colmegna said.

Seroconversion was defined as at least a fourfold serum hemagglutination inhibition (HI) antibody increase from prevaccination level (day 0), and seroprotection was defined as percent with HI titers of 1:40 or greater at postvaccination day 28.

After the researchers controlled for age, vaccine type, treatment type in the 3 months prior to vaccination and during the study period, Charlson comorbidity index, and RA duration, the only significant predictors of vaccine seroresponse were vaccine dose and age.

The findings are notable because RA patients have a nearly threefold increase in the risk of contracting influenza infection or related illness, compared with age-matched healthy controls, because of “inherent immune dysfunction associated with RA, comorbidities, the age of our patients, and immunosuppressive therapy,” Dr. Colmegna said.


For this reason, RA patients are a priority group for annual vaccination. However, while vaccination remains the most effective method for preventing influenza and its associated complications, vaccine-induced antibody responses and protection in RA are suboptimal, she explained, noting that this puts them at increased risk for severe influenza.

“There is a high priority to develop new approaches to try to decrease this risk,” she said.

It was unknown whether HD-TIV – the only currently available high-dose influenza vaccine – would safely enhance antibody production in RA as it does in the elderly, so she and her colleagues recruited patients from a tertiary care center during the 2016-2017 and 2017-2018 Northern Hemisphere influenza seasons for this study.

The mean age of the patients was 61 years, and 80% were women. All were on stable treatment with either disease-modifying antirheumatic drugs (DMARDs) or biologics for at least 3 months prior to vaccination; treatment types included DMARDs in 138 patients (49.5%), anticytokine therapy in 92 patients (33%), and anti-B-cell therapy and small molecules in 49 patients (17.6%). An analysis by treatment type showed a possible reduction in the rate of seroconversion in patients who received anti-B-cell therapy and small molecules, but the number of patients in the group was too small to make definitive conclusions, Dr. Colmegna said.

Treatment in all groups was safe, with no differences in adverse events between those receiving high- or standard-dose vaccine, and none of the adverse events were related to treatment.

Further, the high-dose vaccine was not associated with an increase in disease activity.

“We believe that these results will likely change clinical practice,” she concluded.

Dr. Colmegna reported having no disclosures.

[email protected]

SOURCE: Colmegna I et al. Arthritis Rheumatol. 2018;70(Suppl 10): Abstract 837.

CHICAGO – The administration of high-dose vs. standard-dose influenza vaccine provided substantially better immune responses in seropositive rheumatoid arthritis patients in a randomized, active-controlled trial.
 

High-dose trivalent influenza vaccine is known to improve immune responses in the elderly, but the current findings, which were presented at the annual meeting of the American College of Rheumatology, are the first to document a successful intervention to enhance vaccine responses in immunocompromised patients, according to Inés Colmegna, MD, of McGill University, Montreal.

Dr. Colmegna and her colleagues assessed antibody responses to either standard-dose (15 mcg of hemagglutinin per strain) quadrivalent inactivated influenza vaccine (SD-QIV) or high-dose (60 mcg of hemagglutinin per strain) trivalent inactivated influenza vaccine (HD-TIV) in 140 and 139 patients, respectively.

Seroprotection rates prior to vaccination were comparable in the two groups, but the high-dose recipients had consistently higher overall responses to vaccination.

Seroconversion rates were 22.3% vs. 8.6% (odds ratio, 2.93) for the H3N2 strain (A/HongKong/4801/2014), and 44.6% vs. 28.6% (OR, 1.93) for the B Victoria Lin strain (B/Brisbane/60/2008). For the H1N1 strain A/California/7/2009 in 2016-2017 and closely related A/Michigan/45/2015 in 2017-2018, the seroconversion rates were 51.1% vs. 30.0% (OR, 2.91) and 46.4% vs. 24.6% (OR, 2.79), respectively. Seroprotection rates for the H3N2 strain were 48.5% vs. 30.9%, and for the B Victoria Lin strain, 60.0% vs. 50.7%. The seroprotection rates for the H1N1 strains together were and 80.4% vs. 73.5%, Dr. Colmegna said.

Seroconversion was defined as at least a fourfold serum hemagglutination inhibition (HI) antibody increase from prevaccination level (day 0), and seroprotection was defined as percent with HI titers of 1:40 or greater at postvaccination day 28.

After the researchers controlled for age, vaccine type, treatment type in the 3 months prior to vaccination and during the study period, Charlson comorbidity index, and RA duration, the only significant predictors of vaccine seroresponse were vaccine dose and age.

The findings are notable because RA patients have a nearly threefold increase in the risk of contracting influenza infection or related illness, compared with age-matched healthy controls, because of “inherent immune dysfunction associated with RA, comorbidities, the age of our patients, and immunosuppressive therapy,” Dr. Colmegna said.


For this reason, RA patients are a priority group for annual vaccination. However, while vaccination remains the most effective method for preventing influenza and its associated complications, vaccine-induced antibody responses and protection in RA are suboptimal, she explained, noting that this puts them at increased risk for severe influenza.

“There is a high priority to develop new approaches to try to decrease this risk,” she said.

It was unknown whether HD-TIV – the only currently available high-dose influenza vaccine – would safely enhance antibody production in RA as it does in the elderly, so she and her colleagues recruited patients from a tertiary care center during the 2016-2017 and 2017-2018 Northern Hemisphere influenza seasons for this study.

The mean age of the patients was 61 years, and 80% were women. All were on stable treatment with either disease-modifying antirheumatic drugs (DMARDs) or biologics for at least 3 months prior to vaccination; treatment types included DMARDs in 138 patients (49.5%), anticytokine therapy in 92 patients (33%), and anti-B-cell therapy and small molecules in 49 patients (17.6%). An analysis by treatment type showed a possible reduction in the rate of seroconversion in patients who received anti-B-cell therapy and small molecules, but the number of patients in the group was too small to make definitive conclusions, Dr. Colmegna said.

Treatment in all groups was safe, with no differences in adverse events between those receiving high- or standard-dose vaccine, and none of the adverse events were related to treatment.

Further, the high-dose vaccine was not associated with an increase in disease activity.

“We believe that these results will likely change clinical practice,” she concluded.

Dr. Colmegna reported having no disclosures.

[email protected]

SOURCE: Colmegna I et al. Arthritis Rheumatol. 2018;70(Suppl 10): Abstract 837.

CHICAGO – The administration of high-dose vs. standard-dose influenza vaccine provided substantially better immune responses in seropositive rheumatoid arthritis patients in a randomized, active-controlled trial.
 

High-dose trivalent influenza vaccine is known to improve immune responses in the elderly, but the current findings, which were presented at the annual meeting of the American College of Rheumatology, are the first to document a successful intervention to enhance vaccine responses in immunocompromised patients, according to Inés Colmegna, MD, of McGill University, Montreal.

Dr. Colmegna and her colleagues assessed antibody responses to either standard-dose (15 mcg of hemagglutinin per strain) quadrivalent inactivated influenza vaccine (SD-QIV) or high-dose (60 mcg of hemagglutinin per strain) trivalent inactivated influenza vaccine (HD-TIV) in 140 and 139 patients, respectively.

Seroprotection rates prior to vaccination were comparable in the two groups, but the high-dose recipients had consistently higher overall responses to vaccination.

Seroconversion rates were 22.3% vs. 8.6% (odds ratio, 2.93) for the H3N2 strain (A/HongKong/4801/2014), and 44.6% vs. 28.6% (OR, 1.93) for the B Victoria Lin strain (B/Brisbane/60/2008). For the H1N1 strain A/California/7/2009 in 2016-2017 and closely related A/Michigan/45/2015 in 2017-2018, the seroconversion rates were 51.1% vs. 30.0% (OR, 2.91) and 46.4% vs. 24.6% (OR, 2.79), respectively. Seroprotection rates for the H3N2 strain were 48.5% vs. 30.9%, and for the B Victoria Lin strain, 60.0% vs. 50.7%. The seroprotection rates for the H1N1 strains together were and 80.4% vs. 73.5%, Dr. Colmegna said.

Seroconversion was defined as at least a fourfold serum hemagglutination inhibition (HI) antibody increase from prevaccination level (day 0), and seroprotection was defined as percent with HI titers of 1:40 or greater at postvaccination day 28.

After the researchers controlled for age, vaccine type, treatment type in the 3 months prior to vaccination and during the study period, Charlson comorbidity index, and RA duration, the only significant predictors of vaccine seroresponse were vaccine dose and age.

The findings are notable because RA patients have a nearly threefold increase in the risk of contracting influenza infection or related illness, compared with age-matched healthy controls, because of “inherent immune dysfunction associated with RA, comorbidities, the age of our patients, and immunosuppressive therapy,” Dr. Colmegna said.


For this reason, RA patients are a priority group for annual vaccination. However, while vaccination remains the most effective method for preventing influenza and its associated complications, vaccine-induced antibody responses and protection in RA are suboptimal, she explained, noting that this puts them at increased risk for severe influenza.

“There is a high priority to develop new approaches to try to decrease this risk,” she said.

It was unknown whether HD-TIV – the only currently available high-dose influenza vaccine – would safely enhance antibody production in RA as it does in the elderly, so she and her colleagues recruited patients from a tertiary care center during the 2016-2017 and 2017-2018 Northern Hemisphere influenza seasons for this study.

The mean age of the patients was 61 years, and 80% were women. All were on stable treatment with either disease-modifying antirheumatic drugs (DMARDs) or biologics for at least 3 months prior to vaccination; treatment types included DMARDs in 138 patients (49.5%), anticytokine therapy in 92 patients (33%), and anti-B-cell therapy and small molecules in 49 patients (17.6%). An analysis by treatment type showed a possible reduction in the rate of seroconversion in patients who received anti-B-cell therapy and small molecules, but the number of patients in the group was too small to make definitive conclusions, Dr. Colmegna said.

Treatment in all groups was safe, with no differences in adverse events between those receiving high- or standard-dose vaccine, and none of the adverse events were related to treatment.

Further, the high-dose vaccine was not associated with an increase in disease activity.

“We believe that these results will likely change clinical practice,” she concluded.

Dr. Colmegna reported having no disclosures.

[email protected]

SOURCE: Colmegna I et al. Arthritis Rheumatol. 2018;70(Suppl 10): Abstract 837.

Editors’ Note: Curbside Consult is an occasional column aimed at helping psychiatrists think through family and cultural considerations when treating patients. It examines case vignettes and is written by two Group for the Advancement of Psychiatry (GAP) committees – the Committee on Family Psychiatry and the Committee on Cultural Psychiatry. The contributors have revised selected patient details to shield the identities of the patients/cases and to comply with HIPAA requirements.

Case vignette

Bill is a 25-year-old man of Chinese descent who sought psychiatric evaluation of his psychosis risk. His parents emigrated from China to Canada more than 30 years ago; Bill was born in Canada, and moved to the United States with his parents and two siblings at age 7.

His family has a strong history of mental illness. His older sister was diagnosed with schizophrenia; she frequently got into verbal altercations with her parents. When Bill was 15, she walked out of the house after a fight with the family and never returned. Bill’s family thinks his father has had paranoid delusions. In the past, he attempted to call the police multiple times because he suspected the neighbors had planted a listening device in his front yard. The family stopped him from making the actual calls. However, the family never brought him to psychiatric evaluation because of perceived stigma and social discrimination in their community. He also was emotionally and physically abusive to Bill during his childhood by calling him names and hitting him with a belt. As an adult, Bill still has posttraumatic stress disorder symptoms including flashbacks, nightmares, and avoidance when thinking about his father.

Bill identifies himself as Chinese American and speaks English only. He often perceives himself as a newcomer to U.S. society, making comments such as: “I guess I should live my life like this to fulfill the American dream.” Bill’s parents placed a strong emphasis on academic success, often at the expense of their children’s social interaction and playtime activities. Bill describes himself as a “loner” with few friends. He maintained high academic achievement during high school and was accepted by a prestigious college. Although he was interested in music composition, Bill was “forced” by his parents to major in courses deemed good preparation for law school.

During college, he suffered severe depression with insomnia, low energy, hopelessness, anhedonia, social withdrawal, poor appetite with weight loss, and ruminative thoughts but without delusional thoughts or perceptual disturbances. He had one near-lethal suicide attempt, during which he impulsively took the contents of an entire bottle of Tylenol in the context of family conflicts, resulting in psychiatric hospitalization. Bill recalled with animosity the inpatient psychiatrists who put him on psychotropic medications during a 3-day hospitalization. He was not adherent to the medication and did not follow up with postdischarge outpatient care. He did not remember the medication trial he had during the hospitalization, nor did he give consent to obtain medical records from there. Bill withdrew from college in sophomore year, because of his declining academic performance secondary to his mental illness. He currently works at a gas station.

Over the last year, Bill’s interpersonal communication has become disorganized in both work and social settings, and he has developed thought blocking, causing him substantial distress. He intermittently hears voices of strangers in the background; these have gradually become more frequent, now occurring 3-4 times a week. Bill also is more depressed, with frequent crying episodes and worsening social isolation. He often thinks that life is not worth living, but he has no active suicidal plans or intent.

Bill’s supervisor and coworkers strongly suggested that he seek medical evaluation. As an outpatient, Bill started weekly cognitive-behavioral therapy (CBT) and biweekly medication sessions for early psychosis symptoms, receiving low-dose risperidone (1 mg b.i.d.) and fluoxetine (20 mg daily). Despite initial improvement, he was very skeptical about continuing the medications because of concern that they will cause a “change in his identity” by altering his body chemistry. His parents have been reluctant to join family meetings, because they were ambivalent about Bill’s ongoing psychiatric treatment.
 

Treatment team’s impressions

Clinical high risk (CHR) syndrome refers to the prodromal phase before a full psychotic disorder. As one of the three subcategories of CHR, genetic risk and deterioration (GRD) prodromal syndrome is defined by having a genetic risk for psychosis (first-degree relative with a psychotic disorder or meeting criteria for schizotypal personality disorder) and a recent decline in daily functioning equivalent to a 30% drop in Global Assessment of Functioning rating.¹ Due to Bill’s family history of psychosis, new difficulties in self-care, psychotic-spectrum symptoms, and declining social/executive function, he meets criteria for GRD prodromal syndrome. In addition, major depressive disorder should be considered on his differential diagnosis.

Bill has not received a diagnosis of acute psychosis, and instead is judged to be in the CHR spectrum for psychosis, because of his level of insight that the occasional perceptual disturbance and abnormal thought content are in his own mind. Since 26% of individuals with CHR in mainland China² and 35% in the general U.S. population develop fully psychotic symptoms within 2-3 years, Bill’s current presentation warrants secondary preventive care (early intervention) to promote improved clinical outcomes. Given the high rates of comorbid depressive and anxiety disorders among individuals with CHR, Bill’s mood symptoms and passive suicidality also require psychiatric intervention. The treatment team raised three questions, which are answered below.
 

1. How can we understand Bill’s and his family’s resistance to mental health treatment?

Chinese Americans tend to access mental health services at a lower rate than that of the general U.S. population.³ They also tend to exhibit elevated discontinuation from mental health care, compared with non-Latino whites.⁴ Since first- and second-generation Chinese Americans have similar use rates, it is likely the barriers to care are not immigration specific but also related to factors that endure across generations, including culture-related aspects. These include cultural concepts of illness and how to interpret prodromal symptoms such as Bill’s, stigma and interpersonal shame regarding mental illness and psychiatric treatment, and value orientations such as self-reliance, avoidance of direct expressions of interpersonal conflict, and family privacy.

Exploring cultural concepts of distress common among Chinese American families might help clinicians address barriers to mental health service use and persistence. For example, Chinese Americans tend to emphasize the physical-symptom components of psychiatric problems, partly because of mind-body holism – which combines physical and psychological symptoms into cultural syndromes and idioms of distress – and partly because of concerns about stigma and shame regarding mental health symptoms. Hence, they are more likely to seek help from primary care clinicians for psychological distress before any mental health provider. Many Chinese Americans interpret mild to moderate psychological distress as “mental weakness” or “excessive thinking” (xiang tai duo), which does not require clinical evaluation. In this view, only alarmingly bizarre or disruptive behaviors warrant formal psychiatric treatment.

2. How does Bill’s cultural and social context affect his prognosis?

Individuals with psychosis and their close relatives are generally vulnerable to stigma and discrimination. Mental health stigma has a substantial effect on the lives of patients with psychosis and their family members. The magnitude of the perceived stigma tends to be greater if the patient has more severe positive symptoms, is more educated, or resides in a highly urbanized area.

Acutely ill patients usually face more negative community responses than do milder cases, since their close relatives are blamed for failing to uphold the moral and legal responsibility of ensuring that the patients control their behavior. The effect of stigma in Chinese society also is greater among male patients with early-onset illness, because of the expectation that men marry and become the family breadwinner to attain higher social status. Hence, young males who are unable to achieve these socially determined adult milestones can be considered socially inferior, and suffer more community discrimination and exclusion, which are risk factors for clinical deterioration and functional impairment.

Social stigma can intensify relationship conflicts within the family and magnify expressed emotion (EE), which is defined as caregivers’ attitude toward a person with mental illness as reflected by their comments and interaction patterns. “High EE” comprises three behavioral patterns: criticism, hostility, and emotional overinvolvement. High EE is associated with psychiatric symptom relapse among individuals with schizophrenia and other disorders.⁹

Currently, most of the literature on EE is limited to white samples in Western countries. Some researchers have studied the relationship between the EE index of emotional overinvolvement and schizophrenia relapse among Hispanic populations.¹⁰ However, there are limited data on cultural congruence of EE research in Asian populations. Therefore, clinicians should carefully evaluate the contribution of high EE to Bill’s family’s situation during his course of treatment.

Higher education often is associated with greater levels of EE and can result in anxious and fearful responses to the person’s illness.¹¹ This may be attributable to more negative reactions to actual or feared stigma and discrimination, possibly because relatives feel they have more to lose regarding the family’s social status, especially in densely populated urban areas where it might be harder to keep the patient’s mental illness as a “family secret.”

On the other hand, certain explanatory models of psychosis can modulate Chinese community members’ perceptions and allow ill individuals to remain socially integrated. Cultural idioms such as “excessive thinking” (xiang tai duo), “taking things too hard” (xiang bu kai), and “narrow-mindedness” (xiao xin yan) promote socially accommodating behaviors that facilitate acceptance of mildly to moderately ill individuals as full-status community members.¹²

Another important contributor to psychosis risk is Bill’s acculturative stress about his cultural identity. Linguistic challenges, limited social support, perceived discrimination, and an acculturation gap between parents and children are major sources of acculturative stress among Chinese American college students.¹³ Greater acculturative stress elevates the risk of mental illness and symptom deterioration. However, highly acculturated Chinese Americans with above-average bicultural self-efficacy tend to express more positive attitudes toward mental health services.
 

3. Are there culturally appropriate interventions that can help Bill and his family?

A major predictor among Chinese Americans of the intent to use services is the perceived credibility of the treatment and the provider. Ethnic-specific services staffed by bicultural/bilingual mental health clinicians delivering culturally responsive interventions are increasingly available in many metropolitan areas with major Asian communities. These programs have shown clinical efficacy in encouraging service use and promoting treatment persistence. Bill and his family may benefit from referral to ethnic-specific services, where they can obtain culturally sensitive psychoeducation about his mental illness and treatment plan.

Other services that might be useful for Bill and his family include family psychoeducation programs and supportive groups specifically designed for Chinese American families; these can improve the entire family’s psychosocial health, promote medication adherence, and reduce the risk of symptom relapse through family-centered intervention models.¹⁴ Connecting with local National Alliance on Mental Illness (NAMI) programs might help Bill’s parents obtain social support from Chinese American families with similar caregiver experiences.

However, services that are not designed specifically for Chinese-origin patients also can provide excellent care for these patients, and be perceived as credible and effective. A thorough cultural assessment is necessary, as well as inclusion of the information obtained in the treatment plan. As described in the DSM-5 Outline for Cultural Formulation and operationalized in the Cultural Formulation Interview, clinicians should assess possible cultural differences among Bill, his family, his community, and his clinicians regarding their cultural concepts of distress and illness and expectations of care in order to formulate a treatment plan acceptable to patient and family. Practical cultural barriers should be addressed, such as Bill’s parents’ limited English proficiency, in which case a bilingual clinician or trained interpreter should be included in the treatment team.

With Bill’s consent, the treatment team also should consider reaching out to his parents, especially his mother, to understand and empathize with their cultural concepts of distress and illness as well as expectations for care. In addition to providing psychoeducation, the clinicians should validate the parents’ experience of shame, fear, and worry about their son. Bill’s brother, for example, might be a useful bridge in communicating with the parents given his higher acculturation and potentially greater acceptance of psychiatric care. He might help alleviate the tension between Bill and his parents and encourage them to seek family-based help.
 

Take-home points

• Clinical training programs should offer cultural competency training about underserved populations, including communities of color.
• Certain key concepts, such as traditional idioms of distress and explanatory models, social stigma, and acculturative stress, should be included in these trainings and evaluated in a comprehensive psychosocial assessment.
• High expressed emotion among family caregivers is associated with higher rates of psychiatric symptom relapse, whereas families with above-average bicultural self-efficacy have more positive attitudes toward mental health services.
• Clinicians should incorporate culturally appropriate educational materials (for example, CHR warning signs) and interventions to engage underserved patients and their families in mental health treatment.

Contributors

Emily Wu, MD – Harvard Medical School, Boston

Francis Lu, MD – University of California, Davis

John Sargent, MD – Tufts Medical Center, Boston

Roberto Lewis-Fernández, MD – Columbia College of Physicians & Surgeons, New York



If you would like to a submit case in which your understanding and treatment are affected by challenging cultural and family values, send it to [email protected]. We will then write back with our best answers about how one might proceed in such a case. Your case and our response will then be published at mdedge.com/psychiatry. This column is meant to be educational and does not constitute medical advice. The opinions expressed are those of the contributors and do not represent those of the organizations they are employed by or affiliated with or the Group for the Advancement of Psychiatry.

References

1. J Nerv Ment Dis. 2013 Jun;20(6);484-9.

2. Schizophr Res. 2014 Feb;152(2-3):391-9.

3. Perspect Psychiatr Care. 2013;49(4):288-92.

4. Ment Health Serv Res. 2001 Dec;3(4):201-14.

5. Br J Psychiatry. 2000 Jul;177;20-5.

6. Cultr Divers Ethnic Minor Psychol. 2008 Jan;14(1):10-8.

7. Couns Psychol. 2003 May1;31:343-61.

8. Emotion. 2002 Dec;2(4):341-60.

9. Am J Psychiatry. 1986 Nov;143(11):1361-73.

10. J Nerv Ment Dis. 2013 Oct;201(10):833-40.

11. Schizophr Bull. 1981;7(1):43-4.

12. Schizophr Bull. 2010 Jul;36(4):836-45.

13. Am J Orthopsychiatry. 2011 Oct;81(4):489-97.

14. Patient Educ Couns. 2009 Apr;75(1):67-76.

Editors’ Note: Curbside Consult is an occasional column aimed at helping psychiatrists think through family and cultural considerations when treating patients. It examines case vignettes and is written by two Group for the Advancement of Psychiatry (GAP) committees – the Committee on Family Psychiatry and the Committee on Cultural Psychiatry. The contributors have revised selected patient details to shield the identities of the patients/cases and to comply with HIPAA requirements.

Case vignette

Bill is a 25-year-old man of Chinese descent who sought psychiatric evaluation of his psychosis risk. His parents emigrated from China to Canada more than 30 years ago; Bill was born in Canada, and moved to the United States with his parents and two siblings at age 7.

His family has a strong history of mental illness. His older sister was diagnosed with schizophrenia; she frequently got into verbal altercations with her parents. When Bill was 15, she walked out of the house after a fight with the family and never returned. Bill’s family thinks his father has had paranoid delusions. In the past, he attempted to call the police multiple times because he suspected the neighbors had planted a listening device in his front yard. The family stopped him from making the actual calls. However, the family never brought him to psychiatric evaluation because of perceived stigma and social discrimination in their community. He also was emotionally and physically abusive to Bill during his childhood by calling him names and hitting him with a belt. As an adult, Bill still has posttraumatic stress disorder symptoms including flashbacks, nightmares, and avoidance when thinking about his father.

Bill identifies himself as Chinese American and speaks English only. He often perceives himself as a newcomer to U.S. society, making comments such as: “I guess I should live my life like this to fulfill the American dream.” Bill’s parents placed a strong emphasis on academic success, often at the expense of their children’s social interaction and playtime activities. Bill describes himself as a “loner” with few friends. He maintained high academic achievement during high school and was accepted by a prestigious college. Although he was interested in music composition, Bill was “forced” by his parents to major in courses deemed good preparation for law school.

During college, he suffered severe depression with insomnia, low energy, hopelessness, anhedonia, social withdrawal, poor appetite with weight loss, and ruminative thoughts but without delusional thoughts or perceptual disturbances. He had one near-lethal suicide attempt, during which he impulsively took the contents of an entire bottle of Tylenol in the context of family conflicts, resulting in psychiatric hospitalization. Bill recalled with animosity the inpatient psychiatrists who put him on psychotropic medications during a 3-day hospitalization. He was not adherent to the medication and did not follow up with postdischarge outpatient care. He did not remember the medication trial he had during the hospitalization, nor did he give consent to obtain medical records from there. Bill withdrew from college in sophomore year, because of his declining academic performance secondary to his mental illness. He currently works at a gas station.

Over the last year, Bill’s interpersonal communication has become disorganized in both work and social settings, and he has developed thought blocking, causing him substantial distress. He intermittently hears voices of strangers in the background; these have gradually become more frequent, now occurring 3-4 times a week. Bill also is more depressed, with frequent crying episodes and worsening social isolation. He often thinks that life is not worth living, but he has no active suicidal plans or intent.

Bill’s supervisor and coworkers strongly suggested that he seek medical evaluation. As an outpatient, Bill started weekly cognitive-behavioral therapy (CBT) and biweekly medication sessions for early psychosis symptoms, receiving low-dose risperidone (1 mg b.i.d.) and fluoxetine (20 mg daily). Despite initial improvement, he was very skeptical about continuing the medications because of concern that they will cause a “change in his identity” by altering his body chemistry. His parents have been reluctant to join family meetings, because they were ambivalent about Bill’s ongoing psychiatric treatment.
 

Treatment team’s impressions

Clinical high risk (CHR) syndrome refers to the prodromal phase before a full psychotic disorder. As one of the three subcategories of CHR, genetic risk and deterioration (GRD) prodromal syndrome is defined by having a genetic risk for psychosis (first-degree relative with a psychotic disorder or meeting criteria for schizotypal personality disorder) and a recent decline in daily functioning equivalent to a 30% drop in Global Assessment of Functioning rating.¹ Due to Bill’s family history of psychosis, new difficulties in self-care, psychotic-spectrum symptoms, and declining social/executive function, he meets criteria for GRD prodromal syndrome. In addition, major depressive disorder should be considered on his differential diagnosis.

Bill has not received a diagnosis of acute psychosis, and instead is judged to be in the CHR spectrum for psychosis, because of his level of insight that the occasional perceptual disturbance and abnormal thought content are in his own mind. Since 26% of individuals with CHR in mainland China² and 35% in the general U.S. population develop fully psychotic symptoms within 2-3 years, Bill’s current presentation warrants secondary preventive care (early intervention) to promote improved clinical outcomes. Given the high rates of comorbid depressive and anxiety disorders among individuals with CHR, Bill’s mood symptoms and passive suicidality also require psychiatric intervention. The treatment team raised three questions, which are answered below.
 

1. How can we understand Bill’s and his family’s resistance to mental health treatment?

Chinese Americans tend to access mental health services at a lower rate than that of the general U.S. population.³ They also tend to exhibit elevated discontinuation from mental health care, compared with non-Latino whites.⁴ Since first- and second-generation Chinese Americans have similar use rates, it is likely the barriers to care are not immigration specific but also related to factors that endure across generations, including culture-related aspects. These include cultural concepts of illness and how to interpret prodromal symptoms such as Bill’s, stigma and interpersonal shame regarding mental illness and psychiatric treatment, and value orientations such as self-reliance, avoidance of direct expressions of interpersonal conflict, and family privacy.

Exploring cultural concepts of distress common among Chinese American families might help clinicians address barriers to mental health service use and persistence. For example, Chinese Americans tend to emphasize the physical-symptom components of psychiatric problems, partly because of mind-body holism – which combines physical and psychological symptoms into cultural syndromes and idioms of distress – and partly because of concerns about stigma and shame regarding mental health symptoms. Hence, they are more likely to seek help from primary care clinicians for psychological distress before any mental health provider. Many Chinese Americans interpret mild to moderate psychological distress as “mental weakness” or “excessive thinking” (xiang tai duo), which does not require clinical evaluation. In this view, only alarmingly bizarre or disruptive behaviors warrant formal psychiatric treatment.

2. How does Bill’s cultural and social context affect his prognosis?

Individuals with psychosis and their close relatives are generally vulnerable to stigma and discrimination. Mental health stigma has a substantial effect on the lives of patients with psychosis and their family members. The magnitude of the perceived stigma tends to be greater if the patient has more severe positive symptoms, is more educated, or resides in a highly urbanized area.

Acutely ill patients usually face more negative community responses than do milder cases, since their close relatives are blamed for failing to uphold the moral and legal responsibility of ensuring that the patients control their behavior. The effect of stigma in Chinese society also is greater among male patients with early-onset illness, because of the expectation that men marry and become the family breadwinner to attain higher social status. Hence, young males who are unable to achieve these socially determined adult milestones can be considered socially inferior, and suffer more community discrimination and exclusion, which are risk factors for clinical deterioration and functional impairment.

Social stigma can intensify relationship conflicts within the family and magnify expressed emotion (EE), which is defined as caregivers’ attitude toward a person with mental illness as reflected by their comments and interaction patterns. “High EE” comprises three behavioral patterns: criticism, hostility, and emotional overinvolvement. High EE is associated with psychiatric symptom relapse among individuals with schizophrenia and other disorders.⁹

Currently, most of the literature on EE is limited to white samples in Western countries. Some researchers have studied the relationship between the EE index of emotional overinvolvement and schizophrenia relapse among Hispanic populations.¹⁰ However, there are limited data on cultural congruence of EE research in Asian populations. Therefore, clinicians should carefully evaluate the contribution of high EE to Bill’s family’s situation during his course of treatment.

Higher education often is associated with greater levels of EE and can result in anxious and fearful responses to the person’s illness.¹¹ This may be attributable to more negative reactions to actual or feared stigma and discrimination, possibly because relatives feel they have more to lose regarding the family’s social status, especially in densely populated urban areas where it might be harder to keep the patient’s mental illness as a “family secret.”

On the other hand, certain explanatory models of psychosis can modulate Chinese community members’ perceptions and allow ill individuals to remain socially integrated. Cultural idioms such as “excessive thinking” (xiang tai duo), “taking things too hard” (xiang bu kai), and “narrow-mindedness” (xiao xin yan) promote socially accommodating behaviors that facilitate acceptance of mildly to moderately ill individuals as full-status community members.¹²

Another important contributor to psychosis risk is Bill’s acculturative stress about his cultural identity. Linguistic challenges, limited social support, perceived discrimination, and an acculturation gap between parents and children are major sources of acculturative stress among Chinese American college students.¹³ Greater acculturative stress elevates the risk of mental illness and symptom deterioration. However, highly acculturated Chinese Americans with above-average bicultural self-efficacy tend to express more positive attitudes toward mental health services.
 

3. Are there culturally appropriate interventions that can help Bill and his family?

A major predictor among Chinese Americans of the intent to use services is the perceived credibility of the treatment and the provider. Ethnic-specific services staffed by bicultural/bilingual mental health clinicians delivering culturally responsive interventions are increasingly available in many metropolitan areas with major Asian communities. These programs have shown clinical efficacy in encouraging service use and promoting treatment persistence. Bill and his family may benefit from referral to ethnic-specific services, where they can obtain culturally sensitive psychoeducation about his mental illness and treatment plan.

Other services that might be useful for Bill and his family include family psychoeducation programs and supportive groups specifically designed for Chinese American families; these can improve the entire family’s psychosocial health, promote medication adherence, and reduce the risk of symptom relapse through family-centered intervention models.¹⁴ Connecting with local National Alliance on Mental Illness (NAMI) programs might help Bill’s parents obtain social support from Chinese American families with similar caregiver experiences.

However, services that are not designed specifically for Chinese-origin patients also can provide excellent care for these patients, and be perceived as credible and effective. A thorough cultural assessment is necessary, as well as inclusion of the information obtained in the treatment plan. As described in the DSM-5 Outline for Cultural Formulation and operationalized in the Cultural Formulation Interview, clinicians should assess possible cultural differences among Bill, his family, his community, and his clinicians regarding their cultural concepts of distress and illness and expectations of care in order to formulate a treatment plan acceptable to patient and family. Practical cultural barriers should be addressed, such as Bill’s parents’ limited English proficiency, in which case a bilingual clinician or trained interpreter should be included in the treatment team.

With Bill’s consent, the treatment team also should consider reaching out to his parents, especially his mother, to understand and empathize with their cultural concepts of distress and illness as well as expectations for care. In addition to providing psychoeducation, the clinicians should validate the parents’ experience of shame, fear, and worry about their son. Bill’s brother, for example, might be a useful bridge in communicating with the parents given his higher acculturation and potentially greater acceptance of psychiatric care. He might help alleviate the tension between Bill and his parents and encourage them to seek family-based help.
 

Take-home points

• Clinical training programs should offer cultural competency training about underserved populations, including communities of color.
• Certain key concepts, such as traditional idioms of distress and explanatory models, social stigma, and acculturative stress, should be included in these trainings and evaluated in a comprehensive psychosocial assessment.
• High expressed emotion among family caregivers is associated with higher rates of psychiatric symptom relapse, whereas families with above-average bicultural self-efficacy have more positive attitudes toward mental health services.
• Clinicians should incorporate culturally appropriate educational materials (for example, CHR warning signs) and interventions to engage underserved patients and their families in mental health treatment.

Contributors

Emily Wu, MD – Harvard Medical School, Boston

Francis Lu, MD – University of California, Davis

John Sargent, MD – Tufts Medical Center, Boston

Roberto Lewis-Fernández, MD – Columbia College of Physicians & Surgeons, New York



If you would like to a submit case in which your understanding and treatment are affected by challenging cultural and family values, send it to [email protected]. We will then write back with our best answers about how one might proceed in such a case. Your case and our response will then be published at mdedge.com/psychiatry. This column is meant to be educational and does not constitute medical advice. The opinions expressed are those of the contributors and do not represent those of the organizations they are employed by or affiliated with or the Group for the Advancement of Psychiatry.

References

1. J Nerv Ment Dis. 2013 Jun;20(6);484-9.

2. Schizophr Res. 2014 Feb;152(2-3):391-9.

3. Perspect Psychiatr Care. 2013;49(4):288-92.

4. Ment Health Serv Res. 2001 Dec;3(4):201-14.

5. Br J Psychiatry. 2000 Jul;177;20-5.

6. Cultr Divers Ethnic Minor Psychol. 2008 Jan;14(1):10-8.

7. Couns Psychol. 2003 May1;31:343-61.

8. Emotion. 2002 Dec;2(4):341-60.

9. Am J Psychiatry. 1986 Nov;143(11):1361-73.

10. J Nerv Ment Dis. 2013 Oct;201(10):833-40.

11. Schizophr Bull. 1981;7(1):43-4.

12. Schizophr Bull. 2010 Jul;36(4):836-45.

13. Am J Orthopsychiatry. 2011 Oct;81(4):489-97.

14. Patient Educ Couns. 2009 Apr;75(1):67-76.

Editors’ Note: Curbside Consult is an occasional column aimed at helping psychiatrists think through family and cultural considerations when treating patients. It examines case vignettes and is written by two Group for the Advancement of Psychiatry (GAP) committees – the Committee on Family Psychiatry and the Committee on Cultural Psychiatry. The contributors have revised selected patient details to shield the identities of the patients/cases and to comply with HIPAA requirements.

Case vignette

Bill is a 25-year-old man of Chinese descent who sought psychiatric evaluation of his psychosis risk. His parents emigrated from China to Canada more than 30 years ago; Bill was born in Canada, and moved to the United States with his parents and two siblings at age 7.

His family has a strong history of mental illness. His older sister was diagnosed with schizophrenia; she frequently got into verbal altercations with her parents. When Bill was 15, she walked out of the house after a fight with the family and never returned. Bill’s family thinks his father has had paranoid delusions. In the past, he attempted to call the police multiple times because he suspected the neighbors had planted a listening device in his front yard. The family stopped him from making the actual calls. However, the family never brought him to psychiatric evaluation because of perceived stigma and social discrimination in their community. He also was emotionally and physically abusive to Bill during his childhood by calling him names and hitting him with a belt. As an adult, Bill still has posttraumatic stress disorder symptoms including flashbacks, nightmares, and avoidance when thinking about his father.

Bill identifies himself as Chinese American and speaks English only. He often perceives himself as a newcomer to U.S. society, making comments such as: “I guess I should live my life like this to fulfill the American dream.” Bill’s parents placed a strong emphasis on academic success, often at the expense of their children’s social interaction and playtime activities. Bill describes himself as a “loner” with few friends. He maintained high academic achievement during high school and was accepted by a prestigious college. Although he was interested in music composition, Bill was “forced” by his parents to major in courses deemed good preparation for law school.

During college, he suffered severe depression with insomnia, low energy, hopelessness, anhedonia, social withdrawal, poor appetite with weight loss, and ruminative thoughts but without delusional thoughts or perceptual disturbances. He had one near-lethal suicide attempt, during which he impulsively took the contents of an entire bottle of Tylenol in the context of family conflicts, resulting in psychiatric hospitalization. Bill recalled with animosity the inpatient psychiatrists who put him on psychotropic medications during a 3-day hospitalization. He was not adherent to the medication and did not follow up with postdischarge outpatient care. He did not remember the medication trial he had during the hospitalization, nor did he give consent to obtain medical records from there. Bill withdrew from college in sophomore year, because of his declining academic performance secondary to his mental illness. He currently works at a gas station.

Over the last year, Bill’s interpersonal communication has become disorganized in both work and social settings, and he has developed thought blocking, causing him substantial distress. He intermittently hears voices of strangers in the background; these have gradually become more frequent, now occurring 3-4 times a week. Bill also is more depressed, with frequent crying episodes and worsening social isolation. He often thinks that life is not worth living, but he has no active suicidal plans or intent.

Bill’s supervisor and coworkers strongly suggested that he seek medical evaluation. As an outpatient, Bill started weekly cognitive-behavioral therapy (CBT) and biweekly medication sessions for early psychosis symptoms, receiving low-dose risperidone (1 mg b.i.d.) and fluoxetine (20 mg daily). Despite initial improvement, he was very skeptical about continuing the medications because of concern that they will cause a “change in his identity” by altering his body chemistry. His parents have been reluctant to join family meetings, because they were ambivalent about Bill’s ongoing psychiatric treatment.
 

Treatment team’s impressions

Clinical high risk (CHR) syndrome refers to the prodromal phase before a full psychotic disorder. As one of the three subcategories of CHR, genetic risk and deterioration (GRD) prodromal syndrome is defined by having a genetic risk for psychosis (first-degree relative with a psychotic disorder or meeting criteria for schizotypal personality disorder) and a recent decline in daily functioning equivalent to a 30% drop in Global Assessment of Functioning rating.¹ Due to Bill’s family history of psychosis, new difficulties in self-care, psychotic-spectrum symptoms, and declining social/executive function, he meets criteria for GRD prodromal syndrome. In addition, major depressive disorder should be considered on his differential diagnosis.

Bill has not received a diagnosis of acute psychosis, and instead is judged to be in the CHR spectrum for psychosis, because of his level of insight that the occasional perceptual disturbance and abnormal thought content are in his own mind. Since 26% of individuals with CHR in mainland China² and 35% in the general U.S. population develop fully psychotic symptoms within 2-3 years, Bill’s current presentation warrants secondary preventive care (early intervention) to promote improved clinical outcomes. Given the high rates of comorbid depressive and anxiety disorders among individuals with CHR, Bill’s mood symptoms and passive suicidality also require psychiatric intervention. The treatment team raised three questions, which are answered below.
 

1. How can we understand Bill’s and his family’s resistance to mental health treatment?

Chinese Americans tend to access mental health services at a lower rate than that of the general U.S. population.³ They also tend to exhibit elevated discontinuation from mental health care, compared with non-Latino whites.⁴ Since first- and second-generation Chinese Americans have similar use rates, it is likely the barriers to care are not immigration specific but also related to factors that endure across generations, including culture-related aspects. These include cultural concepts of illness and how to interpret prodromal symptoms such as Bill’s, stigma and interpersonal shame regarding mental illness and psychiatric treatment, and value orientations such as self-reliance, avoidance of direct expressions of interpersonal conflict, and family privacy.

Exploring cultural concepts of distress common among Chinese American families might help clinicians address barriers to mental health service use and persistence. For example, Chinese Americans tend to emphasize the physical-symptom components of psychiatric problems, partly because of mind-body holism – which combines physical and psychological symptoms into cultural syndromes and idioms of distress – and partly because of concerns about stigma and shame regarding mental health symptoms. Hence, they are more likely to seek help from primary care clinicians for psychological distress before any mental health provider. Many Chinese Americans interpret mild to moderate psychological distress as “mental weakness” or “excessive thinking” (xiang tai duo), which does not require clinical evaluation. In this view, only alarmingly bizarre or disruptive behaviors warrant formal psychiatric treatment.

2. How does Bill’s cultural and social context affect his prognosis?

Individuals with psychosis and their close relatives are generally vulnerable to stigma and discrimination. Mental health stigma has a substantial effect on the lives of patients with psychosis and their family members. The magnitude of the perceived stigma tends to be greater if the patient has more severe positive symptoms, is more educated, or resides in a highly urbanized area.

Acutely ill patients usually face more negative community responses than do milder cases, since their close relatives are blamed for failing to uphold the moral and legal responsibility of ensuring that the patients control their behavior. The effect of stigma in Chinese society also is greater among male patients with early-onset illness, because of the expectation that men marry and become the family breadwinner to attain higher social status. Hence, young males who are unable to achieve these socially determined adult milestones can be considered socially inferior, and suffer more community discrimination and exclusion, which are risk factors for clinical deterioration and functional impairment.

Social stigma can intensify relationship conflicts within the family and magnify expressed emotion (EE), which is defined as caregivers’ attitude toward a person with mental illness as reflected by their comments and interaction patterns. “High EE” comprises three behavioral patterns: criticism, hostility, and emotional overinvolvement. High EE is associated with psychiatric symptom relapse among individuals with schizophrenia and other disorders.⁹

Currently, most of the literature on EE is limited to white samples in Western countries. Some researchers have studied the relationship between the EE index of emotional overinvolvement and schizophrenia relapse among Hispanic populations.¹⁰ However, there are limited data on cultural congruence of EE research in Asian populations. Therefore, clinicians should carefully evaluate the contribution of high EE to Bill’s family’s situation during his course of treatment.

Higher education often is associated with greater levels of EE and can result in anxious and fearful responses to the person’s illness.¹¹ This may be attributable to more negative reactions to actual or feared stigma and discrimination, possibly because relatives feel they have more to lose regarding the family’s social status, especially in densely populated urban areas where it might be harder to keep the patient’s mental illness as a “family secret.”

On the other hand, certain explanatory models of psychosis can modulate Chinese community members’ perceptions and allow ill individuals to remain socially integrated. Cultural idioms such as “excessive thinking” (xiang tai duo), “taking things too hard” (xiang bu kai), and “narrow-mindedness” (xiao xin yan) promote socially accommodating behaviors that facilitate acceptance of mildly to moderately ill individuals as full-status community members.¹²

Another important contributor to psychosis risk is Bill’s acculturative stress about his cultural identity. Linguistic challenges, limited social support, perceived discrimination, and an acculturation gap between parents and children are major sources of acculturative stress among Chinese American college students.¹³ Greater acculturative stress elevates the risk of mental illness and symptom deterioration. However, highly acculturated Chinese Americans with above-average bicultural self-efficacy tend to express more positive attitudes toward mental health services.
 

3. Are there culturally appropriate interventions that can help Bill and his family?

A major predictor among Chinese Americans of the intent to use services is the perceived credibility of the treatment and the provider. Ethnic-specific services staffed by bicultural/bilingual mental health clinicians delivering culturally responsive interventions are increasingly available in many metropolitan areas with major Asian communities. These programs have shown clinical efficacy in encouraging service use and promoting treatment persistence. Bill and his family may benefit from referral to ethnic-specific services, where they can obtain culturally sensitive psychoeducation about his mental illness and treatment plan.

Other services that might be useful for Bill and his family include family psychoeducation programs and supportive groups specifically designed for Chinese American families; these can improve the entire family’s psychosocial health, promote medication adherence, and reduce the risk of symptom relapse through family-centered intervention models.¹⁴ Connecting with local National Alliance on Mental Illness (NAMI) programs might help Bill’s parents obtain social support from Chinese American families with similar caregiver experiences.

However, services that are not designed specifically for Chinese-origin patients also can provide excellent care for these patients, and be perceived as credible and effective. A thorough cultural assessment is necessary, as well as inclusion of the information obtained in the treatment plan. As described in the DSM-5 Outline for Cultural Formulation and operationalized in the Cultural Formulation Interview, clinicians should assess possible cultural differences among Bill, his family, his community, and his clinicians regarding their cultural concepts of distress and illness and expectations of care in order to formulate a treatment plan acceptable to patient and family. Practical cultural barriers should be addressed, such as Bill’s parents’ limited English proficiency, in which case a bilingual clinician or trained interpreter should be included in the treatment team.

With Bill’s consent, the treatment team also should consider reaching out to his parents, especially his mother, to understand and empathize with their cultural concepts of distress and illness as well as expectations for care. In addition to providing psychoeducation, the clinicians should validate the parents’ experience of shame, fear, and worry about their son. Bill’s brother, for example, might be a useful bridge in communicating with the parents given his higher acculturation and potentially greater acceptance of psychiatric care. He might help alleviate the tension between Bill and his parents and encourage them to seek family-based help.
 

Take-home points

• Clinical training programs should offer cultural competency training about underserved populations, including communities of color.
• Certain key concepts, such as traditional idioms of distress and explanatory models, social stigma, and acculturative stress, should be included in these trainings and evaluated in a comprehensive psychosocial assessment.
• High expressed emotion among family caregivers is associated with higher rates of psychiatric symptom relapse, whereas families with above-average bicultural self-efficacy have more positive attitudes toward mental health services.
• Clinicians should incorporate culturally appropriate educational materials (for example, CHR warning signs) and interventions to engage underserved patients and their families in mental health treatment.

Contributors

Emily Wu, MD – Harvard Medical School, Boston

Francis Lu, MD – University of California, Davis

John Sargent, MD – Tufts Medical Center, Boston

Roberto Lewis-Fernández, MD – Columbia College of Physicians & Surgeons, New York



If you would like to a submit case in which your understanding and treatment are affected by challenging cultural and family values, send it to [email protected]. We will then write back with our best answers about how one might proceed in such a case. Your case and our response will then be published at mdedge.com/psychiatry. This column is meant to be educational and does not constitute medical advice. The opinions expressed are those of the contributors and do not represent those of the organizations they are employed by or affiliated with or the Group for the Advancement of Psychiatry.

References

1. J Nerv Ment Dis. 2013 Jun;20(6);484-9.

2. Schizophr Res. 2014 Feb;152(2-3):391-9.

3. Perspect Psychiatr Care. 2013;49(4):288-92.

4. Ment Health Serv Res. 2001 Dec;3(4):201-14.

5. Br J Psychiatry. 2000 Jul;177;20-5.

6. Cultr Divers Ethnic Minor Psychol. 2008 Jan;14(1):10-8.

7. Couns Psychol. 2003 May1;31:343-61.

8. Emotion. 2002 Dec;2(4):341-60.

9. Am J Psychiatry. 1986 Nov;143(11):1361-73.

10. J Nerv Ment Dis. 2013 Oct;201(10):833-40.

11. Schizophr Bull. 1981;7(1):43-4.

12. Schizophr Bull. 2010 Jul;36(4):836-45.

13. Am J Orthopsychiatry. 2011 Oct;81(4):489-97.

14. Patient Educ Couns. 2009 Apr;75(1):67-76.

SAN DIEGO – Between 2002 and April 2018, about one in five civil monetary penalty payments linked to Emergency Medical Treatment and Labor Act (EMTALA) violations involved psychiatric emergencies, an analysis of national data found.

“Penalties were twice as high for psychiatric cases as for nonpsychiatric cases, with failure to stabilize being more common,” Sophie Terp, MD, MPH, said at the annual meeting of the American College of Emergency Physicians. “Recent large penalties suggest the need to improve care for psychiatric emergencies.”

In an effort to characterize U.S. Office of Inspector General (OIG) penalties resulting from EMTALA violations involving psychiatric emergencies, Dr. Terp, of the department of emergency medicine at the University of Southern California, Los Angeles, and her colleagues reviewed all OIG penalties between 2002 and April 2018. Characteristics of penalties involving psychiatric emergencies were described and compared with other penalties.

Of the 229 civil monetary penalties levied during the study period, 44 (19%) were related to psychiatric emergencies and the average fine was $85,488, which was significantly higher than the average fine of $32,042 for nonpsychiatric-related civil monetary penalties (P = .004). The three largest penalties during the study period were all related to psychiatric emergencies, including one for $360,000 in 2012, one for $1,295,000 in 2017, and one for $200,000 in 2018.


“Settlements have been particularly high in recent years,” Dr. Terp said. By comparison, the largest civil monetary penalty for a nonpsychiatric case was $170,000.

Failure to provide a medical screening exam was the most common reason for civil monetary settlements in both psychiatric and nonpsychiatric cases (84% vs. 74%; P = .147), but “failure to stabilize” occurred in a significantly greater proportion of psychiatric versus nonpsychiatric cases (68% vs. 51%; P = .041). About one-third of all psychiatric cases occurred in Centers for Medicare & Medicaid Services Region 4, “which is a region known to have a very high rate of EMTALA enforcement overall,” Dr. Terp said. “About half of those cases occurred in Florida, and another 20% occurred in South Carolina. About 20% occurred in CMS Region 6, and about half of those were in Texas. But the overall proportions of psychiatric versus nonpsychiatric cases that distributed over the CMS regions did not significantly differ.”

Dr. Terp reported having no financial disclosures.

[email protected]

SOURCE: Terp S et al. ACEP18, Abstract 46.

SAN DIEGO – Between 2002 and April 2018, about one in five civil monetary penalty payments linked to Emergency Medical Treatment and Labor Act (EMTALA) violations involved psychiatric emergencies, an analysis of national data found.

“Penalties were twice as high for psychiatric cases as for nonpsychiatric cases, with failure to stabilize being more common,” Sophie Terp, MD, MPH, said at the annual meeting of the American College of Emergency Physicians. “Recent large penalties suggest the need to improve care for psychiatric emergencies.”

In an effort to characterize U.S. Office of Inspector General (OIG) penalties resulting from EMTALA violations involving psychiatric emergencies, Dr. Terp, of the department of emergency medicine at the University of Southern California, Los Angeles, and her colleagues reviewed all OIG penalties between 2002 and April 2018. Characteristics of penalties involving psychiatric emergencies were described and compared with other penalties.

Of the 229 civil monetary penalties levied during the study period, 44 (19%) were related to psychiatric emergencies and the average fine was $85,488, which was significantly higher than the average fine of $32,042 for nonpsychiatric-related civil monetary penalties (P = .004). The three largest penalties during the study period were all related to psychiatric emergencies, including one for $360,000 in 2012, one for $1,295,000 in 2017, and one for $200,000 in 2018.


“Settlements have been particularly high in recent years,” Dr. Terp said. By comparison, the largest civil monetary penalty for a nonpsychiatric case was $170,000.

Failure to provide a medical screening exam was the most common reason for civil monetary settlements in both psychiatric and nonpsychiatric cases (84% vs. 74%; P = .147), but “failure to stabilize” occurred in a significantly greater proportion of psychiatric versus nonpsychiatric cases (68% vs. 51%; P = .041). About one-third of all psychiatric cases occurred in Centers for Medicare & Medicaid Services Region 4, “which is a region known to have a very high rate of EMTALA enforcement overall,” Dr. Terp said. “About half of those cases occurred in Florida, and another 20% occurred in South Carolina. About 20% occurred in CMS Region 6, and about half of those were in Texas. But the overall proportions of psychiatric versus nonpsychiatric cases that distributed over the CMS regions did not significantly differ.”

Dr. Terp reported having no financial disclosures.

[email protected]

SOURCE: Terp S et al. ACEP18, Abstract 46.

SAN DIEGO – Between 2002 and April 2018, about one in five civil monetary penalty payments linked to Emergency Medical Treatment and Labor Act (EMTALA) violations involved psychiatric emergencies, an analysis of national data found.

“Penalties were twice as high for psychiatric cases as for nonpsychiatric cases, with failure to stabilize being more common,” Sophie Terp, MD, MPH, said at the annual meeting of the American College of Emergency Physicians. “Recent large penalties suggest the need to improve care for psychiatric emergencies.”

In an effort to characterize U.S. Office of Inspector General (OIG) penalties resulting from EMTALA violations involving psychiatric emergencies, Dr. Terp, of the department of emergency medicine at the University of Southern California, Los Angeles, and her colleagues reviewed all OIG penalties between 2002 and April 2018. Characteristics of penalties involving psychiatric emergencies were described and compared with other penalties.

Of the 229 civil monetary penalties levied during the study period, 44 (19%) were related to psychiatric emergencies and the average fine was $85,488, which was significantly higher than the average fine of $32,042 for nonpsychiatric-related civil monetary penalties (P = .004). The three largest penalties during the study period were all related to psychiatric emergencies, including one for $360,000 in 2012, one for $1,295,000 in 2017, and one for $200,000 in 2018.


“Settlements have been particularly high in recent years,” Dr. Terp said. By comparison, the largest civil monetary penalty for a nonpsychiatric case was $170,000.

Failure to provide a medical screening exam was the most common reason for civil monetary settlements in both psychiatric and nonpsychiatric cases (84% vs. 74%; P = .147), but “failure to stabilize” occurred in a significantly greater proportion of psychiatric versus nonpsychiatric cases (68% vs. 51%; P = .041). About one-third of all psychiatric cases occurred in Centers for Medicare & Medicaid Services Region 4, “which is a region known to have a very high rate of EMTALA enforcement overall,” Dr. Terp said. “About half of those cases occurred in Florida, and another 20% occurred in South Carolina. About 20% occurred in CMS Region 6, and about half of those were in Texas. But the overall proportions of psychiatric versus nonpsychiatric cases that distributed over the CMS regions did not significantly differ.”

Dr. Terp reported having no financial disclosures.

[email protected]

SOURCE: Terp S et al. ACEP18, Abstract 46.

Cardiomyopathy induced by antimalarial treatment for systemic lupus erythematosus may not be as rare as previously thought. Also today, low bone mineral density and spinal syndesmophytes predict radiographic progression in axial spondyloarthritis, sensory feedback modalities tackle gait and balance problems in Parkinson’s disease, and clinically meaningful change is determined for RAPID-3 in active RA.
Amazon Alexa
Apple Podcasts
Spotify

Cardiomyopathy induced by antimalarial treatment for systemic lupus erythematosus may not be as rare as previously thought. Also today, low bone mineral density and spinal syndesmophytes predict radiographic progression in axial spondyloarthritis, sensory feedback modalities tackle gait and balance problems in Parkinson’s disease, and clinically meaningful change is determined for RAPID-3 in active RA.
Amazon Alexa
Apple Podcasts
Spotify

Cardiomyopathy induced by antimalarial treatment for systemic lupus erythematosus may not be as rare as previously thought. Also today, low bone mineral density and spinal syndesmophytes predict radiographic progression in axial spondyloarthritis, sensory feedback modalities tackle gait and balance problems in Parkinson’s disease, and clinically meaningful change is determined for RAPID-3 in active RA.
Amazon Alexa
Apple Podcasts
Spotify