Administering antenatal corticosteroids to pregnant women at high risk for preterm birth was a cost-effective intervention that improved infant respiratory outcomes, according to a new study.

“This intervention has a potential cost saving in the United States of approximately $100 million dollars annually from the benefit in the immediate neonatal outcome alone,” Cynthia Gyamfi-Bannerman, MD, of Columbia University, New York, and her associates reported in JAMA Pediatrics. “Because late preterm birth comprises a large proportion of all preterm births, our findings have the potential for a large influence on public health.”

The researchers conducted a retrospective secondary analysis of the randomized Antenatal Late Preterm Steroids (ALPS) clinical trial October 2010 to February 2015. The trial enrolled randomly assigned antenatal administration of betamethasone or placebo to women pregnant with a singleton and at high risk for preterm birth while between 34 weeks, 6 days, and 36 weeks, 0 days, of gestation.

Antenatal corticosteroid administration was regarded as effective if a newborn did not require treatment in the first 72 hours for respiratory distress or illness. Treatment could include “continuous positive airway pressure or high-flow nasal cannula for 2 hours or more, supplemental oxygen with a fraction of inspired oxygen of 30% or more for 4 hours or more, and extracorporeal membrane oxygenation or mechanical ventilation,” Dr. Gyamfi-Bannerman and her associates wrote.

To tally the costs, the researchers used Medicaid rates to estimate the total in 2015 U.S. dollars for betamethasone, outpatient visits or inpatient stays to administer it, and all direct newborn care costs, including neonatal ICU daily costs stratified by respiratory illness severity. Betamethasone administration included an initial 12-mg intramuscular dose followed by another after 24 hours if the infant had not been delivered.

“Because therapy often persists for longer than this 72-hour duration, we measured costs through hospital discharge,” the authors wrote. “The analysis took the perspective of a third-party payer in which we included direct medical costs and associated overhead accruing to hospitals and medical payers for the care of enrolled patients and their infants.”

Among 2,821 mothers not lost to follow-up during the secondary analysis, 1,426 received betamethasone and 1,395 received placebo. For mothers who received betamethasone antenatally, the total mean cost was $4,681 per mother-infant pair. Total mean cost for those in the placebo group was $5,379 per pair, resulting in a significant mean $698 savings (P = .02). Respiratory morbidity was 2.9% lower in infants whose mothers received antenatal corticosteroid treatment.

“Thus, because the treated group had lower costs and this strategy was more effective, administration of betamethasone to women at risk for late preterm birth was judged to be a dominant strategy, which is defined as one in which costs are lower and effectiveness is higher than a comparator (incremental cost-effectiveness ratio [ICER], −23 986),” Dr. Gyamfi-Bannerman and her associates reported. ICER is defined as the difference in mean total cost per patient in the betamethasone and placebo arms divided by the difference in the effectiveness.

Study limitations were an inability to estimate costs according to quality-adjusted life years or to include families’/caregivers’ costs.

SOURCE: Gyamfi-Bannerman C. JAMA Pediatr. 2019 Mar 11. doi: 10.1001/jamapediatrics.2019.0032.

Administering antenatal corticosteroids to pregnant women at high risk for preterm birth was a cost-effective intervention that improved infant respiratory outcomes, according to a new study.

“This intervention has a potential cost saving in the United States of approximately $100 million dollars annually from the benefit in the immediate neonatal outcome alone,” Cynthia Gyamfi-Bannerman, MD, of Columbia University, New York, and her associates reported in JAMA Pediatrics. “Because late preterm birth comprises a large proportion of all preterm births, our findings have the potential for a large influence on public health.”

The researchers conducted a retrospective secondary analysis of the randomized Antenatal Late Preterm Steroids (ALPS) clinical trial October 2010 to February 2015. The trial enrolled randomly assigned antenatal administration of betamethasone or placebo to women pregnant with a singleton and at high risk for preterm birth while between 34 weeks, 6 days, and 36 weeks, 0 days, of gestation.

Antenatal corticosteroid administration was regarded as effective if a newborn did not require treatment in the first 72 hours for respiratory distress or illness. Treatment could include “continuous positive airway pressure or high-flow nasal cannula for 2 hours or more, supplemental oxygen with a fraction of inspired oxygen of 30% or more for 4 hours or more, and extracorporeal membrane oxygenation or mechanical ventilation,” Dr. Gyamfi-Bannerman and her associates wrote.

To tally the costs, the researchers used Medicaid rates to estimate the total in 2015 U.S. dollars for betamethasone, outpatient visits or inpatient stays to administer it, and all direct newborn care costs, including neonatal ICU daily costs stratified by respiratory illness severity. Betamethasone administration included an initial 12-mg intramuscular dose followed by another after 24 hours if the infant had not been delivered.

“Because therapy often persists for longer than this 72-hour duration, we measured costs through hospital discharge,” the authors wrote. “The analysis took the perspective of a third-party payer in which we included direct medical costs and associated overhead accruing to hospitals and medical payers for the care of enrolled patients and their infants.”

Among 2,821 mothers not lost to follow-up during the secondary analysis, 1,426 received betamethasone and 1,395 received placebo. For mothers who received betamethasone antenatally, the total mean cost was $4,681 per mother-infant pair. Total mean cost for those in the placebo group was $5,379 per pair, resulting in a significant mean $698 savings (P = .02). Respiratory morbidity was 2.9% lower in infants whose mothers received antenatal corticosteroid treatment.

“Thus, because the treated group had lower costs and this strategy was more effective, administration of betamethasone to women at risk for late preterm birth was judged to be a dominant strategy, which is defined as one in which costs are lower and effectiveness is higher than a comparator (incremental cost-effectiveness ratio [ICER], −23 986),” Dr. Gyamfi-Bannerman and her associates reported. ICER is defined as the difference in mean total cost per patient in the betamethasone and placebo arms divided by the difference in the effectiveness.

Study limitations were an inability to estimate costs according to quality-adjusted life years or to include families’/caregivers’ costs.

SOURCE: Gyamfi-Bannerman C. JAMA Pediatr. 2019 Mar 11. doi: 10.1001/jamapediatrics.2019.0032.

Administering antenatal corticosteroids to pregnant women at high risk for preterm birth was a cost-effective intervention that improved infant respiratory outcomes, according to a new study.

“This intervention has a potential cost saving in the United States of approximately $100 million dollars annually from the benefit in the immediate neonatal outcome alone,” Cynthia Gyamfi-Bannerman, MD, of Columbia University, New York, and her associates reported in JAMA Pediatrics. “Because late preterm birth comprises a large proportion of all preterm births, our findings have the potential for a large influence on public health.”

The researchers conducted a retrospective secondary analysis of the randomized Antenatal Late Preterm Steroids (ALPS) clinical trial October 2010 to February 2015. The trial enrolled randomly assigned antenatal administration of betamethasone or placebo to women pregnant with a singleton and at high risk for preterm birth while between 34 weeks, 6 days, and 36 weeks, 0 days, of gestation.

Antenatal corticosteroid administration was regarded as effective if a newborn did not require treatment in the first 72 hours for respiratory distress or illness. Treatment could include “continuous positive airway pressure or high-flow nasal cannula for 2 hours or more, supplemental oxygen with a fraction of inspired oxygen of 30% or more for 4 hours or more, and extracorporeal membrane oxygenation or mechanical ventilation,” Dr. Gyamfi-Bannerman and her associates wrote.

To tally the costs, the researchers used Medicaid rates to estimate the total in 2015 U.S. dollars for betamethasone, outpatient visits or inpatient stays to administer it, and all direct newborn care costs, including neonatal ICU daily costs stratified by respiratory illness severity. Betamethasone administration included an initial 12-mg intramuscular dose followed by another after 24 hours if the infant had not been delivered.

“Because therapy often persists for longer than this 72-hour duration, we measured costs through hospital discharge,” the authors wrote. “The analysis took the perspective of a third-party payer in which we included direct medical costs and associated overhead accruing to hospitals and medical payers for the care of enrolled patients and their infants.”

Among 2,821 mothers not lost to follow-up during the secondary analysis, 1,426 received betamethasone and 1,395 received placebo. For mothers who received betamethasone antenatally, the total mean cost was $4,681 per mother-infant pair. Total mean cost for those in the placebo group was $5,379 per pair, resulting in a significant mean $698 savings (P = .02). Respiratory morbidity was 2.9% lower in infants whose mothers received antenatal corticosteroid treatment.

“Thus, because the treated group had lower costs and this strategy was more effective, administration of betamethasone to women at risk for late preterm birth was judged to be a dominant strategy, which is defined as one in which costs are lower and effectiveness is higher than a comparator (incremental cost-effectiveness ratio [ICER], −23 986),” Dr. Gyamfi-Bannerman and her associates reported. ICER is defined as the difference in mean total cost per patient in the betamethasone and placebo arms divided by the difference in the effectiveness.

Study limitations were an inability to estimate costs according to quality-adjusted life years or to include families’/caregivers’ costs.

SOURCE: Gyamfi-Bannerman C. JAMA Pediatr. 2019 Mar 11. doi: 10.1001/jamapediatrics.2019.0032.

Daily aspirin use could reduce the risk of acute exacerbations of chronic obstructive pulmonary disease, new data suggest.

copyright Darren Hester/Fotolia.com

Researchers reported the outcomes of an observational cohort study of 1,698 individuals with COPD, 45% of whom said they were taking daily aspirin at baseline. Their findings were published in Chest.

After a median follow up of 2.7 years, aspirin users had an overall 22% lower incidence of acute COPD exacerbations compared with nonusers. This was largely accounted for by a 25% reduction in moderate exacerbations, but there was no significant difference between aspirin users and nonusers in severe exacerbations.

A similar pattern was seen after just 1 year of follow-up, with an overall 30% reduction in the incidence of exacerbations, a 37% reduction in moderate exacerbations, but no significant reduction in severe exacerbations.

“Though aspirin use has previously been linked with reduced mortality risk in patients with COPD, to our knowledge, this is the first study to investigate the association of daily aspirin use with respiratory morbidity in COPD,” wrote Ashraf Fawzy, MD, of the division of pulmonary and critical care medicine at Johns Hopkins University, Baltimore, and his coauthors.

The association between aspirin use and reduced incidence of exacerbations was stronger among individuals with chronic bronchitis, which prompted the authors to suggest that future studies of aspirin in COPD should focus on participants with chronic bronchitis.

However, the association was not affected by COPD severity, emphysema presence or severity, or cardiometabolic phenotype.

Aspirin users reported better respiratory-specific quality of life than that of nonusers, including 34% lower odds of reporting moderate to severe dyspnea, and better baseline COPD health status.

“Findings of this study add to the existing literature by highlighting that aspirin use is also associated with reduced respiratory morbidity across several domains – including exacerbation risk, quality of life, and dyspnea – factors related to patient well-being and healthcare utilization,” the authors wrote.

Aspirin users were more likely to be white, male, and obese, and less likely to be smokers. They had better lung function but more cardiovascular comorbidities at baseline, although the aspirin users and nonusers were matched on baseline characteristics.

Speculating on the mechanisms by which aspirin might impact COPD exacerbations, the authors noted that the drug has both systemic and local pulmonary mechanisms of action.

For example, a pathway that results in elevated levels of a urinary metabolite in patients with COPD is irreversibly blocked by aspirin. Aspirin also attenuates the elevation of inflammatory markers interleukin-6 and C-reactive protein, which are part of the inflammatory phenotype of COPD. Aspirin has been shown to reduce proinflammatory cytokines in the lung.

The authors did note that aspirin use was self-reported, so they did not have data on dosage or duration of use.

The National Institutes of Health funded the study. Six authors declared advisory board positions, research support, and other funding from the pharmaceutical sector. One author was also a founder of a company commercializing lung image analysis software. No other conflicts of interest were declared.

SOURCE: Fawzy A et al. Chest. 2019 Mar;155(3): 519-27. doi: 10.1016/j.chest.2018.11.028.

Daily aspirin use could reduce the risk of acute exacerbations of chronic obstructive pulmonary disease, new data suggest.

copyright Darren Hester/Fotolia.com

Researchers reported the outcomes of an observational cohort study of 1,698 individuals with COPD, 45% of whom said they were taking daily aspirin at baseline. Their findings were published in Chest.

After a median follow up of 2.7 years, aspirin users had an overall 22% lower incidence of acute COPD exacerbations compared with nonusers. This was largely accounted for by a 25% reduction in moderate exacerbations, but there was no significant difference between aspirin users and nonusers in severe exacerbations.

A similar pattern was seen after just 1 year of follow-up, with an overall 30% reduction in the incidence of exacerbations, a 37% reduction in moderate exacerbations, but no significant reduction in severe exacerbations.

“Though aspirin use has previously been linked with reduced mortality risk in patients with COPD, to our knowledge, this is the first study to investigate the association of daily aspirin use with respiratory morbidity in COPD,” wrote Ashraf Fawzy, MD, of the division of pulmonary and critical care medicine at Johns Hopkins University, Baltimore, and his coauthors.

The association between aspirin use and reduced incidence of exacerbations was stronger among individuals with chronic bronchitis, which prompted the authors to suggest that future studies of aspirin in COPD should focus on participants with chronic bronchitis.

However, the association was not affected by COPD severity, emphysema presence or severity, or cardiometabolic phenotype.

Aspirin users reported better respiratory-specific quality of life than that of nonusers, including 34% lower odds of reporting moderate to severe dyspnea, and better baseline COPD health status.

“Findings of this study add to the existing literature by highlighting that aspirin use is also associated with reduced respiratory morbidity across several domains – including exacerbation risk, quality of life, and dyspnea – factors related to patient well-being and healthcare utilization,” the authors wrote.

Aspirin users were more likely to be white, male, and obese, and less likely to be smokers. They had better lung function but more cardiovascular comorbidities at baseline, although the aspirin users and nonusers were matched on baseline characteristics.

Speculating on the mechanisms by which aspirin might impact COPD exacerbations, the authors noted that the drug has both systemic and local pulmonary mechanisms of action.

For example, a pathway that results in elevated levels of a urinary metabolite in patients with COPD is irreversibly blocked by aspirin. Aspirin also attenuates the elevation of inflammatory markers interleukin-6 and C-reactive protein, which are part of the inflammatory phenotype of COPD. Aspirin has been shown to reduce proinflammatory cytokines in the lung.

The authors did note that aspirin use was self-reported, so they did not have data on dosage or duration of use.

The National Institutes of Health funded the study. Six authors declared advisory board positions, research support, and other funding from the pharmaceutical sector. One author was also a founder of a company commercializing lung image analysis software. No other conflicts of interest were declared.

SOURCE: Fawzy A et al. Chest. 2019 Mar;155(3): 519-27. doi: 10.1016/j.chest.2018.11.028.

Daily aspirin use could reduce the risk of acute exacerbations of chronic obstructive pulmonary disease, new data suggest.

copyright Darren Hester/Fotolia.com

Researchers reported the outcomes of an observational cohort study of 1,698 individuals with COPD, 45% of whom said they were taking daily aspirin at baseline. Their findings were published in Chest.

After a median follow up of 2.7 years, aspirin users had an overall 22% lower incidence of acute COPD exacerbations compared with nonusers. This was largely accounted for by a 25% reduction in moderate exacerbations, but there was no significant difference between aspirin users and nonusers in severe exacerbations.

A similar pattern was seen after just 1 year of follow-up, with an overall 30% reduction in the incidence of exacerbations, a 37% reduction in moderate exacerbations, but no significant reduction in severe exacerbations.

“Though aspirin use has previously been linked with reduced mortality risk in patients with COPD, to our knowledge, this is the first study to investigate the association of daily aspirin use with respiratory morbidity in COPD,” wrote Ashraf Fawzy, MD, of the division of pulmonary and critical care medicine at Johns Hopkins University, Baltimore, and his coauthors.

The association between aspirin use and reduced incidence of exacerbations was stronger among individuals with chronic bronchitis, which prompted the authors to suggest that future studies of aspirin in COPD should focus on participants with chronic bronchitis.

However, the association was not affected by COPD severity, emphysema presence or severity, or cardiometabolic phenotype.

Aspirin users reported better respiratory-specific quality of life than that of nonusers, including 34% lower odds of reporting moderate to severe dyspnea, and better baseline COPD health status.

“Findings of this study add to the existing literature by highlighting that aspirin use is also associated with reduced respiratory morbidity across several domains – including exacerbation risk, quality of life, and dyspnea – factors related to patient well-being and healthcare utilization,” the authors wrote.

Aspirin users were more likely to be white, male, and obese, and less likely to be smokers. They had better lung function but more cardiovascular comorbidities at baseline, although the aspirin users and nonusers were matched on baseline characteristics.

Speculating on the mechanisms by which aspirin might impact COPD exacerbations, the authors noted that the drug has both systemic and local pulmonary mechanisms of action.

For example, a pathway that results in elevated levels of a urinary metabolite in patients with COPD is irreversibly blocked by aspirin. Aspirin also attenuates the elevation of inflammatory markers interleukin-6 and C-reactive protein, which are part of the inflammatory phenotype of COPD. Aspirin has been shown to reduce proinflammatory cytokines in the lung.

The authors did note that aspirin use was self-reported, so they did not have data on dosage or duration of use.

The National Institutes of Health funded the study. Six authors declared advisory board positions, research support, and other funding from the pharmaceutical sector. One author was also a founder of a company commercializing lung image analysis software. No other conflicts of interest were declared.

SOURCE: Fawzy A et al. Chest. 2019 Mar;155(3): 519-27. doi: 10.1016/j.chest.2018.11.028.

Black patients who undergo bariatric surgery have a higher rate of overall complications and a lower postsurgery quality of life than white patients, according to a study of bariatric surgery patients in Michigan.

“Per this analysis, there are significant racial disparities in perioperative outcomes, weight loss, and quality of life after bariatric surgery,” wrote lead author Michael H. Wood, MD, of Wayne State University, Detroit, and his coauthors, adding that, “while biological differences may explain some of the disparity in outcomes, environmental, social, and behavioral factors likely play a role.” The study was published online in JAMA Surgery.

This study reviewed data from 14,210 participants in the Michigan Bariatric Surgery Collaborative (MBSC), a state-wide consortium and clinical registry of bariatric surgery patients. Matching cohorts were established for black (n = 7,105) and white (n = 7,105) patients who underwent a primary bariatric operation (Roux-en-Y gastric bypass, sleeve gastrectomy, or adjustable gastric banding) between June 2006 and January 2017. The only significant differences between cohorts – clarified as “never more than 1 or 2 percentage points” – were in regard to income brackets and procedure type.

At 30-day follow-up, the rate of overall complications was higher in black patients (628, 8.8%) than in white patients (481, 6.8%; adjusted odds ratio, 1.33; 95% confidence interval, 1.17-1.51; P = .02), as was the length of stay (mean, 2.2 days vs. 1.9 days; aOR, 0.30; 95% CI, 0.20-0.40; P less than .001). Black patients also had a higher rate of both ED visits (541 [11.6%] vs. 826 [7.6%]; aOR, 1.60; 95% CI, 1.43-1.79; P less than .001) and readmissions (414 [5.8%] vs. 245 [3.5%]; aOR, 1.73; 95% CI, 1.47-2.03; P less than .001).

In addition, at 1-year follow-up, black patients had a lower mean weight loss (32.0 kg vs. 38.3 kg; P less than .001) and percentage of total weight loss (26% vs. 29%; P less than .001) compared with white patients. And though black patients were more likely than white patients to report a high quality of life before surgery (2,672 [49.5%] vs. 2,354 [41.4%]; P less than .001), they were less likely to do so 1 year afterward (1,379 [87.2%] vs. 2,133 [90.4%]; P = .002).

The coauthors acknowledged the limitations of their study, including potential unmeasured factors between cohorts such as disease duration or severity. They also noted that a wider time horizon than 30 days post surgery could have altered the results, although “serious adverse events and resource use tend to be highest within the first month after surgery, and we anticipate that this effect would have been negligible.”

The study was funded by Blue Cross Blue Shield Michigan/Blue Care Network. Dr. Wood reported no conflicts of interest. Three of his coauthors reported receiving salary support from Blue Cross Blue Shield Michigan/Blue Care Network for their work with the MBSC, and one other coauthor reported receiving an honorarium for being the MBSC’s executive committee chair.

SOURCE: Wood MH et al. JAMA Surg. 2019 Mar 6. doi: 10.1001/jamasurg.2019.0029.

Black patients who undergo bariatric surgery have a higher rate of overall complications and a lower postsurgery quality of life than white patients, according to a study of bariatric surgery patients in Michigan.

“Per this analysis, there are significant racial disparities in perioperative outcomes, weight loss, and quality of life after bariatric surgery,” wrote lead author Michael H. Wood, MD, of Wayne State University, Detroit, and his coauthors, adding that, “while biological differences may explain some of the disparity in outcomes, environmental, social, and behavioral factors likely play a role.” The study was published online in JAMA Surgery.

This study reviewed data from 14,210 participants in the Michigan Bariatric Surgery Collaborative (MBSC), a state-wide consortium and clinical registry of bariatric surgery patients. Matching cohorts were established for black (n = 7,105) and white (n = 7,105) patients who underwent a primary bariatric operation (Roux-en-Y gastric bypass, sleeve gastrectomy, or adjustable gastric banding) between June 2006 and January 2017. The only significant differences between cohorts – clarified as “never more than 1 or 2 percentage points” – were in regard to income brackets and procedure type.

At 30-day follow-up, the rate of overall complications was higher in black patients (628, 8.8%) than in white patients (481, 6.8%; adjusted odds ratio, 1.33; 95% confidence interval, 1.17-1.51; P = .02), as was the length of stay (mean, 2.2 days vs. 1.9 days; aOR, 0.30; 95% CI, 0.20-0.40; P less than .001). Black patients also had a higher rate of both ED visits (541 [11.6%] vs. 826 [7.6%]; aOR, 1.60; 95% CI, 1.43-1.79; P less than .001) and readmissions (414 [5.8%] vs. 245 [3.5%]; aOR, 1.73; 95% CI, 1.47-2.03; P less than .001).

In addition, at 1-year follow-up, black patients had a lower mean weight loss (32.0 kg vs. 38.3 kg; P less than .001) and percentage of total weight loss (26% vs. 29%; P less than .001) compared with white patients. And though black patients were more likely than white patients to report a high quality of life before surgery (2,672 [49.5%] vs. 2,354 [41.4%]; P less than .001), they were less likely to do so 1 year afterward (1,379 [87.2%] vs. 2,133 [90.4%]; P = .002).

The coauthors acknowledged the limitations of their study, including potential unmeasured factors between cohorts such as disease duration or severity. They also noted that a wider time horizon than 30 days post surgery could have altered the results, although “serious adverse events and resource use tend to be highest within the first month after surgery, and we anticipate that this effect would have been negligible.”

The study was funded by Blue Cross Blue Shield Michigan/Blue Care Network. Dr. Wood reported no conflicts of interest. Three of his coauthors reported receiving salary support from Blue Cross Blue Shield Michigan/Blue Care Network for their work with the MBSC, and one other coauthor reported receiving an honorarium for being the MBSC’s executive committee chair.

SOURCE: Wood MH et al. JAMA Surg. 2019 Mar 6. doi: 10.1001/jamasurg.2019.0029.

Black patients who undergo bariatric surgery have a higher rate of overall complications and a lower postsurgery quality of life than white patients, according to a study of bariatric surgery patients in Michigan.

“Per this analysis, there are significant racial disparities in perioperative outcomes, weight loss, and quality of life after bariatric surgery,” wrote lead author Michael H. Wood, MD, of Wayne State University, Detroit, and his coauthors, adding that, “while biological differences may explain some of the disparity in outcomes, environmental, social, and behavioral factors likely play a role.” The study was published online in JAMA Surgery.

This study reviewed data from 14,210 participants in the Michigan Bariatric Surgery Collaborative (MBSC), a state-wide consortium and clinical registry of bariatric surgery patients. Matching cohorts were established for black (n = 7,105) and white (n = 7,105) patients who underwent a primary bariatric operation (Roux-en-Y gastric bypass, sleeve gastrectomy, or adjustable gastric banding) between June 2006 and January 2017. The only significant differences between cohorts – clarified as “never more than 1 or 2 percentage points” – were in regard to income brackets and procedure type.

At 30-day follow-up, the rate of overall complications was higher in black patients (628, 8.8%) than in white patients (481, 6.8%; adjusted odds ratio, 1.33; 95% confidence interval, 1.17-1.51; P = .02), as was the length of stay (mean, 2.2 days vs. 1.9 days; aOR, 0.30; 95% CI, 0.20-0.40; P less than .001). Black patients also had a higher rate of both ED visits (541 [11.6%] vs. 826 [7.6%]; aOR, 1.60; 95% CI, 1.43-1.79; P less than .001) and readmissions (414 [5.8%] vs. 245 [3.5%]; aOR, 1.73; 95% CI, 1.47-2.03; P less than .001).

In addition, at 1-year follow-up, black patients had a lower mean weight loss (32.0 kg vs. 38.3 kg; P less than .001) and percentage of total weight loss (26% vs. 29%; P less than .001) compared with white patients. And though black patients were more likely than white patients to report a high quality of life before surgery (2,672 [49.5%] vs. 2,354 [41.4%]; P less than .001), they were less likely to do so 1 year afterward (1,379 [87.2%] vs. 2,133 [90.4%]; P = .002).

The coauthors acknowledged the limitations of their study, including potential unmeasured factors between cohorts such as disease duration or severity. They also noted that a wider time horizon than 30 days post surgery could have altered the results, although “serious adverse events and resource use tend to be highest within the first month after surgery, and we anticipate that this effect would have been negligible.”

The study was funded by Blue Cross Blue Shield Michigan/Blue Care Network. Dr. Wood reported no conflicts of interest. Three of his coauthors reported receiving salary support from Blue Cross Blue Shield Michigan/Blue Care Network for their work with the MBSC, and one other coauthor reported receiving an honorarium for being the MBSC’s executive committee chair.

SOURCE: Wood MH et al. JAMA Surg. 2019 Mar 6. doi: 10.1001/jamasurg.2019.0029.

Federal health care providers live under a microscope, so it seems only fair that we at Fed Pract honor that reality and open ourselves up to scrutiny as well.¹ We hope that by shedding light on our peer-review process and manuscript acceptance rate, we will not only highlight our accomplishments, but identify areas for improvement.

Free access to Fed Pract content has always been our priority. While many journals charge authors or readers, Fed Pract has been and will remain free for readers and authors.² Advertising enables the journal to support this free model of publishing, but we take care to ensure that advertisements do not influence content in any way. Our advertising policy can be found at www.mdedge.com/fedprac/page/advertising.

In January 2019, Fed Pract placed > 400 peer-reviewed articles published since January 2015 in the PubMed Central (PMC) database (ncbi.nlm.nih.gov/pmc). The full text of these and all future Fed Pract peer-reviewed articles will be available at PMC (no registration required), and the citations also will be included in PubMed. We hope that this process will make it even easier for anyone to access our authors’ works.

In 2018 about 36,000 federal health care providers (HCPs) received hard copies of this journal. The print journal is free, but circulation is limited to HCPs who work at the US Department of Veterans Affairs (VA), US Department of Defense (DoD), and the US Public Health Service (PHS). The mdedge.com/fedprac website, which includes every article published since 2003, had 1.4 million page views in 2018. After reading 3 online articles, readers in the US are asked to complete a simple registration form to help us better customize the reader experience. In some cases, international readers may be asked to pay for access to articles online; however, any VA, DoD, or PHS officer stationed overseas can contact the editorial staff ([email protected]) to ensure that they can access the articles for free.

In 2018 the journal received 164 manuscripts and published 94 articles written by 357 different federal HCPs. The 164 manuscript submissions represented a 45% growth over previous years. Not surprisingly, the increased rate of submissions began shortly after the May 2018 announcement that journal articles would be included in PMC. Most of those articles (83%) were submitted unsolicited.

Fed Pract has always prided itself on being an early promoter of interdisciplinary health care professional publications. Nearly half of its listed authors were physicians (48%), while pharmacists made up the next largest cohort (18%). There were smaller numbers of PhDs, nurses, social workers, and physical therapists. The majority were written by HCPs affiliated with the VA (95% of articles and 93% of authors), and no articles in 2018 were written by PHS officers. Physicians comprise about two-thirds of the audience, while pharmacists make up 17% and nurses 9%. PHS and DoD HCPs make up 19% of the Fed Pract audience, suggesting that the journal needs to do more work to encourage these HCPs to contribute articles to the journal.³

Articles published in 2018 covered a broad range of topics from “Anesthesia Care Practice Models in the VHA” and “Army Behavioral Health System” to “Vitreous Hemorrhage in the Setting of a Vascular Loop” and “A Workforce Assessment of VA Home-Based Primary Care Pharmacists.” Categorizing the articles is a challenge. Few health care topics fit neatly into a single topic or specialty. This is especially true in federal health care where much of the care is delivered by multidisciplinary patient-centered medical homes or patient aligned care teams. Nevertheless, a few broad outlines can be discerned. Articles were roughly split between primary care and hospital-based and/or specialty care topics; one-quarter of the articles were case studies or case series articles, and about 20% were editorials or opinion columns. Nineteen articles dealt explicitly with chronic conditions, and 10 articles focused on mental health care.

Peer reviewers are an essential part of the process. Reviewers are blinded to the identityof the authors, ensuring fairness and reducing potential conflicts of interest. We are extremely grateful to each and every reviewer for the time and energy they contribute to the journal. Peer reviewers do not get nearly enough recognition for their important work. In 2018 Fed Pract invited 1,205 reviewers for 164 manuscript submissions and 94 manuscript revisions. More than 200 different reviewers submitted 487 reviews with a median (SD) of 2 reviews (1.8) and a range of 1 to 10. The top 20 reviewers completed 134 reviews with a median (SD) of 6 reviews (1.2). The results stand in contrast to some journals that must offer many invitations per review and depend on a small number of reviewers.^1,4-6

The reviewers recommended to reject 14% and to revise 26% of the articles, which is a much lower rejection rate than many other journals (Table).⁴ 

These data suggest that Fed Pract and its peer-review process is on a sound foundation but needs to make improvements. Moving into 2019, the journal expects that an increasing number of submissions will require a higher rejection rate. Moreover, we will need to do a better job reaching out to underrepresented portions of our audience. To decrease the time to publication for accepted manuscripts, in 2019 we will publish more articles online ahead of the print publication as we strive to improve the experience for authors, reviewers, readers, and the entire Fed Pract audience.

None of this work can be done without our small and dedicated staff. I would like to thank Managing Editor Joyce Brody who sent out each and every one of those reviewer invitations, Deputy Editor Robert Fee, who manages the special issues, Web Editor Teraya Smith, who runs our entire digital operation, and of course, Editor in Chief Cynthia Geppert, who oversees it all. Finally, it is important that you let us know how we are doing and whether we are meeting your needs. Visit mdedge.com/fedprac to take the readership survey or reach out to me at [email protected].

Federal health care providers live under a microscope, so it seems only fair that we at Fed Pract honor that reality and open ourselves up to scrutiny as well.¹ We hope that by shedding light on our peer-review process and manuscript acceptance rate, we will not only highlight our accomplishments, but identify areas for improvement.

Free access to Fed Pract content has always been our priority. While many journals charge authors or readers, Fed Pract has been and will remain free for readers and authors.² Advertising enables the journal to support this free model of publishing, but we take care to ensure that advertisements do not influence content in any way. Our advertising policy can be found at www.mdedge.com/fedprac/page/advertising.

In January 2019, Fed Pract placed > 400 peer-reviewed articles published since January 2015 in the PubMed Central (PMC) database (ncbi.nlm.nih.gov/pmc). The full text of these and all future Fed Pract peer-reviewed articles will be available at PMC (no registration required), and the citations also will be included in PubMed. We hope that this process will make it even easier for anyone to access our authors’ works.

In 2018 about 36,000 federal health care providers (HCPs) received hard copies of this journal. The print journal is free, but circulation is limited to HCPs who work at the US Department of Veterans Affairs (VA), US Department of Defense (DoD), and the US Public Health Service (PHS). The mdedge.com/fedprac website, which includes every article published since 2003, had 1.4 million page views in 2018. After reading 3 online articles, readers in the US are asked to complete a simple registration form to help us better customize the reader experience. In some cases, international readers may be asked to pay for access to articles online; however, any VA, DoD, or PHS officer stationed overseas can contact the editorial staff ([email protected]) to ensure that they can access the articles for free.

In 2018 the journal received 164 manuscripts and published 94 articles written by 357 different federal HCPs. The 164 manuscript submissions represented a 45% growth over previous years. Not surprisingly, the increased rate of submissions began shortly after the May 2018 announcement that journal articles would be included in PMC. Most of those articles (83%) were submitted unsolicited.

Fed Pract has always prided itself on being an early promoter of interdisciplinary health care professional publications. Nearly half of its listed authors were physicians (48%), while pharmacists made up the next largest cohort (18%). There were smaller numbers of PhDs, nurses, social workers, and physical therapists. The majority were written by HCPs affiliated with the VA (95% of articles and 93% of authors), and no articles in 2018 were written by PHS officers. Physicians comprise about two-thirds of the audience, while pharmacists make up 17% and nurses 9%. PHS and DoD HCPs make up 19% of the Fed Pract audience, suggesting that the journal needs to do more work to encourage these HCPs to contribute articles to the journal.³

Articles published in 2018 covered a broad range of topics from “Anesthesia Care Practice Models in the VHA” and “Army Behavioral Health System” to “Vitreous Hemorrhage in the Setting of a Vascular Loop” and “A Workforce Assessment of VA Home-Based Primary Care Pharmacists.” Categorizing the articles is a challenge. Few health care topics fit neatly into a single topic or specialty. This is especially true in federal health care where much of the care is delivered by multidisciplinary patient-centered medical homes or patient aligned care teams. Nevertheless, a few broad outlines can be discerned. Articles were roughly split between primary care and hospital-based and/or specialty care topics; one-quarter of the articles were case studies or case series articles, and about 20% were editorials or opinion columns. Nineteen articles dealt explicitly with chronic conditions, and 10 articles focused on mental health care.

Peer reviewers are an essential part of the process. Reviewers are blinded to the identityof the authors, ensuring fairness and reducing potential conflicts of interest. We are extremely grateful to each and every reviewer for the time and energy they contribute to the journal. Peer reviewers do not get nearly enough recognition for their important work. In 2018 Fed Pract invited 1,205 reviewers for 164 manuscript submissions and 94 manuscript revisions. More than 200 different reviewers submitted 487 reviews with a median (SD) of 2 reviews (1.8) and a range of 1 to 10. The top 20 reviewers completed 134 reviews with a median (SD) of 6 reviews (1.2). The results stand in contrast to some journals that must offer many invitations per review and depend on a small number of reviewers.^1,4-6

The reviewers recommended to reject 14% and to revise 26% of the articles, which is a much lower rejection rate than many other journals (Table).⁴ 

These data suggest that Fed Pract and its peer-review process is on a sound foundation but needs to make improvements. Moving into 2019, the journal expects that an increasing number of submissions will require a higher rejection rate. Moreover, we will need to do a better job reaching out to underrepresented portions of our audience. To decrease the time to publication for accepted manuscripts, in 2019 we will publish more articles online ahead of the print publication as we strive to improve the experience for authors, reviewers, readers, and the entire Fed Pract audience.

None of this work can be done without our small and dedicated staff. I would like to thank Managing Editor Joyce Brody who sent out each and every one of those reviewer invitations, Deputy Editor Robert Fee, who manages the special issues, Web Editor Teraya Smith, who runs our entire digital operation, and of course, Editor in Chief Cynthia Geppert, who oversees it all. Finally, it is important that you let us know how we are doing and whether we are meeting your needs. Visit mdedge.com/fedprac to take the readership survey or reach out to me at [email protected].

Federal health care providers live under a microscope, so it seems only fair that we at Fed Pract honor that reality and open ourselves up to scrutiny as well.¹ We hope that by shedding light on our peer-review process and manuscript acceptance rate, we will not only highlight our accomplishments, but identify areas for improvement.

Free access to Fed Pract content has always been our priority. While many journals charge authors or readers, Fed Pract has been and will remain free for readers and authors.² Advertising enables the journal to support this free model of publishing, but we take care to ensure that advertisements do not influence content in any way. Our advertising policy can be found at www.mdedge.com/fedprac/page/advertising.

In January 2019, Fed Pract placed > 400 peer-reviewed articles published since January 2015 in the PubMed Central (PMC) database (ncbi.nlm.nih.gov/pmc). The full text of these and all future Fed Pract peer-reviewed articles will be available at PMC (no registration required), and the citations also will be included in PubMed. We hope that this process will make it even easier for anyone to access our authors’ works.

In 2018 about 36,000 federal health care providers (HCPs) received hard copies of this journal. The print journal is free, but circulation is limited to HCPs who work at the US Department of Veterans Affairs (VA), US Department of Defense (DoD), and the US Public Health Service (PHS). The mdedge.com/fedprac website, which includes every article published since 2003, had 1.4 million page views in 2018. After reading 3 online articles, readers in the US are asked to complete a simple registration form to help us better customize the reader experience. In some cases, international readers may be asked to pay for access to articles online; however, any VA, DoD, or PHS officer stationed overseas can contact the editorial staff ([email protected]) to ensure that they can access the articles for free.

In 2018 the journal received 164 manuscripts and published 94 articles written by 357 different federal HCPs. The 164 manuscript submissions represented a 45% growth over previous years. Not surprisingly, the increased rate of submissions began shortly after the May 2018 announcement that journal articles would be included in PMC. Most of those articles (83%) were submitted unsolicited.

Fed Pract has always prided itself on being an early promoter of interdisciplinary health care professional publications. Nearly half of its listed authors were physicians (48%), while pharmacists made up the next largest cohort (18%). There were smaller numbers of PhDs, nurses, social workers, and physical therapists. The majority were written by HCPs affiliated with the VA (95% of articles and 93% of authors), and no articles in 2018 were written by PHS officers. Physicians comprise about two-thirds of the audience, while pharmacists make up 17% and nurses 9%. PHS and DoD HCPs make up 19% of the Fed Pract audience, suggesting that the journal needs to do more work to encourage these HCPs to contribute articles to the journal.³

Articles published in 2018 covered a broad range of topics from “Anesthesia Care Practice Models in the VHA” and “Army Behavioral Health System” to “Vitreous Hemorrhage in the Setting of a Vascular Loop” and “A Workforce Assessment of VA Home-Based Primary Care Pharmacists.” Categorizing the articles is a challenge. Few health care topics fit neatly into a single topic or specialty. This is especially true in federal health care where much of the care is delivered by multidisciplinary patient-centered medical homes or patient aligned care teams. Nevertheless, a few broad outlines can be discerned. Articles were roughly split between primary care and hospital-based and/or specialty care topics; one-quarter of the articles were case studies or case series articles, and about 20% were editorials or opinion columns. Nineteen articles dealt explicitly with chronic conditions, and 10 articles focused on mental health care.

Peer reviewers are an essential part of the process. Reviewers are blinded to the identityof the authors, ensuring fairness and reducing potential conflicts of interest. We are extremely grateful to each and every reviewer for the time and energy they contribute to the journal. Peer reviewers do not get nearly enough recognition for their important work. In 2018 Fed Pract invited 1,205 reviewers for 164 manuscript submissions and 94 manuscript revisions. More than 200 different reviewers submitted 487 reviews with a median (SD) of 2 reviews (1.8) and a range of 1 to 10. The top 20 reviewers completed 134 reviews with a median (SD) of 6 reviews (1.2). The results stand in contrast to some journals that must offer many invitations per review and depend on a small number of reviewers.^1,4-6

The reviewers recommended to reject 14% and to revise 26% of the articles, which is a much lower rejection rate than many other journals (Table).⁴ 

These data suggest that Fed Pract and its peer-review process is on a sound foundation but needs to make improvements. Moving into 2019, the journal expects that an increasing number of submissions will require a higher rejection rate. Moreover, we will need to do a better job reaching out to underrepresented portions of our audience. To decrease the time to publication for accepted manuscripts, in 2019 we will publish more articles online ahead of the print publication as we strive to improve the experience for authors, reviewers, readers, and the entire Fed Pract audience.

None of this work can be done without our small and dedicated staff. I would like to thank Managing Editor Joyce Brody who sent out each and every one of those reviewer invitations, Deputy Editor Robert Fee, who manages the special issues, Web Editor Teraya Smith, who runs our entire digital operation, and of course, Editor in Chief Cynthia Geppert, who oversees it all. Finally, it is important that you let us know how we are doing and whether we are meeting your needs. Visit mdedge.com/fedprac to take the readership survey or reach out to me at [email protected].

Juvenile idiopathic arthritis (JIA) is a clinically heterogeneous group of arthritides that are characterized by onset before 16 years of age and defined in part as lasting ≥6 weeks.¹ Significantly, the etiology of JIA is unknown, making it a diagnosis of exclusion.²

The most common autoimmune condition of childhood, JIA has a prevalence of 3.8 to 400 affected children for every 100,000 people.^3,4 As the leading cause of musculoskeletal disability in children,⁵ and comprising 7 categories of disease, JIA must be managed with appropriate initial and ongoing intervention.

The amalgam of care that a JIA patient requires—medical, social, physical, psychological—calls for a primary care physician’s expert ability to collaborate and coordinate with medical specialists and subspecialists, including rheumatology, ophthalmology, social work, physical and occupational therapy, and psychology. The goal? As this article describes, the goal is to provide prompt diagnosis, suitable and effective intervention, and continuity of care. (JIA is a lifelong disease, in many cases.)

How JIA is classifiedfor diagnosis and treatment

JIA comprises 7 categories, or classes.⁶ The scheme devised by the International League of Associations for Rheumatology (ILAR), now widely accepted, classifies JIA on the basis of clinical and biochemical markers that aid detection and treatment of the disorder, as well as research. (See “How efforts to classify JIA have caused confusion.”^7-10) The ILAR classes (TABLE¹¹) are:

• enthesitis-related arthritis (ERA)
• extended oligo-articular JIA (eoJIA), which involves ≤4 joints
• juvenile psoriatic arthritis (jPsA)
• rheumatoid factor (RF)-positive polyarticular JIA (RF+ pJIA)
• RF-negative polyarticular JIA (RF– pJIA)
• systemic-onset JIA (sJIA)
• undifferentiated JIA, which, generally, involves ≥4 joints.

Updated guidelines regarding the 7 ILAR classes of JIA emphasize heterogeneity among disease subtypes, with overlapping and exclusive features noted from class to class.¹¹

Extended oligo-articular JIA (27%-56%), pJIA (13%-35%), sJIA (4%-17%), and ERA,(3%-11%) are the most common JIA subtypes,¹² with age of onset and sex predilection differing according to JIA class.¹¹ The disease occurs more often in girls than in boys,¹¹ and the predisposition is higher among Whites and Asians. The incidence of JIA (all classes taken together, for every 100,000 people) is: in Japan, 10 to 15 cases¹³; in Turkey, 64 cases¹⁴; in Norway, 65 cases¹⁵; and in the United States and Canada, taken together, 10 to 15 cases.¹⁶

What causes JIA?

The etiology of JIA remains unclear. It is known that the disease involves inflammation of the synovium and destruction of hard and soft tissues in joints.¹⁷ It has been postulated, therefore, that a combination of genetic, environmental, and immunogenic mechanisms might be responsible for JIA.

Continue to: For example, there is an increased...

For example, there is an increased frequency of autoimmune diseases among JIA patients.¹⁸ There are also reports documenting an increased rate of infection, including with enteric pathogens, parvovirus B,¹⁹ rubella, mumps, hepatitis B, Epstein-Barr virus, mycoplasma, and chlamydia.¹⁹ Stress and trauma have also been implicated.¹²

The T-lymphocyte percentage is increased in the synovial fluid of JIA patients, although that percentage varies from subtype to subtype.²⁰ This elevation results in an increase in the number of macrophages, which are induced by secreted cytokines to produce interleukin (IL)-1, IL-6, and tumor necrosis factor alpha (TNF-a). This activity of cellular immunity leads to joint destruction.²¹

Clinical features

The most common signs and symptoms of JIA are arthralgias (39%), arthritis (25%), fever (18%), limping (9%), rash (8%), abdominal pain (1.3%), and uveitis (1.3%).¹⁵ Forty percent of JIA patients are reported to have temporomandibular joint involvement at some point in their life; mandibular asymmetry secondary to condylar resorption and remodeling¹⁷ is the most common presenting complaint—not arthralgia or pain, as would be expected.

Most JIA patients (52%) first present to the emergency department; another 42% present to the office of a general medical practitioner.¹⁵ On average, 3 visits to a physician, over the course of approximately 3 months, are made before a definitive diagnosis (usually by a pediatric rheumatologist) is made.¹⁵

Pertinent questions to ask a patient who has a confirmed diagnosis of JIA include the nature, severity, and duration of morning stiffness and pain, as well as any encumbering factors to regular functioning at home or school.²² Different scoring charts can be used to determine the extent of pain and disability, including the Juvenile Arthritis Disease Activity Score (JADAS)²³ and the clinical JADAS (cJADAS),²⁴ which measure minimal disease activity²⁵ and clinically inactive disease²⁶ cutoffs.

Continue to: Macrophage-activating syndrome increases risk of morbidity, mortality

An overactivation and expansion of T lymphocytes and macrophagic histiocytes with hemophagocytic activity, macrophage-activating syndrome (MAS) occurs in approximately 10% of JIA patients,²⁷ increasing their risk of morbidity and mortality. The syndrome, which typically presents as fever, seizures, hypotension, purpura, hepatitis, splenomegaly, and occasionally, multisystem organ failure, is seen in 30% to 40% of sJIA patients; approximately 11% of them experience sudden death as a consequence.²⁸

The clinical setting of MAS includes presenting symptoms of fever and a salmon-pink macular rash (FIGURE). For many sJIA patients with MAS, the diagnosis is made when laboratory results show hyperferritinemia, thrombocytopenia, anemia, leukopenia, coagulopathy, and elevated levels of C-reactive protein and D-dimer.²⁷

Different classes, different features

The following clinical profiles have been documented in different classes of JIA:

Systemic JIA presents with intermittent fever of at least 2 weeks’ duration, arthritis, and occasionally, a rash.

Extended oligo-articular JIA involves pain, in a mono-articular lower-extremity joint, that can develop suddenly or insidiously, and is characterized by early-morning stiffness and uveitis (especially in early-onset, antinuclear antibody-positive JIA patients).

Continue to: Poly-articular JIA

Poly-articular JIA patients present with mild fever, weight loss, and anemia.

Enthesis-related arthritis patients have findings of enthesopathy; asymmetric arthritis of the lower extremities, particularly the Achilles tendon²⁹; and recurrent acute, symptomatic iridocyclitis.³⁰

Juvenile psoriatic arthritis can involve any joint but is readily differentiated from pJIA by involvement of distal interphalangeal joints and psoriatic skin and nail changes.²⁹

Investigations

Imaging

Radiography is still the most widely used imaging tool for making the diagnosis of JIA. Plain films demonstrate structural joint damage and disturbances of growth and maturation in bones. Radiography has poor sensitivity for detecting acute synovitis and limited utility in visualizing erosion changes early in the course of disease, however, which has led to increased use of ultrasonography (US) and contrast-enhanced magnetic resonance imaging (MRI) to diagnose JIA.³⁰

Contrast-enhanced MRI is superior to US for detecting early inflammation and monitoring subsequent joint disease. Of course, MRI is more expensive than US, and less widely available. Other imaging options are computed tomography and positron emission tomography, but these scans are not as sensitive as contrast-enhanced MRI and have the disadvantage of radiation exposure (in the former) and cost (in the latter).

Continue to: Laboratory testing

Mandibular asymmetry secondary to condylar resorption and remodeling is the most common presenting complaint of juvenile idiopathic arthritis—not arthralgia or pain, as you might expect.

No diagnostic tests for JIA exist. Assays of acute-phase reactants, including C-reactive protein, the erythrocyte sedimentation rate, and serum amyloid-A proteins, can be utilized to demonstrate inflammation but not to confirm the diagnosis. For some classes of JIA, various tests, including rheumatoid factor, antinuclear antibody, human leukocyte antigen B-27, and cyclic citrullated peptide antibodies, can be used to confirm a specific class but, again, are not recommended for confirming JIA.⁶

The complete blood count, blood cultures, and tests of uric acid and lactate dehydrogenase can be ordered during treatment to monitor for complications, such as malignancy, infection, MAS, and sepsis.

Treatment is based on disease class

Nonsteroidal anti-inflammatory drugs (NSAIDs) and intra-articular steroids are used in all JIA classes, as an adjunct to class-specific treatment, or as induction agents.³¹ These therapies, although they alleviate acute signs and symptoms, such as pain, inflammation, swelling and joint contractures, are not useful for long-term treatment of JIA because they do not halt disease progression.

Systemic steroids can be utilized in exceptional cases, including chronic uveitis with arthritis or in patients with destructive arthritis and poor prognostic features, including cyclic citrullated peptide antibodies, positive RF, erosions, and joint-space narrowing.³²

Other drugs. Options include traditional disease-modifying anti-rheumatic drugs (csDMARDs), such as methotrexate and leflunomide; biologic agents, such as TNF-a inhibitors (eg, etanercept, adalimumab, and infliximab); and anti-IL monoclonal antibody drugs (eg, the IL-6 inhibitor tocilizumab and IL-1 inhibitors anakinra, and canakinumab).³¹ Indications by class include:

• csDMARDs as first-line therapy in persistent eoJIA and pJIA;
• TNF-Symbolα inhibitors for refractory eoJIA and for pJIA episodes³¹;
• tocilizumab, recommended for sJIA patients who have persistent systemic signs; and
• anakinra and canakinumab for refractory SJIA patients.³²

Continue to: Failure

When treatment of JIA fails with a given drug, options include increasing the dosage; switching to another agent in the same drug class; switching to a different class; and combining an NSAID with a csDMARD or a biologic agent.³² In class-specific JIA cases, a change in a drug regimen is warranted on the basis of the evidence-based historical clinical response rate.³²

What is the prognosis?

Treatment of JIA with novel agents, such as biologics, has opened up the possibility that JIA patients can live not just with suppressed symptoms but immunologically inactive disease. This is the result of better understanding of the pathogenesis of JIA and the mechanism of action of targeted drugs, and identification of biomarkers that are helpful in predicting prognosis, adverse effects, and response to treatment.

On average, it takes 3 visits to a physician, over the course of about 3 months, before definitive diagnosis of JIA is made.

JIA is often a lifelong disease; one-third of patients continue to exhibit symptoms into adulthood.⁴ If their disease is properly managed, however, these patients do not develop typical features of rheumatoid arthritis, including hand, limb, and spine deformities. Last, patients with JIA who have only intermittent disease tend to do better over the long term than those whose disease is continual.³²

The mortality rate of JIA has dropped: from 1% to 4% in the mid-1970s to 0.3% to 1% today⁴—an improvement in life expectancy that is echoed in enhanced quality of life for patients. According to the 4-level Steinbrocker functional classification scale³³ (used to rate the extent of physical disability), 15% of JIA patients were Class III (limited to few or no activities of the patient’s usual occupation) or Class IV (bedridden with little or no self-care) in the period from 1976 to 1994—a percentage that had declined to 5% by 2002.³⁴

The family physician plays pivotal role in JIA care

For the family physician, appropriate initial intervention in the management of JIA is imperative. This includes ordering imaging (whether plain films or MRI), laboratory tests as described earlier (although not to make the diagnosis), and the use of NSAIDs, intra-articular steroids, and other induction agents. Once the diagnosis is made, and a drug regimen is put in place, you will need to monitor for adverse effects. This monitoring will need to occur when a patient is escalated to csDMARDs, biological agents, or systemic steroids; is maintained on an NSAID; or is placed on a combination regimen.

Continue to: Before beginning therapy with a biologic agent...

Before beginning therapy with a biologic agent, it’s important to screen for hepatitis B, hepatitis C, human immunodeficiency virus infection, tuberculosis, and fungal infection (eg, Histoplasma capsulatum, Coccidioides immitis³²). Be sure to make a timely referral to the ophthalmology service for a bi-annual eye exam and, in the event that surgery is necessary, conduct a preoperative evaluation, with the knowledge of how long before surgery a biologic agent must be withheld (duration varies by drug).³²

CORRESPONDENCE
Tobe Momah, MD, Department of Family Medicine, Clinical Science Building, 4th Floor, University of Mississippi Medical Center, 2500 North State Street, Jackson, MS 39216; [email protected].

Juvenile idiopathic arthritis (JIA) is a clinically heterogeneous group of arthritides that are characterized by onset before 16 years of age and defined in part as lasting ≥6 weeks.¹ Significantly, the etiology of JIA is unknown, making it a diagnosis of exclusion.²

The most common autoimmune condition of childhood, JIA has a prevalence of 3.8 to 400 affected children for every 100,000 people.^3,4 As the leading cause of musculoskeletal disability in children,⁵ and comprising 7 categories of disease, JIA must be managed with appropriate initial and ongoing intervention.

The amalgam of care that a JIA patient requires—medical, social, physical, psychological—calls for a primary care physician’s expert ability to collaborate and coordinate with medical specialists and subspecialists, including rheumatology, ophthalmology, social work, physical and occupational therapy, and psychology. The goal? As this article describes, the goal is to provide prompt diagnosis, suitable and effective intervention, and continuity of care. (JIA is a lifelong disease, in many cases.)

How JIA is classifiedfor diagnosis and treatment

JIA comprises 7 categories, or classes.⁶ The scheme devised by the International League of Associations for Rheumatology (ILAR), now widely accepted, classifies JIA on the basis of clinical and biochemical markers that aid detection and treatment of the disorder, as well as research. (See “How efforts to classify JIA have caused confusion.”^7-10) The ILAR classes (TABLE¹¹) are:

• enthesitis-related arthritis (ERA)
• extended oligo-articular JIA (eoJIA), which involves ≤4 joints
• juvenile psoriatic arthritis (jPsA)
• rheumatoid factor (RF)-positive polyarticular JIA (RF+ pJIA)
• RF-negative polyarticular JIA (RF– pJIA)
• systemic-onset JIA (sJIA)
• undifferentiated JIA, which, generally, involves ≥4 joints.

Updated guidelines regarding the 7 ILAR classes of JIA emphasize heterogeneity among disease subtypes, with overlapping and exclusive features noted from class to class.¹¹

Extended oligo-articular JIA (27%-56%), pJIA (13%-35%), sJIA (4%-17%), and ERA,(3%-11%) are the most common JIA subtypes,¹² with age of onset and sex predilection differing according to JIA class.¹¹ The disease occurs more often in girls than in boys,¹¹ and the predisposition is higher among Whites and Asians. The incidence of JIA (all classes taken together, for every 100,000 people) is: in Japan, 10 to 15 cases¹³; in Turkey, 64 cases¹⁴; in Norway, 65 cases¹⁵; and in the United States and Canada, taken together, 10 to 15 cases.¹⁶

What causes JIA?

The etiology of JIA remains unclear. It is known that the disease involves inflammation of the synovium and destruction of hard and soft tissues in joints.¹⁷ It has been postulated, therefore, that a combination of genetic, environmental, and immunogenic mechanisms might be responsible for JIA.

Continue to: For example, there is an increased...

For example, there is an increased frequency of autoimmune diseases among JIA patients.¹⁸ There are also reports documenting an increased rate of infection, including with enteric pathogens, parvovirus B,¹⁹ rubella, mumps, hepatitis B, Epstein-Barr virus, mycoplasma, and chlamydia.¹⁹ Stress and trauma have also been implicated.¹²

The T-lymphocyte percentage is increased in the synovial fluid of JIA patients, although that percentage varies from subtype to subtype.²⁰ This elevation results in an increase in the number of macrophages, which are induced by secreted cytokines to produce interleukin (IL)-1, IL-6, and tumor necrosis factor alpha (TNF-a). This activity of cellular immunity leads to joint destruction.²¹

Clinical features

The most common signs and symptoms of JIA are arthralgias (39%), arthritis (25%), fever (18%), limping (9%), rash (8%), abdominal pain (1.3%), and uveitis (1.3%).¹⁵ Forty percent of JIA patients are reported to have temporomandibular joint involvement at some point in their life; mandibular asymmetry secondary to condylar resorption and remodeling¹⁷ is the most common presenting complaint—not arthralgia or pain, as would be expected.

Most JIA patients (52%) first present to the emergency department; another 42% present to the office of a general medical practitioner.¹⁵ On average, 3 visits to a physician, over the course of approximately 3 months, are made before a definitive diagnosis (usually by a pediatric rheumatologist) is made.¹⁵

Pertinent questions to ask a patient who has a confirmed diagnosis of JIA include the nature, severity, and duration of morning stiffness and pain, as well as any encumbering factors to regular functioning at home or school.²² Different scoring charts can be used to determine the extent of pain and disability, including the Juvenile Arthritis Disease Activity Score (JADAS)²³ and the clinical JADAS (cJADAS),²⁴ which measure minimal disease activity²⁵ and clinically inactive disease²⁶ cutoffs.

Continue to: Macrophage-activating syndrome increases risk of morbidity, mortality

An overactivation and expansion of T lymphocytes and macrophagic histiocytes with hemophagocytic activity, macrophage-activating syndrome (MAS) occurs in approximately 10% of JIA patients,²⁷ increasing their risk of morbidity and mortality. The syndrome, which typically presents as fever, seizures, hypotension, purpura, hepatitis, splenomegaly, and occasionally, multisystem organ failure, is seen in 30% to 40% of sJIA patients; approximately 11% of them experience sudden death as a consequence.²⁸

The clinical setting of MAS includes presenting symptoms of fever and a salmon-pink macular rash (FIGURE). For many sJIA patients with MAS, the diagnosis is made when laboratory results show hyperferritinemia, thrombocytopenia, anemia, leukopenia, coagulopathy, and elevated levels of C-reactive protein and D-dimer.²⁷

Different classes, different features

The following clinical profiles have been documented in different classes of JIA:

Systemic JIA presents with intermittent fever of at least 2 weeks’ duration, arthritis, and occasionally, a rash.

Extended oligo-articular JIA involves pain, in a mono-articular lower-extremity joint, that can develop suddenly or insidiously, and is characterized by early-morning stiffness and uveitis (especially in early-onset, antinuclear antibody-positive JIA patients).

Continue to: Poly-articular JIA

Poly-articular JIA patients present with mild fever, weight loss, and anemia.

Enthesis-related arthritis patients have findings of enthesopathy; asymmetric arthritis of the lower extremities, particularly the Achilles tendon²⁹; and recurrent acute, symptomatic iridocyclitis.³⁰

Juvenile psoriatic arthritis can involve any joint but is readily differentiated from pJIA by involvement of distal interphalangeal joints and psoriatic skin and nail changes.²⁹

Investigations

Imaging

Radiography is still the most widely used imaging tool for making the diagnosis of JIA. Plain films demonstrate structural joint damage and disturbances of growth and maturation in bones. Radiography has poor sensitivity for detecting acute synovitis and limited utility in visualizing erosion changes early in the course of disease, however, which has led to increased use of ultrasonography (US) and contrast-enhanced magnetic resonance imaging (MRI) to diagnose JIA.³⁰

Contrast-enhanced MRI is superior to US for detecting early inflammation and monitoring subsequent joint disease. Of course, MRI is more expensive than US, and less widely available. Other imaging options are computed tomography and positron emission tomography, but these scans are not as sensitive as contrast-enhanced MRI and have the disadvantage of radiation exposure (in the former) and cost (in the latter).

Continue to: Laboratory testing

Mandibular asymmetry secondary to condylar resorption and remodeling is the most common presenting complaint of juvenile idiopathic arthritis—not arthralgia or pain, as you might expect.

No diagnostic tests for JIA exist. Assays of acute-phase reactants, including C-reactive protein, the erythrocyte sedimentation rate, and serum amyloid-A proteins, can be utilized to demonstrate inflammation but not to confirm the diagnosis. For some classes of JIA, various tests, including rheumatoid factor, antinuclear antibody, human leukocyte antigen B-27, and cyclic citrullated peptide antibodies, can be used to confirm a specific class but, again, are not recommended for confirming JIA.⁶

The complete blood count, blood cultures, and tests of uric acid and lactate dehydrogenase can be ordered during treatment to monitor for complications, such as malignancy, infection, MAS, and sepsis.

Treatment is based on disease class

Nonsteroidal anti-inflammatory drugs (NSAIDs) and intra-articular steroids are used in all JIA classes, as an adjunct to class-specific treatment, or as induction agents.³¹ These therapies, although they alleviate acute signs and symptoms, such as pain, inflammation, swelling and joint contractures, are not useful for long-term treatment of JIA because they do not halt disease progression.

Systemic steroids can be utilized in exceptional cases, including chronic uveitis with arthritis or in patients with destructive arthritis and poor prognostic features, including cyclic citrullated peptide antibodies, positive RF, erosions, and joint-space narrowing.³²

Other drugs. Options include traditional disease-modifying anti-rheumatic drugs (csDMARDs), such as methotrexate and leflunomide; biologic agents, such as TNF-a inhibitors (eg, etanercept, adalimumab, and infliximab); and anti-IL monoclonal antibody drugs (eg, the IL-6 inhibitor tocilizumab and IL-1 inhibitors anakinra, and canakinumab).³¹ Indications by class include:

• csDMARDs as first-line therapy in persistent eoJIA and pJIA;
• TNF-Symbolα inhibitors for refractory eoJIA and for pJIA episodes³¹;
• tocilizumab, recommended for sJIA patients who have persistent systemic signs; and
• anakinra and canakinumab for refractory SJIA patients.³²

Continue to: Failure

When treatment of JIA fails with a given drug, options include increasing the dosage; switching to another agent in the same drug class; switching to a different class; and combining an NSAID with a csDMARD or a biologic agent.³² In class-specific JIA cases, a change in a drug regimen is warranted on the basis of the evidence-based historical clinical response rate.³²

What is the prognosis?

Treatment of JIA with novel agents, such as biologics, has opened up the possibility that JIA patients can live not just with suppressed symptoms but immunologically inactive disease. This is the result of better understanding of the pathogenesis of JIA and the mechanism of action of targeted drugs, and identification of biomarkers that are helpful in predicting prognosis, adverse effects, and response to treatment.

On average, it takes 3 visits to a physician, over the course of about 3 months, before definitive diagnosis of JIA is made.

JIA is often a lifelong disease; one-third of patients continue to exhibit symptoms into adulthood.⁴ If their disease is properly managed, however, these patients do not develop typical features of rheumatoid arthritis, including hand, limb, and spine deformities. Last, patients with JIA who have only intermittent disease tend to do better over the long term than those whose disease is continual.³²

The mortality rate of JIA has dropped: from 1% to 4% in the mid-1970s to 0.3% to 1% today⁴—an improvement in life expectancy that is echoed in enhanced quality of life for patients. According to the 4-level Steinbrocker functional classification scale³³ (used to rate the extent of physical disability), 15% of JIA patients were Class III (limited to few or no activities of the patient’s usual occupation) or Class IV (bedridden with little or no self-care) in the period from 1976 to 1994—a percentage that had declined to 5% by 2002.³⁴

The family physician plays pivotal role in JIA care

For the family physician, appropriate initial intervention in the management of JIA is imperative. This includes ordering imaging (whether plain films or MRI), laboratory tests as described earlier (although not to make the diagnosis), and the use of NSAIDs, intra-articular steroids, and other induction agents. Once the diagnosis is made, and a drug regimen is put in place, you will need to monitor for adverse effects. This monitoring will need to occur when a patient is escalated to csDMARDs, biological agents, or systemic steroids; is maintained on an NSAID; or is placed on a combination regimen.

Continue to: Before beginning therapy with a biologic agent...

Before beginning therapy with a biologic agent, it’s important to screen for hepatitis B, hepatitis C, human immunodeficiency virus infection, tuberculosis, and fungal infection (eg, Histoplasma capsulatum, Coccidioides immitis³²). Be sure to make a timely referral to the ophthalmology service for a bi-annual eye exam and, in the event that surgery is necessary, conduct a preoperative evaluation, with the knowledge of how long before surgery a biologic agent must be withheld (duration varies by drug).³²

CORRESPONDENCE
Tobe Momah, MD, Department of Family Medicine, Clinical Science Building, 4th Floor, University of Mississippi Medical Center, 2500 North State Street, Jackson, MS 39216; [email protected].

Juvenile idiopathic arthritis (JIA) is a clinically heterogeneous group of arthritides that are characterized by onset before 16 years of age and defined in part as lasting ≥6 weeks.¹ Significantly, the etiology of JIA is unknown, making it a diagnosis of exclusion.²

The most common autoimmune condition of childhood, JIA has a prevalence of 3.8 to 400 affected children for every 100,000 people.^3,4 As the leading cause of musculoskeletal disability in children,⁵ and comprising 7 categories of disease, JIA must be managed with appropriate initial and ongoing intervention.

The amalgam of care that a JIA patient requires—medical, social, physical, psychological—calls for a primary care physician’s expert ability to collaborate and coordinate with medical specialists and subspecialists, including rheumatology, ophthalmology, social work, physical and occupational therapy, and psychology. The goal? As this article describes, the goal is to provide prompt diagnosis, suitable and effective intervention, and continuity of care. (JIA is a lifelong disease, in many cases.)

How JIA is classifiedfor diagnosis and treatment

JIA comprises 7 categories, or classes.⁶ The scheme devised by the International League of Associations for Rheumatology (ILAR), now widely accepted, classifies JIA on the basis of clinical and biochemical markers that aid detection and treatment of the disorder, as well as research. (See “How efforts to classify JIA have caused confusion.”^7-10) The ILAR classes (TABLE¹¹) are:

• enthesitis-related arthritis (ERA)
• extended oligo-articular JIA (eoJIA), which involves ≤4 joints
• juvenile psoriatic arthritis (jPsA)
• rheumatoid factor (RF)-positive polyarticular JIA (RF+ pJIA)
• RF-negative polyarticular JIA (RF– pJIA)
• systemic-onset JIA (sJIA)
• undifferentiated JIA, which, generally, involves ≥4 joints.

Updated guidelines regarding the 7 ILAR classes of JIA emphasize heterogeneity among disease subtypes, with overlapping and exclusive features noted from class to class.¹¹

Extended oligo-articular JIA (27%-56%), pJIA (13%-35%), sJIA (4%-17%), and ERA,(3%-11%) are the most common JIA subtypes,¹² with age of onset and sex predilection differing according to JIA class.¹¹ The disease occurs more often in girls than in boys,¹¹ and the predisposition is higher among Whites and Asians. The incidence of JIA (all classes taken together, for every 100,000 people) is: in Japan, 10 to 15 cases¹³; in Turkey, 64 cases¹⁴; in Norway, 65 cases¹⁵; and in the United States and Canada, taken together, 10 to 15 cases.¹⁶

What causes JIA?

The etiology of JIA remains unclear. It is known that the disease involves inflammation of the synovium and destruction of hard and soft tissues in joints.¹⁷ It has been postulated, therefore, that a combination of genetic, environmental, and immunogenic mechanisms might be responsible for JIA.

Continue to: For example, there is an increased...

For example, there is an increased frequency of autoimmune diseases among JIA patients.¹⁸ There are also reports documenting an increased rate of infection, including with enteric pathogens, parvovirus B,¹⁹ rubella, mumps, hepatitis B, Epstein-Barr virus, mycoplasma, and chlamydia.¹⁹ Stress and trauma have also been implicated.¹²

The T-lymphocyte percentage is increased in the synovial fluid of JIA patients, although that percentage varies from subtype to subtype.²⁰ This elevation results in an increase in the number of macrophages, which are induced by secreted cytokines to produce interleukin (IL)-1, IL-6, and tumor necrosis factor alpha (TNF-a). This activity of cellular immunity leads to joint destruction.²¹

Clinical features

The most common signs and symptoms of JIA are arthralgias (39%), arthritis (25%), fever (18%), limping (9%), rash (8%), abdominal pain (1.3%), and uveitis (1.3%).¹⁵ Forty percent of JIA patients are reported to have temporomandibular joint involvement at some point in their life; mandibular asymmetry secondary to condylar resorption and remodeling¹⁷ is the most common presenting complaint—not arthralgia or pain, as would be expected.

Most JIA patients (52%) first present to the emergency department; another 42% present to the office of a general medical practitioner.¹⁵ On average, 3 visits to a physician, over the course of approximately 3 months, are made before a definitive diagnosis (usually by a pediatric rheumatologist) is made.¹⁵

Pertinent questions to ask a patient who has a confirmed diagnosis of JIA include the nature, severity, and duration of morning stiffness and pain, as well as any encumbering factors to regular functioning at home or school.²² Different scoring charts can be used to determine the extent of pain and disability, including the Juvenile Arthritis Disease Activity Score (JADAS)²³ and the clinical JADAS (cJADAS),²⁴ which measure minimal disease activity²⁵ and clinically inactive disease²⁶ cutoffs.

Continue to: Macrophage-activating syndrome increases risk of morbidity, mortality

An overactivation and expansion of T lymphocytes and macrophagic histiocytes with hemophagocytic activity, macrophage-activating syndrome (MAS) occurs in approximately 10% of JIA patients,²⁷ increasing their risk of morbidity and mortality. The syndrome, which typically presents as fever, seizures, hypotension, purpura, hepatitis, splenomegaly, and occasionally, multisystem organ failure, is seen in 30% to 40% of sJIA patients; approximately 11% of them experience sudden death as a consequence.²⁸

The clinical setting of MAS includes presenting symptoms of fever and a salmon-pink macular rash (FIGURE). For many sJIA patients with MAS, the diagnosis is made when laboratory results show hyperferritinemia, thrombocytopenia, anemia, leukopenia, coagulopathy, and elevated levels of C-reactive protein and D-dimer.²⁷

Different classes, different features

The following clinical profiles have been documented in different classes of JIA:

Systemic JIA presents with intermittent fever of at least 2 weeks’ duration, arthritis, and occasionally, a rash.

Extended oligo-articular JIA involves pain, in a mono-articular lower-extremity joint, that can develop suddenly or insidiously, and is characterized by early-morning stiffness and uveitis (especially in early-onset, antinuclear antibody-positive JIA patients).

Continue to: Poly-articular JIA

Poly-articular JIA patients present with mild fever, weight loss, and anemia.

Enthesis-related arthritis patients have findings of enthesopathy; asymmetric arthritis of the lower extremities, particularly the Achilles tendon²⁹; and recurrent acute, symptomatic iridocyclitis.³⁰

Juvenile psoriatic arthritis can involve any joint but is readily differentiated from pJIA by involvement of distal interphalangeal joints and psoriatic skin and nail changes.²⁹

Investigations

Imaging

Radiography is still the most widely used imaging tool for making the diagnosis of JIA. Plain films demonstrate structural joint damage and disturbances of growth and maturation in bones. Radiography has poor sensitivity for detecting acute synovitis and limited utility in visualizing erosion changes early in the course of disease, however, which has led to increased use of ultrasonography (US) and contrast-enhanced magnetic resonance imaging (MRI) to diagnose JIA.³⁰

Contrast-enhanced MRI is superior to US for detecting early inflammation and monitoring subsequent joint disease. Of course, MRI is more expensive than US, and less widely available. Other imaging options are computed tomography and positron emission tomography, but these scans are not as sensitive as contrast-enhanced MRI and have the disadvantage of radiation exposure (in the former) and cost (in the latter).

Continue to: Laboratory testing

Mandibular asymmetry secondary to condylar resorption and remodeling is the most common presenting complaint of juvenile idiopathic arthritis—not arthralgia or pain, as you might expect.

No diagnostic tests for JIA exist. Assays of acute-phase reactants, including C-reactive protein, the erythrocyte sedimentation rate, and serum amyloid-A proteins, can be utilized to demonstrate inflammation but not to confirm the diagnosis. For some classes of JIA, various tests, including rheumatoid factor, antinuclear antibody, human leukocyte antigen B-27, and cyclic citrullated peptide antibodies, can be used to confirm a specific class but, again, are not recommended for confirming JIA.⁶

The complete blood count, blood cultures, and tests of uric acid and lactate dehydrogenase can be ordered during treatment to monitor for complications, such as malignancy, infection, MAS, and sepsis.

Treatment is based on disease class

Nonsteroidal anti-inflammatory drugs (NSAIDs) and intra-articular steroids are used in all JIA classes, as an adjunct to class-specific treatment, or as induction agents.³¹ These therapies, although they alleviate acute signs and symptoms, such as pain, inflammation, swelling and joint contractures, are not useful for long-term treatment of JIA because they do not halt disease progression.

Systemic steroids can be utilized in exceptional cases, including chronic uveitis with arthritis or in patients with destructive arthritis and poor prognostic features, including cyclic citrullated peptide antibodies, positive RF, erosions, and joint-space narrowing.³²

Other drugs. Options include traditional disease-modifying anti-rheumatic drugs (csDMARDs), such as methotrexate and leflunomide; biologic agents, such as TNF-a inhibitors (eg, etanercept, adalimumab, and infliximab); and anti-IL monoclonal antibody drugs (eg, the IL-6 inhibitor tocilizumab and IL-1 inhibitors anakinra, and canakinumab).³¹ Indications by class include:

• csDMARDs as first-line therapy in persistent eoJIA and pJIA;
• TNF-Symbolα inhibitors for refractory eoJIA and for pJIA episodes³¹;
• tocilizumab, recommended for sJIA patients who have persistent systemic signs; and
• anakinra and canakinumab for refractory SJIA patients.³²

Continue to: Failure

When treatment of JIA fails with a given drug, options include increasing the dosage; switching to another agent in the same drug class; switching to a different class; and combining an NSAID with a csDMARD or a biologic agent.³² In class-specific JIA cases, a change in a drug regimen is warranted on the basis of the evidence-based historical clinical response rate.³²

What is the prognosis?

Treatment of JIA with novel agents, such as biologics, has opened up the possibility that JIA patients can live not just with suppressed symptoms but immunologically inactive disease. This is the result of better understanding of the pathogenesis of JIA and the mechanism of action of targeted drugs, and identification of biomarkers that are helpful in predicting prognosis, adverse effects, and response to treatment.

On average, it takes 3 visits to a physician, over the course of about 3 months, before definitive diagnosis of JIA is made.

JIA is often a lifelong disease; one-third of patients continue to exhibit symptoms into adulthood.⁴ If their disease is properly managed, however, these patients do not develop typical features of rheumatoid arthritis, including hand, limb, and spine deformities. Last, patients with JIA who have only intermittent disease tend to do better over the long term than those whose disease is continual.³²

The mortality rate of JIA has dropped: from 1% to 4% in the mid-1970s to 0.3% to 1% today⁴—an improvement in life expectancy that is echoed in enhanced quality of life for patients. According to the 4-level Steinbrocker functional classification scale³³ (used to rate the extent of physical disability), 15% of JIA patients were Class III (limited to few or no activities of the patient’s usual occupation) or Class IV (bedridden with little or no self-care) in the period from 1976 to 1994—a percentage that had declined to 5% by 2002.³⁴

The family physician plays pivotal role in JIA care

For the family physician, appropriate initial intervention in the management of JIA is imperative. This includes ordering imaging (whether plain films or MRI), laboratory tests as described earlier (although not to make the diagnosis), and the use of NSAIDs, intra-articular steroids, and other induction agents. Once the diagnosis is made, and a drug regimen is put in place, you will need to monitor for adverse effects. This monitoring will need to occur when a patient is escalated to csDMARDs, biological agents, or systemic steroids; is maintained on an NSAID; or is placed on a combination regimen.

Continue to: Before beginning therapy with a biologic agent...

Before beginning therapy with a biologic agent, it’s important to screen for hepatitis B, hepatitis C, human immunodeficiency virus infection, tuberculosis, and fungal infection (eg, Histoplasma capsulatum, Coccidioides immitis³²). Be sure to make a timely referral to the ophthalmology service for a bi-annual eye exam and, in the event that surgery is necessary, conduct a preoperative evaluation, with the knowledge of how long before surgery a biologic agent must be withheld (duration varies by drug).³²

CORRESPONDENCE
Tobe Momah, MD, Department of Family Medicine, Clinical Science Building, 4th Floor, University of Mississippi Medical Center, 2500 North State Street, Jackson, MS 39216; [email protected].

Octavio has prostate cancer. His prostate growth is large but localized.

“What do your doctors suggest?” I asked him.

“They sent me to two specialists at the medical center,” he said. “One does robotic surgery, the other does radiation. Each one told me why they recommend their technique.”

“How will you decide?”

“I’ll do some reading,” he said.

“What about the doctor who sent you to them?”

“He hasn’t discussed the choice with me, just sent me to get opinions. I have to make up own mind.”

Out of training for some time, I gather from students and family medical interactions that patient autonomy is now a reigning principle. Here is one definition:

Patient autonomy: The right of patients to make decisions about their medical care without their health care provider trying to influence the decision. Patient autonomy does allow for health care providers to educate the patient but does not allow the health care provider to make the decision for the patient.


This sounds sensible, even admirable: no more paternalistic physicians talking down to patients and ordering them around. Yet a closer look shows a contradiction:

1. The second sentence says that patient autonomy “does not allow the health care provider to make the decision for the patient.”

2. But the first one says that patients should decide, “without their health care provider trying to influence the decision.”

Is “trying to influence” the same as making the decision for the patient?

Some would argue that it is: The power discrepancy between the parties makes a doctor’s attempt to influence amount to coercion.

Do you agree, esteemed colleagues, those of you who, like me, treat patients all day? If the choice is between freezing an actinic keratosis, burning it, or using topical chemotherapy, do you just lay all three options out there and ask the patient to pick one? What if your patient works in public and doesn’t have 2 weeks to wait while the reaction to topical 5-fluorouracil that makes his skin look like raw lobster subsides? Can you point that out? Or would that be “trying to influence” and thus not allowed?

FatCamera/Getty Images

You and I can think of many other examples, about medical choices large and small, where we could pose similar questions. This is not abstract philosophy; it is what we do all day.

Look up robot-assisted surgery and radiation for prostate cancer. You will find proponents of both, each making claims concerning survival, recurrence, discomfort, complications. Which is more important – a 15% greater chance of living 2 years longer or a 22% lower risk of incontinence? Will reading such statistics make your choice easier? What if other studies show different numbers?

Octavio chose surgery. I asked him how he decided.

“I talked with an internist I know socially,” he said. “He shared his experience with patients he’s referred for my problem and advised surgery as the better choice. I also saw a story online about a lawyer who chose one method, then 5 years later had to do the other.”

Octavio is sophisticated and well read. He lives near Boston, the self-described hub of medical expertise and academic excellence. Yet he makes up his mind the way everybody does: by asking a trusted adviser, by hearing an arresting anecdote. It’s not science. It’s how people think.

You don’t have to be a behavioral psychologist to know how hard it is for patients, especially frightened ones, to interpret statistical variances or compare disparate categories. Which is better – shorter life with less pain or longer life with more? How much less? How much more? There are ways to address such questions, but having an expert, trusted, and sympathetic adviser is a pretty good way to start. Only an abstract ethicist with no practical exposure to (or sympathy with) actual existing patients and their actual existing providers could possibly think otherwise.

“Let’s freeze those actinics off,” I suggest to a patient. “That won’t scar, you won’t need a dozen shots of lidocaine, and you won’t have to hide for 3 weeks.”

Dr. Rockoff practices dermatology in Brookline, Mass., and is a longtime contributor to Dermatology News. He serves on the clinical faculty at Tufts University, Boston, and has taught senior medical students and other trainees for 30 years. His second book, “Act Like a Doctor, Think Like a Patient,” is available at amazon.com and barnesandnoble.com. Write to him at [email protected].

Octavio has prostate cancer. His prostate growth is large but localized.

“What do your doctors suggest?” I asked him.

“They sent me to two specialists at the medical center,” he said. “One does robotic surgery, the other does radiation. Each one told me why they recommend their technique.”

“How will you decide?”

“I’ll do some reading,” he said.

“What about the doctor who sent you to them?”

“He hasn’t discussed the choice with me, just sent me to get opinions. I have to make up own mind.”

Out of training for some time, I gather from students and family medical interactions that patient autonomy is now a reigning principle. Here is one definition:

Patient autonomy: The right of patients to make decisions about their medical care without their health care provider trying to influence the decision. Patient autonomy does allow for health care providers to educate the patient but does not allow the health care provider to make the decision for the patient.


This sounds sensible, even admirable: no more paternalistic physicians talking down to patients and ordering them around. Yet a closer look shows a contradiction:

1. The second sentence says that patient autonomy “does not allow the health care provider to make the decision for the patient.”

2. But the first one says that patients should decide, “without their health care provider trying to influence the decision.”

Is “trying to influence” the same as making the decision for the patient?

Some would argue that it is: The power discrepancy between the parties makes a doctor’s attempt to influence amount to coercion.

Do you agree, esteemed colleagues, those of you who, like me, treat patients all day? If the choice is between freezing an actinic keratosis, burning it, or using topical chemotherapy, do you just lay all three options out there and ask the patient to pick one? What if your patient works in public and doesn’t have 2 weeks to wait while the reaction to topical 5-fluorouracil that makes his skin look like raw lobster subsides? Can you point that out? Or would that be “trying to influence” and thus not allowed?

FatCamera/Getty Images

You and I can think of many other examples, about medical choices large and small, where we could pose similar questions. This is not abstract philosophy; it is what we do all day.

Look up robot-assisted surgery and radiation for prostate cancer. You will find proponents of both, each making claims concerning survival, recurrence, discomfort, complications. Which is more important – a 15% greater chance of living 2 years longer or a 22% lower risk of incontinence? Will reading such statistics make your choice easier? What if other studies show different numbers?

Octavio chose surgery. I asked him how he decided.

“I talked with an internist I know socially,” he said. “He shared his experience with patients he’s referred for my problem and advised surgery as the better choice. I also saw a story online about a lawyer who chose one method, then 5 years later had to do the other.”

Octavio is sophisticated and well read. He lives near Boston, the self-described hub of medical expertise and academic excellence. Yet he makes up his mind the way everybody does: by asking a trusted adviser, by hearing an arresting anecdote. It’s not science. It’s how people think.

You don’t have to be a behavioral psychologist to know how hard it is for patients, especially frightened ones, to interpret statistical variances or compare disparate categories. Which is better – shorter life with less pain or longer life with more? How much less? How much more? There are ways to address such questions, but having an expert, trusted, and sympathetic adviser is a pretty good way to start. Only an abstract ethicist with no practical exposure to (or sympathy with) actual existing patients and their actual existing providers could possibly think otherwise.

“Let’s freeze those actinics off,” I suggest to a patient. “That won’t scar, you won’t need a dozen shots of lidocaine, and you won’t have to hide for 3 weeks.”

Dr. Rockoff practices dermatology in Brookline, Mass., and is a longtime contributor to Dermatology News. He serves on the clinical faculty at Tufts University, Boston, and has taught senior medical students and other trainees for 30 years. His second book, “Act Like a Doctor, Think Like a Patient,” is available at amazon.com and barnesandnoble.com. Write to him at [email protected].

Octavio has prostate cancer. His prostate growth is large but localized.

“What do your doctors suggest?” I asked him.

“They sent me to two specialists at the medical center,” he said. “One does robotic surgery, the other does radiation. Each one told me why they recommend their technique.”

“How will you decide?”

“I’ll do some reading,” he said.

“What about the doctor who sent you to them?”

“He hasn’t discussed the choice with me, just sent me to get opinions. I have to make up own mind.”

Out of training for some time, I gather from students and family medical interactions that patient autonomy is now a reigning principle. Here is one definition:

Patient autonomy: The right of patients to make decisions about their medical care without their health care provider trying to influence the decision. Patient autonomy does allow for health care providers to educate the patient but does not allow the health care provider to make the decision for the patient.


This sounds sensible, even admirable: no more paternalistic physicians talking down to patients and ordering them around. Yet a closer look shows a contradiction:

1. The second sentence says that patient autonomy “does not allow the health care provider to make the decision for the patient.”

2. But the first one says that patients should decide, “without their health care provider trying to influence the decision.”

Is “trying to influence” the same as making the decision for the patient?

Some would argue that it is: The power discrepancy between the parties makes a doctor’s attempt to influence amount to coercion.

Do you agree, esteemed colleagues, those of you who, like me, treat patients all day? If the choice is between freezing an actinic keratosis, burning it, or using topical chemotherapy, do you just lay all three options out there and ask the patient to pick one? What if your patient works in public and doesn’t have 2 weeks to wait while the reaction to topical 5-fluorouracil that makes his skin look like raw lobster subsides? Can you point that out? Or would that be “trying to influence” and thus not allowed?

FatCamera/Getty Images

You and I can think of many other examples, about medical choices large and small, where we could pose similar questions. This is not abstract philosophy; it is what we do all day.

Look up robot-assisted surgery and radiation for prostate cancer. You will find proponents of both, each making claims concerning survival, recurrence, discomfort, complications. Which is more important – a 15% greater chance of living 2 years longer or a 22% lower risk of incontinence? Will reading such statistics make your choice easier? What if other studies show different numbers?

Octavio chose surgery. I asked him how he decided.

“I talked with an internist I know socially,” he said. “He shared his experience with patients he’s referred for my problem and advised surgery as the better choice. I also saw a story online about a lawyer who chose one method, then 5 years later had to do the other.”

Octavio is sophisticated and well read. He lives near Boston, the self-described hub of medical expertise and academic excellence. Yet he makes up his mind the way everybody does: by asking a trusted adviser, by hearing an arresting anecdote. It’s not science. It’s how people think.

You don’t have to be a behavioral psychologist to know how hard it is for patients, especially frightened ones, to interpret statistical variances or compare disparate categories. Which is better – shorter life with less pain or longer life with more? How much less? How much more? There are ways to address such questions, but having an expert, trusted, and sympathetic adviser is a pretty good way to start. Only an abstract ethicist with no practical exposure to (or sympathy with) actual existing patients and their actual existing providers could possibly think otherwise.

“Let’s freeze those actinics off,” I suggest to a patient. “That won’t scar, you won’t need a dozen shots of lidocaine, and you won’t have to hide for 3 weeks.”

Dr. Rockoff practices dermatology in Brookline, Mass., and is a longtime contributor to Dermatology News. He serves on the clinical faculty at Tufts University, Boston, and has taught senior medical students and other trainees for 30 years. His second book, “Act Like a Doctor, Think Like a Patient,” is available at amazon.com and barnesandnoble.com. Write to him at [email protected].

DALLAS – Stem cell tourism – the unethical practice of offering unproven cellular preparations to patients for a variety of conditions – is increasingly sought by patients with incurable conditions such as multiple sclerosis and amyotrophic lateral sclerosis, results from a novel survey suggest.

Doug Brunk/MDedge News

In fact, most academic neurologists have been approached by patients with incurable conditions who ask them about stem cell therapy, while about two-thirds have had at least one patient who has undergone stem cell therapy.

“It’s really scary,” Wijdan Rai, MBBS, the study’s first author, said in an interview at the meeting held by the Americas Committee for Treatment and Research in Multiple Sclerosis. “This is a more prevalent issue than we think, and the complication rates are higher than we think.”

According to the study’s senior author, Jaime Imitola, MD, who directs the Progressive Multiple Sclerosis Multidisciplinary Clinic and Translational Research Program at the Ohio State University Wexner Medical Center, Columbus, the results “call for the creation of a nationwide registry where neurologists can document adverse reactions to stem cell procedures and further support dedicated patient and neurologist education as we have proposed before” (See Semin Neurol. 2018; 38[2]:176-81 and JAMA Neurol. 2015;72[11]:1342-5).


In an effort to understand the experiences and attitudes of academic neurologists regarding stem cell tourism and patient-reported complications, the researchers developed a 25-question survey disseminated via Synapse, a web tool from the American Academy of Neurology. Respondents were asked about demographic information, frequency of patient questioning, perception of physician competence, patient complications and experiences, and attitudes toward increased physician education.

Dr. Rai, who is a senior neurology resident at the medical center, presented findings from 204 neurologist respondents, of whom 31% identified themselves as MS specialists. Nearly all respondents (91%) said they have been approached by patients with incurable conditions seeking information about stem cells (37% of whom had diagnosis of MS). In addition, 65% have had at least one patient that has undergone “stem cell therapy,” and 73% said it would be “helpful” or “very helpful” to have an evidence-based patient education tool on the topic. “Patients most often wanted general information,” Dr. Rai said. “However, 50% requested permission to undergo a stem cell procedure, and 31% approached their neurologist after the procedure.”

Survey respondents reported that 33% of the stem cell interventions were performed in the United States and 22% abroad, while 37% reported both in the U.S. and abroad. Patients underwent the procedures in China, Germany, the Bahamas, Mexico, Russia, and Costa Rica. Three-quarters of respondents (75%) indicated no patient experiencing complications from the stem cell interventions. However, 25% reported patients experiencing a variety of complications from the procedures, including strokes, meningoencephalitis, quadriparesis, MS deterioration, sepsis, hepatitis C, seizures, meningitis from intrathecal cell injections, infections, and spinal cord tumors. “At least three respondents had a patient who died as a direct complication from stem cell therapy,” Dr. Rai said.

In their poster, the researchers recommended a “multipronged approach to improve education of MS patients from exploitation and engaging multiple stakeholders in the field, including MS academic societies, licensing boards, and legislative bodies. Specifically, we call for creation of evidence-based education for both neurologists and patients, including physical resources that neurologists can use when discussing stem cell interventions with patients and videos on proper counseling during these visits.”

Colleagues from OSU’s Laboratory for Neural Stem Cells and Functional Neurogenetics contributed to this work. The researchers reported having no financial disclosures.

[email protected]

SOURCE: Rai W et al. ACTRIMS Forum 2019, Poster 237.

DALLAS – Stem cell tourism – the unethical practice of offering unproven cellular preparations to patients for a variety of conditions – is increasingly sought by patients with incurable conditions such as multiple sclerosis and amyotrophic lateral sclerosis, results from a novel survey suggest.

Doug Brunk/MDedge News

In fact, most academic neurologists have been approached by patients with incurable conditions who ask them about stem cell therapy, while about two-thirds have had at least one patient who has undergone stem cell therapy.

“It’s really scary,” Wijdan Rai, MBBS, the study’s first author, said in an interview at the meeting held by the Americas Committee for Treatment and Research in Multiple Sclerosis. “This is a more prevalent issue than we think, and the complication rates are higher than we think.”

According to the study’s senior author, Jaime Imitola, MD, who directs the Progressive Multiple Sclerosis Multidisciplinary Clinic and Translational Research Program at the Ohio State University Wexner Medical Center, Columbus, the results “call for the creation of a nationwide registry where neurologists can document adverse reactions to stem cell procedures and further support dedicated patient and neurologist education as we have proposed before” (See Semin Neurol. 2018; 38[2]:176-81 and JAMA Neurol. 2015;72[11]:1342-5).


In an effort to understand the experiences and attitudes of academic neurologists regarding stem cell tourism and patient-reported complications, the researchers developed a 25-question survey disseminated via Synapse, a web tool from the American Academy of Neurology. Respondents were asked about demographic information, frequency of patient questioning, perception of physician competence, patient complications and experiences, and attitudes toward increased physician education.

Dr. Rai, who is a senior neurology resident at the medical center, presented findings from 204 neurologist respondents, of whom 31% identified themselves as MS specialists. Nearly all respondents (91%) said they have been approached by patients with incurable conditions seeking information about stem cells (37% of whom had diagnosis of MS). In addition, 65% have had at least one patient that has undergone “stem cell therapy,” and 73% said it would be “helpful” or “very helpful” to have an evidence-based patient education tool on the topic. “Patients most often wanted general information,” Dr. Rai said. “However, 50% requested permission to undergo a stem cell procedure, and 31% approached their neurologist after the procedure.”

Survey respondents reported that 33% of the stem cell interventions were performed in the United States and 22% abroad, while 37% reported both in the U.S. and abroad. Patients underwent the procedures in China, Germany, the Bahamas, Mexico, Russia, and Costa Rica. Three-quarters of respondents (75%) indicated no patient experiencing complications from the stem cell interventions. However, 25% reported patients experiencing a variety of complications from the procedures, including strokes, meningoencephalitis, quadriparesis, MS deterioration, sepsis, hepatitis C, seizures, meningitis from intrathecal cell injections, infections, and spinal cord tumors. “At least three respondents had a patient who died as a direct complication from stem cell therapy,” Dr. Rai said.

In their poster, the researchers recommended a “multipronged approach to improve education of MS patients from exploitation and engaging multiple stakeholders in the field, including MS academic societies, licensing boards, and legislative bodies. Specifically, we call for creation of evidence-based education for both neurologists and patients, including physical resources that neurologists can use when discussing stem cell interventions with patients and videos on proper counseling during these visits.”

Colleagues from OSU’s Laboratory for Neural Stem Cells and Functional Neurogenetics contributed to this work. The researchers reported having no financial disclosures.

[email protected]

SOURCE: Rai W et al. ACTRIMS Forum 2019, Poster 237.

DALLAS – Stem cell tourism – the unethical practice of offering unproven cellular preparations to patients for a variety of conditions – is increasingly sought by patients with incurable conditions such as multiple sclerosis and amyotrophic lateral sclerosis, results from a novel survey suggest.

Doug Brunk/MDedge News

In fact, most academic neurologists have been approached by patients with incurable conditions who ask them about stem cell therapy, while about two-thirds have had at least one patient who has undergone stem cell therapy.

“It’s really scary,” Wijdan Rai, MBBS, the study’s first author, said in an interview at the meeting held by the Americas Committee for Treatment and Research in Multiple Sclerosis. “This is a more prevalent issue than we think, and the complication rates are higher than we think.”

According to the study’s senior author, Jaime Imitola, MD, who directs the Progressive Multiple Sclerosis Multidisciplinary Clinic and Translational Research Program at the Ohio State University Wexner Medical Center, Columbus, the results “call for the creation of a nationwide registry where neurologists can document adverse reactions to stem cell procedures and further support dedicated patient and neurologist education as we have proposed before” (See Semin Neurol. 2018; 38[2]:176-81 and JAMA Neurol. 2015;72[11]:1342-5).


In an effort to understand the experiences and attitudes of academic neurologists regarding stem cell tourism and patient-reported complications, the researchers developed a 25-question survey disseminated via Synapse, a web tool from the American Academy of Neurology. Respondents were asked about demographic information, frequency of patient questioning, perception of physician competence, patient complications and experiences, and attitudes toward increased physician education.

Dr. Rai, who is a senior neurology resident at the medical center, presented findings from 204 neurologist respondents, of whom 31% identified themselves as MS specialists. Nearly all respondents (91%) said they have been approached by patients with incurable conditions seeking information about stem cells (37% of whom had diagnosis of MS). In addition, 65% have had at least one patient that has undergone “stem cell therapy,” and 73% said it would be “helpful” or “very helpful” to have an evidence-based patient education tool on the topic. “Patients most often wanted general information,” Dr. Rai said. “However, 50% requested permission to undergo a stem cell procedure, and 31% approached their neurologist after the procedure.”

Survey respondents reported that 33% of the stem cell interventions were performed in the United States and 22% abroad, while 37% reported both in the U.S. and abroad. Patients underwent the procedures in China, Germany, the Bahamas, Mexico, Russia, and Costa Rica. Three-quarters of respondents (75%) indicated no patient experiencing complications from the stem cell interventions. However, 25% reported patients experiencing a variety of complications from the procedures, including strokes, meningoencephalitis, quadriparesis, MS deterioration, sepsis, hepatitis C, seizures, meningitis from intrathecal cell injections, infections, and spinal cord tumors. “At least three respondents had a patient who died as a direct complication from stem cell therapy,” Dr. Rai said.

In their poster, the researchers recommended a “multipronged approach to improve education of MS patients from exploitation and engaging multiple stakeholders in the field, including MS academic societies, licensing boards, and legislative bodies. Specifically, we call for creation of evidence-based education for both neurologists and patients, including physical resources that neurologists can use when discussing stem cell interventions with patients and videos on proper counseling during these visits.”

Colleagues from OSU’s Laboratory for Neural Stem Cells and Functional Neurogenetics contributed to this work. The researchers reported having no financial disclosures.

[email protected]

SOURCE: Rai W et al. ACTRIMS Forum 2019, Poster 237.

WASHINGTON – The “therapeutic drought” in available therapies for atopic dermatitis (AD) is “finally ending,” in part because understanding of the pathogenesis of the disease has grown, Emma Guttman-Yassky, MD, PhD, said during a presentation at the annual meeting of the American Academy of Dermatology.

“It’s due to the increased understanding we now have in atopic dermatitis,” Dr. Guttman-Yassky, professor and vice chair for research in the department of dermatology at the Icahn School of Medicine at Mount Sinai, New York, said in her presentation.

According to Dr. Guttman-Yassky, therapeutic development was prevented in AD because of the abnormalities present in the disease immune responses and barrier abnormalities. “Frankly, pharma[ceutical] companies didn’t know what they should go after,” she said. “Should they go after the immune abnormalities, or should they go after the barrier? I think that’s why we’re so far behind psoriasis – but don’t worry, we are catching up quite fast because now ... we understand what we need to go after.”


It was when researchers began to look at AD in the same way as psoriasis that they realized the two were “polar” immune diseases, with psoriasis having Th17/interleukin-17 involvement while atopic dermatitis had Th2/IL-13 involvement. The same approach of “bedside-to-bench pathogenic dissection and translational testing of therapeutics” that led to successful advancements in therapies for psoriasis can also be applied to AD, Dr. Guttman-Yassky said.

To create a translational approach to AD, researchers need to have a well-defined molecular phenotype and understanding of inflammatory pathways, good baseline biomarkers of disease activity and treatment responses, and drugs that would selectively target the immune system. Th2-type cytokines such as IL-4 and IL-13 could help link the barrier and immune defects in AD. In addition, all variations of AD subtypes across white, black, Asian, and pediatric populations have “robust Th2 activation” but differ in other areas. “We’ll need to stratify biomarkers specific to different atopic dermatitis phenotypes to really develop a personalized medicine approach in atopic dermatitis,” she said.

High-level systemic immune activation shows that AD is emerging as a systemic disease that leads to atopic comorbidities such as allergy and asthma, as well as cardiovascular and infectious comorbidities. “We need to think about it when we treat our patients, because we really need to give them systemic treatment approaches when they have this moderate to severe disease,” Dr. Guttman-Yassky said. “When adult patients have moderate to severe disease, what is nonlesional today may be lesional tomorrow, and to treat them effectively, you have to offer them some systemic approaches.”

There is evidence that dupilumab, a human monoclonal antibody that targets IL-4 receptor alpha, is “proving the immune hypothesis” of AD, Dr. Guttman-Yassky said. She cited a recent study from her own group that found use of dupilumab to inhibit IL-4/IL-13 signaling improved disease activity for patients with AD, including reducing the expression of genes that caused type 2 inflammation, epidermal hyperplasia, T cells, dendritic cells, and Th17/Th22 activity (J Allergy Clin Immunol. 2019 Jan;143(1):155-72).

“We could postulate it before, but we couldn’t prove it,” she said. “Basically, this opened the door to all the therapy that we now have in atopic dermatitis.”

According to Dr. Guttman-Yassky, the future of AD will be in creating personalized treatments for patients by stratifying biomarkers specific to different AD phenotypes.

“It’s a very hopeful time in atopic dermatitis with this growing knowledge that we have of the biology of [the disease],” she said. “We have many more agents to treat our patients, and I think the future will be about personalized medicine so we really are treating the disease very well.”

Dr. Guttman-Yassky reported relationships with AbbVie, Allergan, Almirall, Anacor Pharmaceuticals, Asana BioSciences, Celgene, Dermira, Eli Lilly, Escalier Biosciences, Galderma Research & Development, Glenmark Generics, Janssen, Kyowa Hakko Kirin, Leo Pharma, Medimmune, Novartis, Pfizer, Regeneron, Sanofi-Aventis, Sanofi/Regeneron, Stiefel, Theravance Biopharma, and Vitae Pharmaceuticals.

WASHINGTON – The “therapeutic drought” in available therapies for atopic dermatitis (AD) is “finally ending,” in part because understanding of the pathogenesis of the disease has grown, Emma Guttman-Yassky, MD, PhD, said during a presentation at the annual meeting of the American Academy of Dermatology.

“It’s due to the increased understanding we now have in atopic dermatitis,” Dr. Guttman-Yassky, professor and vice chair for research in the department of dermatology at the Icahn School of Medicine at Mount Sinai, New York, said in her presentation.

According to Dr. Guttman-Yassky, therapeutic development was prevented in AD because of the abnormalities present in the disease immune responses and barrier abnormalities. “Frankly, pharma[ceutical] companies didn’t know what they should go after,” she said. “Should they go after the immune abnormalities, or should they go after the barrier? I think that’s why we’re so far behind psoriasis – but don’t worry, we are catching up quite fast because now ... we understand what we need to go after.”


It was when researchers began to look at AD in the same way as psoriasis that they realized the two were “polar” immune diseases, with psoriasis having Th17/interleukin-17 involvement while atopic dermatitis had Th2/IL-13 involvement. The same approach of “bedside-to-bench pathogenic dissection and translational testing of therapeutics” that led to successful advancements in therapies for psoriasis can also be applied to AD, Dr. Guttman-Yassky said.

To create a translational approach to AD, researchers need to have a well-defined molecular phenotype and understanding of inflammatory pathways, good baseline biomarkers of disease activity and treatment responses, and drugs that would selectively target the immune system. Th2-type cytokines such as IL-4 and IL-13 could help link the barrier and immune defects in AD. In addition, all variations of AD subtypes across white, black, Asian, and pediatric populations have “robust Th2 activation” but differ in other areas. “We’ll need to stratify biomarkers specific to different atopic dermatitis phenotypes to really develop a personalized medicine approach in atopic dermatitis,” she said.

High-level systemic immune activation shows that AD is emerging as a systemic disease that leads to atopic comorbidities such as allergy and asthma, as well as cardiovascular and infectious comorbidities. “We need to think about it when we treat our patients, because we really need to give them systemic treatment approaches when they have this moderate to severe disease,” Dr. Guttman-Yassky said. “When adult patients have moderate to severe disease, what is nonlesional today may be lesional tomorrow, and to treat them effectively, you have to offer them some systemic approaches.”

There is evidence that dupilumab, a human monoclonal antibody that targets IL-4 receptor alpha, is “proving the immune hypothesis” of AD, Dr. Guttman-Yassky said. She cited a recent study from her own group that found use of dupilumab to inhibit IL-4/IL-13 signaling improved disease activity for patients with AD, including reducing the expression of genes that caused type 2 inflammation, epidermal hyperplasia, T cells, dendritic cells, and Th17/Th22 activity (J Allergy Clin Immunol. 2019 Jan;143(1):155-72).

“We could postulate it before, but we couldn’t prove it,” she said. “Basically, this opened the door to all the therapy that we now have in atopic dermatitis.”

According to Dr. Guttman-Yassky, the future of AD will be in creating personalized treatments for patients by stratifying biomarkers specific to different AD phenotypes.

“It’s a very hopeful time in atopic dermatitis with this growing knowledge that we have of the biology of [the disease],” she said. “We have many more agents to treat our patients, and I think the future will be about personalized medicine so we really are treating the disease very well.”

Dr. Guttman-Yassky reported relationships with AbbVie, Allergan, Almirall, Anacor Pharmaceuticals, Asana BioSciences, Celgene, Dermira, Eli Lilly, Escalier Biosciences, Galderma Research & Development, Glenmark Generics, Janssen, Kyowa Hakko Kirin, Leo Pharma, Medimmune, Novartis, Pfizer, Regeneron, Sanofi-Aventis, Sanofi/Regeneron, Stiefel, Theravance Biopharma, and Vitae Pharmaceuticals.

WASHINGTON – The “therapeutic drought” in available therapies for atopic dermatitis (AD) is “finally ending,” in part because understanding of the pathogenesis of the disease has grown, Emma Guttman-Yassky, MD, PhD, said during a presentation at the annual meeting of the American Academy of Dermatology.

“It’s due to the increased understanding we now have in atopic dermatitis,” Dr. Guttman-Yassky, professor and vice chair for research in the department of dermatology at the Icahn School of Medicine at Mount Sinai, New York, said in her presentation.

According to Dr. Guttman-Yassky, therapeutic development was prevented in AD because of the abnormalities present in the disease immune responses and barrier abnormalities. “Frankly, pharma[ceutical] companies didn’t know what they should go after,” she said. “Should they go after the immune abnormalities, or should they go after the barrier? I think that’s why we’re so far behind psoriasis – but don’t worry, we are catching up quite fast because now ... we understand what we need to go after.”


It was when researchers began to look at AD in the same way as psoriasis that they realized the two were “polar” immune diseases, with psoriasis having Th17/interleukin-17 involvement while atopic dermatitis had Th2/IL-13 involvement. The same approach of “bedside-to-bench pathogenic dissection and translational testing of therapeutics” that led to successful advancements in therapies for psoriasis can also be applied to AD, Dr. Guttman-Yassky said.

To create a translational approach to AD, researchers need to have a well-defined molecular phenotype and understanding of inflammatory pathways, good baseline biomarkers of disease activity and treatment responses, and drugs that would selectively target the immune system. Th2-type cytokines such as IL-4 and IL-13 could help link the barrier and immune defects in AD. In addition, all variations of AD subtypes across white, black, Asian, and pediatric populations have “robust Th2 activation” but differ in other areas. “We’ll need to stratify biomarkers specific to different atopic dermatitis phenotypes to really develop a personalized medicine approach in atopic dermatitis,” she said.

High-level systemic immune activation shows that AD is emerging as a systemic disease that leads to atopic comorbidities such as allergy and asthma, as well as cardiovascular and infectious comorbidities. “We need to think about it when we treat our patients, because we really need to give them systemic treatment approaches when they have this moderate to severe disease,” Dr. Guttman-Yassky said. “When adult patients have moderate to severe disease, what is nonlesional today may be lesional tomorrow, and to treat them effectively, you have to offer them some systemic approaches.”

There is evidence that dupilumab, a human monoclonal antibody that targets IL-4 receptor alpha, is “proving the immune hypothesis” of AD, Dr. Guttman-Yassky said. She cited a recent study from her own group that found use of dupilumab to inhibit IL-4/IL-13 signaling improved disease activity for patients with AD, including reducing the expression of genes that caused type 2 inflammation, epidermal hyperplasia, T cells, dendritic cells, and Th17/Th22 activity (J Allergy Clin Immunol. 2019 Jan;143(1):155-72).

“We could postulate it before, but we couldn’t prove it,” she said. “Basically, this opened the door to all the therapy that we now have in atopic dermatitis.”

According to Dr. Guttman-Yassky, the future of AD will be in creating personalized treatments for patients by stratifying biomarkers specific to different AD phenotypes.

“It’s a very hopeful time in atopic dermatitis with this growing knowledge that we have of the biology of [the disease],” she said. “We have many more agents to treat our patients, and I think the future will be about personalized medicine so we really are treating the disease very well.”

Dr. Guttman-Yassky reported relationships with AbbVie, Allergan, Almirall, Anacor Pharmaceuticals, Asana BioSciences, Celgene, Dermira, Eli Lilly, Escalier Biosciences, Galderma Research & Development, Glenmark Generics, Janssen, Kyowa Hakko Kirin, Leo Pharma, Medimmune, Novartis, Pfizer, Regeneron, Sanofi-Aventis, Sanofi/Regeneron, Stiefel, Theravance Biopharma, and Vitae Pharmaceuticals.

Odds of sudden unexpected infant death (SUID) more than doubled with maternal prenatal smoking and increased linearly with each additional cigarette mothers smoked during pregnancy, but quitting smoking during pregnancy cut SUID risk, according to a new study in Pediatrics.

Jasmin Merdan/fotolia

“As prevalence of prone sleeping has declined, the relative contribution of prenatal maternal smoking to the risk of sudden infant death has increased,” Tatiana M. Anderson, PhD, of the Seattle Children’s Research Institute and her associates reported. When the researchers considered causality, they estimated that approximately 800 infants (22% of all SUID cases) per year in the United States could be attributed to maternal smoking during pregnancy.

The researchers analyzed 19,127 SUID cases among 20,685,463 births included in the Centers for Disease Control and Prevention Birth Cohort Linked Birth/Infant Death Data Set for 2007-2011. A SUID diagnosis included sudden infant death syndrome, infant death from ill-defined or unknown cause, and accidental suffocation or strangulation in bed for any infants under 1 year old.

When the authors calculated odds related to prenatal maternal smoking and SUID, they adjusted for infant sex and birth weight, gestational length of pregnancy, delivery method (vaginal or cesarean), total prenatal visits, live birth order, maternal marital status and education, and maternal and paternal age and race/ethnicity.

Any maternal smoking at all during pregnancy was associated with more than twice the odds of SUID (adjusted odds ratio, 2.44). Odds of SUID also doubled for smoking one cigarette daily during pregnancy versus smoking none. For each additional cigarette smoked daily during pregnancy, odds of SUID increased by 0.07 up until 20 cigarettes, when the risk evened out, which suggests “that smoking cessation efforts may have greater impact on decreasing SUID rates when directed toward those who smoke fewer than 1 pack per day versus the more traditionally targeted heavy ([more than] 20 cigarettes per day) smokers,” the authors wrote.

Odds of SUID dropped 12% when mothers cut down on smoking during pregnancy and dropped 23% when they quit altogether (aORs, 0.88 and 0.77, respectively). “However, there may be some selection bias because the group who reduced smoking started at a higher average number of cigarettes in the first trimester, whereas those who successfully quit smoked fewer cigarettes in the first trimester,” the authors noted.

Among the 11.6% of mothers who said in 2011 that they smoked in the 3 months leading up to pregnancy, only a quarter quit while pregnant, the authors wrote. Quitting after having smoked before pregnancy was linked to a 47% increased risk of SUID, although the researchers noted that second- and third-hand smoke may have played a role since mothers who smoke may begin smoking again post partum and/or often have a partner who smokes.

“This group may have also included women who stopped smoking as soon as they knew they were pregnant and thus reported that they were nonsmokers in the first trimester, but the fetus had been exposed to maternal smoking during the period before pregnancy was diagnosed,” the authors wrote. They also acknowledged the possibility of residual confounding, particularly from socioeconomic factors or alcohol consumption during pregnancy.

The research was funded by the National Institutes of Health, Microsoft, and the Aaron Matthew Sudden Infant Death Syndrome Research Guild. One author has testified as a paid expert in a SUID case. No other authors reported conflicts of interest.

SOURCE: Anderson TM et al. Pediatrics. 2019 March 11. doi: 10.1542/peds.2018-3325.

Odds of sudden unexpected infant death (SUID) more than doubled with maternal prenatal smoking and increased linearly with each additional cigarette mothers smoked during pregnancy, but quitting smoking during pregnancy cut SUID risk, according to a new study in Pediatrics.

Jasmin Merdan/fotolia

“As prevalence of prone sleeping has declined, the relative contribution of prenatal maternal smoking to the risk of sudden infant death has increased,” Tatiana M. Anderson, PhD, of the Seattle Children’s Research Institute and her associates reported. When the researchers considered causality, they estimated that approximately 800 infants (22% of all SUID cases) per year in the United States could be attributed to maternal smoking during pregnancy.

The researchers analyzed 19,127 SUID cases among 20,685,463 births included in the Centers for Disease Control and Prevention Birth Cohort Linked Birth/Infant Death Data Set for 2007-2011. A SUID diagnosis included sudden infant death syndrome, infant death from ill-defined or unknown cause, and accidental suffocation or strangulation in bed for any infants under 1 year old.

When the authors calculated odds related to prenatal maternal smoking and SUID, they adjusted for infant sex and birth weight, gestational length of pregnancy, delivery method (vaginal or cesarean), total prenatal visits, live birth order, maternal marital status and education, and maternal and paternal age and race/ethnicity.

Any maternal smoking at all during pregnancy was associated with more than twice the odds of SUID (adjusted odds ratio, 2.44). Odds of SUID also doubled for smoking one cigarette daily during pregnancy versus smoking none. For each additional cigarette smoked daily during pregnancy, odds of SUID increased by 0.07 up until 20 cigarettes, when the risk evened out, which suggests “that smoking cessation efforts may have greater impact on decreasing SUID rates when directed toward those who smoke fewer than 1 pack per day versus the more traditionally targeted heavy ([more than] 20 cigarettes per day) smokers,” the authors wrote.

Odds of SUID dropped 12% when mothers cut down on smoking during pregnancy and dropped 23% when they quit altogether (aORs, 0.88 and 0.77, respectively). “However, there may be some selection bias because the group who reduced smoking started at a higher average number of cigarettes in the first trimester, whereas those who successfully quit smoked fewer cigarettes in the first trimester,” the authors noted.

Among the 11.6% of mothers who said in 2011 that they smoked in the 3 months leading up to pregnancy, only a quarter quit while pregnant, the authors wrote. Quitting after having smoked before pregnancy was linked to a 47% increased risk of SUID, although the researchers noted that second- and third-hand smoke may have played a role since mothers who smoke may begin smoking again post partum and/or often have a partner who smokes.

“This group may have also included women who stopped smoking as soon as they knew they were pregnant and thus reported that they were nonsmokers in the first trimester, but the fetus had been exposed to maternal smoking during the period before pregnancy was diagnosed,” the authors wrote. They also acknowledged the possibility of residual confounding, particularly from socioeconomic factors or alcohol consumption during pregnancy.

The research was funded by the National Institutes of Health, Microsoft, and the Aaron Matthew Sudden Infant Death Syndrome Research Guild. One author has testified as a paid expert in a SUID case. No other authors reported conflicts of interest.

SOURCE: Anderson TM et al. Pediatrics. 2019 March 11. doi: 10.1542/peds.2018-3325.

Odds of sudden unexpected infant death (SUID) more than doubled with maternal prenatal smoking and increased linearly with each additional cigarette mothers smoked during pregnancy, but quitting smoking during pregnancy cut SUID risk, according to a new study in Pediatrics.

Jasmin Merdan/fotolia

“As prevalence of prone sleeping has declined, the relative contribution of prenatal maternal smoking to the risk of sudden infant death has increased,” Tatiana M. Anderson, PhD, of the Seattle Children’s Research Institute and her associates reported. When the researchers considered causality, they estimated that approximately 800 infants (22% of all SUID cases) per year in the United States could be attributed to maternal smoking during pregnancy.

The researchers analyzed 19,127 SUID cases among 20,685,463 births included in the Centers for Disease Control and Prevention Birth Cohort Linked Birth/Infant Death Data Set for 2007-2011. A SUID diagnosis included sudden infant death syndrome, infant death from ill-defined or unknown cause, and accidental suffocation or strangulation in bed for any infants under 1 year old.

When the authors calculated odds related to prenatal maternal smoking and SUID, they adjusted for infant sex and birth weight, gestational length of pregnancy, delivery method (vaginal or cesarean), total prenatal visits, live birth order, maternal marital status and education, and maternal and paternal age and race/ethnicity.

Any maternal smoking at all during pregnancy was associated with more than twice the odds of SUID (adjusted odds ratio, 2.44). Odds of SUID also doubled for smoking one cigarette daily during pregnancy versus smoking none. For each additional cigarette smoked daily during pregnancy, odds of SUID increased by 0.07 up until 20 cigarettes, when the risk evened out, which suggests “that smoking cessation efforts may have greater impact on decreasing SUID rates when directed toward those who smoke fewer than 1 pack per day versus the more traditionally targeted heavy ([more than] 20 cigarettes per day) smokers,” the authors wrote.

Odds of SUID dropped 12% when mothers cut down on smoking during pregnancy and dropped 23% when they quit altogether (aORs, 0.88 and 0.77, respectively). “However, there may be some selection bias because the group who reduced smoking started at a higher average number of cigarettes in the first trimester, whereas those who successfully quit smoked fewer cigarettes in the first trimester,” the authors noted.

Among the 11.6% of mothers who said in 2011 that they smoked in the 3 months leading up to pregnancy, only a quarter quit while pregnant, the authors wrote. Quitting after having smoked before pregnancy was linked to a 47% increased risk of SUID, although the researchers noted that second- and third-hand smoke may have played a role since mothers who smoke may begin smoking again post partum and/or often have a partner who smokes.

“This group may have also included women who stopped smoking as soon as they knew they were pregnant and thus reported that they were nonsmokers in the first trimester, but the fetus had been exposed to maternal smoking during the period before pregnancy was diagnosed,” the authors wrote. They also acknowledged the possibility of residual confounding, particularly from socioeconomic factors or alcohol consumption during pregnancy.

The research was funded by the National Institutes of Health, Microsoft, and the Aaron Matthew Sudden Infant Death Syndrome Research Guild. One author has testified as a paid expert in a SUID case. No other authors reported conflicts of interest.

SOURCE: Anderson TM et al. Pediatrics. 2019 March 11. doi: 10.1542/peds.2018-3325.

CASE A 53-year-old woman you are seeing for the first time has been taking 10 mg of prednisone daily for a month, prescribed by another practitioner for polymyalgia rheumatica. Testing is negative for hepatitis B surface antigen but is positive for hepatitis B core antibody total, indicating a resolved hepatitis B infection. The absence of hepatitis B DNA is confirmed.

How would you proceed with this patient?

Patients with resolved hepatitis B virus (HBV) or chronic hepatitis B (CHB) infections are at risk for HBV reactivation (HBVr) if they undergo immunosuppressive therapy for a condition such as cancer. HBVr can in turn lead to delays in treatment and increased morbidity and mortality.

HBVr is a well-documented adverse outcome in patients treated with rituximab and in those undergoing stem cell transplantation. Current oncology guidelines recommend screening for HBV prior to initiating these treatments.^1,2 More recent evidence shows that many other immunosuppressive therapies can also lead to HBVr.³ Such treatments are now used across a multitude of specialties and conditions. For many of these conditions, there are no consistent guidelines regarding HBV screening.

In 2013, the US Food and Drug Administration (FDA) announced the requirement of a Boxed Warning for the immunosuppressive drugs ofatumumab and rituximab. In 2016, the FDA announced the same requirement for certain direct-acting antiviral medicines for hepatitis C virus.

Among patients who are positive for hepatitis-B surface antigen (HBsAg) and who are treated with immunosuppression, the frequency of HBVr has ranged from 0% to 39%.^4,5

As the list of immunosuppressive therapies that can cause HBVr grows, specialty guidelines are evolving to address the risk that HBVr poses.

Continue to: An underrecognized problem

An underrecognized problem. CHB affects an estimated 350 million people worldwide⁶ but remains underrecognized and underdiagnosed. An estimated 1.4 million Americans⁶ have CHB, but only a minority of them are aware of their positive status and are followed by a hepatologist or receive medical care for their disease.⁷ Compared with the natural-born US population, a higher prevalence of CHB exists among immigrants to this country from the Asian Pacific and Eastern Mediterranean regions, sub-Saharan Africa, and certain parts of South America.^8-10 In 2008, the Centers for Disease Control and Prevention (CDC) updated its recommendations on screening for HBV to include immigrants to the United States from intermediate and high endemic areas.⁶ Unfortunately, data published on physicians’ adherence to the CDC guidelines for screening show that only 60% correctly screened at-risk patients.¹¹

Individuals with CHB are at risk and rely on a robust immune system to keep their disease from becoming active. During infection, the virus gains entry into the hepatocytes and the double-stranded viral genome is imported into the nucleus of the cell, where it is repaired into covalently closed circular DNA (cccDNA). Research has demonstrated the stability of cccDNA and its persistence as a latent reservoir for HBV reactivation, even decades after recovery from infection.¹²

Also at risk are individuals who have unrecovered from HBV infection and are HBsAg negative and anti-HBc positive. To avert reverse seroconversion, they also rely on a robust immune system.¹³ Reverse seroconversion is defined as a reappearance of HBV DNA and HBsAg positivity in individuals who were previously negative.¹³ In these individuals, HBV DNA may not be quantifiable in circulation, but trace amounts of viral DNA found in the liver are enough to pose a reactivation risk in the setting of immune suppression.¹⁴

Moreover, often overlooked is the fact that reactivation or reverse seroconversion can necessitate disruptions and delays in immunosuppressive treatment for other life-threatening disease processes.^14,15

Universal screening reduces risk for HBVr. Patients with CHB are at risk for reactivation, as are patients with resolved HBV infection. Many patients, however, do not know their status. By screening all patients before beginning immunosuppressive therapy, physicians can provide effective prophylaxis, which has been shown to significantly reduce the risk for HBVr.^8.15

Continue to: Recognizing the onset of HBVr

Recognizing the onset of HBVr

In patients with CHB, HBVr is defined as at least a 3-fold increase in aspart aminotransferase (AST) and alanine aminotransferase (ALT) and at least a 10-fold increase from baseline in HBV DNA. In patients with resolved HBV infection, there may be reverse seroconversion from HbsAg-negative to HBsAg-positive status (TABLE 1^13,16).

Not all elevations in AST/ALT in patients undergoing chemotherapy or immunosuppressive therapy indicate HBVr. Very often, derangements in AST/ALT may be related to the toxic effects of therapy or to the underlying disease process. However, as immunosuppressive therapy is now used for a wide array of medical conditions, consider HBVr as a potential cause of abnormal liver function in all patients receiving such therapy.

A patient is at risk for HBVr when starting immunosuppression and up to a year following the completion of therapy. With suppression of the immune system, HBV replication increases and serum AST/ALT concentrations may rise. HBVr may also present with the appearance of HBV DNA in patients with previously undetectable levels.^12,17

Most patients remain asymptomatic, and abnormal AST/ALT levels eventually resolve after completion of immunosuppression. However, some patients' liver enzymes may rise, indicating a more severe hepatic flare. These patients may present with right upper-quadrant tenderness, jaundice, or fatigue. In these cases, recognizing HBVr and starting antivirals may reduce hepatitis flare.

Unfortunately, despite early recognition of HBVr and initiation of appropriate therapy, some patients can progress to hepatic decompensation and even fulminant hepatic failure that may have been prevented with prophylaxis.

Continue to: The justification for universal screening

Although nongastroenterology societies differ in their recommendations on screening for HBV, universal screening before implementing prolonged immunosuppressive treatment is recommended by the CDC,⁶ the American Association for the Study of Liver Diseases,¹⁸ the Asian Pacific Association for the Study of the Liver,¹⁹ the European Association for the Study of the Liver,²⁰ and the American Gastroenterological Association (AGA).²¹

Older guidelines recommended screening only high-risk populations. But such screening has downfalls. It requires that patients or their physicians recognize that they are at high risk. In one study, nearly 65% of an infected Asian-American population was unaware of their positive HBV status.²² Risk-based screening also requires that physicians ask the appropriate questions and that patients admit to high-risk behavior. Screening patients based only on risk factors may easily overlook patients who need prophylaxis against HBVr.

Common arguments against universal screening include the cost of testing, the possibility of false-positive results, and the implications of a new diagnosis of hepatitis B. However, the potential benefits of screening are significant, and HBV screening in the general population has been shown to be cost effective when the prevalence of HBV is 0.3%.²¹ In the United States, conservative estimates are a prevalence of HBsAg positivity of 0.4% and past infection of 3%, making screening a cost-effective recommendation.¹⁶ It is therefore prudent to screen all patients before starting immunosuppressive therapy.

How to screen

All guidelines agree on how to test for HBV. Measuring levels of HBsAg and hepatitis B core antibody (anti-HBc total) allows the clinician to ascertain whether the patient’s HBV infection status is acute, chronic, or resolved (TABLE 2²³) and to perform HBVr risk stratification (discussed later).

Patients with acute infections should be referred to a hepatologist. With chronic or resolved HBV, stratify patients into a prophylaxis group or monitoring group (FIGURE¹⁴). Stratification involves identifying HBV status (chronic or resolved) and selecting a type of immunosuppressive therapy. Whether the patient falls into prophylaxis or monitoring, obtain a baseline level of viral DNA, as this has proven to be the best predictor of HBV reactivation.¹⁶

Continue to: In screening, be sure the appropriate...

In screening, be sure the appropriate anti-HBc testing is covered. Common usage of the term anti-HBc may refer to immunoglobulin G (IgG) or immunoglobulin M (IgM)or total core antibody, containing both IgG and IgM. But in this context, accurate screening requires either total core antibody or anti-HBc IgG. Anti-IgM alone is inadequate. Many commercial laboratories offer acute hepatitis panels or hepatitis profiles (TABLE 3^24,25), and it is important to confirm that such order sets contain the tests necessary to allow for risk stratification.

Testing for hepatitis B surface antibody (anti-HBs) is not useful in screening. Although it was hypothesized that the presence of this antibody lowered risk, recent studies have proven no change in risk based on this value.²¹

How to assess HBVr risk

Assessing risk for HBVr takes into account both the patient’s serology and intended treatment. Reddy et al delineated patient groups into high, moderate, and low risk (TABLES 4 and 5).²¹ The high-risk group was defined by anticipated incidence of HBVr in > 10% of cases; the moderate-risk group had an anticipated incidence of 1% to 10%; and the low-risk group had an anticipated incidence of <1%.²¹ Evidence was strongest in the high-risk group.

Patients with CHB (HBsAg positive and anti-HBc positive) are considered high risk for reactivation with a wide variety of immunosuppressive therapies. Such patients are 5 to 8 times more likely to develop HBVr than patients with an HBsAg-negative status signifying a resolved infection.¹⁶

Immunosuppressive agents and associated risks. The AGA guidelines consider treatment with B-cell-depleting agents, such as rituximab and ofatumumab, to be high risk, regardless of a patient’s surface antigen status. Additionally, for patients who are HBsAg positive, high-risk treatments include anthracycline derivatives, such as doxorubicin and epirubicin, or high- or moderate-dose steroids. These treatments are considered moderate risk when used in patients who have resolved HBV infection (HBsAg negative/anti-HBc positive). Moderate-risk modalities also include tumor necrosis factor inhibitors and tyrosine kinase inhibitors, regardless of surface antigen status; and low-dose steroids or cytokine or integrin inhibitors in HbsAg-positive individuals.²¹

Continue to: Other immunosuppression modalities...

Other immunosuppression modalities considered to be moderate risk independent of HBV serology include proteasome inhibitors, such as bortezomib, used for multiple myeloma treatment, and histone deacetylase inhibitors, such as romidepsin, used to treat T-cell lymphoma.¹³ Low-dose steroids or cytokine or integrin inhibitors are considered to be low risk in surface antigen-negative individuals; azathioprine, mercaptopurine, or methotrexate are low risk regardless of HBsAg status.²¹ Intra-articular steroid injections are considered extremely low risk in HbsAg-positive individuals, and are unclassified for HbsAg-negative individuals.¹³

More recent evidence has implicated other medication classes in triggering HBVr — (eg, direct-acting antivirals.)²⁶

Prophylaxis options: High to moderate risk vs low risk

The consensus of major guideline issuers is to offer prophylaxis to high-risk patients and to monitor low-risk patients. The AGA additionally recommends prophylaxis for patients at moderate risk.

Controversy surrounding the moderate-risk group. Some authors argue that monitoring HBV DNA in the moderate-risk group is preferable to committing patients to long periods of prophylaxis, and that rescue treatment could be initiated as needed. However, the ideal monitoring period has not been determined, and the effectiveness of prophylaxis over monitoring is so significant that monitoring is losing favor.

Perrillo et al performed a meta-analysis of 5 randomized controlled trials evaluating antiviral agents vs no prophylaxis.¹⁶ The analysis included 139 patients receiving prophylaxis and 137 controls. The pooled results demonstrated an 87% relative risk reduction with prophylaxis, supporting the trend toward treating patients with moderate risk.¹⁶

Continue to: Prophylactic treatment options are safe...

Prophylactic treatment options are safe and well tolerated. For this reason, committing a high- or moderate-risk patient to a course of treatment should be less of a concern than the risk for HBVr.

A recent meta-analysis demonstrated that tenofovir and entecavir are preferable to lamivudine in preventing HBVr.

In the early randomized controlled trials for HBVr prophylaxis, lamivudine, although effective, unfortunately led to a high incidence of viral resistance after prolonged use, thus diminishing its desirability.¹⁸ Newer agents, such as entecavir and tenofovir, have proven just as effective as lamivudine and are largely unaffected by viral resistance.²⁷

In retrospective and prospective studies on HBVr prophylaxis, patients treated with entecavir had less HBV-related hepatitis, less delay in chemotherapy, and a lower rate of HBVr when compared with lamivudine.^28,29 Tenofovir is recommended, however, if patients were previously treated with lamivudine.³⁰

A recent meta-analysis demonstrated that tenofovir and entecavir are preferable to lamivudine in preventing HBVr.³¹

Looking ahead

Screening for HBsAg and anti-HBc total before starting immunosuppressive therapy can reduce morbidity and mortality in patients undergoing such treatment. The AGA recommends screening all patients about to begin high- or moderate-risk therapy or patients in populations with a prevalence of CHB ≥2%, per the CDC.^6,21

Continue to: Classes of medications...

Classes of medications other than immunosuppressants may also trigger HBVr. The FDA has issued a warning regarding direct-acting antivirals, but optimal management of these patients is still evolving.

Once HBV status is established, a patient’s risk for HBVr can be specified as high, moderate, or low using their HBV status and the type of therapy being initiated. The AGA recommends prophylactic treatment with well-tolerated and effective agents for patients classified as high or moderate risk. If a patient’s risk is low, regular monitoring of HBV DNA and AST and ALT levels is sufficient. Recommendations of monitoring intervals span from monthly to every 3 months.^13,14

CASE Given the patient’s status of resolved HBV infection and her current moderate-dose regimen of prednisone, her risk for HBV reactivation is moderate. She could either receive antiviral prophylaxis or undergo regular monitoring. Following a discussion of the options, she opts for referral to a hepatologist to discuss possible prophylactic treatment.

Increased awareness of HBVr risk associated with immunosuppressive therapy, coupled with a planned approach to appropriate screening and risk stratification, can help health care providers prevent the reactivation of HBV or initiate early intervention for CHB.

CORRESPONDENCE
Ronan Farrell, MD, Rhode Island Hospital, 593 Eddy Street, Providence, RI 02903; [email protected].

CASE A 53-year-old woman you are seeing for the first time has been taking 10 mg of prednisone daily for a month, prescribed by another practitioner for polymyalgia rheumatica. Testing is negative for hepatitis B surface antigen but is positive for hepatitis B core antibody total, indicating a resolved hepatitis B infection. The absence of hepatitis B DNA is confirmed.

How would you proceed with this patient?

Patients with resolved hepatitis B virus (HBV) or chronic hepatitis B (CHB) infections are at risk for HBV reactivation (HBVr) if they undergo immunosuppressive therapy for a condition such as cancer. HBVr can in turn lead to delays in treatment and increased morbidity and mortality.

HBVr is a well-documented adverse outcome in patients treated with rituximab and in those undergoing stem cell transplantation. Current oncology guidelines recommend screening for HBV prior to initiating these treatments.^1,2 More recent evidence shows that many other immunosuppressive therapies can also lead to HBVr.³ Such treatments are now used across a multitude of specialties and conditions. For many of these conditions, there are no consistent guidelines regarding HBV screening.

In 2013, the US Food and Drug Administration (FDA) announced the requirement of a Boxed Warning for the immunosuppressive drugs ofatumumab and rituximab. In 2016, the FDA announced the same requirement for certain direct-acting antiviral medicines for hepatitis C virus.

Among patients who are positive for hepatitis-B surface antigen (HBsAg) and who are treated with immunosuppression, the frequency of HBVr has ranged from 0% to 39%.^4,5

As the list of immunosuppressive therapies that can cause HBVr grows, specialty guidelines are evolving to address the risk that HBVr poses.

Continue to: An underrecognized problem

An underrecognized problem. CHB affects an estimated 350 million people worldwide⁶ but remains underrecognized and underdiagnosed. An estimated 1.4 million Americans⁶ have CHB, but only a minority of them are aware of their positive status and are followed by a hepatologist or receive medical care for their disease.⁷ Compared with the natural-born US population, a higher prevalence of CHB exists among immigrants to this country from the Asian Pacific and Eastern Mediterranean regions, sub-Saharan Africa, and certain parts of South America.^8-10 In 2008, the Centers for Disease Control and Prevention (CDC) updated its recommendations on screening for HBV to include immigrants to the United States from intermediate and high endemic areas.⁶ Unfortunately, data published on physicians’ adherence to the CDC guidelines for screening show that only 60% correctly screened at-risk patients.¹¹

Individuals with CHB are at risk and rely on a robust immune system to keep their disease from becoming active. During infection, the virus gains entry into the hepatocytes and the double-stranded viral genome is imported into the nucleus of the cell, where it is repaired into covalently closed circular DNA (cccDNA). Research has demonstrated the stability of cccDNA and its persistence as a latent reservoir for HBV reactivation, even decades after recovery from infection.¹²

Also at risk are individuals who have unrecovered from HBV infection and are HBsAg negative and anti-HBc positive. To avert reverse seroconversion, they also rely on a robust immune system.¹³ Reverse seroconversion is defined as a reappearance of HBV DNA and HBsAg positivity in individuals who were previously negative.¹³ In these individuals, HBV DNA may not be quantifiable in circulation, but trace amounts of viral DNA found in the liver are enough to pose a reactivation risk in the setting of immune suppression.¹⁴

Moreover, often overlooked is the fact that reactivation or reverse seroconversion can necessitate disruptions and delays in immunosuppressive treatment for other life-threatening disease processes.^14,15

Universal screening reduces risk for HBVr. Patients with CHB are at risk for reactivation, as are patients with resolved HBV infection. Many patients, however, do not know their status. By screening all patients before beginning immunosuppressive therapy, physicians can provide effective prophylaxis, which has been shown to significantly reduce the risk for HBVr.^8.15

Continue to: Recognizing the onset of HBVr

Recognizing the onset of HBVr

In patients with CHB, HBVr is defined as at least a 3-fold increase in aspart aminotransferase (AST) and alanine aminotransferase (ALT) and at least a 10-fold increase from baseline in HBV DNA. In patients with resolved HBV infection, there may be reverse seroconversion from HbsAg-negative to HBsAg-positive status (TABLE 1^13,16).

Not all elevations in AST/ALT in patients undergoing chemotherapy or immunosuppressive therapy indicate HBVr. Very often, derangements in AST/ALT may be related to the toxic effects of therapy or to the underlying disease process. However, as immunosuppressive therapy is now used for a wide array of medical conditions, consider HBVr as a potential cause of abnormal liver function in all patients receiving such therapy.

A patient is at risk for HBVr when starting immunosuppression and up to a year following the completion of therapy. With suppression of the immune system, HBV replication increases and serum AST/ALT concentrations may rise. HBVr may also present with the appearance of HBV DNA in patients with previously undetectable levels.^12,17

Most patients remain asymptomatic, and abnormal AST/ALT levels eventually resolve after completion of immunosuppression. However, some patients' liver enzymes may rise, indicating a more severe hepatic flare. These patients may present with right upper-quadrant tenderness, jaundice, or fatigue. In these cases, recognizing HBVr and starting antivirals may reduce hepatitis flare.

Unfortunately, despite early recognition of HBVr and initiation of appropriate therapy, some patients can progress to hepatic decompensation and even fulminant hepatic failure that may have been prevented with prophylaxis.

Continue to: The justification for universal screening

Although nongastroenterology societies differ in their recommendations on screening for HBV, universal screening before implementing prolonged immunosuppressive treatment is recommended by the CDC,⁶ the American Association for the Study of Liver Diseases,¹⁸ the Asian Pacific Association for the Study of the Liver,¹⁹ the European Association for the Study of the Liver,²⁰ and the American Gastroenterological Association (AGA).²¹

Older guidelines recommended screening only high-risk populations. But such screening has downfalls. It requires that patients or their physicians recognize that they are at high risk. In one study, nearly 65% of an infected Asian-American population was unaware of their positive HBV status.²² Risk-based screening also requires that physicians ask the appropriate questions and that patients admit to high-risk behavior. Screening patients based only on risk factors may easily overlook patients who need prophylaxis against HBVr.

Common arguments against universal screening include the cost of testing, the possibility of false-positive results, and the implications of a new diagnosis of hepatitis B. However, the potential benefits of screening are significant, and HBV screening in the general population has been shown to be cost effective when the prevalence of HBV is 0.3%.²¹ In the United States, conservative estimates are a prevalence of HBsAg positivity of 0.4% and past infection of 3%, making screening a cost-effective recommendation.¹⁶ It is therefore prudent to screen all patients before starting immunosuppressive therapy.

How to screen

All guidelines agree on how to test for HBV. Measuring levels of HBsAg and hepatitis B core antibody (anti-HBc total) allows the clinician to ascertain whether the patient’s HBV infection status is acute, chronic, or resolved (TABLE 2²³) and to perform HBVr risk stratification (discussed later).

Patients with acute infections should be referred to a hepatologist. With chronic or resolved HBV, stratify patients into a prophylaxis group or monitoring group (FIGURE¹⁴). Stratification involves identifying HBV status (chronic or resolved) and selecting a type of immunosuppressive therapy. Whether the patient falls into prophylaxis or monitoring, obtain a baseline level of viral DNA, as this has proven to be the best predictor of HBV reactivation.¹⁶

Continue to: In screening, be sure the appropriate...

In screening, be sure the appropriate anti-HBc testing is covered. Common usage of the term anti-HBc may refer to immunoglobulin G (IgG) or immunoglobulin M (IgM)or total core antibody, containing both IgG and IgM. But in this context, accurate screening requires either total core antibody or anti-HBc IgG. Anti-IgM alone is inadequate. Many commercial laboratories offer acute hepatitis panels or hepatitis profiles (TABLE 3^24,25), and it is important to confirm that such order sets contain the tests necessary to allow for risk stratification.

Testing for hepatitis B surface antibody (anti-HBs) is not useful in screening. Although it was hypothesized that the presence of this antibody lowered risk, recent studies have proven no change in risk based on this value.²¹

How to assess HBVr risk

Assessing risk for HBVr takes into account both the patient’s serology and intended treatment. Reddy et al delineated patient groups into high, moderate, and low risk (TABLES 4 and 5).²¹ The high-risk group was defined by anticipated incidence of HBVr in > 10% of cases; the moderate-risk group had an anticipated incidence of 1% to 10%; and the low-risk group had an anticipated incidence of <1%.²¹ Evidence was strongest in the high-risk group.

Patients with CHB (HBsAg positive and anti-HBc positive) are considered high risk for reactivation with a wide variety of immunosuppressive therapies. Such patients are 5 to 8 times more likely to develop HBVr than patients with an HBsAg-negative status signifying a resolved infection.¹⁶

Immunosuppressive agents and associated risks. The AGA guidelines consider treatment with B-cell-depleting agents, such as rituximab and ofatumumab, to be high risk, regardless of a patient’s surface antigen status. Additionally, for patients who are HBsAg positive, high-risk treatments include anthracycline derivatives, such as doxorubicin and epirubicin, or high- or moderate-dose steroids. These treatments are considered moderate risk when used in patients who have resolved HBV infection (HBsAg negative/anti-HBc positive). Moderate-risk modalities also include tumor necrosis factor inhibitors and tyrosine kinase inhibitors, regardless of surface antigen status; and low-dose steroids or cytokine or integrin inhibitors in HbsAg-positive individuals.²¹

Continue to: Other immunosuppression modalities...

Other immunosuppression modalities considered to be moderate risk independent of HBV serology include proteasome inhibitors, such as bortezomib, used for multiple myeloma treatment, and histone deacetylase inhibitors, such as romidepsin, used to treat T-cell lymphoma.¹³ Low-dose steroids or cytokine or integrin inhibitors are considered to be low risk in surface antigen-negative individuals; azathioprine, mercaptopurine, or methotrexate are low risk regardless of HBsAg status.²¹ Intra-articular steroid injections are considered extremely low risk in HbsAg-positive individuals, and are unclassified for HbsAg-negative individuals.¹³

More recent evidence has implicated other medication classes in triggering HBVr — (eg, direct-acting antivirals.)²⁶

Prophylaxis options: High to moderate risk vs low risk

The consensus of major guideline issuers is to offer prophylaxis to high-risk patients and to monitor low-risk patients. The AGA additionally recommends prophylaxis for patients at moderate risk.

Controversy surrounding the moderate-risk group. Some authors argue that monitoring HBV DNA in the moderate-risk group is preferable to committing patients to long periods of prophylaxis, and that rescue treatment could be initiated as needed. However, the ideal monitoring period has not been determined, and the effectiveness of prophylaxis over monitoring is so significant that monitoring is losing favor.

Perrillo et al performed a meta-analysis of 5 randomized controlled trials evaluating antiviral agents vs no prophylaxis.¹⁶ The analysis included 139 patients receiving prophylaxis and 137 controls. The pooled results demonstrated an 87% relative risk reduction with prophylaxis, supporting the trend toward treating patients with moderate risk.¹⁶

Continue to: Prophylactic treatment options are safe...

Prophylactic treatment options are safe and well tolerated. For this reason, committing a high- or moderate-risk patient to a course of treatment should be less of a concern than the risk for HBVr.

A recent meta-analysis demonstrated that tenofovir and entecavir are preferable to lamivudine in preventing HBVr.

In the early randomized controlled trials for HBVr prophylaxis, lamivudine, although effective, unfortunately led to a high incidence of viral resistance after prolonged use, thus diminishing its desirability.¹⁸ Newer agents, such as entecavir and tenofovir, have proven just as effective as lamivudine and are largely unaffected by viral resistance.²⁷

In retrospective and prospective studies on HBVr prophylaxis, patients treated with entecavir had less HBV-related hepatitis, less delay in chemotherapy, and a lower rate of HBVr when compared with lamivudine.^28,29 Tenofovir is recommended, however, if patients were previously treated with lamivudine.³⁰

A recent meta-analysis demonstrated that tenofovir and entecavir are preferable to lamivudine in preventing HBVr.³¹

Looking ahead

Screening for HBsAg and anti-HBc total before starting immunosuppressive therapy can reduce morbidity and mortality in patients undergoing such treatment. The AGA recommends screening all patients about to begin high- or moderate-risk therapy or patients in populations with a prevalence of CHB ≥2%, per the CDC.^6,21

Continue to: Classes of medications...

Classes of medications other than immunosuppressants may also trigger HBVr. The FDA has issued a warning regarding direct-acting antivirals, but optimal management of these patients is still evolving.

Once HBV status is established, a patient’s risk for HBVr can be specified as high, moderate, or low using their HBV status and the type of therapy being initiated. The AGA recommends prophylactic treatment with well-tolerated and effective agents for patients classified as high or moderate risk. If a patient’s risk is low, regular monitoring of HBV DNA and AST and ALT levels is sufficient. Recommendations of monitoring intervals span from monthly to every 3 months.^13,14

CASE Given the patient’s status of resolved HBV infection and her current moderate-dose regimen of prednisone, her risk for HBV reactivation is moderate. She could either receive antiviral prophylaxis or undergo regular monitoring. Following a discussion of the options, she opts for referral to a hepatologist to discuss possible prophylactic treatment.

Increased awareness of HBVr risk associated with immunosuppressive therapy, coupled with a planned approach to appropriate screening and risk stratification, can help health care providers prevent the reactivation of HBV or initiate early intervention for CHB.

CORRESPONDENCE
Ronan Farrell, MD, Rhode Island Hospital, 593 Eddy Street, Providence, RI 02903; [email protected].

CASE A 53-year-old woman you are seeing for the first time has been taking 10 mg of prednisone daily for a month, prescribed by another practitioner for polymyalgia rheumatica. Testing is negative for hepatitis B surface antigen but is positive for hepatitis B core antibody total, indicating a resolved hepatitis B infection. The absence of hepatitis B DNA is confirmed.

How would you proceed with this patient?

Patients with resolved hepatitis B virus (HBV) or chronic hepatitis B (CHB) infections are at risk for HBV reactivation (HBVr) if they undergo immunosuppressive therapy for a condition such as cancer. HBVr can in turn lead to delays in treatment and increased morbidity and mortality.

HBVr is a well-documented adverse outcome in patients treated with rituximab and in those undergoing stem cell transplantation. Current oncology guidelines recommend screening for HBV prior to initiating these treatments.^1,2 More recent evidence shows that many other immunosuppressive therapies can also lead to HBVr.³ Such treatments are now used across a multitude of specialties and conditions. For many of these conditions, there are no consistent guidelines regarding HBV screening.

In 2013, the US Food and Drug Administration (FDA) announced the requirement of a Boxed Warning for the immunosuppressive drugs ofatumumab and rituximab. In 2016, the FDA announced the same requirement for certain direct-acting antiviral medicines for hepatitis C virus.

Among patients who are positive for hepatitis-B surface antigen (HBsAg) and who are treated with immunosuppression, the frequency of HBVr has ranged from 0% to 39%.^4,5

As the list of immunosuppressive therapies that can cause HBVr grows, specialty guidelines are evolving to address the risk that HBVr poses.

Continue to: An underrecognized problem

An underrecognized problem. CHB affects an estimated 350 million people worldwide⁶ but remains underrecognized and underdiagnosed. An estimated 1.4 million Americans⁶ have CHB, but only a minority of them are aware of their positive status and are followed by a hepatologist or receive medical care for their disease.⁷ Compared with the natural-born US population, a higher prevalence of CHB exists among immigrants to this country from the Asian Pacific and Eastern Mediterranean regions, sub-Saharan Africa, and certain parts of South America.^8-10 In 2008, the Centers for Disease Control and Prevention (CDC) updated its recommendations on screening for HBV to include immigrants to the United States from intermediate and high endemic areas.⁶ Unfortunately, data published on physicians’ adherence to the CDC guidelines for screening show that only 60% correctly screened at-risk patients.¹¹

Individuals with CHB are at risk and rely on a robust immune system to keep their disease from becoming active. During infection, the virus gains entry into the hepatocytes and the double-stranded viral genome is imported into the nucleus of the cell, where it is repaired into covalently closed circular DNA (cccDNA). Research has demonstrated the stability of cccDNA and its persistence as a latent reservoir for HBV reactivation, even decades after recovery from infection.¹²

Also at risk are individuals who have unrecovered from HBV infection and are HBsAg negative and anti-HBc positive. To avert reverse seroconversion, they also rely on a robust immune system.¹³ Reverse seroconversion is defined as a reappearance of HBV DNA and HBsAg positivity in individuals who were previously negative.¹³ In these individuals, HBV DNA may not be quantifiable in circulation, but trace amounts of viral DNA found in the liver are enough to pose a reactivation risk in the setting of immune suppression.¹⁴

Moreover, often overlooked is the fact that reactivation or reverse seroconversion can necessitate disruptions and delays in immunosuppressive treatment for other life-threatening disease processes.^14,15

Universal screening reduces risk for HBVr. Patients with CHB are at risk for reactivation, as are patients with resolved HBV infection. Many patients, however, do not know their status. By screening all patients before beginning immunosuppressive therapy, physicians can provide effective prophylaxis, which has been shown to significantly reduce the risk for HBVr.^8.15

Continue to: Recognizing the onset of HBVr

Recognizing the onset of HBVr

In patients with CHB, HBVr is defined as at least a 3-fold increase in aspart aminotransferase (AST) and alanine aminotransferase (ALT) and at least a 10-fold increase from baseline in HBV DNA. In patients with resolved HBV infection, there may be reverse seroconversion from HbsAg-negative to HBsAg-positive status (TABLE 1^13,16).

Not all elevations in AST/ALT in patients undergoing chemotherapy or immunosuppressive therapy indicate HBVr. Very often, derangements in AST/ALT may be related to the toxic effects of therapy or to the underlying disease process. However, as immunosuppressive therapy is now used for a wide array of medical conditions, consider HBVr as a potential cause of abnormal liver function in all patients receiving such therapy.

A patient is at risk for HBVr when starting immunosuppression and up to a year following the completion of therapy. With suppression of the immune system, HBV replication increases and serum AST/ALT concentrations may rise. HBVr may also present with the appearance of HBV DNA in patients with previously undetectable levels.^12,17

Most patients remain asymptomatic, and abnormal AST/ALT levels eventually resolve after completion of immunosuppression. However, some patients' liver enzymes may rise, indicating a more severe hepatic flare. These patients may present with right upper-quadrant tenderness, jaundice, or fatigue. In these cases, recognizing HBVr and starting antivirals may reduce hepatitis flare.

Unfortunately, despite early recognition of HBVr and initiation of appropriate therapy, some patients can progress to hepatic decompensation and even fulminant hepatic failure that may have been prevented with prophylaxis.

Continue to: The justification for universal screening

Although nongastroenterology societies differ in their recommendations on screening for HBV, universal screening before implementing prolonged immunosuppressive treatment is recommended by the CDC,⁶ the American Association for the Study of Liver Diseases,¹⁸ the Asian Pacific Association for the Study of the Liver,¹⁹ the European Association for the Study of the Liver,²⁰ and the American Gastroenterological Association (AGA).²¹

Older guidelines recommended screening only high-risk populations. But such screening has downfalls. It requires that patients or their physicians recognize that they are at high risk. In one study, nearly 65% of an infected Asian-American population was unaware of their positive HBV status.²² Risk-based screening also requires that physicians ask the appropriate questions and that patients admit to high-risk behavior. Screening patients based only on risk factors may easily overlook patients who need prophylaxis against HBVr.

Common arguments against universal screening include the cost of testing, the possibility of false-positive results, and the implications of a new diagnosis of hepatitis B. However, the potential benefits of screening are significant, and HBV screening in the general population has been shown to be cost effective when the prevalence of HBV is 0.3%.²¹ In the United States, conservative estimates are a prevalence of HBsAg positivity of 0.4% and past infection of 3%, making screening a cost-effective recommendation.¹⁶ It is therefore prudent to screen all patients before starting immunosuppressive therapy.

How to screen

All guidelines agree on how to test for HBV. Measuring levels of HBsAg and hepatitis B core antibody (anti-HBc total) allows the clinician to ascertain whether the patient’s HBV infection status is acute, chronic, or resolved (TABLE 2²³) and to perform HBVr risk stratification (discussed later).

Patients with acute infections should be referred to a hepatologist. With chronic or resolved HBV, stratify patients into a prophylaxis group or monitoring group (FIGURE¹⁴). Stratification involves identifying HBV status (chronic or resolved) and selecting a type of immunosuppressive therapy. Whether the patient falls into prophylaxis or monitoring, obtain a baseline level of viral DNA, as this has proven to be the best predictor of HBV reactivation.¹⁶

Continue to: In screening, be sure the appropriate...

In screening, be sure the appropriate anti-HBc testing is covered. Common usage of the term anti-HBc may refer to immunoglobulin G (IgG) or immunoglobulin M (IgM)or total core antibody, containing both IgG and IgM. But in this context, accurate screening requires either total core antibody or anti-HBc IgG. Anti-IgM alone is inadequate. Many commercial laboratories offer acute hepatitis panels or hepatitis profiles (TABLE 3^24,25), and it is important to confirm that such order sets contain the tests necessary to allow for risk stratification.

Testing for hepatitis B surface antibody (anti-HBs) is not useful in screening. Although it was hypothesized that the presence of this antibody lowered risk, recent studies have proven no change in risk based on this value.²¹

How to assess HBVr risk

Assessing risk for HBVr takes into account both the patient’s serology and intended treatment. Reddy et al delineated patient groups into high, moderate, and low risk (TABLES 4 and 5).²¹ The high-risk group was defined by anticipated incidence of HBVr in > 10% of cases; the moderate-risk group had an anticipated incidence of 1% to 10%; and the low-risk group had an anticipated incidence of <1%.²¹ Evidence was strongest in the high-risk group.

Patients with CHB (HBsAg positive and anti-HBc positive) are considered high risk for reactivation with a wide variety of immunosuppressive therapies. Such patients are 5 to 8 times more likely to develop HBVr than patients with an HBsAg-negative status signifying a resolved infection.¹⁶

Immunosuppressive agents and associated risks. The AGA guidelines consider treatment with B-cell-depleting agents, such as rituximab and ofatumumab, to be high risk, regardless of a patient’s surface antigen status. Additionally, for patients who are HBsAg positive, high-risk treatments include anthracycline derivatives, such as doxorubicin and epirubicin, or high- or moderate-dose steroids. These treatments are considered moderate risk when used in patients who have resolved HBV infection (HBsAg negative/anti-HBc positive). Moderate-risk modalities also include tumor necrosis factor inhibitors and tyrosine kinase inhibitors, regardless of surface antigen status; and low-dose steroids or cytokine or integrin inhibitors in HbsAg-positive individuals.²¹

Continue to: Other immunosuppression modalities...

Other immunosuppression modalities considered to be moderate risk independent of HBV serology include proteasome inhibitors, such as bortezomib, used for multiple myeloma treatment, and histone deacetylase inhibitors, such as romidepsin, used to treat T-cell lymphoma.¹³ Low-dose steroids or cytokine or integrin inhibitors are considered to be low risk in surface antigen-negative individuals; azathioprine, mercaptopurine, or methotrexate are low risk regardless of HBsAg status.²¹ Intra-articular steroid injections are considered extremely low risk in HbsAg-positive individuals, and are unclassified for HbsAg-negative individuals.¹³

More recent evidence has implicated other medication classes in triggering HBVr — (eg, direct-acting antivirals.)²⁶

Prophylaxis options: High to moderate risk vs low risk

The consensus of major guideline issuers is to offer prophylaxis to high-risk patients and to monitor low-risk patients. The AGA additionally recommends prophylaxis for patients at moderate risk.

Controversy surrounding the moderate-risk group. Some authors argue that monitoring HBV DNA in the moderate-risk group is preferable to committing patients to long periods of prophylaxis, and that rescue treatment could be initiated as needed. However, the ideal monitoring period has not been determined, and the effectiveness of prophylaxis over monitoring is so significant that monitoring is losing favor.

Perrillo et al performed a meta-analysis of 5 randomized controlled trials evaluating antiviral agents vs no prophylaxis.¹⁶ The analysis included 139 patients receiving prophylaxis and 137 controls. The pooled results demonstrated an 87% relative risk reduction with prophylaxis, supporting the trend toward treating patients with moderate risk.¹⁶

Continue to: Prophylactic treatment options are safe...

Prophylactic treatment options are safe and well tolerated. For this reason, committing a high- or moderate-risk patient to a course of treatment should be less of a concern than the risk for HBVr.

A recent meta-analysis demonstrated that tenofovir and entecavir are preferable to lamivudine in preventing HBVr.

In the early randomized controlled trials for HBVr prophylaxis, lamivudine, although effective, unfortunately led to a high incidence of viral resistance after prolonged use, thus diminishing its desirability.¹⁸ Newer agents, such as entecavir and tenofovir, have proven just as effective as lamivudine and are largely unaffected by viral resistance.²⁷

In retrospective and prospective studies on HBVr prophylaxis, patients treated with entecavir had less HBV-related hepatitis, less delay in chemotherapy, and a lower rate of HBVr when compared with lamivudine.^28,29 Tenofovir is recommended, however, if patients were previously treated with lamivudine.³⁰

A recent meta-analysis demonstrated that tenofovir and entecavir are preferable to lamivudine in preventing HBVr.³¹

Looking ahead

Screening for HBsAg and anti-HBc total before starting immunosuppressive therapy can reduce morbidity and mortality in patients undergoing such treatment. The AGA recommends screening all patients about to begin high- or moderate-risk therapy or patients in populations with a prevalence of CHB ≥2%, per the CDC.^6,21

Continue to: Classes of medications...

Classes of medications other than immunosuppressants may also trigger HBVr. The FDA has issued a warning regarding direct-acting antivirals, but optimal management of these patients is still evolving.

Once HBV status is established, a patient’s risk for HBVr can be specified as high, moderate, or low using their HBV status and the type of therapy being initiated. The AGA recommends prophylactic treatment with well-tolerated and effective agents for patients classified as high or moderate risk. If a patient’s risk is low, regular monitoring of HBV DNA and AST and ALT levels is sufficient. Recommendations of monitoring intervals span from monthly to every 3 months.^13,14

CASE Given the patient’s status of resolved HBV infection and her current moderate-dose regimen of prednisone, her risk for HBV reactivation is moderate. She could either receive antiviral prophylaxis or undergo regular monitoring. Following a discussion of the options, she opts for referral to a hepatologist to discuss possible prophylactic treatment.

Increased awareness of HBVr risk associated with immunosuppressive therapy, coupled with a planned approach to appropriate screening and risk stratification, can help health care providers prevent the reactivation of HBV or initiate early intervention for CHB.

CORRESPONDENCE
Ronan Farrell, MD, Rhode Island Hospital, 593 Eddy Street, Providence, RI 02903; [email protected].