SCOTTSDALE, ARIZ. – Psoriasis of all severities was linked to a 3.5-fold increase in risk of cutaneous T-cell lymphoma, and severe psoriasis upped the associated risk of Hodgkin lymphoma by about 2.5 times, in a large, longitudinal, population-based cohort study.

Psoriasis also was tied to a smaller but statistically significant increase in the risk of non-Hodgkin lymphoma, said Zelma Chiesa Fuxench, MD, of the department of dermatology, the University of Pennsylvania, Philadelphia. Overall, lymphoma risk was highest in people with severe psoriasis, independent of traditional risk factors and exposure to immunosuppressive medications, Dr. Fuxench said at the annual meeting of the Society for Investigative Dermatology.

Courtesy of the Centers for Disease Control and Prevention (CDC)

Psoriasis affects more than 125 million people worldwide, and severe cases are a major cause of cancer-related mortality. “Prior studies have suggested an increased risk of lymphoma in psoriasis patients, but it is unclear if this due to chronic inflammation, exposure to immunosuppressive therapies, or a combination of both factors,” Dr. Fuxench said.

To further explore these links, she and her associates analyzed electronic medical records from THIN (The Health Information Network), which includes about 12 million patients across the United Kingdom. Adults with psoriasis were matched to up to five nonpsoriatic controls based on date and clinic location. Patients who needed systemic medications or phototherapy were categorized as having severe psoriasis. The final dataset included more than 12,000 such patients, as well as 184,000 patients with mild psoriasis and more than 965,000 patients without psoriasis.

Psoriasis patients were younger and more likely to be overweight, male, and smoke and drink alcohol than patients without psoriasis, Dr. Fuxench said. Almost 80% of patients with severe disease had received systemic therapies, most often methotrexate (70% of systemic treatments) or cyclosporine (10%), while only 1% had received biologics.

Patients with severe psoriasis were more likely to be diagnosed with Hodgkin disease, non-Hodgkin lymphoma, and cutaneous T-cell lymphoma than were patients with mild psoriasis or controls. Over a median follow-up of 5.3 years, 34 patients with severe psoriasis were diagnosed with any type of lymphoma, for an incidence of 5.2 cases per 10,000 person-years (95% confidence interval, 3.7-7.3). In contrast, incidence rates for patients with mild psoriasis and controls were 3.3 and 3.2 cases per 10,000 person-years, respectively, Dr. Fuxench said.

In the multivariable analysis, patients with psoriasis were about 18% more likely to develop any type of lymphoma than were controls, an association that reached statistical significance (adjusted hazard ratio, 1.18; 95% CI, 1.06-1.31). Mild psoriasis increased lymphoma risk by 14%, and severe psoriasis upped it by about 83%, and both associations were statistically significant.

The increase in risk of non-Hodgkin lymphoma was 13% greater with mild psoriasis and 56% greater with severe disease, compared with controls, and these associations also reached statistical significance. Mild psoriasis was not linked to Hodgkin lymphoma, but patients with severe psoriasis were about 250% more likely to develop it than controls, with a trend toward statistical significance (aHR, 2.54; 95% CI, 0.94-6.87).

Finally, severe psoriasis was linked to a more than ninefold increase in risk of cutaneous T-cell lymphoma (aHR, 9.3; 95% CI, 4.1-21.4), while mild psoriasis was linked to about a threefold increase in risk.

“These results were robust in multiple sensitivity analyses, including analyses that excluded patients with rheumatoid arthritis, psoriatic arthritis, or a history of exposure to methotrexate, cyclosporine, or biologics,” Dr. Fuxench said. Future studies should explore the effect of treatment timing and selection on cancer risk, she added. “For those of us who care for these patients, we are increasingly using systemic agents that selectively target the immune system, and these questions will arise in clinics.”

The study’s design made it possible to pinpoint dates of diagnosis more effectively than investigators could estimate disease duration or confirm whether patients initially diagnosed with psoriasis actually had cutaneous T-cell lymphoma, Dr. Fuxench noted. “Ideally, we could have another cohort study of incident psoriasis with prospective follow-up, but lymphoma is so rare that there is currently not enough power [in the THIN database] to determine associations.”

The study was funded by grants from the National Institutes of Health and the National Institute of Arthritis and Musculoskeletal and Skin Diseases. Dr. Fuxench disclosed unrestricted research funding from Pfizer outside the submitted work.

SCOTTSDALE, ARIZ. – Psoriasis of all severities was linked to a 3.5-fold increase in risk of cutaneous T-cell lymphoma, and severe psoriasis upped the associated risk of Hodgkin lymphoma by about 2.5 times, in a large, longitudinal, population-based cohort study.

Psoriasis also was tied to a smaller but statistically significant increase in the risk of non-Hodgkin lymphoma, said Zelma Chiesa Fuxench, MD, of the department of dermatology, the University of Pennsylvania, Philadelphia. Overall, lymphoma risk was highest in people with severe psoriasis, independent of traditional risk factors and exposure to immunosuppressive medications, Dr. Fuxench said at the annual meeting of the Society for Investigative Dermatology.

Courtesy of the Centers for Disease Control and Prevention (CDC)

Psoriasis affects more than 125 million people worldwide, and severe cases are a major cause of cancer-related mortality. “Prior studies have suggested an increased risk of lymphoma in psoriasis patients, but it is unclear if this due to chronic inflammation, exposure to immunosuppressive therapies, or a combination of both factors,” Dr. Fuxench said.

To further explore these links, she and her associates analyzed electronic medical records from THIN (The Health Information Network), which includes about 12 million patients across the United Kingdom. Adults with psoriasis were matched to up to five nonpsoriatic controls based on date and clinic location. Patients who needed systemic medications or phototherapy were categorized as having severe psoriasis. The final dataset included more than 12,000 such patients, as well as 184,000 patients with mild psoriasis and more than 965,000 patients without psoriasis.

Psoriasis patients were younger and more likely to be overweight, male, and smoke and drink alcohol than patients without psoriasis, Dr. Fuxench said. Almost 80% of patients with severe disease had received systemic therapies, most often methotrexate (70% of systemic treatments) or cyclosporine (10%), while only 1% had received biologics.

Patients with severe psoriasis were more likely to be diagnosed with Hodgkin disease, non-Hodgkin lymphoma, and cutaneous T-cell lymphoma than were patients with mild psoriasis or controls. Over a median follow-up of 5.3 years, 34 patients with severe psoriasis were diagnosed with any type of lymphoma, for an incidence of 5.2 cases per 10,000 person-years (95% confidence interval, 3.7-7.3). In contrast, incidence rates for patients with mild psoriasis and controls were 3.3 and 3.2 cases per 10,000 person-years, respectively, Dr. Fuxench said.

In the multivariable analysis, patients with psoriasis were about 18% more likely to develop any type of lymphoma than were controls, an association that reached statistical significance (adjusted hazard ratio, 1.18; 95% CI, 1.06-1.31). Mild psoriasis increased lymphoma risk by 14%, and severe psoriasis upped it by about 83%, and both associations were statistically significant.

The increase in risk of non-Hodgkin lymphoma was 13% greater with mild psoriasis and 56% greater with severe disease, compared with controls, and these associations also reached statistical significance. Mild psoriasis was not linked to Hodgkin lymphoma, but patients with severe psoriasis were about 250% more likely to develop it than controls, with a trend toward statistical significance (aHR, 2.54; 95% CI, 0.94-6.87).

Finally, severe psoriasis was linked to a more than ninefold increase in risk of cutaneous T-cell lymphoma (aHR, 9.3; 95% CI, 4.1-21.4), while mild psoriasis was linked to about a threefold increase in risk.

“These results were robust in multiple sensitivity analyses, including analyses that excluded patients with rheumatoid arthritis, psoriatic arthritis, or a history of exposure to methotrexate, cyclosporine, or biologics,” Dr. Fuxench said. Future studies should explore the effect of treatment timing and selection on cancer risk, she added. “For those of us who care for these patients, we are increasingly using systemic agents that selectively target the immune system, and these questions will arise in clinics.”

The study’s design made it possible to pinpoint dates of diagnosis more effectively than investigators could estimate disease duration or confirm whether patients initially diagnosed with psoriasis actually had cutaneous T-cell lymphoma, Dr. Fuxench noted. “Ideally, we could have another cohort study of incident psoriasis with prospective follow-up, but lymphoma is so rare that there is currently not enough power [in the THIN database] to determine associations.”

The study was funded by grants from the National Institutes of Health and the National Institute of Arthritis and Musculoskeletal and Skin Diseases. Dr. Fuxench disclosed unrestricted research funding from Pfizer outside the submitted work.

SCOTTSDALE, ARIZ. – Psoriasis of all severities was linked to a 3.5-fold increase in risk of cutaneous T-cell lymphoma, and severe psoriasis upped the associated risk of Hodgkin lymphoma by about 2.5 times, in a large, longitudinal, population-based cohort study.

Psoriasis also was tied to a smaller but statistically significant increase in the risk of non-Hodgkin lymphoma, said Zelma Chiesa Fuxench, MD, of the department of dermatology, the University of Pennsylvania, Philadelphia. Overall, lymphoma risk was highest in people with severe psoriasis, independent of traditional risk factors and exposure to immunosuppressive medications, Dr. Fuxench said at the annual meeting of the Society for Investigative Dermatology.

Courtesy of the Centers for Disease Control and Prevention (CDC)

Psoriasis affects more than 125 million people worldwide, and severe cases are a major cause of cancer-related mortality. “Prior studies have suggested an increased risk of lymphoma in psoriasis patients, but it is unclear if this due to chronic inflammation, exposure to immunosuppressive therapies, or a combination of both factors,” Dr. Fuxench said.

To further explore these links, she and her associates analyzed electronic medical records from THIN (The Health Information Network), which includes about 12 million patients across the United Kingdom. Adults with psoriasis were matched to up to five nonpsoriatic controls based on date and clinic location. Patients who needed systemic medications or phototherapy were categorized as having severe psoriasis. The final dataset included more than 12,000 such patients, as well as 184,000 patients with mild psoriasis and more than 965,000 patients without psoriasis.

Psoriasis patients were younger and more likely to be overweight, male, and smoke and drink alcohol than patients without psoriasis, Dr. Fuxench said. Almost 80% of patients with severe disease had received systemic therapies, most often methotrexate (70% of systemic treatments) or cyclosporine (10%), while only 1% had received biologics.

Patients with severe psoriasis were more likely to be diagnosed with Hodgkin disease, non-Hodgkin lymphoma, and cutaneous T-cell lymphoma than were patients with mild psoriasis or controls. Over a median follow-up of 5.3 years, 34 patients with severe psoriasis were diagnosed with any type of lymphoma, for an incidence of 5.2 cases per 10,000 person-years (95% confidence interval, 3.7-7.3). In contrast, incidence rates for patients with mild psoriasis and controls were 3.3 and 3.2 cases per 10,000 person-years, respectively, Dr. Fuxench said.

In the multivariable analysis, patients with psoriasis were about 18% more likely to develop any type of lymphoma than were controls, an association that reached statistical significance (adjusted hazard ratio, 1.18; 95% CI, 1.06-1.31). Mild psoriasis increased lymphoma risk by 14%, and severe psoriasis upped it by about 83%, and both associations were statistically significant.

The increase in risk of non-Hodgkin lymphoma was 13% greater with mild psoriasis and 56% greater with severe disease, compared with controls, and these associations also reached statistical significance. Mild psoriasis was not linked to Hodgkin lymphoma, but patients with severe psoriasis were about 250% more likely to develop it than controls, with a trend toward statistical significance (aHR, 2.54; 95% CI, 0.94-6.87).

Finally, severe psoriasis was linked to a more than ninefold increase in risk of cutaneous T-cell lymphoma (aHR, 9.3; 95% CI, 4.1-21.4), while mild psoriasis was linked to about a threefold increase in risk.

“These results were robust in multiple sensitivity analyses, including analyses that excluded patients with rheumatoid arthritis, psoriatic arthritis, or a history of exposure to methotrexate, cyclosporine, or biologics,” Dr. Fuxench said. Future studies should explore the effect of treatment timing and selection on cancer risk, she added. “For those of us who care for these patients, we are increasingly using systemic agents that selectively target the immune system, and these questions will arise in clinics.”

The study’s design made it possible to pinpoint dates of diagnosis more effectively than investigators could estimate disease duration or confirm whether patients initially diagnosed with psoriasis actually had cutaneous T-cell lymphoma, Dr. Fuxench noted. “Ideally, we could have another cohort study of incident psoriasis with prospective follow-up, but lymphoma is so rare that there is currently not enough power [in the THIN database] to determine associations.”

The study was funded by grants from the National Institutes of Health and the National Institute of Arthritis and Musculoskeletal and Skin Diseases. Dr. Fuxench disclosed unrestricted research funding from Pfizer outside the submitted work.

DENVER – Pregnant women with sleep apnea are more likely to have planned obstetric interventions, results of an Australian population-based cohort study suggest.

The study included all 636,227 in-hospital births during 2002-2012 in New South Wales, Australia’s most populous state. Maternal sleep apnea was also associated with increased rates of planned preterm birth, even though preterm birth is widely considered the greatest contributor to neonatal morbidity and mortality, Yu Sun Bin, PhD, said at the annual meeting of the Associated Professional Sleep Societies.

Bruce Jancin/Frontline Medical News

“Somewhere along the line, clinicians decided that the risks of preterm birth to the baby were outweighed by the risks to the mother of delivering at term,” said Dr. Bin of the University of Sydney.

She and her coinvestigators undertook this study because even though previous studies have linked maternal sleep apnea to increased risks of gestational diabetes and gestational hypertension, most of the prior studies were small, cross-sectional, and/or relied upon snoring as a proxy for sleep apnea, which many sleep specialists consider invalid.

The investigators compared maternal and infant outcomes for mothers with a documented diagnosis of sleep apnea – either central or obstructive – in the year before or during pregnancy with outcomes for mothers without that diagnosis.

There were 519 mothers with diagnosed sleep apnea, for a prevalence of 0.08%. That figure is low in light of other evidence, making it likely that the 635,708 women in the no-sleep-apnea group actually included a substantial number of mothers with undiagnosed sleep apnea. Thus, the investigators’ estimates of the adverse impacts of sleep apnea in pregnancy are “rather conservative,” according to Dr. Bin.

Australian women with sleep apnea were older and less healthy than mothers without sleep apnea were. They had higher baseline rates of obesity, preexisting diabetes, chronic hypertension, and were more likely to be smokers.

The incidence of pregnancy hypertension was 19.7% in the sleep apnea group and 8.7% in controls. In a multivariate regression analysis adjusted for potential confounders, the maternal sleep apnea group had a 40% greater risk of developing hypertension than did controls. However, contrary to previous smaller studies, they did not have a significantly increased rate of gestational diabetes.

Even after controlling for both pregnancy hypertension and gestational diabetes, the sleep apnea group still had a significant 15% increase in the relative likelihood of a planned delivery.

The rate of preterm birth at 36 weeks or earlier was 14.5% in the maternal sleep apnea group, compared with 6.9% in controls, for an adjusted 1.5-fold increased relative risk.

Perinatal death occurred in 1.9% of the sleep apnea group and 0.9% of controls; however, the resultant adjusted 1.73-fold increased risk didn’t attain statistical significance because of the small number of deaths in the study. Dr. Bin said she and her colleagues plan to further investigate this signal to learn whether it is real or an artifact of small numbers.

The incidence of 5-minute Apgar scores below 7 was 4.6% in the sleep apnea group, compared with 2.4% in controls, for an adjusted 1.6-fold increased risk. The rate of neonatal intensive care unit admission in the sleep apnea group was 27.9%, versus 16% in controls, for a 1.61-fold increased relative risk.

The NICU admission rate for preterm infants didn’t differ between the two groups. The difference occurred in term babies, whose NICU admission rate was 20.3% if they were in the sleep apnea group, but just 12.1% in the control group.

“This suggests that maternal sleep apnea is contributing to some condition in the baby that requires additional support,” Dr. Bin observed.

The nature of that condition, however, remains unclear, since all patient data available to the investigators was deidentified.

The incidence of small-for-gestational-age babies was similar in the sleep apnea and control groups. In contrast, the large-for-gestational-age rate was 15.2% in the sleep apnea group, compared with 9.1% in controls, for an adjusted 1.27-fold increased risk.

The two main limitations of the Australian study were the likely underdiagnosis of sleep apnea and the lack of any information on treatment of affected patients, according to Dr. Bin. A key unresolved question, she added, is whether interventions for maternal sleep apnea reduce the risks identified in the New South Wales study. She noted that one 16-patient randomized study of nasal continuous positive airway pressure suggests the answer is yes (Sleep Med. 2007 Dec;9:15-21).

The Australian National Health and Medical Research Council supported the study. Dr. Bin reported having no financial conflicts.

[email protected]

DENVER – Pregnant women with sleep apnea are more likely to have planned obstetric interventions, results of an Australian population-based cohort study suggest.

The study included all 636,227 in-hospital births during 2002-2012 in New South Wales, Australia’s most populous state. Maternal sleep apnea was also associated with increased rates of planned preterm birth, even though preterm birth is widely considered the greatest contributor to neonatal morbidity and mortality, Yu Sun Bin, PhD, said at the annual meeting of the Associated Professional Sleep Societies.

Bruce Jancin/Frontline Medical News

“Somewhere along the line, clinicians decided that the risks of preterm birth to the baby were outweighed by the risks to the mother of delivering at term,” said Dr. Bin of the University of Sydney.

She and her coinvestigators undertook this study because even though previous studies have linked maternal sleep apnea to increased risks of gestational diabetes and gestational hypertension, most of the prior studies were small, cross-sectional, and/or relied upon snoring as a proxy for sleep apnea, which many sleep specialists consider invalid.

The investigators compared maternal and infant outcomes for mothers with a documented diagnosis of sleep apnea – either central or obstructive – in the year before or during pregnancy with outcomes for mothers without that diagnosis.

There were 519 mothers with diagnosed sleep apnea, for a prevalence of 0.08%. That figure is low in light of other evidence, making it likely that the 635,708 women in the no-sleep-apnea group actually included a substantial number of mothers with undiagnosed sleep apnea. Thus, the investigators’ estimates of the adverse impacts of sleep apnea in pregnancy are “rather conservative,” according to Dr. Bin.

Australian women with sleep apnea were older and less healthy than mothers without sleep apnea were. They had higher baseline rates of obesity, preexisting diabetes, chronic hypertension, and were more likely to be smokers.

The incidence of pregnancy hypertension was 19.7% in the sleep apnea group and 8.7% in controls. In a multivariate regression analysis adjusted for potential confounders, the maternal sleep apnea group had a 40% greater risk of developing hypertension than did controls. However, contrary to previous smaller studies, they did not have a significantly increased rate of gestational diabetes.

Even after controlling for both pregnancy hypertension and gestational diabetes, the sleep apnea group still had a significant 15% increase in the relative likelihood of a planned delivery.

The rate of preterm birth at 36 weeks or earlier was 14.5% in the maternal sleep apnea group, compared with 6.9% in controls, for an adjusted 1.5-fold increased relative risk.

Perinatal death occurred in 1.9% of the sleep apnea group and 0.9% of controls; however, the resultant adjusted 1.73-fold increased risk didn’t attain statistical significance because of the small number of deaths in the study. Dr. Bin said she and her colleagues plan to further investigate this signal to learn whether it is real or an artifact of small numbers.

The incidence of 5-minute Apgar scores below 7 was 4.6% in the sleep apnea group, compared with 2.4% in controls, for an adjusted 1.6-fold increased risk. The rate of neonatal intensive care unit admission in the sleep apnea group was 27.9%, versus 16% in controls, for a 1.61-fold increased relative risk.

The NICU admission rate for preterm infants didn’t differ between the two groups. The difference occurred in term babies, whose NICU admission rate was 20.3% if they were in the sleep apnea group, but just 12.1% in the control group.

“This suggests that maternal sleep apnea is contributing to some condition in the baby that requires additional support,” Dr. Bin observed.

The nature of that condition, however, remains unclear, since all patient data available to the investigators was deidentified.

The incidence of small-for-gestational-age babies was similar in the sleep apnea and control groups. In contrast, the large-for-gestational-age rate was 15.2% in the sleep apnea group, compared with 9.1% in controls, for an adjusted 1.27-fold increased risk.

The two main limitations of the Australian study were the likely underdiagnosis of sleep apnea and the lack of any information on treatment of affected patients, according to Dr. Bin. A key unresolved question, she added, is whether interventions for maternal sleep apnea reduce the risks identified in the New South Wales study. She noted that one 16-patient randomized study of nasal continuous positive airway pressure suggests the answer is yes (Sleep Med. 2007 Dec;9:15-21).

The Australian National Health and Medical Research Council supported the study. Dr. Bin reported having no financial conflicts.

[email protected]

DENVER – Pregnant women with sleep apnea are more likely to have planned obstetric interventions, results of an Australian population-based cohort study suggest.

The study included all 636,227 in-hospital births during 2002-2012 in New South Wales, Australia’s most populous state. Maternal sleep apnea was also associated with increased rates of planned preterm birth, even though preterm birth is widely considered the greatest contributor to neonatal morbidity and mortality, Yu Sun Bin, PhD, said at the annual meeting of the Associated Professional Sleep Societies.

Bruce Jancin/Frontline Medical News

“Somewhere along the line, clinicians decided that the risks of preterm birth to the baby were outweighed by the risks to the mother of delivering at term,” said Dr. Bin of the University of Sydney.

She and her coinvestigators undertook this study because even though previous studies have linked maternal sleep apnea to increased risks of gestational diabetes and gestational hypertension, most of the prior studies were small, cross-sectional, and/or relied upon snoring as a proxy for sleep apnea, which many sleep specialists consider invalid.

The investigators compared maternal and infant outcomes for mothers with a documented diagnosis of sleep apnea – either central or obstructive – in the year before or during pregnancy with outcomes for mothers without that diagnosis.

There were 519 mothers with diagnosed sleep apnea, for a prevalence of 0.08%. That figure is low in light of other evidence, making it likely that the 635,708 women in the no-sleep-apnea group actually included a substantial number of mothers with undiagnosed sleep apnea. Thus, the investigators’ estimates of the adverse impacts of sleep apnea in pregnancy are “rather conservative,” according to Dr. Bin.

Australian women with sleep apnea were older and less healthy than mothers without sleep apnea were. They had higher baseline rates of obesity, preexisting diabetes, chronic hypertension, and were more likely to be smokers.

The incidence of pregnancy hypertension was 19.7% in the sleep apnea group and 8.7% in controls. In a multivariate regression analysis adjusted for potential confounders, the maternal sleep apnea group had a 40% greater risk of developing hypertension than did controls. However, contrary to previous smaller studies, they did not have a significantly increased rate of gestational diabetes.

Even after controlling for both pregnancy hypertension and gestational diabetes, the sleep apnea group still had a significant 15% increase in the relative likelihood of a planned delivery.

The rate of preterm birth at 36 weeks or earlier was 14.5% in the maternal sleep apnea group, compared with 6.9% in controls, for an adjusted 1.5-fold increased relative risk.

Perinatal death occurred in 1.9% of the sleep apnea group and 0.9% of controls; however, the resultant adjusted 1.73-fold increased risk didn’t attain statistical significance because of the small number of deaths in the study. Dr. Bin said she and her colleagues plan to further investigate this signal to learn whether it is real or an artifact of small numbers.

The incidence of 5-minute Apgar scores below 7 was 4.6% in the sleep apnea group, compared with 2.4% in controls, for an adjusted 1.6-fold increased risk. The rate of neonatal intensive care unit admission in the sleep apnea group was 27.9%, versus 16% in controls, for a 1.61-fold increased relative risk.

The NICU admission rate for preterm infants didn’t differ between the two groups. The difference occurred in term babies, whose NICU admission rate was 20.3% if they were in the sleep apnea group, but just 12.1% in the control group.

“This suggests that maternal sleep apnea is contributing to some condition in the baby that requires additional support,” Dr. Bin observed.

The nature of that condition, however, remains unclear, since all patient data available to the investigators was deidentified.

The incidence of small-for-gestational-age babies was similar in the sleep apnea and control groups. In contrast, the large-for-gestational-age rate was 15.2% in the sleep apnea group, compared with 9.1% in controls, for an adjusted 1.27-fold increased risk.

The two main limitations of the Australian study were the likely underdiagnosis of sleep apnea and the lack of any information on treatment of affected patients, according to Dr. Bin. A key unresolved question, she added, is whether interventions for maternal sleep apnea reduce the risks identified in the New South Wales study. She noted that one 16-patient randomized study of nasal continuous positive airway pressure suggests the answer is yes (Sleep Med. 2007 Dec;9:15-21).

The Australian National Health and Medical Research Council supported the study. Dr. Bin reported having no financial conflicts.

[email protected]

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From the Department of Family and Community Medicine, University of California San Francisco, San Francisco, CA (Ms. Willard-Grace, Dr. Sharma, Dr. Potter) and the California Primary Care Association, Sacramento, CA (Ms. Parker).

Abstract

• Objective: To explore how community health centers engage patients in practice improvement and factors associated with patient involvement on clinic-level strategies, policies, and programs.
• Methods: Cross-sectional web-based survey of community health centers in California, Arizona, Nevada, and Hawaii (n = 97).
• Results: The most common mechanisms used by community health centers to obtain patient feedback were surveys (94%; 91/97) and advisory councils (69%; 67/97). Patient-centered medical home recognition and dedicated funding for patient engagement activities were not associated with reported patient influence on the clinic’s strategic goals, policies, or programs. When other factors were controlled for in multivariable modeling, leadership support (β = 0.31, 95% confidence interval [CI] 0.10–0.53) and having a formal strategy to identify and engage patients as advisors (β = 0.17, 95% CI 0.02–0.31) were positively associated with patient influence on strategic goals. Having a formal strategy to identify and engage patients also was associated with patient impact on polices and programss (β = 0.17, 95% CI 0.01–0.34). The clinic process of setting aside time to discuss patient feedback appeared to be a mechanism by which formal patient engagement strategies resulted in patients having an impact on practice improvement activities (β = 0.35, 95% CI 0.17–0.54 for influence on strategic goals and β = 0.44, 95% CI 0.23–0.65 for influence on policies and programs).
• Conclusion: These findings may provide guidance for primary care practices that wish to engage patients in practice improvement. The relatively simple steps of developing a formal strategy to identify and engage patients and setting aside time in meetings to discuss patient feedback appear to be important prerequisites for success in these activities.

Patient engagement is becoming an increasingly prominent concept within primary care redesign. Called the “next blockbuster drug of the century” and the “holy grail” of health care [1,2], patient engagement has become a key goal for funders such as the Patient-Centered Outcomes Research Institute [3] and accrediting agencies such as the National Committee for Quality Assurance (NCQA).

Patient engagement has been defined as patients working in active partnership at various levels across the health care system to improve health and health care [1]. It can be conceptualized as occurring at 3 levels: at the level of direct care (eg, a clinical encounter), at the level of organizational design and governance, and at the level of policy making [1]. For example, engagement at the level of direct care might involve a patient working with her care team to identify a treatment option that matches her values and preferences. At the level of the health care organization, a patient might provide feedback through a survey or serve on a patient advisory council to improve clinic operations. Patients engaged at the level of policy making might share their opinions with their elected representatives or sit on a national committee. Although research has examined engagement at the direct care level, for example, in studies of shared decision making, there is a paucity of research addressing the impact of patient engagement on clinic-level organizational redesign and practice improvement [4,5].

Relatively few studies describe what primary care practice teams are currently doing at the basic level of soliciting and acting on patient input on the way that their care is delivered. A survey of 112 NCQA-certified patient-centered medical home (PCMH) practices found that 78% conducted patient surveys, 63% gathered qualitative input through focus groups or other feedback, 52% provided a suggestion box, and 32% included patients on advisory councils or teams [6]. Fewer than one-third of PCMH-certified practices were engaging patients or families in more intensive roles as ongoing advisors on practice design or practice improvement [6]. Randomized controlled trials have shown that patient involvement in developing informational materials results in more readable and relevant information [7]. Patient and family involvement in identifying organizational priorities within clinical practice settings resulted in greater alignment with the chronic care model and the PCMH when compared with control groups and resulted in greater agreement between patients and health care professionals [4]. Moreover, a number of innovative health care organizations credit their success in transformation to their patient partnerships [8–10].

Within this context, current practices at community health centers (CHCs) are of particular interest. CHCs are not-for-profit organizations that deliver primary and preventive care to more than 22 million people in the United States [11]. A large proportion of their patients are poor and live in medically underserved communities. More than one-third (37.5%) of CHC patients are uninsured and 38.5% are on Medicaid [12]. Perhaps because of their commitment to caring for medically vulnerable populations that have often had difficulty obtaining needed medical services, some CHCs have been on the forefront of patient engagement [8]. In addition, many CHCs are federally qualified health care centers, which are mandated to engage members of their communities within their governing boards [13]. However, relatively little is known about how CHCs are engaging patients as practice improvement partners or the perceived impact of this engagement on CHC strategic goals, policies, and programs. This study explores these factors and examines the organizational characteristics and processes associated with patients having an impact on practice improvement activities.

Methods

We conducted a cross-sectional, web-based survey of primary care clinician and staff leaders at CHCs in July–August 2014 to assess current strategies, attitudes, facilitators, and barriers toward engaging patients in practice improvement efforts. The study protocol was developed jointly by the San Francisco Bay Area Collaborative Research Network (SFBayCRN), the University of California San Francisco Center for Excellence in Primary Care (CEPC), and the Western Clinicians Network (WCN). The protocol was reviewed by the University of California San Francisco Committee on Human Research and determined to be exempt research (study number 14-13662).

Survey Participants

Participants in the web-based survey were members of the WCN, a peer-led, volunteer, membership-based association of medical leaders of community health centers in California, Arizona, Nevada, and Hawaii. An invitation and link to a web-based survey was sent by email to members working at WCN CHC, who received up to 3 reminders to complete the survey. We allowed one response per CHC surveyed; in cases where more than one CHC leader was a member of WCN, we requested that the person most familiar with patient engagement activities respond to the survey. In the event of multiple respondents from an organization, incomplete responses were dropped and one complete response was randomly selected to represent the organization. Participants in the survey were entered into a drawing for ten $50 gift cards and one iPad.

Conceptual Model

Measures

The primary outcomes of interest were respondents’ perception of patient impact on strategic priorities, policies, and programs. These outcomes were measured by 2 items: “Patient input helps shape strategic goals or priorities” and “Patient feedback has resulted in policy or program changes at our clinic.” Responses were measured on a 5-item Likert scale (1 = Strongly Disagree to 5 = Strongly Agree). Leadership support was measured using a single item that stated, “Our clinic leadership would like to find more ways to involve patients in practice improvement.” Having a formal strategy was measured using a single item that stated, “We have a formal strategy for how we recruit patients to serve in an advisory capacity.” Clinic processes included having dedicated time in meetings to discuss patient input, as measured by the item, “We dedicate time at team meetings to discuss patient feedback and recommendations.”

In addition to the 10 Likert-type items that captured attitudes, beliefs, and practices, we also  asked participants to endorse strategies they used to obtain feedback and suggestions from patients (checklist of options including advisory councils, surveys, suggestion box, etc.). In addition, we assessed practice characteristics such as PCMH recognition status (not applying; in process of applying; received recognition), size of practice (< 5; 5–10; > 10 FTE clinicians), and having dedicated funding such as grant support to pay for patient engagement activities (yes; no).

Data Analysis

Data was analyzed in Stata version 13.0 (College Station, TX). Means and frequencies were used to characterize the sample. Stepwise multivariate modeling was used to identify factors associated with patient engagement outcomes. Organizational characteristics (size of the practice, PCMH recognition status, dedicated funding, leadership support, and having a formal strategy) were included as potential independent variables in Step 1 of the model for each of the 2 hypothesized patient engagement outcomes. Because we theorized that it might be a factor associated with the outcomes that was in turn influenced by clinic characteristics, the process of allocating dedicated time in team meetings to discuss and consider actions to take in response to patient feedback was included as a predictor in Step 2 of each model. Survey items that were not answered were treated as missing data (not imputed). We tested for multiple collinearity using variance influence factors.

Results

The most common mechanisms for receiving patient feedback were surveys (94% of respondents; 91/97) and suggestion boxes (57%; 55/97; Table 1). A third of respondents reported soliciting patient feedback on information materials (33%; 32/97), and almost a third involved patients in selecting referral resources (28%; 27/97). As for ongoing participation, 69% (67/97) of respondents reported involving patients on advisory boards or councils, and 36% (35/97) invited patients to take part in quality improvement committees. Other common activities included inviting patients to conferences or workshops (30%; 29/97) and asking patients to lead self-management or support groups (29%; 28/97).

Most respondents (82%; 77/93) agreed or strongly agreed that patient engagement was worth the time it required. About a third (35%; 32/92) reported having a formal strategy for recruiting and engaging patients in an advisory capacity. About half (52%; 49/94) reported setting aside time in team meetings to discuss patient feedback, although fewer (39%; 35/89) reported that their front line staff met regularly with patients to discuss clinic services and programs. Two-thirds of respondents (68%; 64/94) reported that their leadership would like to find more active ways to involve patients in practice improvement. Less than half (44%; 39/89) felt that they were successful at engaging patient advisors who represented the diversity of the population served. When considering downsides of patient engagement, few agreed that revealing the workings of the clinics to patients would expose the clinic to too much risk (8%; 7/89) or that patients would make unrealistic requests if asked their opinions (14%; 12/89).

Discussion

Among the CHCs surveyed, we found that having a formal strategy for recruiting and engaging patients in practice improvement efforts was associated with patient input shaping strategic goals, programs, and policies. Devoting time in staff team meetings to discuss feedback from patients, such as that received through advisory councils or patient surveys, appeared to be the mechanism by which having a formal strategy for engaging patients influenced the outcomes. Leadership support for patient engagement was also associated with patient input in strategic goals. In contrast, anticipated predictors such as PCMH recognition status, the size of a practice, and having dedicated funding for patient engagement were not associated with these outcomes.

This is the first study known to the authors that examines factors associated with patient engagement outcomes such as patient involvement in clinic-level strategies, policies, and programs. The finding that having a formal process for recruiting and engaging patients and devoting time in team meetings to discuss patient input are significantly associated with patient engagement outcomes is encouraging, because it suggests relatively practical and straightforward actions for primary care leaders interested in engaging patients productively in practice improvement.

The level of patient engagement reported by these respondents is higher than that reported by some other studies. For example, 65% of respondents in this study reported conducting patient surveys and involving patients in ongoing roles as patient advisors, compared to 29% in a 2013 study by Han and colleagues for 112 practices that had received PCMH recognition [6]. This could be partially explained by the fact that many CHCs are federally qualified health centers, which are mandated to have consumer members on their board of directors, and in many cases patient board members may be invited to participate actively in practice improvement. In this study, it is also interesting to note that more than 80% of respondents agreed with the statement that “engaging patients in practice improvement is worth the time and effort it takes,” suggesting that this is a group that valued and prioritized patient engagement.

A lack of time or resources to support patient engagement has been reported as a barrier to effective engagement [15], so it was surprising that having dedicated funding to support patient engagement was not associated with the study outcomes. Only 30% of CHC leaders reported having dedicated funding for patient engagement, while over 80% reported soliciting patient input through longitudinal, bidirectional activities such as committees or advisory councils. While financial support for this vital work is likely important to catalyze and sustain patient engagement at the practice level, it would appear many of the practices surveyed in this study are engaging their patients as partners in practice transformation despite a lack of dedicated resources.

The lack of association that we found between PCMH recognition status and patient influence on strategies, programs, and policies is corroborated by work by Han and colleagues [6], in which they found that the level of PCMH status was not associated with the degree of patient engagement in practice improvement and that only 32% of practices were engaging patients in ongoing roles as advisors.

Devoting time in team meetings to discussing patient feedback seemed to be the mechanism through with having a formal strategy for patient engagement predicted outcomes. Although it may seem self-evident that taking time to discuss patient input could make it more likely to affect clinic practices, we have observed through regular interaction with dozens of health centers that many have comment boxes set up but have no mechanism for systematically reviewing that feedback and considering it as a team. This is also borne out by our survey finding that fewer than 60% of sites that report conducting surveys or having suggestion boxes agree that they set aside time in team meetings to discuss the feedback gleaned from these sources. Thus, the results of this survey suggest that there are simple decisions and structures that may help to turn input from patients into clinic actions.

This study has several limitations. Causation cannot be inferred from this cross-sectional study; additional research is required to understand if helping clinics develop formal strategies for patient recruitment or set aside time in meetings to discuss patient feedback would lead to greater influence of patients on strategic goals, policies, and programs. Data were self-reported by a single person from each CHC, and although members of WCN typically represent clinic leaders who are actively engaged in PCMH-related activities, it is not clear if respondents were aware of the full range of patient engagement strategies used at their clinical site. Front-line clinicians and staff could provide a different perspective on patient engagement. There was no external validation of survey instrument statements regarding the impact of patient input on strategic goals, policies, or programs. The number of respondents (n = 97) is limited, but it is comparable to that in other existing studies [6]. The response rate for this survey was 21%, and respondents may have differed from non-respondents in important ways. When respondents of this study are compared to national samples reporting to the Uniform Data System, the proportion of CHCs with PCMH recognition is lower in our sample (52% versus 65%) [16]. The high level of patient engagement reported by CHC leaders in this study compared to other studies suggests that highly engaged practices may have been more likely to respond than those with lower levels of engagement with their patients. There may have been differences in how patient engagement and advisory roles were interpreted by respondents.

Conclusion

CHC leaders who reported a formal strategy for engaging patients in practice improvement and dedicated time to discuss patient input during team meetings were more likely to report patient input on policies, programs, and strategic goals. Developing a formal strategy to engage patients and establishing protected time on team agendas to discuss patient feedback may be practical ways to promote greater patient engagement in primary care transformation.

Acknowledgements: The authors wish to thank the leadership of Western Clinicians Network. A special thanks to Dr. Carl Heard, Dr. Mike Witte, Dr. Eric Henley, Dr. Kevin Grumbach, Dr. David Thom, Dr. Quynh Bui, Lucia Angel, and Dr. Thomas Bodenheimer for their feedback on survey and manuscript development. Valuable input on the survey questions were also received from the UCSF Lakeshore Family Medicine Center Patient Advisory Council, the San Francisco General Hospital Patient Advisory Council, and the Malden Family Health Center Patient Advisory Council. Finally, thanks to the community health centers who shared their time and experiences through our survey.

Corresponding author: Rachel Willard-Grace, MPH, Department of Family & Community Medicine, UCSF, 1001 Potrero Hill, Ward 83, Building 80, 3rd Fl, San Francisco, CA 94110, [email protected].

Funding/support: Internal departmental funding covered the direct costs of conducting this research. This project was also supported in part by the National Center for Advancing Translational Sciences, National Institutes of Health, through UCSF-CTSI Grant Number UL1 TR000004 which supported Dr. Potter’s time. Dr. Sharma received support from the UCSF primary care research fellowship funded by NRSA grant T32 HP19025. Contents of this manuscript are solely the responsibility of the authors and do not necessarily represent the official views of the NIH.

From the Department of Family and Community Medicine, University of California San Francisco, San Francisco, CA (Ms. Willard-Grace, Dr. Sharma, Dr. Potter) and the California Primary Care Association, Sacramento, CA (Ms. Parker).

Abstract

• Objective: To explore how community health centers engage patients in practice improvement and factors associated with patient involvement on clinic-level strategies, policies, and programs.
• Methods: Cross-sectional web-based survey of community health centers in California, Arizona, Nevada, and Hawaii (n = 97).
• Results: The most common mechanisms used by community health centers to obtain patient feedback were surveys (94%; 91/97) and advisory councils (69%; 67/97). Patient-centered medical home recognition and dedicated funding for patient engagement activities were not associated with reported patient influence on the clinic’s strategic goals, policies, or programs. When other factors were controlled for in multivariable modeling, leadership support (β = 0.31, 95% confidence interval [CI] 0.10–0.53) and having a formal strategy to identify and engage patients as advisors (β = 0.17, 95% CI 0.02–0.31) were positively associated with patient influence on strategic goals. Having a formal strategy to identify and engage patients also was associated with patient impact on polices and programss (β = 0.17, 95% CI 0.01–0.34). The clinic process of setting aside time to discuss patient feedback appeared to be a mechanism by which formal patient engagement strategies resulted in patients having an impact on practice improvement activities (β = 0.35, 95% CI 0.17–0.54 for influence on strategic goals and β = 0.44, 95% CI 0.23–0.65 for influence on policies and programs).
• Conclusion: These findings may provide guidance for primary care practices that wish to engage patients in practice improvement. The relatively simple steps of developing a formal strategy to identify and engage patients and setting aside time in meetings to discuss patient feedback appear to be important prerequisites for success in these activities.

Patient engagement is becoming an increasingly prominent concept within primary care redesign. Called the “next blockbuster drug of the century” and the “holy grail” of health care [1,2], patient engagement has become a key goal for funders such as the Patient-Centered Outcomes Research Institute [3] and accrediting agencies such as the National Committee for Quality Assurance (NCQA).

Patient engagement has been defined as patients working in active partnership at various levels across the health care system to improve health and health care [1]. It can be conceptualized as occurring at 3 levels: at the level of direct care (eg, a clinical encounter), at the level of organizational design and governance, and at the level of policy making [1]. For example, engagement at the level of direct care might involve a patient working with her care team to identify a treatment option that matches her values and preferences. At the level of the health care organization, a patient might provide feedback through a survey or serve on a patient advisory council to improve clinic operations. Patients engaged at the level of policy making might share their opinions with their elected representatives or sit on a national committee. Although research has examined engagement at the direct care level, for example, in studies of shared decision making, there is a paucity of research addressing the impact of patient engagement on clinic-level organizational redesign and practice improvement [4,5].

Relatively few studies describe what primary care practice teams are currently doing at the basic level of soliciting and acting on patient input on the way that their care is delivered. A survey of 112 NCQA-certified patient-centered medical home (PCMH) practices found that 78% conducted patient surveys, 63% gathered qualitative input through focus groups or other feedback, 52% provided a suggestion box, and 32% included patients on advisory councils or teams [6]. Fewer than one-third of PCMH-certified practices were engaging patients or families in more intensive roles as ongoing advisors on practice design or practice improvement [6]. Randomized controlled trials have shown that patient involvement in developing informational materials results in more readable and relevant information [7]. Patient and family involvement in identifying organizational priorities within clinical practice settings resulted in greater alignment with the chronic care model and the PCMH when compared with control groups and resulted in greater agreement between patients and health care professionals [4]. Moreover, a number of innovative health care organizations credit their success in transformation to their patient partnerships [8–10].

Within this context, current practices at community health centers (CHCs) are of particular interest. CHCs are not-for-profit organizations that deliver primary and preventive care to more than 22 million people in the United States [11]. A large proportion of their patients are poor and live in medically underserved communities. More than one-third (37.5%) of CHC patients are uninsured and 38.5% are on Medicaid [12]. Perhaps because of their commitment to caring for medically vulnerable populations that have often had difficulty obtaining needed medical services, some CHCs have been on the forefront of patient engagement [8]. In addition, many CHCs are federally qualified health care centers, which are mandated to engage members of their communities within their governing boards [13]. However, relatively little is known about how CHCs are engaging patients as practice improvement partners or the perceived impact of this engagement on CHC strategic goals, policies, and programs. This study explores these factors and examines the organizational characteristics and processes associated with patients having an impact on practice improvement activities.

Methods

We conducted a cross-sectional, web-based survey of primary care clinician and staff leaders at CHCs in July–August 2014 to assess current strategies, attitudes, facilitators, and barriers toward engaging patients in practice improvement efforts. The study protocol was developed jointly by the San Francisco Bay Area Collaborative Research Network (SFBayCRN), the University of California San Francisco Center for Excellence in Primary Care (CEPC), and the Western Clinicians Network (WCN). The protocol was reviewed by the University of California San Francisco Committee on Human Research and determined to be exempt research (study number 14-13662).

Survey Participants

Participants in the web-based survey were members of the WCN, a peer-led, volunteer, membership-based association of medical leaders of community health centers in California, Arizona, Nevada, and Hawaii. An invitation and link to a web-based survey was sent by email to members working at WCN CHC, who received up to 3 reminders to complete the survey. We allowed one response per CHC surveyed; in cases where more than one CHC leader was a member of WCN, we requested that the person most familiar with patient engagement activities respond to the survey. In the event of multiple respondents from an organization, incomplete responses were dropped and one complete response was randomly selected to represent the organization. Participants in the survey were entered into a drawing for ten $50 gift cards and one iPad.

Conceptual Model

Measures

The primary outcomes of interest were respondents’ perception of patient impact on strategic priorities, policies, and programs. These outcomes were measured by 2 items: “Patient input helps shape strategic goals or priorities” and “Patient feedback has resulted in policy or program changes at our clinic.” Responses were measured on a 5-item Likert scale (1 = Strongly Disagree to 5 = Strongly Agree). Leadership support was measured using a single item that stated, “Our clinic leadership would like to find more ways to involve patients in practice improvement.” Having a formal strategy was measured using a single item that stated, “We have a formal strategy for how we recruit patients to serve in an advisory capacity.” Clinic processes included having dedicated time in meetings to discuss patient input, as measured by the item, “We dedicate time at team meetings to discuss patient feedback and recommendations.”

In addition to the 10 Likert-type items that captured attitudes, beliefs, and practices, we also  asked participants to endorse strategies they used to obtain feedback and suggestions from patients (checklist of options including advisory councils, surveys, suggestion box, etc.). In addition, we assessed practice characteristics such as PCMH recognition status (not applying; in process of applying; received recognition), size of practice (< 5; 5–10; > 10 FTE clinicians), and having dedicated funding such as grant support to pay for patient engagement activities (yes; no).

Data Analysis

Data was analyzed in Stata version 13.0 (College Station, TX). Means and frequencies were used to characterize the sample. Stepwise multivariate modeling was used to identify factors associated with patient engagement outcomes. Organizational characteristics (size of the practice, PCMH recognition status, dedicated funding, leadership support, and having a formal strategy) were included as potential independent variables in Step 1 of the model for each of the 2 hypothesized patient engagement outcomes. Because we theorized that it might be a factor associated with the outcomes that was in turn influenced by clinic characteristics, the process of allocating dedicated time in team meetings to discuss and consider actions to take in response to patient feedback was included as a predictor in Step 2 of each model. Survey items that were not answered were treated as missing data (not imputed). We tested for multiple collinearity using variance influence factors.

Results

The most common mechanisms for receiving patient feedback were surveys (94% of respondents; 91/97) and suggestion boxes (57%; 55/97; Table 1). A third of respondents reported soliciting patient feedback on information materials (33%; 32/97), and almost a third involved patients in selecting referral resources (28%; 27/97). As for ongoing participation, 69% (67/97) of respondents reported involving patients on advisory boards or councils, and 36% (35/97) invited patients to take part in quality improvement committees. Other common activities included inviting patients to conferences or workshops (30%; 29/97) and asking patients to lead self-management or support groups (29%; 28/97).

Most respondents (82%; 77/93) agreed or strongly agreed that patient engagement was worth the time it required. About a third (35%; 32/92) reported having a formal strategy for recruiting and engaging patients in an advisory capacity. About half (52%; 49/94) reported setting aside time in team meetings to discuss patient feedback, although fewer (39%; 35/89) reported that their front line staff met regularly with patients to discuss clinic services and programs. Two-thirds of respondents (68%; 64/94) reported that their leadership would like to find more active ways to involve patients in practice improvement. Less than half (44%; 39/89) felt that they were successful at engaging patient advisors who represented the diversity of the population served. When considering downsides of patient engagement, few agreed that revealing the workings of the clinics to patients would expose the clinic to too much risk (8%; 7/89) or that patients would make unrealistic requests if asked their opinions (14%; 12/89).

Discussion

Among the CHCs surveyed, we found that having a formal strategy for recruiting and engaging patients in practice improvement efforts was associated with patient input shaping strategic goals, programs, and policies. Devoting time in staff team meetings to discuss feedback from patients, such as that received through advisory councils or patient surveys, appeared to be the mechanism by which having a formal strategy for engaging patients influenced the outcomes. Leadership support for patient engagement was also associated with patient input in strategic goals. In contrast, anticipated predictors such as PCMH recognition status, the size of a practice, and having dedicated funding for patient engagement were not associated with these outcomes.

This is the first study known to the authors that examines factors associated with patient engagement outcomes such as patient involvement in clinic-level strategies, policies, and programs. The finding that having a formal process for recruiting and engaging patients and devoting time in team meetings to discuss patient input are significantly associated with patient engagement outcomes is encouraging, because it suggests relatively practical and straightforward actions for primary care leaders interested in engaging patients productively in practice improvement.

The level of patient engagement reported by these respondents is higher than that reported by some other studies. For example, 65% of respondents in this study reported conducting patient surveys and involving patients in ongoing roles as patient advisors, compared to 29% in a 2013 study by Han and colleagues for 112 practices that had received PCMH recognition [6]. This could be partially explained by the fact that many CHCs are federally qualified health centers, which are mandated to have consumer members on their board of directors, and in many cases patient board members may be invited to participate actively in practice improvement. In this study, it is also interesting to note that more than 80% of respondents agreed with the statement that “engaging patients in practice improvement is worth the time and effort it takes,” suggesting that this is a group that valued and prioritized patient engagement.

A lack of time or resources to support patient engagement has been reported as a barrier to effective engagement [15], so it was surprising that having dedicated funding to support patient engagement was not associated with the study outcomes. Only 30% of CHC leaders reported having dedicated funding for patient engagement, while over 80% reported soliciting patient input through longitudinal, bidirectional activities such as committees or advisory councils. While financial support for this vital work is likely important to catalyze and sustain patient engagement at the practice level, it would appear many of the practices surveyed in this study are engaging their patients as partners in practice transformation despite a lack of dedicated resources.

The lack of association that we found between PCMH recognition status and patient influence on strategies, programs, and policies is corroborated by work by Han and colleagues [6], in which they found that the level of PCMH status was not associated with the degree of patient engagement in practice improvement and that only 32% of practices were engaging patients in ongoing roles as advisors.

Devoting time in team meetings to discussing patient feedback seemed to be the mechanism through with having a formal strategy for patient engagement predicted outcomes. Although it may seem self-evident that taking time to discuss patient input could make it more likely to affect clinic practices, we have observed through regular interaction with dozens of health centers that many have comment boxes set up but have no mechanism for systematically reviewing that feedback and considering it as a team. This is also borne out by our survey finding that fewer than 60% of sites that report conducting surveys or having suggestion boxes agree that they set aside time in team meetings to discuss the feedback gleaned from these sources. Thus, the results of this survey suggest that there are simple decisions and structures that may help to turn input from patients into clinic actions.

This study has several limitations. Causation cannot be inferred from this cross-sectional study; additional research is required to understand if helping clinics develop formal strategies for patient recruitment or set aside time in meetings to discuss patient feedback would lead to greater influence of patients on strategic goals, policies, and programs. Data were self-reported by a single person from each CHC, and although members of WCN typically represent clinic leaders who are actively engaged in PCMH-related activities, it is not clear if respondents were aware of the full range of patient engagement strategies used at their clinical site. Front-line clinicians and staff could provide a different perspective on patient engagement. There was no external validation of survey instrument statements regarding the impact of patient input on strategic goals, policies, or programs. The number of respondents (n = 97) is limited, but it is comparable to that in other existing studies [6]. The response rate for this survey was 21%, and respondents may have differed from non-respondents in important ways. When respondents of this study are compared to national samples reporting to the Uniform Data System, the proportion of CHCs with PCMH recognition is lower in our sample (52% versus 65%) [16]. The high level of patient engagement reported by CHC leaders in this study compared to other studies suggests that highly engaged practices may have been more likely to respond than those with lower levels of engagement with their patients. There may have been differences in how patient engagement and advisory roles were interpreted by respondents.

Conclusion

CHC leaders who reported a formal strategy for engaging patients in practice improvement and dedicated time to discuss patient input during team meetings were more likely to report patient input on policies, programs, and strategic goals. Developing a formal strategy to engage patients and establishing protected time on team agendas to discuss patient feedback may be practical ways to promote greater patient engagement in primary care transformation.

Acknowledgements: The authors wish to thank the leadership of Western Clinicians Network. A special thanks to Dr. Carl Heard, Dr. Mike Witte, Dr. Eric Henley, Dr. Kevin Grumbach, Dr. David Thom, Dr. Quynh Bui, Lucia Angel, and Dr. Thomas Bodenheimer for their feedback on survey and manuscript development. Valuable input on the survey questions were also received from the UCSF Lakeshore Family Medicine Center Patient Advisory Council, the San Francisco General Hospital Patient Advisory Council, and the Malden Family Health Center Patient Advisory Council. Finally, thanks to the community health centers who shared their time and experiences through our survey.

Corresponding author: Rachel Willard-Grace, MPH, Department of Family & Community Medicine, UCSF, 1001 Potrero Hill, Ward 83, Building 80, 3rd Fl, San Francisco, CA 94110, [email protected].

Funding/support: Internal departmental funding covered the direct costs of conducting this research. This project was also supported in part by the National Center for Advancing Translational Sciences, National Institutes of Health, through UCSF-CTSI Grant Number UL1 TR000004 which supported Dr. Potter’s time. Dr. Sharma received support from the UCSF primary care research fellowship funded by NRSA grant T32 HP19025. Contents of this manuscript are solely the responsibility of the authors and do not necessarily represent the official views of the NIH.

From the Department of Family and Community Medicine, University of California San Francisco, San Francisco, CA (Ms. Willard-Grace, Dr. Sharma, Dr. Potter) and the California Primary Care Association, Sacramento, CA (Ms. Parker).

Abstract

• Objective: To explore how community health centers engage patients in practice improvement and factors associated with patient involvement on clinic-level strategies, policies, and programs.
• Methods: Cross-sectional web-based survey of community health centers in California, Arizona, Nevada, and Hawaii (n = 97).
• Results: The most common mechanisms used by community health centers to obtain patient feedback were surveys (94%; 91/97) and advisory councils (69%; 67/97). Patient-centered medical home recognition and dedicated funding for patient engagement activities were not associated with reported patient influence on the clinic’s strategic goals, policies, or programs. When other factors were controlled for in multivariable modeling, leadership support (β = 0.31, 95% confidence interval [CI] 0.10–0.53) and having a formal strategy to identify and engage patients as advisors (β = 0.17, 95% CI 0.02–0.31) were positively associated with patient influence on strategic goals. Having a formal strategy to identify and engage patients also was associated with patient impact on polices and programss (β = 0.17, 95% CI 0.01–0.34). The clinic process of setting aside time to discuss patient feedback appeared to be a mechanism by which formal patient engagement strategies resulted in patients having an impact on practice improvement activities (β = 0.35, 95% CI 0.17–0.54 for influence on strategic goals and β = 0.44, 95% CI 0.23–0.65 for influence on policies and programs).
• Conclusion: These findings may provide guidance for primary care practices that wish to engage patients in practice improvement. The relatively simple steps of developing a formal strategy to identify and engage patients and setting aside time in meetings to discuss patient feedback appear to be important prerequisites for success in these activities.

Patient engagement is becoming an increasingly prominent concept within primary care redesign. Called the “next blockbuster drug of the century” and the “holy grail” of health care [1,2], patient engagement has become a key goal for funders such as the Patient-Centered Outcomes Research Institute [3] and accrediting agencies such as the National Committee for Quality Assurance (NCQA).

Patient engagement has been defined as patients working in active partnership at various levels across the health care system to improve health and health care [1]. It can be conceptualized as occurring at 3 levels: at the level of direct care (eg, a clinical encounter), at the level of organizational design and governance, and at the level of policy making [1]. For example, engagement at the level of direct care might involve a patient working with her care team to identify a treatment option that matches her values and preferences. At the level of the health care organization, a patient might provide feedback through a survey or serve on a patient advisory council to improve clinic operations. Patients engaged at the level of policy making might share their opinions with their elected representatives or sit on a national committee. Although research has examined engagement at the direct care level, for example, in studies of shared decision making, there is a paucity of research addressing the impact of patient engagement on clinic-level organizational redesign and practice improvement [4,5].

Relatively few studies describe what primary care practice teams are currently doing at the basic level of soliciting and acting on patient input on the way that their care is delivered. A survey of 112 NCQA-certified patient-centered medical home (PCMH) practices found that 78% conducted patient surveys, 63% gathered qualitative input through focus groups or other feedback, 52% provided a suggestion box, and 32% included patients on advisory councils or teams [6]. Fewer than one-third of PCMH-certified practices were engaging patients or families in more intensive roles as ongoing advisors on practice design or practice improvement [6]. Randomized controlled trials have shown that patient involvement in developing informational materials results in more readable and relevant information [7]. Patient and family involvement in identifying organizational priorities within clinical practice settings resulted in greater alignment with the chronic care model and the PCMH when compared with control groups and resulted in greater agreement between patients and health care professionals [4]. Moreover, a number of innovative health care organizations credit their success in transformation to their patient partnerships [8–10].

Within this context, current practices at community health centers (CHCs) are of particular interest. CHCs are not-for-profit organizations that deliver primary and preventive care to more than 22 million people in the United States [11]. A large proportion of their patients are poor and live in medically underserved communities. More than one-third (37.5%) of CHC patients are uninsured and 38.5% are on Medicaid [12]. Perhaps because of their commitment to caring for medically vulnerable populations that have often had difficulty obtaining needed medical services, some CHCs have been on the forefront of patient engagement [8]. In addition, many CHCs are federally qualified health care centers, which are mandated to engage members of their communities within their governing boards [13]. However, relatively little is known about how CHCs are engaging patients as practice improvement partners or the perceived impact of this engagement on CHC strategic goals, policies, and programs. This study explores these factors and examines the organizational characteristics and processes associated with patients having an impact on practice improvement activities.

Methods

We conducted a cross-sectional, web-based survey of primary care clinician and staff leaders at CHCs in July–August 2014 to assess current strategies, attitudes, facilitators, and barriers toward engaging patients in practice improvement efforts. The study protocol was developed jointly by the San Francisco Bay Area Collaborative Research Network (SFBayCRN), the University of California San Francisco Center for Excellence in Primary Care (CEPC), and the Western Clinicians Network (WCN). The protocol was reviewed by the University of California San Francisco Committee on Human Research and determined to be exempt research (study number 14-13662).

Survey Participants

Participants in the web-based survey were members of the WCN, a peer-led, volunteer, membership-based association of medical leaders of community health centers in California, Arizona, Nevada, and Hawaii. An invitation and link to a web-based survey was sent by email to members working at WCN CHC, who received up to 3 reminders to complete the survey. We allowed one response per CHC surveyed; in cases where more than one CHC leader was a member of WCN, we requested that the person most familiar with patient engagement activities respond to the survey. In the event of multiple respondents from an organization, incomplete responses were dropped and one complete response was randomly selected to represent the organization. Participants in the survey were entered into a drawing for ten $50 gift cards and one iPad.

Conceptual Model

Measures

The primary outcomes of interest were respondents’ perception of patient impact on strategic priorities, policies, and programs. These outcomes were measured by 2 items: “Patient input helps shape strategic goals or priorities” and “Patient feedback has resulted in policy or program changes at our clinic.” Responses were measured on a 5-item Likert scale (1 = Strongly Disagree to 5 = Strongly Agree). Leadership support was measured using a single item that stated, “Our clinic leadership would like to find more ways to involve patients in practice improvement.” Having a formal strategy was measured using a single item that stated, “We have a formal strategy for how we recruit patients to serve in an advisory capacity.” Clinic processes included having dedicated time in meetings to discuss patient input, as measured by the item, “We dedicate time at team meetings to discuss patient feedback and recommendations.”

In addition to the 10 Likert-type items that captured attitudes, beliefs, and practices, we also  asked participants to endorse strategies they used to obtain feedback and suggestions from patients (checklist of options including advisory councils, surveys, suggestion box, etc.). In addition, we assessed practice characteristics such as PCMH recognition status (not applying; in process of applying; received recognition), size of practice (< 5; 5–10; > 10 FTE clinicians), and having dedicated funding such as grant support to pay for patient engagement activities (yes; no).

Data Analysis

Data was analyzed in Stata version 13.0 (College Station, TX). Means and frequencies were used to characterize the sample. Stepwise multivariate modeling was used to identify factors associated with patient engagement outcomes. Organizational characteristics (size of the practice, PCMH recognition status, dedicated funding, leadership support, and having a formal strategy) were included as potential independent variables in Step 1 of the model for each of the 2 hypothesized patient engagement outcomes. Because we theorized that it might be a factor associated with the outcomes that was in turn influenced by clinic characteristics, the process of allocating dedicated time in team meetings to discuss and consider actions to take in response to patient feedback was included as a predictor in Step 2 of each model. Survey items that were not answered were treated as missing data (not imputed). We tested for multiple collinearity using variance influence factors.

Results

The most common mechanisms for receiving patient feedback were surveys (94% of respondents; 91/97) and suggestion boxes (57%; 55/97; Table 1). A third of respondents reported soliciting patient feedback on information materials (33%; 32/97), and almost a third involved patients in selecting referral resources (28%; 27/97). As for ongoing participation, 69% (67/97) of respondents reported involving patients on advisory boards or councils, and 36% (35/97) invited patients to take part in quality improvement committees. Other common activities included inviting patients to conferences or workshops (30%; 29/97) and asking patients to lead self-management or support groups (29%; 28/97).

Most respondents (82%; 77/93) agreed or strongly agreed that patient engagement was worth the time it required. About a third (35%; 32/92) reported having a formal strategy for recruiting and engaging patients in an advisory capacity. About half (52%; 49/94) reported setting aside time in team meetings to discuss patient feedback, although fewer (39%; 35/89) reported that their front line staff met regularly with patients to discuss clinic services and programs. Two-thirds of respondents (68%; 64/94) reported that their leadership would like to find more active ways to involve patients in practice improvement. Less than half (44%; 39/89) felt that they were successful at engaging patient advisors who represented the diversity of the population served. When considering downsides of patient engagement, few agreed that revealing the workings of the clinics to patients would expose the clinic to too much risk (8%; 7/89) or that patients would make unrealistic requests if asked their opinions (14%; 12/89).

Discussion

Among the CHCs surveyed, we found that having a formal strategy for recruiting and engaging patients in practice improvement efforts was associated with patient input shaping strategic goals, programs, and policies. Devoting time in staff team meetings to discuss feedback from patients, such as that received through advisory councils or patient surveys, appeared to be the mechanism by which having a formal strategy for engaging patients influenced the outcomes. Leadership support for patient engagement was also associated with patient input in strategic goals. In contrast, anticipated predictors such as PCMH recognition status, the size of a practice, and having dedicated funding for patient engagement were not associated with these outcomes.

This is the first study known to the authors that examines factors associated with patient engagement outcomes such as patient involvement in clinic-level strategies, policies, and programs. The finding that having a formal process for recruiting and engaging patients and devoting time in team meetings to discuss patient input are significantly associated with patient engagement outcomes is encouraging, because it suggests relatively practical and straightforward actions for primary care leaders interested in engaging patients productively in practice improvement.

The level of patient engagement reported by these respondents is higher than that reported by some other studies. For example, 65% of respondents in this study reported conducting patient surveys and involving patients in ongoing roles as patient advisors, compared to 29% in a 2013 study by Han and colleagues for 112 practices that had received PCMH recognition [6]. This could be partially explained by the fact that many CHCs are federally qualified health centers, which are mandated to have consumer members on their board of directors, and in many cases patient board members may be invited to participate actively in practice improvement. In this study, it is also interesting to note that more than 80% of respondents agreed with the statement that “engaging patients in practice improvement is worth the time and effort it takes,” suggesting that this is a group that valued and prioritized patient engagement.

A lack of time or resources to support patient engagement has been reported as a barrier to effective engagement [15], so it was surprising that having dedicated funding to support patient engagement was not associated with the study outcomes. Only 30% of CHC leaders reported having dedicated funding for patient engagement, while over 80% reported soliciting patient input through longitudinal, bidirectional activities such as committees or advisory councils. While financial support for this vital work is likely important to catalyze and sustain patient engagement at the practice level, it would appear many of the practices surveyed in this study are engaging their patients as partners in practice transformation despite a lack of dedicated resources.

The lack of association that we found between PCMH recognition status and patient influence on strategies, programs, and policies is corroborated by work by Han and colleagues [6], in which they found that the level of PCMH status was not associated with the degree of patient engagement in practice improvement and that only 32% of practices were engaging patients in ongoing roles as advisors.

Devoting time in team meetings to discussing patient feedback seemed to be the mechanism through with having a formal strategy for patient engagement predicted outcomes. Although it may seem self-evident that taking time to discuss patient input could make it more likely to affect clinic practices, we have observed through regular interaction with dozens of health centers that many have comment boxes set up but have no mechanism for systematically reviewing that feedback and considering it as a team. This is also borne out by our survey finding that fewer than 60% of sites that report conducting surveys or having suggestion boxes agree that they set aside time in team meetings to discuss the feedback gleaned from these sources. Thus, the results of this survey suggest that there are simple decisions and structures that may help to turn input from patients into clinic actions.

This study has several limitations. Causation cannot be inferred from this cross-sectional study; additional research is required to understand if helping clinics develop formal strategies for patient recruitment or set aside time in meetings to discuss patient feedback would lead to greater influence of patients on strategic goals, policies, and programs. Data were self-reported by a single person from each CHC, and although members of WCN typically represent clinic leaders who are actively engaged in PCMH-related activities, it is not clear if respondents were aware of the full range of patient engagement strategies used at their clinical site. Front-line clinicians and staff could provide a different perspective on patient engagement. There was no external validation of survey instrument statements regarding the impact of patient input on strategic goals, policies, or programs. The number of respondents (n = 97) is limited, but it is comparable to that in other existing studies [6]. The response rate for this survey was 21%, and respondents may have differed from non-respondents in important ways. When respondents of this study are compared to national samples reporting to the Uniform Data System, the proportion of CHCs with PCMH recognition is lower in our sample (52% versus 65%) [16]. The high level of patient engagement reported by CHC leaders in this study compared to other studies suggests that highly engaged practices may have been more likely to respond than those with lower levels of engagement with their patients. There may have been differences in how patient engagement and advisory roles were interpreted by respondents.

Conclusion

CHC leaders who reported a formal strategy for engaging patients in practice improvement and dedicated time to discuss patient input during team meetings were more likely to report patient input on policies, programs, and strategic goals. Developing a formal strategy to engage patients and establishing protected time on team agendas to discuss patient feedback may be practical ways to promote greater patient engagement in primary care transformation.

Acknowledgements: The authors wish to thank the leadership of Western Clinicians Network. A special thanks to Dr. Carl Heard, Dr. Mike Witte, Dr. Eric Henley, Dr. Kevin Grumbach, Dr. David Thom, Dr. Quynh Bui, Lucia Angel, and Dr. Thomas Bodenheimer for their feedback on survey and manuscript development. Valuable input on the survey questions were also received from the UCSF Lakeshore Family Medicine Center Patient Advisory Council, the San Francisco General Hospital Patient Advisory Council, and the Malden Family Health Center Patient Advisory Council. Finally, thanks to the community health centers who shared their time and experiences through our survey.

Corresponding author: Rachel Willard-Grace, MPH, Department of Family & Community Medicine, UCSF, 1001 Potrero Hill, Ward 83, Building 80, 3rd Fl, San Francisco, CA 94110, [email protected].

Funding/support: Internal departmental funding covered the direct costs of conducting this research. This project was also supported in part by the National Center for Advancing Translational Sciences, National Institutes of Health, through UCSF-CTSI Grant Number UL1 TR000004 which supported Dr. Potter’s time. Dr. Sharma received support from the UCSF primary care research fellowship funded by NRSA grant T32 HP19025. Contents of this manuscript are solely the responsibility of the authors and do not necessarily represent the official views of the NIH.

Taking a step toward the goal of personalized medicine, investigators in the multicenter, adaptive I-SPY 2 trial report that tailoring neoadjuvant therapy combinations to specific cancer subtypes in women with high-risk breast cancer will likely result in higher rates of pathological complete responses for at least two subtypes, including patients with triple-negative disease.

Among women with triple-negative breast cancer (tumors lacking human epidermal growth factor receptor 2 [HER2], estrogen, and progesterone receptors) in the phase II trial, a combination of the poly (ADP-ribose) polymerase (PARP) inhibitor veliparib and carboplatin added to paclitaxel was associated with an estimated 51% pathological complete response (pCR) rate, compared with 26% for patients treated with weekly paclitaxel alone. The predicted probability of success in a phase III trial with the combination was 88%, reported Hope S. Rugo, MD, director of the Breast Oncology Clinical Trials Program at the University of California San Francisco, and her colleagues in I-SPY 2.

“The experience with veliparib-carboplatin in our trial shows the advantage of an adaptively randomized phase II platform trial for matching therapies with biomarker subsets to better inform the design of phase III trials so that they can be more focused, smaller, and faster. Future patients stand to benefit, but trial participants benefit as well in that exposure to ineffective therapy is minimized,” the investigators wrote (N Engl J Med. 2016 July 7. doi: 10.1056/NEJMoa1513749).

Partial results from this trial were reported at the 2013 San Antonio Breast Cancer Symposium.

On the basis of these phase II data, an ongoing phase III neoadjuvant trial is comparing standard chemotherapy alone, with carboplatin, or with veliparib plus carboplatin as treatment for triple-negative breast cancer, Dr. Rugo and her associates said.

In another arm of I-SPY 2 involving a subset of patients with HER2-positive, hormone receptor–negative cancers, the mean estimated pCR rate was 56% for patients treated with the investigational tyrosine-kinase inhibitor (TKI) neratinib, compared with an estimated 33% among patients treated with anti-HER2 agent trastuzumab (Herceptin). All the participants received standard neoadjuvant therapy, which consisted of 12 cycles of paclitaxel, followed by 4 cycles of doxorubicin and cyclophosphamide. The estimated probability of success in phase III with neratinib was 79%, reported John W. Park, MD, of University of California San Francisco, and his coauthors on behalf of I-SPY 2 investigators (N Engl J Med. 2016 July 7. doi: 10.1056/NEJMoa1513750).

On the basis of this phase II study, and to reflect the current standard of dual HER-targeting, the investigators are proceeding with a phase III trial comparing neratinib as neoadjuvant therapy added to pertuzumab (Perjeta), trastuzumab, and a taxane vs. the three latter drugs, and against a combination of neratinib, trastuzumab, and taxane, all followed by doxorubicin and cyclophosphamide.

Partial results of the phase II trial were reported at the 2013 annual meeting of the American Association for Cancer Research.

Nimble trial, tailored therapies

I-SPY 2 (Investigation of Serial Studies to Predict Your Therapeutic Response through Imaging and Molecular Analysis 2) is an ongoing “platform” trial exploring the use of new drugs combined with a standard neoadjuvant therapy backbone for the treatment of high-risk cancers.

Women with stage II or III breast cancers with tumors 2.5 cm or larger are assessed for one of eight biomarker subtypes according to HER2 (human epidermal growth factor receptor 2) status, hormone receptor status, and genetic risk factors based on a 70-gene assay. The patients are then randomized within each biomarker subtype to receive standard therapy with or without an investigational agent.

Each sub-trial has a primary endpoint of an improvement in pathological complete response compared with the standard of care. Changes in tumor volume on MRI are used to predict whether patients will achieve a pCR. Regimens that have a high Bayesian predictive probability of success in a subsequent phase III neoadjuvant trial within the biomarker signature in which they performed well are eligible for moving on to phase III trials.

Triple-negative disease

Among the subgroup of patients with triple-negative disease, 72 were assigned to receive veliparib 50 mg by mouth twice daily for 12 weeks, plus carboplatin at a dose intended to achieve a pharmacologic area under the concentration versus time curve of 6 mg/hour per liter on weeks 1, 4, 7, and 10, plus intravenous paclitaxel at a dose of 80 mg/m². An additional 44 patients (controls) were randomized to receive paclitaxel alone.

Following paclitaxel alone or with the combination, all patients received doxorubicin 60 mg/m² and cyclophosphamide 600 mg/m² every 2-3 weeks for four doses, followed by myeloid growth factor support as appropriate. Following treatment, all patients underwent surgery that included axillary node sampling in accordance with National Comprehensive Cancer Network (NCCN) and local practice guidelines. Adjuvant radiation and endocrine therapy were recommended in accordance with standard guidelines.

The rate of grade 3 or greater hematologic toxic effects in this trial arm was higher in patients treated with veliparib-carboplatin, with neutropenia rates of 71% versus 2% for controls. Adverse events occurring only in patients on veliparib-carboplatin were thrombocytopenia in 21%, anemia in 28%, and febrile neutropenia in 1%. Among patients who had received the combination, toxic effects were higher during doxorubicin-cyclophosphamide therapy.

HR-negative disease

Patients with hormone receptor–negative disease received standard neoadjuvant chemotherapy with 12 weekly cycles of paclitaxel followed by 4 cycles of doxorubicin and cyclophosphamide as described before, with or without oral neratinib 240 mg per day. Patients in the control group who had HER2-positive cancers also received trastuzumab for the first 12 weeks with a loading dose of 4 mg per kilogram of body weight in the first cycle, followed by a maintenance dose of 2 mg per kilogram in cycles 2 through 12.

Surgery, including sentinel-node dissection in patients with node-negative cancer and axillary-node dissection in those with node-positive cancer at diagnosis, was performed according to NCCN and local practice guidelines, and adjuvant radiation and endocrine therapy were recommended according to standard guidelines.

The protocol was modified to included diarrhea prophylaxis with loperamide among patients assigned to receive neratinib.

A total of 127 patients were assigned to neratinib, and 115 of these patients were evaluable for response. Controls included 84 patients, of whom 78 were evaluable. At baseline, more patients in the neratinib group had HER2-positive tumors. Neratinib reached the prespecified efficacy threshold only within the HER2-positive, HR-negative group.

Diarrhea was the most common adverse event, with grade 3 or greater diarrhea occurring among 38% of patients assigned to neratinib. Vomiting and elevated liver enzymes were also more frequent with neratinib.

I-SPY 2 is supported by QuantumLeap Healthcare Collaborative, the Foundation for the National Institutes of Health (from 2010 through 2012) and the National Cancer Institute. Dr. Park reported receiving lecture fees and travel support from Genentech and Pfizer, and receiving royalties from patents. Dr. Rugo reported grants to her institution from BioMarin, and unpaid steering committee participation for BioMarin and AbbVie. Multiple co-authors reported financial relationships of various kinds.

Taking a step toward the goal of personalized medicine, investigators in the multicenter, adaptive I-SPY 2 trial report that tailoring neoadjuvant therapy combinations to specific cancer subtypes in women with high-risk breast cancer will likely result in higher rates of pathological complete responses for at least two subtypes, including patients with triple-negative disease.

Among women with triple-negative breast cancer (tumors lacking human epidermal growth factor receptor 2 [HER2], estrogen, and progesterone receptors) in the phase II trial, a combination of the poly (ADP-ribose) polymerase (PARP) inhibitor veliparib and carboplatin added to paclitaxel was associated with an estimated 51% pathological complete response (pCR) rate, compared with 26% for patients treated with weekly paclitaxel alone. The predicted probability of success in a phase III trial with the combination was 88%, reported Hope S. Rugo, MD, director of the Breast Oncology Clinical Trials Program at the University of California San Francisco, and her colleagues in I-SPY 2.

“The experience with veliparib-carboplatin in our trial shows the advantage of an adaptively randomized phase II platform trial for matching therapies with biomarker subsets to better inform the design of phase III trials so that they can be more focused, smaller, and faster. Future patients stand to benefit, but trial participants benefit as well in that exposure to ineffective therapy is minimized,” the investigators wrote (N Engl J Med. 2016 July 7. doi: 10.1056/NEJMoa1513749).

Partial results from this trial were reported at the 2013 San Antonio Breast Cancer Symposium.

On the basis of these phase II data, an ongoing phase III neoadjuvant trial is comparing standard chemotherapy alone, with carboplatin, or with veliparib plus carboplatin as treatment for triple-negative breast cancer, Dr. Rugo and her associates said.

In another arm of I-SPY 2 involving a subset of patients with HER2-positive, hormone receptor–negative cancers, the mean estimated pCR rate was 56% for patients treated with the investigational tyrosine-kinase inhibitor (TKI) neratinib, compared with an estimated 33% among patients treated with anti-HER2 agent trastuzumab (Herceptin). All the participants received standard neoadjuvant therapy, which consisted of 12 cycles of paclitaxel, followed by 4 cycles of doxorubicin and cyclophosphamide. The estimated probability of success in phase III with neratinib was 79%, reported John W. Park, MD, of University of California San Francisco, and his coauthors on behalf of I-SPY 2 investigators (N Engl J Med. 2016 July 7. doi: 10.1056/NEJMoa1513750).

On the basis of this phase II study, and to reflect the current standard of dual HER-targeting, the investigators are proceeding with a phase III trial comparing neratinib as neoadjuvant therapy added to pertuzumab (Perjeta), trastuzumab, and a taxane vs. the three latter drugs, and against a combination of neratinib, trastuzumab, and taxane, all followed by doxorubicin and cyclophosphamide.

Partial results of the phase II trial were reported at the 2013 annual meeting of the American Association for Cancer Research.

Nimble trial, tailored therapies

I-SPY 2 (Investigation of Serial Studies to Predict Your Therapeutic Response through Imaging and Molecular Analysis 2) is an ongoing “platform” trial exploring the use of new drugs combined with a standard neoadjuvant therapy backbone for the treatment of high-risk cancers.

Women with stage II or III breast cancers with tumors 2.5 cm or larger are assessed for one of eight biomarker subtypes according to HER2 (human epidermal growth factor receptor 2) status, hormone receptor status, and genetic risk factors based on a 70-gene assay. The patients are then randomized within each biomarker subtype to receive standard therapy with or without an investigational agent.

Each sub-trial has a primary endpoint of an improvement in pathological complete response compared with the standard of care. Changes in tumor volume on MRI are used to predict whether patients will achieve a pCR. Regimens that have a high Bayesian predictive probability of success in a subsequent phase III neoadjuvant trial within the biomarker signature in which they performed well are eligible for moving on to phase III trials.

Triple-negative disease

Among the subgroup of patients with triple-negative disease, 72 were assigned to receive veliparib 50 mg by mouth twice daily for 12 weeks, plus carboplatin at a dose intended to achieve a pharmacologic area under the concentration versus time curve of 6 mg/hour per liter on weeks 1, 4, 7, and 10, plus intravenous paclitaxel at a dose of 80 mg/m². An additional 44 patients (controls) were randomized to receive paclitaxel alone.

Following paclitaxel alone or with the combination, all patients received doxorubicin 60 mg/m² and cyclophosphamide 600 mg/m² every 2-3 weeks for four doses, followed by myeloid growth factor support as appropriate. Following treatment, all patients underwent surgery that included axillary node sampling in accordance with National Comprehensive Cancer Network (NCCN) and local practice guidelines. Adjuvant radiation and endocrine therapy were recommended in accordance with standard guidelines.

The rate of grade 3 or greater hematologic toxic effects in this trial arm was higher in patients treated with veliparib-carboplatin, with neutropenia rates of 71% versus 2% for controls. Adverse events occurring only in patients on veliparib-carboplatin were thrombocytopenia in 21%, anemia in 28%, and febrile neutropenia in 1%. Among patients who had received the combination, toxic effects were higher during doxorubicin-cyclophosphamide therapy.

HR-negative disease

Patients with hormone receptor–negative disease received standard neoadjuvant chemotherapy with 12 weekly cycles of paclitaxel followed by 4 cycles of doxorubicin and cyclophosphamide as described before, with or without oral neratinib 240 mg per day. Patients in the control group who had HER2-positive cancers also received trastuzumab for the first 12 weeks with a loading dose of 4 mg per kilogram of body weight in the first cycle, followed by a maintenance dose of 2 mg per kilogram in cycles 2 through 12.

Surgery, including sentinel-node dissection in patients with node-negative cancer and axillary-node dissection in those with node-positive cancer at diagnosis, was performed according to NCCN and local practice guidelines, and adjuvant radiation and endocrine therapy were recommended according to standard guidelines.

The protocol was modified to included diarrhea prophylaxis with loperamide among patients assigned to receive neratinib.

A total of 127 patients were assigned to neratinib, and 115 of these patients were evaluable for response. Controls included 84 patients, of whom 78 were evaluable. At baseline, more patients in the neratinib group had HER2-positive tumors. Neratinib reached the prespecified efficacy threshold only within the HER2-positive, HR-negative group.

Diarrhea was the most common adverse event, with grade 3 or greater diarrhea occurring among 38% of patients assigned to neratinib. Vomiting and elevated liver enzymes were also more frequent with neratinib.

I-SPY 2 is supported by QuantumLeap Healthcare Collaborative, the Foundation for the National Institutes of Health (from 2010 through 2012) and the National Cancer Institute. Dr. Park reported receiving lecture fees and travel support from Genentech and Pfizer, and receiving royalties from patents. Dr. Rugo reported grants to her institution from BioMarin, and unpaid steering committee participation for BioMarin and AbbVie. Multiple co-authors reported financial relationships of various kinds.

Taking a step toward the goal of personalized medicine, investigators in the multicenter, adaptive I-SPY 2 trial report that tailoring neoadjuvant therapy combinations to specific cancer subtypes in women with high-risk breast cancer will likely result in higher rates of pathological complete responses for at least two subtypes, including patients with triple-negative disease.

Among women with triple-negative breast cancer (tumors lacking human epidermal growth factor receptor 2 [HER2], estrogen, and progesterone receptors) in the phase II trial, a combination of the poly (ADP-ribose) polymerase (PARP) inhibitor veliparib and carboplatin added to paclitaxel was associated with an estimated 51% pathological complete response (pCR) rate, compared with 26% for patients treated with weekly paclitaxel alone. The predicted probability of success in a phase III trial with the combination was 88%, reported Hope S. Rugo, MD, director of the Breast Oncology Clinical Trials Program at the University of California San Francisco, and her colleagues in I-SPY 2.

“The experience with veliparib-carboplatin in our trial shows the advantage of an adaptively randomized phase II platform trial for matching therapies with biomarker subsets to better inform the design of phase III trials so that they can be more focused, smaller, and faster. Future patients stand to benefit, but trial participants benefit as well in that exposure to ineffective therapy is minimized,” the investigators wrote (N Engl J Med. 2016 July 7. doi: 10.1056/NEJMoa1513749).

Partial results from this trial were reported at the 2013 San Antonio Breast Cancer Symposium.

On the basis of these phase II data, an ongoing phase III neoadjuvant trial is comparing standard chemotherapy alone, with carboplatin, or with veliparib plus carboplatin as treatment for triple-negative breast cancer, Dr. Rugo and her associates said.

In another arm of I-SPY 2 involving a subset of patients with HER2-positive, hormone receptor–negative cancers, the mean estimated pCR rate was 56% for patients treated with the investigational tyrosine-kinase inhibitor (TKI) neratinib, compared with an estimated 33% among patients treated with anti-HER2 agent trastuzumab (Herceptin). All the participants received standard neoadjuvant therapy, which consisted of 12 cycles of paclitaxel, followed by 4 cycles of doxorubicin and cyclophosphamide. The estimated probability of success in phase III with neratinib was 79%, reported John W. Park, MD, of University of California San Francisco, and his coauthors on behalf of I-SPY 2 investigators (N Engl J Med. 2016 July 7. doi: 10.1056/NEJMoa1513750).

On the basis of this phase II study, and to reflect the current standard of dual HER-targeting, the investigators are proceeding with a phase III trial comparing neratinib as neoadjuvant therapy added to pertuzumab (Perjeta), trastuzumab, and a taxane vs. the three latter drugs, and against a combination of neratinib, trastuzumab, and taxane, all followed by doxorubicin and cyclophosphamide.

Partial results of the phase II trial were reported at the 2013 annual meeting of the American Association for Cancer Research.

Nimble trial, tailored therapies

I-SPY 2 (Investigation of Serial Studies to Predict Your Therapeutic Response through Imaging and Molecular Analysis 2) is an ongoing “platform” trial exploring the use of new drugs combined with a standard neoadjuvant therapy backbone for the treatment of high-risk cancers.

Women with stage II or III breast cancers with tumors 2.5 cm or larger are assessed for one of eight biomarker subtypes according to HER2 (human epidermal growth factor receptor 2) status, hormone receptor status, and genetic risk factors based on a 70-gene assay. The patients are then randomized within each biomarker subtype to receive standard therapy with or without an investigational agent.

Each sub-trial has a primary endpoint of an improvement in pathological complete response compared with the standard of care. Changes in tumor volume on MRI are used to predict whether patients will achieve a pCR. Regimens that have a high Bayesian predictive probability of success in a subsequent phase III neoadjuvant trial within the biomarker signature in which they performed well are eligible for moving on to phase III trials.

Triple-negative disease

Among the subgroup of patients with triple-negative disease, 72 were assigned to receive veliparib 50 mg by mouth twice daily for 12 weeks, plus carboplatin at a dose intended to achieve a pharmacologic area under the concentration versus time curve of 6 mg/hour per liter on weeks 1, 4, 7, and 10, plus intravenous paclitaxel at a dose of 80 mg/m². An additional 44 patients (controls) were randomized to receive paclitaxel alone.

Following paclitaxel alone or with the combination, all patients received doxorubicin 60 mg/m² and cyclophosphamide 600 mg/m² every 2-3 weeks for four doses, followed by myeloid growth factor support as appropriate. Following treatment, all patients underwent surgery that included axillary node sampling in accordance with National Comprehensive Cancer Network (NCCN) and local practice guidelines. Adjuvant radiation and endocrine therapy were recommended in accordance with standard guidelines.

The rate of grade 3 or greater hematologic toxic effects in this trial arm was higher in patients treated with veliparib-carboplatin, with neutropenia rates of 71% versus 2% for controls. Adverse events occurring only in patients on veliparib-carboplatin were thrombocytopenia in 21%, anemia in 28%, and febrile neutropenia in 1%. Among patients who had received the combination, toxic effects were higher during doxorubicin-cyclophosphamide therapy.

HR-negative disease

Patients with hormone receptor–negative disease received standard neoadjuvant chemotherapy with 12 weekly cycles of paclitaxel followed by 4 cycles of doxorubicin and cyclophosphamide as described before, with or without oral neratinib 240 mg per day. Patients in the control group who had HER2-positive cancers also received trastuzumab for the first 12 weeks with a loading dose of 4 mg per kilogram of body weight in the first cycle, followed by a maintenance dose of 2 mg per kilogram in cycles 2 through 12.

Surgery, including sentinel-node dissection in patients with node-negative cancer and axillary-node dissection in those with node-positive cancer at diagnosis, was performed according to NCCN and local practice guidelines, and adjuvant radiation and endocrine therapy were recommended according to standard guidelines.

The protocol was modified to included diarrhea prophylaxis with loperamide among patients assigned to receive neratinib.

A total of 127 patients were assigned to neratinib, and 115 of these patients were evaluable for response. Controls included 84 patients, of whom 78 were evaluable. At baseline, more patients in the neratinib group had HER2-positive tumors. Neratinib reached the prespecified efficacy threshold only within the HER2-positive, HR-negative group.

Diarrhea was the most common adverse event, with grade 3 or greater diarrhea occurring among 38% of patients assigned to neratinib. Vomiting and elevated liver enzymes were also more frequent with neratinib.

I-SPY 2 is supported by QuantumLeap Healthcare Collaborative, the Foundation for the National Institutes of Health (from 2010 through 2012) and the National Cancer Institute. Dr. Park reported receiving lecture fees and travel support from Genentech and Pfizer, and receiving royalties from patents. Dr. Rugo reported grants to her institution from BioMarin, and unpaid steering committee participation for BioMarin and AbbVie. Multiple co-authors reported financial relationships of various kinds.

Clinical question: What is the best management strategy for postoperative atrial fibrillation?

Bottom line: For new-onset atrial fibrillation (AF) following cardiac surgery, both rate control and rhythm control are reasonable strategies. There is no a clear advantage of one over the other. (LOE = 1b)

Reference: Gillinov AM, Bagiella E, Moskowitz AJ, et al. Rate control versus rhythm control for atrial fibrillation after cardiac surgery. N Engl J Med 2016;374(20):1911–1921.

Study design: Randomized controlled trial (nonblinded)

Funding source: Government

Allocation: Concealed

Setting: Inpatient (any location) with outpatient follow-up

Synopsis

Postoperative AF is a common complication of cardiac surgery. In this trial, investigators identified more than 2000 patients who were undergoing coronary-artery bypass grafting and/or cardiac valve surgery. Of these patients, one-third developed new-onset AF and were randomized to receive either rate control or rhythm control.

In the rate-control group, patients received medications to slow heart rate to less than 100 beats per minute. If sinus rhythm was not achieved, these patients could then receive rhythm control per their physician's discretion. In the rhythm-control group, patients received amiodarone with or without rate-lowering medication, followed by cardioversion if AF persisted for 24 to 48 hours. The crossover rate in both groups was approximately 25% due to either drug ineffectiveness in the rate-control group or drug side effects in the rhythm-control group. All patients who remained in AF after 48 hours received anticoagulation.

The 2 groups were similar at baseline: mean age was 69 years, 75% were male, and 94% were white. Intention-to-treat analysis was used to test the primary endpoint of number of days in the emergency department or hospital within 60 days after randomization. There was no significant difference detected in this outcome between the 2 groups, even when the initial length of stay was adjusted for discharge readiness from an AF perspective. A sensitivity analysis accounting for the large number of crossovers also confirmed this finding. More than 90% of patients in both groups had a stable heart rhythm at the 60-day follow-up. Complication rates and 30-day readmission rates were also similar in the 2 groups.

Dr. Kulkarni is an assistant professor of hospital medicine at Northwestern University in Chicago.

Clinical question: What is the best management strategy for postoperative atrial fibrillation?

Bottom line: For new-onset atrial fibrillation (AF) following cardiac surgery, both rate control and rhythm control are reasonable strategies. There is no a clear advantage of one over the other. (LOE = 1b)

Reference: Gillinov AM, Bagiella E, Moskowitz AJ, et al. Rate control versus rhythm control for atrial fibrillation after cardiac surgery. N Engl J Med 2016;374(20):1911–1921.

Study design: Randomized controlled trial (nonblinded)

Funding source: Government

Allocation: Concealed

Setting: Inpatient (any location) with outpatient follow-up

Synopsis

Postoperative AF is a common complication of cardiac surgery. In this trial, investigators identified more than 2000 patients who were undergoing coronary-artery bypass grafting and/or cardiac valve surgery. Of these patients, one-third developed new-onset AF and were randomized to receive either rate control or rhythm control.

In the rate-control group, patients received medications to slow heart rate to less than 100 beats per minute. If sinus rhythm was not achieved, these patients could then receive rhythm control per their physician's discretion. In the rhythm-control group, patients received amiodarone with or without rate-lowering medication, followed by cardioversion if AF persisted for 24 to 48 hours. The crossover rate in both groups was approximately 25% due to either drug ineffectiveness in the rate-control group or drug side effects in the rhythm-control group. All patients who remained in AF after 48 hours received anticoagulation.

The 2 groups were similar at baseline: mean age was 69 years, 75% were male, and 94% were white. Intention-to-treat analysis was used to test the primary endpoint of number of days in the emergency department or hospital within 60 days after randomization. There was no significant difference detected in this outcome between the 2 groups, even when the initial length of stay was adjusted for discharge readiness from an AF perspective. A sensitivity analysis accounting for the large number of crossovers also confirmed this finding. More than 90% of patients in both groups had a stable heart rhythm at the 60-day follow-up. Complication rates and 30-day readmission rates were also similar in the 2 groups.

Dr. Kulkarni is an assistant professor of hospital medicine at Northwestern University in Chicago.

Clinical question: What is the best management strategy for postoperative atrial fibrillation?

Bottom line: For new-onset atrial fibrillation (AF) following cardiac surgery, both rate control and rhythm control are reasonable strategies. There is no a clear advantage of one over the other. (LOE = 1b)

Reference: Gillinov AM, Bagiella E, Moskowitz AJ, et al. Rate control versus rhythm control for atrial fibrillation after cardiac surgery. N Engl J Med 2016;374(20):1911–1921.

Study design: Randomized controlled trial (nonblinded)

Funding source: Government

Allocation: Concealed

Setting: Inpatient (any location) with outpatient follow-up

Synopsis

Postoperative AF is a common complication of cardiac surgery. In this trial, investigators identified more than 2000 patients who were undergoing coronary-artery bypass grafting and/or cardiac valve surgery. Of these patients, one-third developed new-onset AF and were randomized to receive either rate control or rhythm control.

In the rate-control group, patients received medications to slow heart rate to less than 100 beats per minute. If sinus rhythm was not achieved, these patients could then receive rhythm control per their physician's discretion. In the rhythm-control group, patients received amiodarone with or without rate-lowering medication, followed by cardioversion if AF persisted for 24 to 48 hours. The crossover rate in both groups was approximately 25% due to either drug ineffectiveness in the rate-control group or drug side effects in the rhythm-control group. All patients who remained in AF after 48 hours received anticoagulation.

The 2 groups were similar at baseline: mean age was 69 years, 75% were male, and 94% were white. Intention-to-treat analysis was used to test the primary endpoint of number of days in the emergency department or hospital within 60 days after randomization. There was no significant difference detected in this outcome between the 2 groups, even when the initial length of stay was adjusted for discharge readiness from an AF perspective. A sensitivity analysis accounting for the large number of crossovers also confirmed this finding. More than 90% of patients in both groups had a stable heart rhythm at the 60-day follow-up. Complication rates and 30-day readmission rates were also similar in the 2 groups.

Dr. Kulkarni is an assistant professor of hospital medicine at Northwestern University in Chicago.

Clinical question: For critically ill patients with acute kidney injury, does early initiation of renal replacement therapy improve mortality?

Bottom line: In this single-center study, early initiation of renal replacement therapy (RRT) in critically ill patients with acute kidney injury (AKI) decreased the number of deaths at 90 days. Larger studies are required to confirm this finding. Although some patients may prefer to avoid dialysis and its inherent risks, this preference must be balanced with the greater risk of mortality that may occur by not undergoing this treatment early on. (LOE = 1b)

Reference: Zarbock A, Kellum JA, Schmidt C, et al. Effect of early vs delayed initiation of renal replacement therapy on mortality in critically ill patients with acute kidney injury. JAMA 2016;315(20):2190–2199.

Study design: Randomized controlled trial (nonblinded)

Funding source: Foundation

Allocation: Concealed

Setting: Inpatient (ICU only)

Synopsis

To study the optimal time for initiation of RRT for critically ill patients with AKI, these authors recruited patients with severe sepsis, pressor requirements, refractory fluid overload, or nonrenal organ dysfunction who developed stage 2 AKI (urine output < 0.5 mL/kg/h for more than 12 hours or a 2-fold increase in serum creatinine from baseline). Patients with chronic kidney disease, glomerulonephritis, interstitial nephritis, vasculitis, and postrenal obstruction were excluded, among others.

Overall, 231 patients were randomized to receive either early RRT or delayed RRT. RRT was delivered initially as continuous venovenous hemodiafiltration and could be changed to an intermittent procedure such as intermittent hemodialysis or sustained low-efficiency daily dialysis if renal recovery did not occur after 7 days. Early RRT was initiated within 8 hours of diagnosis of stage 2 AKI while delayed RRT was initiated within 12 hours after patients had developed stage 3 AKI (urine output < 0.3mL/kg/h for more than 24 hours or a 3-fold increase in serum creatinine from baseline) or if patients had an absolute indication for RRT. Patients in the 2 groups had similar baseline Sequential Organ Failure Assessment scores and almost all were surgical patients. Although all patients in the early group received RRT, 9% of patients in the delayed group did not, mostly because they did not progress to stage 3 AKI.

Early RRT resulted in a significantly decreased 90-day mortality rate as compared with delayed RRT (39% vs 55%; P = .03). Patients in the early group also had a decreased duration of RRT (9 days vs 25 days; P = .04), decreased length of hospital stay (51 days vs 82 days; P < .001), and greater recovery of renal function at 90 days (54% vs 39%; P = .02). The authors postulate that initiating early RRT may prevent further injury to the kidneys and other organs by reducing systemic inflammation.

Dr. Kulkarni is an assistant professor of hospital medicine at Northwestern University in Chicago.

Clinical question: For critically ill patients with acute kidney injury, does early initiation of renal replacement therapy improve mortality?

Bottom line: In this single-center study, early initiation of renal replacement therapy (RRT) in critically ill patients with acute kidney injury (AKI) decreased the number of deaths at 90 days. Larger studies are required to confirm this finding. Although some patients may prefer to avoid dialysis and its inherent risks, this preference must be balanced with the greater risk of mortality that may occur by not undergoing this treatment early on. (LOE = 1b)

Reference: Zarbock A, Kellum JA, Schmidt C, et al. Effect of early vs delayed initiation of renal replacement therapy on mortality in critically ill patients with acute kidney injury. JAMA 2016;315(20):2190–2199.

Study design: Randomized controlled trial (nonblinded)

Funding source: Foundation

Allocation: Concealed

Setting: Inpatient (ICU only)

Synopsis

To study the optimal time for initiation of RRT for critically ill patients with AKI, these authors recruited patients with severe sepsis, pressor requirements, refractory fluid overload, or nonrenal organ dysfunction who developed stage 2 AKI (urine output < 0.5 mL/kg/h for more than 12 hours or a 2-fold increase in serum creatinine from baseline). Patients with chronic kidney disease, glomerulonephritis, interstitial nephritis, vasculitis, and postrenal obstruction were excluded, among others.

Overall, 231 patients were randomized to receive either early RRT or delayed RRT. RRT was delivered initially as continuous venovenous hemodiafiltration and could be changed to an intermittent procedure such as intermittent hemodialysis or sustained low-efficiency daily dialysis if renal recovery did not occur after 7 days. Early RRT was initiated within 8 hours of diagnosis of stage 2 AKI while delayed RRT was initiated within 12 hours after patients had developed stage 3 AKI (urine output < 0.3mL/kg/h for more than 24 hours or a 3-fold increase in serum creatinine from baseline) or if patients had an absolute indication for RRT. Patients in the 2 groups had similar baseline Sequential Organ Failure Assessment scores and almost all were surgical patients. Although all patients in the early group received RRT, 9% of patients in the delayed group did not, mostly because they did not progress to stage 3 AKI.

Early RRT resulted in a significantly decreased 90-day mortality rate as compared with delayed RRT (39% vs 55%; P = .03). Patients in the early group also had a decreased duration of RRT (9 days vs 25 days; P = .04), decreased length of hospital stay (51 days vs 82 days; P < .001), and greater recovery of renal function at 90 days (54% vs 39%; P = .02). The authors postulate that initiating early RRT may prevent further injury to the kidneys and other organs by reducing systemic inflammation.

Dr. Kulkarni is an assistant professor of hospital medicine at Northwestern University in Chicago.

Clinical question: For critically ill patients with acute kidney injury, does early initiation of renal replacement therapy improve mortality?

Bottom line: In this single-center study, early initiation of renal replacement therapy (RRT) in critically ill patients with acute kidney injury (AKI) decreased the number of deaths at 90 days. Larger studies are required to confirm this finding. Although some patients may prefer to avoid dialysis and its inherent risks, this preference must be balanced with the greater risk of mortality that may occur by not undergoing this treatment early on. (LOE = 1b)

Reference: Zarbock A, Kellum JA, Schmidt C, et al. Effect of early vs delayed initiation of renal replacement therapy on mortality in critically ill patients with acute kidney injury. JAMA 2016;315(20):2190–2199.

Study design: Randomized controlled trial (nonblinded)

Funding source: Foundation

Allocation: Concealed

Setting: Inpatient (ICU only)

Synopsis

To study the optimal time for initiation of RRT for critically ill patients with AKI, these authors recruited patients with severe sepsis, pressor requirements, refractory fluid overload, or nonrenal organ dysfunction who developed stage 2 AKI (urine output < 0.5 mL/kg/h for more than 12 hours or a 2-fold increase in serum creatinine from baseline). Patients with chronic kidney disease, glomerulonephritis, interstitial nephritis, vasculitis, and postrenal obstruction were excluded, among others.

Overall, 231 patients were randomized to receive either early RRT or delayed RRT. RRT was delivered initially as continuous venovenous hemodiafiltration and could be changed to an intermittent procedure such as intermittent hemodialysis or sustained low-efficiency daily dialysis if renal recovery did not occur after 7 days. Early RRT was initiated within 8 hours of diagnosis of stage 2 AKI while delayed RRT was initiated within 12 hours after patients had developed stage 3 AKI (urine output < 0.3mL/kg/h for more than 24 hours or a 3-fold increase in serum creatinine from baseline) or if patients had an absolute indication for RRT. Patients in the 2 groups had similar baseline Sequential Organ Failure Assessment scores and almost all were surgical patients. Although all patients in the early group received RRT, 9% of patients in the delayed group did not, mostly because they did not progress to stage 3 AKI.

Early RRT resulted in a significantly decreased 90-day mortality rate as compared with delayed RRT (39% vs 55%; P = .03). Patients in the early group also had a decreased duration of RRT (9 days vs 25 days; P = .04), decreased length of hospital stay (51 days vs 82 days; P < .001), and greater recovery of renal function at 90 days (54% vs 39%; P = .02). The authors postulate that initiating early RRT may prevent further injury to the kidneys and other organs by reducing systemic inflammation.

Dr. Kulkarni is an assistant professor of hospital medicine at Northwestern University in Chicago.

LONDON – The European League Against Rheumatism and the European Federation of National Associations of Orthopaedics and Traumatology have joined forces to develop recommendations for the prevention and management of fragility fractures.

Such fractures are common in men and women over the age of 50 years and can lead to repeat fracture in some patients. The recommendations are unique as they are the first to consider both acute orthopedic and postfracture rheumatologic care, said Willem F. Lems, MD, PhD, of the Amsterdam Rheumatology and Immunology Centre.

At the European Congress of Rheumatology, Dr. Lems provided an overview of the draft recommendations, noting that there would be several overarching principles, one of which recognized the multidisciplinary nature of caring for someone with a fragility fracture. An important point is not who is taking care of the patient, but that the patient is given the best possible care within the multidisciplinary framework.

Wikimedia Commons/Sjoehest/ CC BY-llSA 3.0

What constitutes optimal care of course depends on the clinical situation, notably the type of fracture and the age of the patient, and optimal care in all phases of presentation (pre-, peri- and postoperative) can have an important effect on a patient’s outcome. The prevention of subsequent fractures is a key focus, with the recommendation that all patients should be investigated systematically and those deemed at high risk for another fracture should be prescribed both pharmacologic and nonpharmacologic interventions as appropriate. Patient education is also considered important.

As for all EULAR-developed recommendations, standard procedures were followed that involved convening an expert scientific advisory committee and using the Delphi technique to come up with the most important research questions that would be used to formulate the final 10 recommendations. Four of the recommendations cover the acute care setting and six provide advice on postfracture care.

The first of the acute care recommendations looks at pre- and perioperative management of a fragility fracture and highlights that, within 24-48 hours of admission, patients should receive adequate pain and fluid management and treatment, including early surgery if appropriate. This is based on evidence that better outcomes can be achieved in terms of both morbidity and mortality if patients can be seen and managed quickly.

Another of the acute care recommendations focuses on orthogeriatric care, noting that the orthopedic surgeon and a dedicated orthogeriatric team should work together, particularly for elderly patients who have suffered a hip fracture. Key elements here are the management of and prevention of delirium, deep vein thrombosis, pressure sores, and malnutrition.

As for actual fracture treatment, a balanced approach is advised when deciding upon a surgical or nonsurgical approach, especially because this is likely to be an older population with other comorbidities. Only one in three vertebral fractures are symptomatic and only about 10% of patients will be hospitalized for pain. Analgesics, modifying activities, and bracing can be options here. Surgical options for distal radial fracture, hip fracture, and trochanteric and femoral neck fractures are included.

The fourth recommendation looks at the organization of postfracture care and the need for a systematic approach to identify those who may be at risk for subsequent fractures, starting with the suggestion that any patient older than 50 years with a recent fracture should be assessed. The fifth recommendation addresses ways to evaluate this risk, such as looking at the clinical risk factors, performing bone scans and imaging, and screening for underlying osteoporosis or metabolic disorders.

Implementation is the next step, and the sixth recommendation suggests ways these recommendations could be integrated into routine practice. Often one of the biggest barriers to effective postfracture care is the lack of patient, and sometimes clinician, awareness of the risk for a subsequent fracture. This recommendation looks at the role of a possible local fracture liaison service or facilitator to coordinate between the various members of the multidisciplinary team from secondary (orthopedic surgeons, rheumatologists, endocrinologists, and geriatricians) to primary care.

The seventh recommendation addresses rehabilitation and the need to initiate physical training and muscle strengthening as early as possible after the initial fracture, with long-term continuation of balance training and fall prevention.

The final three recommendations focus on how to educate patients about their risk factors, need for follow-up, and the duration of any pharmacologic or nonpharmacologic therapy that they may need. Nonpharmacologic options might include stopping smoking, limiting alcohol intake, as well as taking supplements such as calcium or vitamin D. There will be specific guidance on the use of calcium and vitamin D, which have both pros and cons, but the optimal dosage appears to be 1,000–1,200 mg/day for calcium and 800 IU/day for vitamin D.

Pharmacologic options to prevent subsequent fragility fractures include the bisphosphonates alendronate, risedronate, and zoledronic acid (Reclast), and also the monoclonal antibody denosumab (Prolia). These are the only drugs that have been shown to reduced the risk for vertebral, nonvertebral, and hip fractures in primary analyses. Adherence, tolerance, and regular monitoring are key, and a five-step plan is suggested to aid clinical decision making that covers case finding, risk evaluation, differential diagnosis, treatment, and follow-up.

The recommendations are being finalized and should be available for publication later this year. The recommendations task force also plans to propose a research agenda.

Dr. Lems had no relevant disclosures.

LONDON – The European League Against Rheumatism and the European Federation of National Associations of Orthopaedics and Traumatology have joined forces to develop recommendations for the prevention and management of fragility fractures.

Such fractures are common in men and women over the age of 50 years and can lead to repeat fracture in some patients. The recommendations are unique as they are the first to consider both acute orthopedic and postfracture rheumatologic care, said Willem F. Lems, MD, PhD, of the Amsterdam Rheumatology and Immunology Centre.

At the European Congress of Rheumatology, Dr. Lems provided an overview of the draft recommendations, noting that there would be several overarching principles, one of which recognized the multidisciplinary nature of caring for someone with a fragility fracture. An important point is not who is taking care of the patient, but that the patient is given the best possible care within the multidisciplinary framework.

Wikimedia Commons/Sjoehest/ CC BY-llSA 3.0

What constitutes optimal care of course depends on the clinical situation, notably the type of fracture and the age of the patient, and optimal care in all phases of presentation (pre-, peri- and postoperative) can have an important effect on a patient’s outcome. The prevention of subsequent fractures is a key focus, with the recommendation that all patients should be investigated systematically and those deemed at high risk for another fracture should be prescribed both pharmacologic and nonpharmacologic interventions as appropriate. Patient education is also considered important.

As for all EULAR-developed recommendations, standard procedures were followed that involved convening an expert scientific advisory committee and using the Delphi technique to come up with the most important research questions that would be used to formulate the final 10 recommendations. Four of the recommendations cover the acute care setting and six provide advice on postfracture care.

The first of the acute care recommendations looks at pre- and perioperative management of a fragility fracture and highlights that, within 24-48 hours of admission, patients should receive adequate pain and fluid management and treatment, including early surgery if appropriate. This is based on evidence that better outcomes can be achieved in terms of both morbidity and mortality if patients can be seen and managed quickly.

Another of the acute care recommendations focuses on orthogeriatric care, noting that the orthopedic surgeon and a dedicated orthogeriatric team should work together, particularly for elderly patients who have suffered a hip fracture. Key elements here are the management of and prevention of delirium, deep vein thrombosis, pressure sores, and malnutrition.

As for actual fracture treatment, a balanced approach is advised when deciding upon a surgical or nonsurgical approach, especially because this is likely to be an older population with other comorbidities. Only one in three vertebral fractures are symptomatic and only about 10% of patients will be hospitalized for pain. Analgesics, modifying activities, and bracing can be options here. Surgical options for distal radial fracture, hip fracture, and trochanteric and femoral neck fractures are included.

The fourth recommendation looks at the organization of postfracture care and the need for a systematic approach to identify those who may be at risk for subsequent fractures, starting with the suggestion that any patient older than 50 years with a recent fracture should be assessed. The fifth recommendation addresses ways to evaluate this risk, such as looking at the clinical risk factors, performing bone scans and imaging, and screening for underlying osteoporosis or metabolic disorders.

Implementation is the next step, and the sixth recommendation suggests ways these recommendations could be integrated into routine practice. Often one of the biggest barriers to effective postfracture care is the lack of patient, and sometimes clinician, awareness of the risk for a subsequent fracture. This recommendation looks at the role of a possible local fracture liaison service or facilitator to coordinate between the various members of the multidisciplinary team from secondary (orthopedic surgeons, rheumatologists, endocrinologists, and geriatricians) to primary care.

The seventh recommendation addresses rehabilitation and the need to initiate physical training and muscle strengthening as early as possible after the initial fracture, with long-term continuation of balance training and fall prevention.

The final three recommendations focus on how to educate patients about their risk factors, need for follow-up, and the duration of any pharmacologic or nonpharmacologic therapy that they may need. Nonpharmacologic options might include stopping smoking, limiting alcohol intake, as well as taking supplements such as calcium or vitamin D. There will be specific guidance on the use of calcium and vitamin D, which have both pros and cons, but the optimal dosage appears to be 1,000–1,200 mg/day for calcium and 800 IU/day for vitamin D.

Pharmacologic options to prevent subsequent fragility fractures include the bisphosphonates alendronate, risedronate, and zoledronic acid (Reclast), and also the monoclonal antibody denosumab (Prolia). These are the only drugs that have been shown to reduced the risk for vertebral, nonvertebral, and hip fractures in primary analyses. Adherence, tolerance, and regular monitoring are key, and a five-step plan is suggested to aid clinical decision making that covers case finding, risk evaluation, differential diagnosis, treatment, and follow-up.

The recommendations are being finalized and should be available for publication later this year. The recommendations task force also plans to propose a research agenda.

Dr. Lems had no relevant disclosures.

LONDON – The European League Against Rheumatism and the European Federation of National Associations of Orthopaedics and Traumatology have joined forces to develop recommendations for the prevention and management of fragility fractures.

Such fractures are common in men and women over the age of 50 years and can lead to repeat fracture in some patients. The recommendations are unique as they are the first to consider both acute orthopedic and postfracture rheumatologic care, said Willem F. Lems, MD, PhD, of the Amsterdam Rheumatology and Immunology Centre.

At the European Congress of Rheumatology, Dr. Lems provided an overview of the draft recommendations, noting that there would be several overarching principles, one of which recognized the multidisciplinary nature of caring for someone with a fragility fracture. An important point is not who is taking care of the patient, but that the patient is given the best possible care within the multidisciplinary framework.

Wikimedia Commons/Sjoehest/ CC BY-llSA 3.0

What constitutes optimal care of course depends on the clinical situation, notably the type of fracture and the age of the patient, and optimal care in all phases of presentation (pre-, peri- and postoperative) can have an important effect on a patient’s outcome. The prevention of subsequent fractures is a key focus, with the recommendation that all patients should be investigated systematically and those deemed at high risk for another fracture should be prescribed both pharmacologic and nonpharmacologic interventions as appropriate. Patient education is also considered important.

As for all EULAR-developed recommendations, standard procedures were followed that involved convening an expert scientific advisory committee and using the Delphi technique to come up with the most important research questions that would be used to formulate the final 10 recommendations. Four of the recommendations cover the acute care setting and six provide advice on postfracture care.

The first of the acute care recommendations looks at pre- and perioperative management of a fragility fracture and highlights that, within 24-48 hours of admission, patients should receive adequate pain and fluid management and treatment, including early surgery if appropriate. This is based on evidence that better outcomes can be achieved in terms of both morbidity and mortality if patients can be seen and managed quickly.

Another of the acute care recommendations focuses on orthogeriatric care, noting that the orthopedic surgeon and a dedicated orthogeriatric team should work together, particularly for elderly patients who have suffered a hip fracture. Key elements here are the management of and prevention of delirium, deep vein thrombosis, pressure sores, and malnutrition.

As for actual fracture treatment, a balanced approach is advised when deciding upon a surgical or nonsurgical approach, especially because this is likely to be an older population with other comorbidities. Only one in three vertebral fractures are symptomatic and only about 10% of patients will be hospitalized for pain. Analgesics, modifying activities, and bracing can be options here. Surgical options for distal radial fracture, hip fracture, and trochanteric and femoral neck fractures are included.

The fourth recommendation looks at the organization of postfracture care and the need for a systematic approach to identify those who may be at risk for subsequent fractures, starting with the suggestion that any patient older than 50 years with a recent fracture should be assessed. The fifth recommendation addresses ways to evaluate this risk, such as looking at the clinical risk factors, performing bone scans and imaging, and screening for underlying osteoporosis or metabolic disorders.

Implementation is the next step, and the sixth recommendation suggests ways these recommendations could be integrated into routine practice. Often one of the biggest barriers to effective postfracture care is the lack of patient, and sometimes clinician, awareness of the risk for a subsequent fracture. This recommendation looks at the role of a possible local fracture liaison service or facilitator to coordinate between the various members of the multidisciplinary team from secondary (orthopedic surgeons, rheumatologists, endocrinologists, and geriatricians) to primary care.

The seventh recommendation addresses rehabilitation and the need to initiate physical training and muscle strengthening as early as possible after the initial fracture, with long-term continuation of balance training and fall prevention.

The final three recommendations focus on how to educate patients about their risk factors, need for follow-up, and the duration of any pharmacologic or nonpharmacologic therapy that they may need. Nonpharmacologic options might include stopping smoking, limiting alcohol intake, as well as taking supplements such as calcium or vitamin D. There will be specific guidance on the use of calcium and vitamin D, which have both pros and cons, but the optimal dosage appears to be 1,000–1,200 mg/day for calcium and 800 IU/day for vitamin D.

Pharmacologic options to prevent subsequent fragility fractures include the bisphosphonates alendronate, risedronate, and zoledronic acid (Reclast), and also the monoclonal antibody denosumab (Prolia). These are the only drugs that have been shown to reduced the risk for vertebral, nonvertebral, and hip fractures in primary analyses. Adherence, tolerance, and regular monitoring are key, and a five-step plan is suggested to aid clinical decision making that covers case finding, risk evaluation, differential diagnosis, treatment, and follow-up.

The recommendations are being finalized and should be available for publication later this year. The recommendations task force also plans to propose a research agenda.

Dr. Lems had no relevant disclosures.

To the Editor:

Mycosis fungoides (MF) is the most common form of a heterogeneous group of non-Hodgkin lymphomas known as cutaneous T-cell lymphomas. Celiac disease (CD) is associated with increased risk for development of enteropathy-associated T-cell lymphoma and other intraintestinal and extraintestinal non-Hodgkin lymphomas, but a firm association between CD and MF has not been established.¹ The first and second cases of concomitant MF and CD were reported in 1985 and 2009 by Coulson and Sanderson² and Moreira et al,³ respectively. Two other reports of celiac-associated dermatitis herpetiformis and MF exist.^4,5 We report a patient with a unique constellation of MF, CD, and Sjögren syndrome (SS).

A 54-year-old woman presented with a worsening nonpruritic, slightly tender, eczematous patch on the back of 19 years’ duration. She had a history of SS diagnosed by salivary gland biopsy. She also had a diagnosis of CD confirmed with positive antigliadin IgA antibodies, with a dramatic improvement in symptoms on a gluten-free diet (GFD) after having abdominal pain and diarrhea for many years. She had no evidence of dermatitis herpetiformis. Recently, more red-brown areas of confluent light pink erythema without clear-cut borders had appeared on the axillae, trunk, and thigh (Figure). The patient also noted new lesions and more erythema of the patches when not adhering to a GFD. A biopsy specimen from the left side of the lateral trunk revealed a bandlike lymphocytic infiltrate with irregular nuclear contours displaying epidermotropism with a few Pautrier microabscesses. Immunohistochemistry showed strong CD3 and CD4 positivity with loss of CD7 and scattered CD8 staining. Peripheral blood flow cytometry showed no aberrant cell populations. The patient was diagnosed with MF stage IB and treated with topical corticosteroids and natural light with improvement.

It has been hypothesized that early MF is an autoimmune process caused by dysregulation of a lymphocytic reaction against chronic exogenous or endogenous antigens.^4,5 The association of MF with CD supports the possibility of lymphocytic stimulation by a persistent antigen (ie, gluten) in the gastrointestinal tract. Porter et al⁴ suggested that in susceptible individuals, the resulting clonal T cells may migrate into the epidermis, causing MF. This theory also is supported by the finding that adherence to a GFD leads to decreased risk for malignancy and morbidity.⁶ In our patient, the chronic autoimmune stimulation in SS could be a factor in the pathogenesis of MF. Additionally, SS, CD, and MF are all strongly associated with increased incidence of specific but different HLA class II antigens. Mycosis fungoides is associated with HLA-DR5 and DQB1*03 alleles, CD with HLA-DQ2 and DQ8, and SS with HLA-DR15 and DR3. We do not know the HLA type of our patient, but she likely possessed multiple alleles, leading to the unique aggregation of diseases.

Furthermore, studies have shown that lymphocytes in CD patients display impaired regulatory T-cell function, causing increased incidence of autoimmune diseases and malignancy.^7,8 By this theory, the occurrence of MF in patients is facilitated by the inability of CD lymphocytes to control the abnormal T-cell proliferation in the skin. Interestingly, the finding of SS in our patient supports the possibility of impaired regulatory T-cell function.

Although the occurrence of both MF and CD in our patient could be coincidental, the possibility of correlation must be considered as more cases are documented.

To the Editor:

Mycosis fungoides (MF) is the most common form of a heterogeneous group of non-Hodgkin lymphomas known as cutaneous T-cell lymphomas. Celiac disease (CD) is associated with increased risk for development of enteropathy-associated T-cell lymphoma and other intraintestinal and extraintestinal non-Hodgkin lymphomas, but a firm association between CD and MF has not been established.¹ The first and second cases of concomitant MF and CD were reported in 1985 and 2009 by Coulson and Sanderson² and Moreira et al,³ respectively. Two other reports of celiac-associated dermatitis herpetiformis and MF exist.^4,5 We report a patient with a unique constellation of MF, CD, and Sjögren syndrome (SS).

A 54-year-old woman presented with a worsening nonpruritic, slightly tender, eczematous patch on the back of 19 years’ duration. She had a history of SS diagnosed by salivary gland biopsy. She also had a diagnosis of CD confirmed with positive antigliadin IgA antibodies, with a dramatic improvement in symptoms on a gluten-free diet (GFD) after having abdominal pain and diarrhea for many years. She had no evidence of dermatitis herpetiformis. Recently, more red-brown areas of confluent light pink erythema without clear-cut borders had appeared on the axillae, trunk, and thigh (Figure). The patient also noted new lesions and more erythema of the patches when not adhering to a GFD. A biopsy specimen from the left side of the lateral trunk revealed a bandlike lymphocytic infiltrate with irregular nuclear contours displaying epidermotropism with a few Pautrier microabscesses. Immunohistochemistry showed strong CD3 and CD4 positivity with loss of CD7 and scattered CD8 staining. Peripheral blood flow cytometry showed no aberrant cell populations. The patient was diagnosed with MF stage IB and treated with topical corticosteroids and natural light with improvement.

It has been hypothesized that early MF is an autoimmune process caused by dysregulation of a lymphocytic reaction against chronic exogenous or endogenous antigens.^4,5 The association of MF with CD supports the possibility of lymphocytic stimulation by a persistent antigen (ie, gluten) in the gastrointestinal tract. Porter et al⁴ suggested that in susceptible individuals, the resulting clonal T cells may migrate into the epidermis, causing MF. This theory also is supported by the finding that adherence to a GFD leads to decreased risk for malignancy and morbidity.⁶ In our patient, the chronic autoimmune stimulation in SS could be a factor in the pathogenesis of MF. Additionally, SS, CD, and MF are all strongly associated with increased incidence of specific but different HLA class II antigens. Mycosis fungoides is associated with HLA-DR5 and DQB1*03 alleles, CD with HLA-DQ2 and DQ8, and SS with HLA-DR15 and DR3. We do not know the HLA type of our patient, but she likely possessed multiple alleles, leading to the unique aggregation of diseases.

Furthermore, studies have shown that lymphocytes in CD patients display impaired regulatory T-cell function, causing increased incidence of autoimmune diseases and malignancy.^7,8 By this theory, the occurrence of MF in patients is facilitated by the inability of CD lymphocytes to control the abnormal T-cell proliferation in the skin. Interestingly, the finding of SS in our patient supports the possibility of impaired regulatory T-cell function.

Although the occurrence of both MF and CD in our patient could be coincidental, the possibility of correlation must be considered as more cases are documented.

To the Editor:

Mycosis fungoides (MF) is the most common form of a heterogeneous group of non-Hodgkin lymphomas known as cutaneous T-cell lymphomas. Celiac disease (CD) is associated with increased risk for development of enteropathy-associated T-cell lymphoma and other intraintestinal and extraintestinal non-Hodgkin lymphomas, but a firm association between CD and MF has not been established.¹ The first and second cases of concomitant MF and CD were reported in 1985 and 2009 by Coulson and Sanderson² and Moreira et al,³ respectively. Two other reports of celiac-associated dermatitis herpetiformis and MF exist.^4,5 We report a patient with a unique constellation of MF, CD, and Sjögren syndrome (SS).

A 54-year-old woman presented with a worsening nonpruritic, slightly tender, eczematous patch on the back of 19 years’ duration. She had a history of SS diagnosed by salivary gland biopsy. She also had a diagnosis of CD confirmed with positive antigliadin IgA antibodies, with a dramatic improvement in symptoms on a gluten-free diet (GFD) after having abdominal pain and diarrhea for many years. She had no evidence of dermatitis herpetiformis. Recently, more red-brown areas of confluent light pink erythema without clear-cut borders had appeared on the axillae, trunk, and thigh (Figure). The patient also noted new lesions and more erythema of the patches when not adhering to a GFD. A biopsy specimen from the left side of the lateral trunk revealed a bandlike lymphocytic infiltrate with irregular nuclear contours displaying epidermotropism with a few Pautrier microabscesses. Immunohistochemistry showed strong CD3 and CD4 positivity with loss of CD7 and scattered CD8 staining. Peripheral blood flow cytometry showed no aberrant cell populations. The patient was diagnosed with MF stage IB and treated with topical corticosteroids and natural light with improvement.

It has been hypothesized that early MF is an autoimmune process caused by dysregulation of a lymphocytic reaction against chronic exogenous or endogenous antigens.^4,5 The association of MF with CD supports the possibility of lymphocytic stimulation by a persistent antigen (ie, gluten) in the gastrointestinal tract. Porter et al⁴ suggested that in susceptible individuals, the resulting clonal T cells may migrate into the epidermis, causing MF. This theory also is supported by the finding that adherence to a GFD leads to decreased risk for malignancy and morbidity.⁶ In our patient, the chronic autoimmune stimulation in SS could be a factor in the pathogenesis of MF. Additionally, SS, CD, and MF are all strongly associated with increased incidence of specific but different HLA class II antigens. Mycosis fungoides is associated with HLA-DR5 and DQB1*03 alleles, CD with HLA-DQ2 and DQ8, and SS with HLA-DR15 and DR3. We do not know the HLA type of our patient, but she likely possessed multiple alleles, leading to the unique aggregation of diseases.

Furthermore, studies have shown that lymphocytes in CD patients display impaired regulatory T-cell function, causing increased incidence of autoimmune diseases and malignancy.^7,8 By this theory, the occurrence of MF in patients is facilitated by the inability of CD lymphocytes to control the abnormal T-cell proliferation in the skin. Interestingly, the finding of SS in our patient supports the possibility of impaired regulatory T-cell function.

Although the occurrence of both MF and CD in our patient could be coincidental, the possibility of correlation must be considered as more cases are documented.

The Diagnosis: Trigeminal Trophic Syndrome

Trigeminal trophic syndrome (TTS) is a rare condition occurring after injury to the sensory roots of the trigeminal nerve. Trigeminal trophic syndrome was first described in 1933 by Loveman¹ as a complication of ablative treatment of trigeminal neuralgia; however, it has been observed with lesions to the central or peripheral nervous system that damage sensory components of the trigeminal nerve. In our patient, the cause was likely an infarction of the posterior inferior cerebellar artery, which supplies both the cerebellum and the trigeminal nuclei in the brain stem.

Other possible causes of TTS include injury from herpes zoster ophthalmicus; vertebrobasilar insufficiency; trauma; Mycobacterium leprae neuritis; spinal cord degeneration; syringobulbia; or tumors such as astrocytomas, meningiomas, and acoustic neuromas.² The most typical presenting manifestation is a unilateral, crescent-shaped ulceration of the nasal ala, specifically where cartilage is lacking.³ Less frequently, it affects the upper lip, cheeks, forehead, scalp, and ear. It characteristically spares the nasal tip, which derives sensory innervation from the medial branch of the anterior ethmoidal nerve.⁴ The affected dermatomal distribution can show anesthesia or paresthesia, promoting the urge to touch, pick, or rub the area.

Histology of the TTS lesion is nondiagnostic, usually showing a mixed dermal inflammation without evidence of infection, vasculitis, or malignancy. In our patient, Gram stain, Grocott-Gomori methenamine-silver stain, and immunohistochemical stains to rule out leukemia or lymphoma were all negative. In addition, flow cytometry of the forehead tissue also was normal. Tests for human immunodeficiency virus, herpes simplex virus types 1 and 2, hepatitis, syphilis, histoplasmosis, blastomycosis, coccidioides, and tuberculosis were negative.During the biopsy, the patient was noted to have anesthesia of the skin. He also admitted to facial manipulation and was noted to have blood and tissue under the fingernails on mornings when the lesion was left uncovered overnight.

Treatment of TTS often can be difficult, especially if patients do not admit to wound manipulation or if manipulation occurs during sleep. Prevention of further ulceration can sometimes be achieved by occlusive dressing alone with mupirocin. Physical barriers can be supplemented with medications such as amitriptyline, carbamazepine, diazepam, chlorpromazine, and gabapentin to attempt to reduce paresthesia.² Psychiatric consultation can sometimes be necessary and helpful.³ Additionally, negative pressure wound therapy has been used with success in the pediatric setting when digital manipulation is difficult to control.⁵ More aggressive treatments include transcutaneous electrical stimulation, stellate ganglionectomy, radiotherapy, and innervated rotation flaps.^6,7

In summary, recognition of this relatively rare cause of unilateral facial erosions is critical, both to prevent counterproductive treatments such as steroids and to initiate measures to prevent further trauma to the lesion.

The Diagnosis: Trigeminal Trophic Syndrome

Trigeminal trophic syndrome (TTS) is a rare condition occurring after injury to the sensory roots of the trigeminal nerve. Trigeminal trophic syndrome was first described in 1933 by Loveman¹ as a complication of ablative treatment of trigeminal neuralgia; however, it has been observed with lesions to the central or peripheral nervous system that damage sensory components of the trigeminal nerve. In our patient, the cause was likely an infarction of the posterior inferior cerebellar artery, which supplies both the cerebellum and the trigeminal nuclei in the brain stem.

Other possible causes of TTS include injury from herpes zoster ophthalmicus; vertebrobasilar insufficiency; trauma; Mycobacterium leprae neuritis; spinal cord degeneration; syringobulbia; or tumors such as astrocytomas, meningiomas, and acoustic neuromas.² The most typical presenting manifestation is a unilateral, crescent-shaped ulceration of the nasal ala, specifically where cartilage is lacking.³ Less frequently, it affects the upper lip, cheeks, forehead, scalp, and ear. It characteristically spares the nasal tip, which derives sensory innervation from the medial branch of the anterior ethmoidal nerve.⁴ The affected dermatomal distribution can show anesthesia or paresthesia, promoting the urge to touch, pick, or rub the area.

Histology of the TTS lesion is nondiagnostic, usually showing a mixed dermal inflammation without evidence of infection, vasculitis, or malignancy. In our patient, Gram stain, Grocott-Gomori methenamine-silver stain, and immunohistochemical stains to rule out leukemia or lymphoma were all negative. In addition, flow cytometry of the forehead tissue also was normal. Tests for human immunodeficiency virus, herpes simplex virus types 1 and 2, hepatitis, syphilis, histoplasmosis, blastomycosis, coccidioides, and tuberculosis were negative.During the biopsy, the patient was noted to have anesthesia of the skin. He also admitted to facial manipulation and was noted to have blood and tissue under the fingernails on mornings when the lesion was left uncovered overnight.

Treatment of TTS often can be difficult, especially if patients do not admit to wound manipulation or if manipulation occurs during sleep. Prevention of further ulceration can sometimes be achieved by occlusive dressing alone with mupirocin. Physical barriers can be supplemented with medications such as amitriptyline, carbamazepine, diazepam, chlorpromazine, and gabapentin to attempt to reduce paresthesia.² Psychiatric consultation can sometimes be necessary and helpful.³ Additionally, negative pressure wound therapy has been used with success in the pediatric setting when digital manipulation is difficult to control.⁵ More aggressive treatments include transcutaneous electrical stimulation, stellate ganglionectomy, radiotherapy, and innervated rotation flaps.^6,7

In summary, recognition of this relatively rare cause of unilateral facial erosions is critical, both to prevent counterproductive treatments such as steroids and to initiate measures to prevent further trauma to the lesion.

The Diagnosis: Trigeminal Trophic Syndrome

Trigeminal trophic syndrome (TTS) is a rare condition occurring after injury to the sensory roots of the trigeminal nerve. Trigeminal trophic syndrome was first described in 1933 by Loveman¹ as a complication of ablative treatment of trigeminal neuralgia; however, it has been observed with lesions to the central or peripheral nervous system that damage sensory components of the trigeminal nerve. In our patient, the cause was likely an infarction of the posterior inferior cerebellar artery, which supplies both the cerebellum and the trigeminal nuclei in the brain stem.

Other possible causes of TTS include injury from herpes zoster ophthalmicus; vertebrobasilar insufficiency; trauma; Mycobacterium leprae neuritis; spinal cord degeneration; syringobulbia; or tumors such as astrocytomas, meningiomas, and acoustic neuromas.² The most typical presenting manifestation is a unilateral, crescent-shaped ulceration of the nasal ala, specifically where cartilage is lacking.³ Less frequently, it affects the upper lip, cheeks, forehead, scalp, and ear. It characteristically spares the nasal tip, which derives sensory innervation from the medial branch of the anterior ethmoidal nerve.⁴ The affected dermatomal distribution can show anesthesia or paresthesia, promoting the urge to touch, pick, or rub the area.

Histology of the TTS lesion is nondiagnostic, usually showing a mixed dermal inflammation without evidence of infection, vasculitis, or malignancy. In our patient, Gram stain, Grocott-Gomori methenamine-silver stain, and immunohistochemical stains to rule out leukemia or lymphoma were all negative. In addition, flow cytometry of the forehead tissue also was normal. Tests for human immunodeficiency virus, herpes simplex virus types 1 and 2, hepatitis, syphilis, histoplasmosis, blastomycosis, coccidioides, and tuberculosis were negative.During the biopsy, the patient was noted to have anesthesia of the skin. He also admitted to facial manipulation and was noted to have blood and tissue under the fingernails on mornings when the lesion was left uncovered overnight.

Treatment of TTS often can be difficult, especially if patients do not admit to wound manipulation or if manipulation occurs during sleep. Prevention of further ulceration can sometimes be achieved by occlusive dressing alone with mupirocin. Physical barriers can be supplemented with medications such as amitriptyline, carbamazepine, diazepam, chlorpromazine, and gabapentin to attempt to reduce paresthesia.² Psychiatric consultation can sometimes be necessary and helpful.³ Additionally, negative pressure wound therapy has been used with success in the pediatric setting when digital manipulation is difficult to control.⁵ More aggressive treatments include transcutaneous electrical stimulation, stellate ganglionectomy, radiotherapy, and innervated rotation flaps.^6,7

In summary, recognition of this relatively rare cause of unilateral facial erosions is critical, both to prevent counterproductive treatments such as steroids and to initiate measures to prevent further trauma to the lesion.