Doctor and cancer patient

Photo courtesy of NCI

and Mathews Media Group

Survey results suggest the use of aggressive treatment at the end of life is on the rise among older cancer patients, and these patients often fail to employ advanced care planning measures.

Researchers reviewed nearly 2000 surveys of people whose loved ones died of cancer and found that, from 2000 to 2012, there was a 51% increase in reports that patients received “all care possible” at the end of life.

There was a 22% increase in power-of-attorney assignment over the same period, but the use of living wills and discussions about end-of-life preferences decreased slightly.

“Although more cancer patients are assigning power-of-attorney privileges to someone they know and trust to make their medical decisions when they can’t, this practice may be the least helpful among advanced care planning tactics because it may be least associated with treatment intensity at the end of life,” said Amol Narang, MD, of The Johns Hopkins Hospital in Baltimore, Maryland.

Dr Narang and his colleagues described this research in JAMA Oncology.

The team analyzed survey data from 1985 next-of-kin surrogates of cancer patients. The patients were older than 50 years of age, had taken part in the Health and Retirement Study, and died between 2000 and 2012.

The data included in-depth “exit” interviews conducted with the surrogates after a patient died. Seventy-nine percent of exit survey respondents said they were the primary decision-maker in the patient’s medical care.

The data showed a significant increase in power-of-attorney assignments, from 52% in 2000 to 74% in 2012 (P=0.03). But the use of living wills decreased slightly, from 49% to 40% (P=0.63), as did discussions about end-of-life preferences, which fell from 68% to 60% (P=0.62).

“We found that many cancer patients still do not communicate their preferences for end-of-life care, despite the potential benefits to patients’ quality of life and caregiver bereavement,” Dr Narang said.

Survey results also suggested a significant increase in the percentage of patients who received “all care possible” at the end of life, from 7% in 2000 to 58% in 2012 (P=0.004). But there was no significant change in the rates of terminal hospitalizations, which fell from 29% to 27% (P=0.70).

The researchers found that granting power-of-attorney privileges significantly decreased the odds that patients would die in the hospital as opposed to hospice or their homes (adjusted odds ratio [AOR]=0.70, P<0.05). However, granting power of attorney was not associated with a significant change in limiting or withholding treatment at the end of life (AOR=1.52).

On the other hand, patients who created living wills or had end-of-life discussions were significantly more likely than their peers to limit or withhold certain treatments. The AOR was 2.51 for living wills (P<0.001) and 1.93 for end-of-life discussions (P=0.002).

The researchers said they observed the same trends regardless of who completed the exit survey.

Dr Narang noted that this study had its limitations. The survey questions were subjective, answers could have been hampered by a respondent’s lapse in memory, and answers could be biased by a respondent’s desire to meet social norms.

“But we were looking at trends over time,” he said, “so respondents’ bias would not likely change over time.”

Doctor and cancer patient

Photo courtesy of NCI

and Mathews Media Group

Survey results suggest the use of aggressive treatment at the end of life is on the rise among older cancer patients, and these patients often fail to employ advanced care planning measures.

Researchers reviewed nearly 2000 surveys of people whose loved ones died of cancer and found that, from 2000 to 2012, there was a 51% increase in reports that patients received “all care possible” at the end of life.

There was a 22% increase in power-of-attorney assignment over the same period, but the use of living wills and discussions about end-of-life preferences decreased slightly.

“Although more cancer patients are assigning power-of-attorney privileges to someone they know and trust to make their medical decisions when they can’t, this practice may be the least helpful among advanced care planning tactics because it may be least associated with treatment intensity at the end of life,” said Amol Narang, MD, of The Johns Hopkins Hospital in Baltimore, Maryland.

Dr Narang and his colleagues described this research in JAMA Oncology.

The team analyzed survey data from 1985 next-of-kin surrogates of cancer patients. The patients were older than 50 years of age, had taken part in the Health and Retirement Study, and died between 2000 and 2012.

The data included in-depth “exit” interviews conducted with the surrogates after a patient died. Seventy-nine percent of exit survey respondents said they were the primary decision-maker in the patient’s medical care.

The data showed a significant increase in power-of-attorney assignments, from 52% in 2000 to 74% in 2012 (P=0.03). But the use of living wills decreased slightly, from 49% to 40% (P=0.63), as did discussions about end-of-life preferences, which fell from 68% to 60% (P=0.62).

“We found that many cancer patients still do not communicate their preferences for end-of-life care, despite the potential benefits to patients’ quality of life and caregiver bereavement,” Dr Narang said.

Survey results also suggested a significant increase in the percentage of patients who received “all care possible” at the end of life, from 7% in 2000 to 58% in 2012 (P=0.004). But there was no significant change in the rates of terminal hospitalizations, which fell from 29% to 27% (P=0.70).

The researchers found that granting power-of-attorney privileges significantly decreased the odds that patients would die in the hospital as opposed to hospice or their homes (adjusted odds ratio [AOR]=0.70, P<0.05). However, granting power of attorney was not associated with a significant change in limiting or withholding treatment at the end of life (AOR=1.52).

On the other hand, patients who created living wills or had end-of-life discussions were significantly more likely than their peers to limit or withhold certain treatments. The AOR was 2.51 for living wills (P<0.001) and 1.93 for end-of-life discussions (P=0.002).

The researchers said they observed the same trends regardless of who completed the exit survey.

Dr Narang noted that this study had its limitations. The survey questions were subjective, answers could have been hampered by a respondent’s lapse in memory, and answers could be biased by a respondent’s desire to meet social norms.

“But we were looking at trends over time,” he said, “so respondents’ bias would not likely change over time.”

Doctor and cancer patient

Photo courtesy of NCI

and Mathews Media Group

Survey results suggest the use of aggressive treatment at the end of life is on the rise among older cancer patients, and these patients often fail to employ advanced care planning measures.

Researchers reviewed nearly 2000 surveys of people whose loved ones died of cancer and found that, from 2000 to 2012, there was a 51% increase in reports that patients received “all care possible” at the end of life.

There was a 22% increase in power-of-attorney assignment over the same period, but the use of living wills and discussions about end-of-life preferences decreased slightly.

“Although more cancer patients are assigning power-of-attorney privileges to someone they know and trust to make their medical decisions when they can’t, this practice may be the least helpful among advanced care planning tactics because it may be least associated with treatment intensity at the end of life,” said Amol Narang, MD, of The Johns Hopkins Hospital in Baltimore, Maryland.

Dr Narang and his colleagues described this research in JAMA Oncology.

The team analyzed survey data from 1985 next-of-kin surrogates of cancer patients. The patients were older than 50 years of age, had taken part in the Health and Retirement Study, and died between 2000 and 2012.

The data included in-depth “exit” interviews conducted with the surrogates after a patient died. Seventy-nine percent of exit survey respondents said they were the primary decision-maker in the patient’s medical care.

The data showed a significant increase in power-of-attorney assignments, from 52% in 2000 to 74% in 2012 (P=0.03). But the use of living wills decreased slightly, from 49% to 40% (P=0.63), as did discussions about end-of-life preferences, which fell from 68% to 60% (P=0.62).

“We found that many cancer patients still do not communicate their preferences for end-of-life care, despite the potential benefits to patients’ quality of life and caregiver bereavement,” Dr Narang said.

Survey results also suggested a significant increase in the percentage of patients who received “all care possible” at the end of life, from 7% in 2000 to 58% in 2012 (P=0.004). But there was no significant change in the rates of terminal hospitalizations, which fell from 29% to 27% (P=0.70).

The researchers found that granting power-of-attorney privileges significantly decreased the odds that patients would die in the hospital as opposed to hospice or their homes (adjusted odds ratio [AOR]=0.70, P<0.05). However, granting power of attorney was not associated with a significant change in limiting or withholding treatment at the end of life (AOR=1.52).

On the other hand, patients who created living wills or had end-of-life discussions were significantly more likely than their peers to limit or withhold certain treatments. The AOR was 2.51 for living wills (P<0.001) and 1.93 for end-of-life discussions (P=0.002).

The researchers said they observed the same trends regardless of who completed the exit survey.

Dr Narang noted that this study had its limitations. The survey questions were subjective, answers could have been hampered by a respondent’s lapse in memory, and answers could be biased by a respondent’s desire to meet social norms.

“But we were looking at trends over time,” he said, “so respondents’ bias would not likely change over time.”

 

 

NK cell destroying a cancer cell

Image by Joshua Strokes

 

Researchers say they have determined how lymphoma cells evade natural killer (NK) cells, and this discovery has revealed potential solutions to the problem.

The team found that NK-cell activation and a second, “triggering” event are both necessary for NK cells to exhibit cytotoxicity in the presence of B-cell lymphoma.

Previous research demonstrated this 2-step process in vitro. Now, researchers have shown that it occurs in vivo.

Dr Ralph Mocikat, of Helmholtz Zentrum München in Munich, Germany, and his colleagues described this research in the European Journal of Immunology.

The team conducted experiments using transplantable tumors, a λ-myc-transgenic model of endogenously arising lymphoma that mimics human Burkitt lymphoma, and mice deficient in the NK group 2 D (NKG2D) receptor.

The experiments showed that NK cells could eliminate lymphoma cells after receiving 2 signals. The first was NK-cell activation, which gave rise to IFN-γ expression.

The researchers found that NK cells could be activated in the presence of MHC class I_low tumor cells or by injecting bone marrow-derived dendritic cells. Previous research had shown that interleukin 2 (IL-2) and IL-15 could activate NK cells.

The second step involved the NKG2D receptor and its ligands. NKG2D ligands are located on the surface of tumor cells and bind to NK cells. The researchers found that, if these ligands are down-regulated, the NK cells cannot carry out cytotoxic activity.

However, the team found they could increase NKG2D ligand levels. They introduced bortezomib to the tumor cell line 291 and saw a roughly 4-fold increase in NKG2D ligand levels.

“Our results show that the transfer of NK cells is a possible strategic option to treat B-cell lymphoma,” Dr Mocikat said. “According to our findings, this therapeutic approach can be optimized when transferred NK cells are already activated in vitro prior to their injection, thus bypassing the missing activation potential in the tumor microenvironment. An additional injection of IFN-γ or of antibodies against IL-10 could further support the immune activity.”

 

 

NK cell destroying a cancer cell

Image by Joshua Strokes

 

Researchers say they have determined how lymphoma cells evade natural killer (NK) cells, and this discovery has revealed potential solutions to the problem.

The team found that NK-cell activation and a second, “triggering” event are both necessary for NK cells to exhibit cytotoxicity in the presence of B-cell lymphoma.

Previous research demonstrated this 2-step process in vitro. Now, researchers have shown that it occurs in vivo.

Dr Ralph Mocikat, of Helmholtz Zentrum München in Munich, Germany, and his colleagues described this research in the European Journal of Immunology.

The team conducted experiments using transplantable tumors, a λ-myc-transgenic model of endogenously arising lymphoma that mimics human Burkitt lymphoma, and mice deficient in the NK group 2 D (NKG2D) receptor.

The experiments showed that NK cells could eliminate lymphoma cells after receiving 2 signals. The first was NK-cell activation, which gave rise to IFN-γ expression.

The researchers found that NK cells could be activated in the presence of MHC class I_low tumor cells or by injecting bone marrow-derived dendritic cells. Previous research had shown that interleukin 2 (IL-2) and IL-15 could activate NK cells.

The second step involved the NKG2D receptor and its ligands. NKG2D ligands are located on the surface of tumor cells and bind to NK cells. The researchers found that, if these ligands are down-regulated, the NK cells cannot carry out cytotoxic activity.

However, the team found they could increase NKG2D ligand levels. They introduced bortezomib to the tumor cell line 291 and saw a roughly 4-fold increase in NKG2D ligand levels.

“Our results show that the transfer of NK cells is a possible strategic option to treat B-cell lymphoma,” Dr Mocikat said. “According to our findings, this therapeutic approach can be optimized when transferred NK cells are already activated in vitro prior to their injection, thus bypassing the missing activation potential in the tumor microenvironment. An additional injection of IFN-γ or of antibodies against IL-10 could further support the immune activity.”

 

 

NK cell destroying a cancer cell

Image by Joshua Strokes

 

Researchers say they have determined how lymphoma cells evade natural killer (NK) cells, and this discovery has revealed potential solutions to the problem.

The team found that NK-cell activation and a second, “triggering” event are both necessary for NK cells to exhibit cytotoxicity in the presence of B-cell lymphoma.

Previous research demonstrated this 2-step process in vitro. Now, researchers have shown that it occurs in vivo.

Dr Ralph Mocikat, of Helmholtz Zentrum München in Munich, Germany, and his colleagues described this research in the European Journal of Immunology.

The team conducted experiments using transplantable tumors, a λ-myc-transgenic model of endogenously arising lymphoma that mimics human Burkitt lymphoma, and mice deficient in the NK group 2 D (NKG2D) receptor.

The experiments showed that NK cells could eliminate lymphoma cells after receiving 2 signals. The first was NK-cell activation, which gave rise to IFN-γ expression.

The researchers found that NK cells could be activated in the presence of MHC class I_low tumor cells or by injecting bone marrow-derived dendritic cells. Previous research had shown that interleukin 2 (IL-2) and IL-15 could activate NK cells.

The second step involved the NKG2D receptor and its ligands. NKG2D ligands are located on the surface of tumor cells and bind to NK cells. The researchers found that, if these ligands are down-regulated, the NK cells cannot carry out cytotoxic activity.

However, the team found they could increase NKG2D ligand levels. They introduced bortezomib to the tumor cell line 291 and saw a roughly 4-fold increase in NKG2D ligand levels.

“Our results show that the transfer of NK cells is a possible strategic option to treat B-cell lymphoma,” Dr Mocikat said. “According to our findings, this therapeutic approach can be optimized when transferred NK cells are already activated in vitro prior to their injection, thus bypassing the missing activation potential in the tumor microenvironment. An additional injection of IFN-γ or of antibodies against IL-10 could further support the immune activity.”

Doctor consults with cancer

patient and her father

Photo by Rhoda Baer

In a retrospective study, a majority of adolescents and young adults (AYAs) with terminal cancer received aggressive end-of-life (EOL) care.

Investigators looked at the use of intensive care, emergency room visits, chemotherapy use, and hospitalization among more than 600 AYAs with cancer who were treated at Kaiser Permanente in California.

Nearly 70% of patients made use of at least one of these measures in the last month of their life.

The investigators noted that their findings, which were published in JAMA Oncology, may not reflect care for the wider US population. But the study does suggest a need for more research into whether this

pattern reflects AYA cancer patients’ preferences for EOL care.

“A young person facing the end of life is a particularly difficult issue,” said study author Jennifer Mack, MD, MPH, of the Dana-Farber Cancer Institute in Boston, Massachusetts.

“While use of aggressive measures might be an informed decision by young people who would do anything they could to live longer, some interventions come with a cost, which is a poorer quality of life. This study raises questions about what kind of care they’re getting and how we can get them to the best quality of life at the end of their lives.”

The study included 633 patients, ages 15 to 39, who died of cancer between 2001 and 2010. The patients, who received care at Kaiser Permanente Southern California, had either been diagnosed with stage IV cancer or had a recurrence of stage I-III cancer. An initial review of a subset of 111 patients showed that death had been anticipated in 98% of cases.

The most common cancer diagnosis was gastrointestinal cancer (17%), while other common diagnoses were breast cancer (15%), genitourinary cancers (11%), leukemia (14%), and lymphoma (10%).

The investigators measured the use of 4 aggressive treatment measures—intensive care, emergency room visits, chemotherapy, and hospitalization—in patients’ last month of life.

Overall, 68% of patients (449/663) received at least one of these medically intensive EOL care measures. Eleven percent of patients (72/663) received chemotherapy, 22% (144/663) were admitted to the intensive care unit, 22% (147/663) had more than one emergency department visit, and 62% (413/663) were hospitalized.

Rates of hospitalization were higher among patients diagnosed with stage IV disease (66%) than among patients with stage I to III disease—66% and 58%, respectively (P=0.04).

The percentage of patients who received at least one medically intensive EOL care measure was higher in the stage IV cohort as well—71% and 63%, respectively (P=0.03). But there were no significant differences between the cohorts with regard to the other measures.

The investigators said these findings suggest the need to better understand EOL care preferences and decision-making in AYAs with cancer.

“We should think about talking with younger patients earlier about their prognoses, identifying their preferences, and working with them to deliver care that reflects those preferences,” Dr Mack said. “It may be that aggressive care is what they want, but they may end up on this pathway without thoughtful conversation and may be without recognition that they are dying.”

Doctor consults with cancer

patient and her father

Photo by Rhoda Baer

In a retrospective study, a majority of adolescents and young adults (AYAs) with terminal cancer received aggressive end-of-life (EOL) care.

Investigators looked at the use of intensive care, emergency room visits, chemotherapy use, and hospitalization among more than 600 AYAs with cancer who were treated at Kaiser Permanente in California.

Nearly 70% of patients made use of at least one of these measures in the last month of their life.

The investigators noted that their findings, which were published in JAMA Oncology, may not reflect care for the wider US population. But the study does suggest a need for more research into whether this

pattern reflects AYA cancer patients’ preferences for EOL care.

“A young person facing the end of life is a particularly difficult issue,” said study author Jennifer Mack, MD, MPH, of the Dana-Farber Cancer Institute in Boston, Massachusetts.

“While use of aggressive measures might be an informed decision by young people who would do anything they could to live longer, some interventions come with a cost, which is a poorer quality of life. This study raises questions about what kind of care they’re getting and how we can get them to the best quality of life at the end of their lives.”

The study included 633 patients, ages 15 to 39, who died of cancer between 2001 and 2010. The patients, who received care at Kaiser Permanente Southern California, had either been diagnosed with stage IV cancer or had a recurrence of stage I-III cancer. An initial review of a subset of 111 patients showed that death had been anticipated in 98% of cases.

The most common cancer diagnosis was gastrointestinal cancer (17%), while other common diagnoses were breast cancer (15%), genitourinary cancers (11%), leukemia (14%), and lymphoma (10%).

The investigators measured the use of 4 aggressive treatment measures—intensive care, emergency room visits, chemotherapy, and hospitalization—in patients’ last month of life.

Overall, 68% of patients (449/663) received at least one of these medically intensive EOL care measures. Eleven percent of patients (72/663) received chemotherapy, 22% (144/663) were admitted to the intensive care unit, 22% (147/663) had more than one emergency department visit, and 62% (413/663) were hospitalized.

Rates of hospitalization were higher among patients diagnosed with stage IV disease (66%) than among patients with stage I to III disease—66% and 58%, respectively (P=0.04).

The percentage of patients who received at least one medically intensive EOL care measure was higher in the stage IV cohort as well—71% and 63%, respectively (P=0.03). But there were no significant differences between the cohorts with regard to the other measures.

The investigators said these findings suggest the need to better understand EOL care preferences and decision-making in AYAs with cancer.

“We should think about talking with younger patients earlier about their prognoses, identifying their preferences, and working with them to deliver care that reflects those preferences,” Dr Mack said. “It may be that aggressive care is what they want, but they may end up on this pathway without thoughtful conversation and may be without recognition that they are dying.”

Doctor consults with cancer

patient and her father

Photo by Rhoda Baer

In a retrospective study, a majority of adolescents and young adults (AYAs) with terminal cancer received aggressive end-of-life (EOL) care.

Investigators looked at the use of intensive care, emergency room visits, chemotherapy use, and hospitalization among more than 600 AYAs with cancer who were treated at Kaiser Permanente in California.

Nearly 70% of patients made use of at least one of these measures in the last month of their life.

The investigators noted that their findings, which were published in JAMA Oncology, may not reflect care for the wider US population. But the study does suggest a need for more research into whether this

pattern reflects AYA cancer patients’ preferences for EOL care.

“A young person facing the end of life is a particularly difficult issue,” said study author Jennifer Mack, MD, MPH, of the Dana-Farber Cancer Institute in Boston, Massachusetts.

“While use of aggressive measures might be an informed decision by young people who would do anything they could to live longer, some interventions come with a cost, which is a poorer quality of life. This study raises questions about what kind of care they’re getting and how we can get them to the best quality of life at the end of their lives.”

The study included 633 patients, ages 15 to 39, who died of cancer between 2001 and 2010. The patients, who received care at Kaiser Permanente Southern California, had either been diagnosed with stage IV cancer or had a recurrence of stage I-III cancer. An initial review of a subset of 111 patients showed that death had been anticipated in 98% of cases.

The most common cancer diagnosis was gastrointestinal cancer (17%), while other common diagnoses were breast cancer (15%), genitourinary cancers (11%), leukemia (14%), and lymphoma (10%).

The investigators measured the use of 4 aggressive treatment measures—intensive care, emergency room visits, chemotherapy, and hospitalization—in patients’ last month of life.

Overall, 68% of patients (449/663) received at least one of these medically intensive EOL care measures. Eleven percent of patients (72/663) received chemotherapy, 22% (144/663) were admitted to the intensive care unit, 22% (147/663) had more than one emergency department visit, and 62% (413/663) were hospitalized.

Rates of hospitalization were higher among patients diagnosed with stage IV disease (66%) than among patients with stage I to III disease—66% and 58%, respectively (P=0.04).

The percentage of patients who received at least one medically intensive EOL care measure was higher in the stage IV cohort as well—71% and 63%, respectively (P=0.03). But there were no significant differences between the cohorts with regard to the other measures.

The investigators said these findings suggest the need to better understand EOL care preferences and decision-making in AYAs with cancer.

“We should think about talking with younger patients earlier about their prognoses, identifying their preferences, and working with them to deliver care that reflects those preferences,” Dr Mack said. “It may be that aggressive care is what they want, but they may end up on this pathway without thoughtful conversation and may be without recognition that they are dying.”

The Food and Drug Administration has taken new action to strengthen existing warning labels about the increased risk of heart attack or stroke with the use of prescription and over-the-counter nonaspirin nonsteroidal anti-inflammatory drugs.

In a July 9 drug safety communication, the agency did not provide the exact language that will be used on NSAID labels, but said that they “will be revised to reflect” information describing that:

• The risk of heart attack or stroke can occur as early as the first weeks of using an NSAID.

• The risk may increase with longer use and at higher doses of the NSAID.

Courtesy Wikimedia Commons/FitzColinGerald/Creative Commons License

• The drugs can increase the risk of heart attack or stroke even in patients without heart disease or risk factors for heart disease, but patients with heart disease or risk factors for it have a greater likelihood of heart attack or stroke following NSAID use.

• Treatment with NSAIDs following a first heart attack increases the risk of death in the first year after the heart attack, compared with patients who were not treated with NSAIDs after their first heart attack.

• NSAID use increases the risk of heart failure.

The new wording will also note that although newer information may suggest that the risk for heart attack or stroke is not the same for all NSAIDs, it “is not sufficient for us to determine that the risk of any particular NSAID is definitely higher or lower than that of any other particular NSAID.”

*The update to NSAID labels follows the recommendations given by panel members from a joint meeting of the FDA’s Arthritis Advisory Committee and the Drug Safety and Risk Management Advisory Committee in February 2014 in which there was a split vote (14-11) that was slightly in favor of rewording the warning labeling for NSAIDs in regard to the drug class’s current labeling, which implies that the cardiovascular thrombotic risk is not substantial with short treatment courses. At that meeting, the panelists also voted 16-9 that there were not enough data to suggest that naproxen presented a substantially lower risk of CV events than did either ibuprofen or selective NSAIDs, such as cyclooxygenase-2 inhibitors.

The FDA made its decision based on a comprehensive review of the data presented during that meeting.

*Correction, 7/16/2015: An earlier version of this story misstated the FDA panels’ recommendation for labeling changes.

[email protected]

The Food and Drug Administration has taken new action to strengthen existing warning labels about the increased risk of heart attack or stroke with the use of prescription and over-the-counter nonaspirin nonsteroidal anti-inflammatory drugs.

In a July 9 drug safety communication, the agency did not provide the exact language that will be used on NSAID labels, but said that they “will be revised to reflect” information describing that:

• The risk of heart attack or stroke can occur as early as the first weeks of using an NSAID.

• The risk may increase with longer use and at higher doses of the NSAID.

Courtesy Wikimedia Commons/FitzColinGerald/Creative Commons License

• The drugs can increase the risk of heart attack or stroke even in patients without heart disease or risk factors for heart disease, but patients with heart disease or risk factors for it have a greater likelihood of heart attack or stroke following NSAID use.

• Treatment with NSAIDs following a first heart attack increases the risk of death in the first year after the heart attack, compared with patients who were not treated with NSAIDs after their first heart attack.

• NSAID use increases the risk of heart failure.

The new wording will also note that although newer information may suggest that the risk for heart attack or stroke is not the same for all NSAIDs, it “is not sufficient for us to determine that the risk of any particular NSAID is definitely higher or lower than that of any other particular NSAID.”

*The update to NSAID labels follows the recommendations given by panel members from a joint meeting of the FDA’s Arthritis Advisory Committee and the Drug Safety and Risk Management Advisory Committee in February 2014 in which there was a split vote (14-11) that was slightly in favor of rewording the warning labeling for NSAIDs in regard to the drug class’s current labeling, which implies that the cardiovascular thrombotic risk is not substantial with short treatment courses. At that meeting, the panelists also voted 16-9 that there were not enough data to suggest that naproxen presented a substantially lower risk of CV events than did either ibuprofen or selective NSAIDs, such as cyclooxygenase-2 inhibitors.

The FDA made its decision based on a comprehensive review of the data presented during that meeting.

*Correction, 7/16/2015: An earlier version of this story misstated the FDA panels’ recommendation for labeling changes.

[email protected]

The Food and Drug Administration has taken new action to strengthen existing warning labels about the increased risk of heart attack or stroke with the use of prescription and over-the-counter nonaspirin nonsteroidal anti-inflammatory drugs.

In a July 9 drug safety communication, the agency did not provide the exact language that will be used on NSAID labels, but said that they “will be revised to reflect” information describing that:

• The risk of heart attack or stroke can occur as early as the first weeks of using an NSAID.

• The risk may increase with longer use and at higher doses of the NSAID.

Courtesy Wikimedia Commons/FitzColinGerald/Creative Commons License

• The drugs can increase the risk of heart attack or stroke even in patients without heart disease or risk factors for heart disease, but patients with heart disease or risk factors for it have a greater likelihood of heart attack or stroke following NSAID use.

• Treatment with NSAIDs following a first heart attack increases the risk of death in the first year after the heart attack, compared with patients who were not treated with NSAIDs after their first heart attack.

• NSAID use increases the risk of heart failure.

The new wording will also note that although newer information may suggest that the risk for heart attack or stroke is not the same for all NSAIDs, it “is not sufficient for us to determine that the risk of any particular NSAID is definitely higher or lower than that of any other particular NSAID.”

*The update to NSAID labels follows the recommendations given by panel members from a joint meeting of the FDA’s Arthritis Advisory Committee and the Drug Safety and Risk Management Advisory Committee in February 2014 in which there was a split vote (14-11) that was slightly in favor of rewording the warning labeling for NSAIDs in regard to the drug class’s current labeling, which implies that the cardiovascular thrombotic risk is not substantial with short treatment courses. At that meeting, the panelists also voted 16-9 that there were not enough data to suggest that naproxen presented a substantially lower risk of CV events than did either ibuprofen or selective NSAIDs, such as cyclooxygenase-2 inhibitors.

The FDA made its decision based on a comprehensive review of the data presented during that meeting.

*Correction, 7/16/2015: An earlier version of this story misstated the FDA panels’ recommendation for labeling changes.

[email protected]

Rosai-Dorfman disease (RDD), also known as sinus histiocytosis with massive lymphadenopathy, is a rare benign histioproliferative disorder of unknown etiology.¹ Clinically, it is most frequently characterized by massive painless cervical lymphadenopathy with other systemic manifestations, including fever, night sweats, and weight loss. Accompanying laboratory findings include leukocytosis with neutrophilia, elevated erythrocyte sedimentation rate, and polyclonal hypergammaglobulinemia. Extranodal involvement has been noted in more than 40% of cases, and cutaneous lesions represent the most common form of extranodal disease.² Cutaneous RDD is a distinct and rare entity limited to the skin without lymphadenopathy or other extracutaneous involvement.³ Patients with cutaneous RDD typically present with papules and plaques that can grow to form nodules with satellite lesions that resolve into fibrotic plaques before spontaneous regression.⁴

Histologic examination of cutaneous lesions of RDD reveals a dense nodular dermal and often subcutaneous infiltrate of characteristic large polygonal histiocytes termed Rosai-Dorfman cells, which feature abundant pale to eosinophilic cytoplasm, indistinct borders, and large vesicular nuclei with prominent nucleoli (Figure 1).^4,5 Some multinucleate forms may be seen. These Rosai-Dorfman cells display positive staining for CD68 and S-100, and negative staining for CD1a on immunohistochemistry. Lymphocytes and plasma cells often are admixed with the Rosai-Dorfman cells, and neutrophils and eosinophils also may be present in the infiltrate.⁴ The histologic hallmark of RDD is emperipolesis, a phenomenon whereby inflammatory cells such as lymphocytes and plasma cells reside intact within the cytoplasm of histiocytes (Figure 2).⁵

Figure 1. Sheets of large polygonal histiocytes with admixed lymphocytes and plasma cells seen in Rosai-Dorfman disease (H&E, original magnification ×200).

Figure 2. Emperipolesis (histiocyte-engulfing lymphocytes) demonstrated in Rosai-Dorfman disease (H&E, original magnification ×600).

The histologic differential diagnosis of cutaneous lesions of RDD includes other histiocytic and xanthomatous diseases, including eruptive xanthoma, juvenile xanthogranuloma, Langerhans cell histiocytosis, and solitary reticulohistiocytoma, which should not display emperipolesis. Eruptive xanthomas display collections of foamy histiocytes in the dermis and typically contain extracellular lipid. They may contain infiltrates of lymphocytes (Figure 3). Juvenile xanthogranuloma also features a dense infiltrate of histiocytes in the papillary and reticular dermis but distinctly shows Touton giant cells and lipidization of histiocytes (Figure 4). Both eruptive xanthomas and juvenile xanthogranulomas typically stain negatively for S-100. Langerhans cell histiocytosis is histologically characterized by a dermal infiltrate of Langerhans cells that have their own distinctive morphologic features. They are uniformly ovoid with abundant eosinophilic cytoplasm. Their nuclei are smaller than those of Rosai-Dorfman cells and have a kidney bean shape with inconspicuous nucleoli (Figure 5). Epidermotropism of these cells can be observed. Immunohistochemically, Langerhans cell histiocytosis typically is S-100 positive, CD1a positive, and langerin positive. Reticulohistiocytoma features histiocytes that have a characteristic dusty rose or ground glass cytoplasm with two-toned darker and lighter areas (Figure 6). Reticulohistiocytoma cells stain positively for CD68 but typically stain negatively for both CD1a and S-100.

Figure 3. Lipid-laden macrophages with foamy cytoplasm and extracellular lipid seen in eruptive xanthoma (H&E, original magnification ×400).			Figure 4. Touton giant cell (wreath of nuclei surrounded by foamy cytoplasm) featured in juvenile xanthogranuloma (H&E, original magnification ×600).
Figure 5. Dermal infiltrate of ovoid Langerhans cells with reniform nuclei in Langerhans cell histiocytosis (H&E, original magnification ×600).			Figure 6. Histiocytes with dusty rose–colored cytoplasm and admixed lymphocytes in a reticulohistiocytoma (H&E, original magnification ×400).

Rosai-Dorfman disease (RDD), also known as sinus histiocytosis with massive lymphadenopathy, is a rare benign histioproliferative disorder of unknown etiology.¹ Clinically, it is most frequently characterized by massive painless cervical lymphadenopathy with other systemic manifestations, including fever, night sweats, and weight loss. Accompanying laboratory findings include leukocytosis with neutrophilia, elevated erythrocyte sedimentation rate, and polyclonal hypergammaglobulinemia. Extranodal involvement has been noted in more than 40% of cases, and cutaneous lesions represent the most common form of extranodal disease.² Cutaneous RDD is a distinct and rare entity limited to the skin without lymphadenopathy or other extracutaneous involvement.³ Patients with cutaneous RDD typically present with papules and plaques that can grow to form nodules with satellite lesions that resolve into fibrotic plaques before spontaneous regression.⁴

Histologic examination of cutaneous lesions of RDD reveals a dense nodular dermal and often subcutaneous infiltrate of characteristic large polygonal histiocytes termed Rosai-Dorfman cells, which feature abundant pale to eosinophilic cytoplasm, indistinct borders, and large vesicular nuclei with prominent nucleoli (Figure 1).^4,5 Some multinucleate forms may be seen. These Rosai-Dorfman cells display positive staining for CD68 and S-100, and negative staining for CD1a on immunohistochemistry. Lymphocytes and plasma cells often are admixed with the Rosai-Dorfman cells, and neutrophils and eosinophils also may be present in the infiltrate.⁴ The histologic hallmark of RDD is emperipolesis, a phenomenon whereby inflammatory cells such as lymphocytes and plasma cells reside intact within the cytoplasm of histiocytes (Figure 2).⁵

Figure 1. Sheets of large polygonal histiocytes with admixed lymphocytes and plasma cells seen in Rosai-Dorfman disease (H&E, original magnification ×200).

Figure 2. Emperipolesis (histiocyte-engulfing lymphocytes) demonstrated in Rosai-Dorfman disease (H&E, original magnification ×600).

The histologic differential diagnosis of cutaneous lesions of RDD includes other histiocytic and xanthomatous diseases, including eruptive xanthoma, juvenile xanthogranuloma, Langerhans cell histiocytosis, and solitary reticulohistiocytoma, which should not display emperipolesis. Eruptive xanthomas display collections of foamy histiocytes in the dermis and typically contain extracellular lipid. They may contain infiltrates of lymphocytes (Figure 3). Juvenile xanthogranuloma also features a dense infiltrate of histiocytes in the papillary and reticular dermis but distinctly shows Touton giant cells and lipidization of histiocytes (Figure 4). Both eruptive xanthomas and juvenile xanthogranulomas typically stain negatively for S-100. Langerhans cell histiocytosis is histologically characterized by a dermal infiltrate of Langerhans cells that have their own distinctive morphologic features. They are uniformly ovoid with abundant eosinophilic cytoplasm. Their nuclei are smaller than those of Rosai-Dorfman cells and have a kidney bean shape with inconspicuous nucleoli (Figure 5). Epidermotropism of these cells can be observed. Immunohistochemically, Langerhans cell histiocytosis typically is S-100 positive, CD1a positive, and langerin positive. Reticulohistiocytoma features histiocytes that have a characteristic dusty rose or ground glass cytoplasm with two-toned darker and lighter areas (Figure 6). Reticulohistiocytoma cells stain positively for CD68 but typically stain negatively for both CD1a and S-100.

Figure 3. Lipid-laden macrophages with foamy cytoplasm and extracellular lipid seen in eruptive xanthoma (H&E, original magnification ×400).			Figure 4. Touton giant cell (wreath of nuclei surrounded by foamy cytoplasm) featured in juvenile xanthogranuloma (H&E, original magnification ×600).
Figure 5. Dermal infiltrate of ovoid Langerhans cells with reniform nuclei in Langerhans cell histiocytosis (H&E, original magnification ×600).			Figure 6. Histiocytes with dusty rose–colored cytoplasm and admixed lymphocytes in a reticulohistiocytoma (H&E, original magnification ×400).

Rosai-Dorfman disease (RDD), also known as sinus histiocytosis with massive lymphadenopathy, is a rare benign histioproliferative disorder of unknown etiology.¹ Clinically, it is most frequently characterized by massive painless cervical lymphadenopathy with other systemic manifestations, including fever, night sweats, and weight loss. Accompanying laboratory findings include leukocytosis with neutrophilia, elevated erythrocyte sedimentation rate, and polyclonal hypergammaglobulinemia. Extranodal involvement has been noted in more than 40% of cases, and cutaneous lesions represent the most common form of extranodal disease.² Cutaneous RDD is a distinct and rare entity limited to the skin without lymphadenopathy or other extracutaneous involvement.³ Patients with cutaneous RDD typically present with papules and plaques that can grow to form nodules with satellite lesions that resolve into fibrotic plaques before spontaneous regression.⁴

Histologic examination of cutaneous lesions of RDD reveals a dense nodular dermal and often subcutaneous infiltrate of characteristic large polygonal histiocytes termed Rosai-Dorfman cells, which feature abundant pale to eosinophilic cytoplasm, indistinct borders, and large vesicular nuclei with prominent nucleoli (Figure 1).^4,5 Some multinucleate forms may be seen. These Rosai-Dorfman cells display positive staining for CD68 and S-100, and negative staining for CD1a on immunohistochemistry. Lymphocytes and plasma cells often are admixed with the Rosai-Dorfman cells, and neutrophils and eosinophils also may be present in the infiltrate.⁴ The histologic hallmark of RDD is emperipolesis, a phenomenon whereby inflammatory cells such as lymphocytes and plasma cells reside intact within the cytoplasm of histiocytes (Figure 2).⁵

Figure 1. Sheets of large polygonal histiocytes with admixed lymphocytes and plasma cells seen in Rosai-Dorfman disease (H&E, original magnification ×200).

Figure 2. Emperipolesis (histiocyte-engulfing lymphocytes) demonstrated in Rosai-Dorfman disease (H&E, original magnification ×600).

The histologic differential diagnosis of cutaneous lesions of RDD includes other histiocytic and xanthomatous diseases, including eruptive xanthoma, juvenile xanthogranuloma, Langerhans cell histiocytosis, and solitary reticulohistiocytoma, which should not display emperipolesis. Eruptive xanthomas display collections of foamy histiocytes in the dermis and typically contain extracellular lipid. They may contain infiltrates of lymphocytes (Figure 3). Juvenile xanthogranuloma also features a dense infiltrate of histiocytes in the papillary and reticular dermis but distinctly shows Touton giant cells and lipidization of histiocytes (Figure 4). Both eruptive xanthomas and juvenile xanthogranulomas typically stain negatively for S-100. Langerhans cell histiocytosis is histologically characterized by a dermal infiltrate of Langerhans cells that have their own distinctive morphologic features. They are uniformly ovoid with abundant eosinophilic cytoplasm. Their nuclei are smaller than those of Rosai-Dorfman cells and have a kidney bean shape with inconspicuous nucleoli (Figure 5). Epidermotropism of these cells can be observed. Immunohistochemically, Langerhans cell histiocytosis typically is S-100 positive, CD1a positive, and langerin positive. Reticulohistiocytoma features histiocytes that have a characteristic dusty rose or ground glass cytoplasm with two-toned darker and lighter areas (Figure 6). Reticulohistiocytoma cells stain positively for CD68 but typically stain negatively for both CD1a and S-100.

Figure 3. Lipid-laden macrophages with foamy cytoplasm and extracellular lipid seen in eruptive xanthoma (H&E, original magnification ×400).			Figure 4. Touton giant cell (wreath of nuclei surrounded by foamy cytoplasm) featured in juvenile xanthogranuloma (H&E, original magnification ×600).
Figure 5. Dermal infiltrate of ovoid Langerhans cells with reniform nuclei in Langerhans cell histiocytosis (H&E, original magnification ×600).			Figure 6. Histiocytes with dusty rose–colored cytoplasm and admixed lymphocytes in a reticulohistiocytoma (H&E, original magnification ×400).

There is an old saying, “Sticks and stones may break my bones, but words will never hurt me.” When it comes to our patients’ impressions of us, nothing could be farther from the truth. As a matter of fact, their words, expressed in post-discharge patient satisfaction surveys, can play a tremendous role in the financial stability of our hospitals.

Throughout the years, hospitals have employed a wide variety of methods to evaluate their patients’ experiences, if only to improve their service and strengthen their brand. The Hospital Consumer Assessment of Healthcare Providers and Systems (HCAHPS) initiative has taken patient satisfaction to a new level by creating the first national, standardized survey tool to measure patients’ perspectives of the care they received while hospitalized. In addition, HCAHPS was designed to provide objective, meaningful comparisons of hospitals, and these comparisons are publicly reported, which increases transparency of the quality of care provided to hospitalized patients.

The survey is administered between 48 hours and 6 weeks post discharge to a random sample of adult patients by mail, telephone, mail and telephone, or Interactive Voice Response (IVR). Discharged patients are asked 27 questions about their recent hospitalization including communication with doctors and nurses, pain management, discharge information, communication about medication, overall hospital rating, and whether they would recommend the hospital to others.

Four times per year, the Centers for Medicaid & Medicare Services publishes HCAHPS scores of participating hospitals on the Hospital Compare website (www.hospitalcompare.hhs.gov), though the survey is not restricted to Medicare patients. Patients can pick and choose which hospitals they like, and which ones they would avoid like the plague.

Of course, it’s not realistic to think that we are going to please all of our patients all of the time, but this initiative does have the potential to create a new sense of accountability, as well as competitiveness for hospital systems and providers alike. No one wants to be at the bottom of the pack.

So, how do we increase our scores? Many models and companies claim to help improve patient satisfaction. Just do an Internet search. Keep in mind, what works well for one group may be ineffective for another.

For instance, 5-minute per patient multidisciplinary bedside rounding – including the provider, nurse, pharmacist, and case manager – may be easy to implement and skyrocket patient satisfaction in some institutions. In others, getting appropriate staffing may be prohibitive. Regardless of the approach that may be right for your group, it is important to keep in mind that the tide of health care is ever changing. Patients are demanding, and receiving, a bigger role in their health care. We all want to be in the forefront, not at the tail end, of that tide.

Dr. Hester is a hospitalist at Baltimore-Washington Medical Center in Glen Burnie, Md. She is the creator of the Patient Whiz, a patient-engagement app for iOS. Reach her at [email protected].

There is an old saying, “Sticks and stones may break my bones, but words will never hurt me.” When it comes to our patients’ impressions of us, nothing could be farther from the truth. As a matter of fact, their words, expressed in post-discharge patient satisfaction surveys, can play a tremendous role in the financial stability of our hospitals.

Throughout the years, hospitals have employed a wide variety of methods to evaluate their patients’ experiences, if only to improve their service and strengthen their brand. The Hospital Consumer Assessment of Healthcare Providers and Systems (HCAHPS) initiative has taken patient satisfaction to a new level by creating the first national, standardized survey tool to measure patients’ perspectives of the care they received while hospitalized. In addition, HCAHPS was designed to provide objective, meaningful comparisons of hospitals, and these comparisons are publicly reported, which increases transparency of the quality of care provided to hospitalized patients.

The survey is administered between 48 hours and 6 weeks post discharge to a random sample of adult patients by mail, telephone, mail and telephone, or Interactive Voice Response (IVR). Discharged patients are asked 27 questions about their recent hospitalization including communication with doctors and nurses, pain management, discharge information, communication about medication, overall hospital rating, and whether they would recommend the hospital to others.

Four times per year, the Centers for Medicaid & Medicare Services publishes HCAHPS scores of participating hospitals on the Hospital Compare website (www.hospitalcompare.hhs.gov), though the survey is not restricted to Medicare patients. Patients can pick and choose which hospitals they like, and which ones they would avoid like the plague.

Of course, it’s not realistic to think that we are going to please all of our patients all of the time, but this initiative does have the potential to create a new sense of accountability, as well as competitiveness for hospital systems and providers alike. No one wants to be at the bottom of the pack.

So, how do we increase our scores? Many models and companies claim to help improve patient satisfaction. Just do an Internet search. Keep in mind, what works well for one group may be ineffective for another.

For instance, 5-minute per patient multidisciplinary bedside rounding – including the provider, nurse, pharmacist, and case manager – may be easy to implement and skyrocket patient satisfaction in some institutions. In others, getting appropriate staffing may be prohibitive. Regardless of the approach that may be right for your group, it is important to keep in mind that the tide of health care is ever changing. Patients are demanding, and receiving, a bigger role in their health care. We all want to be in the forefront, not at the tail end, of that tide.

Dr. Hester is a hospitalist at Baltimore-Washington Medical Center in Glen Burnie, Md. She is the creator of the Patient Whiz, a patient-engagement app for iOS. Reach her at [email protected].

There is an old saying, “Sticks and stones may break my bones, but words will never hurt me.” When it comes to our patients’ impressions of us, nothing could be farther from the truth. As a matter of fact, their words, expressed in post-discharge patient satisfaction surveys, can play a tremendous role in the financial stability of our hospitals.

Throughout the years, hospitals have employed a wide variety of methods to evaluate their patients’ experiences, if only to improve their service and strengthen their brand. The Hospital Consumer Assessment of Healthcare Providers and Systems (HCAHPS) initiative has taken patient satisfaction to a new level by creating the first national, standardized survey tool to measure patients’ perspectives of the care they received while hospitalized. In addition, HCAHPS was designed to provide objective, meaningful comparisons of hospitals, and these comparisons are publicly reported, which increases transparency of the quality of care provided to hospitalized patients.

The survey is administered between 48 hours and 6 weeks post discharge to a random sample of adult patients by mail, telephone, mail and telephone, or Interactive Voice Response (IVR). Discharged patients are asked 27 questions about their recent hospitalization including communication with doctors and nurses, pain management, discharge information, communication about medication, overall hospital rating, and whether they would recommend the hospital to others.

Four times per year, the Centers for Medicaid & Medicare Services publishes HCAHPS scores of participating hospitals on the Hospital Compare website (www.hospitalcompare.hhs.gov), though the survey is not restricted to Medicare patients. Patients can pick and choose which hospitals they like, and which ones they would avoid like the plague.

Of course, it’s not realistic to think that we are going to please all of our patients all of the time, but this initiative does have the potential to create a new sense of accountability, as well as competitiveness for hospital systems and providers alike. No one wants to be at the bottom of the pack.

So, how do we increase our scores? Many models and companies claim to help improve patient satisfaction. Just do an Internet search. Keep in mind, what works well for one group may be ineffective for another.

For instance, 5-minute per patient multidisciplinary bedside rounding – including the provider, nurse, pharmacist, and case manager – may be easy to implement and skyrocket patient satisfaction in some institutions. In others, getting appropriate staffing may be prohibitive. Regardless of the approach that may be right for your group, it is important to keep in mind that the tide of health care is ever changing. Patients are demanding, and receiving, a bigger role in their health care. We all want to be in the forefront, not at the tail end, of that tide.

Dr. Hester is a hospitalist at Baltimore-Washington Medical Center in Glen Burnie, Md. She is the creator of the Patient Whiz, a patient-engagement app for iOS. Reach her at [email protected].

A 43-year-old woman presented with pain and paresthesia of the bilateral legs of 3 months’ duration with skin tightness and discoloration, which she attributed to a car accident that occurred 7 months prior. She also reported abdominal pain, shortness of breath, fever, double vision, dysphagia, voice changes, temperature sensitivity, and hair loss. The patient underwent outpatient steroid injections with limited symptomatic relief. She denied any antecedent exposure to vinyl chloride, rapeseed oil, or L-tryptophan. Physical examination revealed thickened skin on the bilateral legs (top), reddish discoloration of the feet, decreased sensation to light touch, and edema of the ankles and wrists, as well as a peau d’orange appearance of the skin on the arms (bottom), legs, and abdomen.

The Diagnosis: Eosinophilic Fasciitis

Eosinophilic fasciitis is a rare autoimmune disease of uncertain etiology first described by Shulman¹ in 1974. It is similar in presentation and is perhaps related to scleroderma. Classic differentiating features include a peculiar peau d’orange appearance, peripheral eosinophilia, and lack of Raynaud phenomenon, thus it is regarded as a unique disease.² Despite the name of the disease, eosinophilia has been known to be absent in later stages of eosinophilic fasciitis.¹

Figure 1. Groove sign on the left forearm characteristic of eosinophilic fasciitis.

On physical examination, “prayer and groove signs” can sometimes be evident.³ Although it was not initially observed in our case, a groove sign was noted on the left forearm on a second inspection (Figure 1). In contrast with systemic sclerosis, visceral involvement rarely is seen with eosinophilic fasciitis. There are, however, 3 major exceptions to this rule. First, there can be widespread nerve deficits, esophageal dysmotility, and nonspecific electromyography findings (ie, denervation, reinnervation, fasciculations).⁴ There also can be a concomitant hematologic disorder or Hashimoto thyroiditis.⁵ Because eosinophilic fasciitis has been associated with monoclonal gammopathy, which our patient also demonstrated, it is important to conduct a workup with serum or urine protein electrophoresis. If the test is negative, it should be followed up with an immunofixation assay or serum light chain assays.

Some proposed risk factors for eosinophilic fasciitis include trauma, extensive exercise, and Borrelia burgdorferi infection, but many cases have none of these associations.⁸ Although not firmly proven in the literature, there have been reports of eosinophilic fasciitis after isolated trauma.⁵ A causal link could not be established between our patient’s car accident and eosinophilic fasciitis, but the coincidence was notable.

The treatment of eosinophilic fasciitis is similar to scleroderma. Corticosteroids are effective in most cases and recovery often occurs with monotherapy.⁵ Case series have demonstrated efficacy in adding methotrexate, azathioprine, colchicine, and hydroxychloroquine in refractory patients.^2,9 Our patient demonstrated a good response with a combination of prednisone and methotrexate. Relapses have been known to occur.²

A punch biopsy obtained from the right arm showed thickened acellular collagen bundles throughout the dermis and extending into the underlying subcutis. There also was obliteration of adnexal structures, loss of perieccrine fat, and sparse perivascular and interstitial lymphoplasmacytic infiltrate (Figure 2), consistent with a sclerosing disorder such as scleroderma or eosinophilic fasciitis.

Figure 2. A punch biopsy from the right arm showed thickened acellular collagen bundles throughout the dermis and extending into the underlying subcutis. There also was obliteration of adnexal structures, loss of perieccrine fat, and sparse perivascular and interstitial lymphoplasmacytic infiltrate (H&amp;E, original magnification ×10).

A complete blood cell count revealed eosinophil levels of 12.5% (reference range, 2.7%). Rheumatologic workup was negative for antinuclear antibody, double-stranded DNA, thyroid-stimulating hormone, anticentromere antibodies, and Scl-70 autoantibodies. Computed tomography of the chest and pelvis revealed a thickened patulous esophagus. Endoscopy showed dysmotility of the lower esophagus. At this point the differential diagnosis included scleredema versus eosinophilic fasciitis, and the patient was started on oral prednisone 60 mg daily. She showed rapid improvement in sclerosis, joint mobility, and ability to swallow. Magnetic resonance imaging was then performed and revealed thickening and contrast enhancement of the forearm fascia, particularly along the distal aspect, confirming a diagnosis of eosinophilic fasciitis. Further workup including immunofixation assay and serum light chain assays were performed, revealing IgG λ hypergammaglobulinemia. She was then additionally treated with oral methotrexate 15 mg weekly. Due to the rapid improvement of symptoms on oral prednisone over 2 weeks, the peripheral eosinophilia, the magnetic resonance imaging findings, and the results of skin biopsy, a diagnosis of eosinophilic fasciitis was heavily favored over scleroderma and scleredema.

A 43-year-old woman presented with pain and paresthesia of the bilateral legs of 3 months’ duration with skin tightness and discoloration, which she attributed to a car accident that occurred 7 months prior. She also reported abdominal pain, shortness of breath, fever, double vision, dysphagia, voice changes, temperature sensitivity, and hair loss. The patient underwent outpatient steroid injections with limited symptomatic relief. She denied any antecedent exposure to vinyl chloride, rapeseed oil, or L-tryptophan. Physical examination revealed thickened skin on the bilateral legs (top), reddish discoloration of the feet, decreased sensation to light touch, and edema of the ankles and wrists, as well as a peau d’orange appearance of the skin on the arms (bottom), legs, and abdomen.

The Diagnosis: Eosinophilic Fasciitis

Eosinophilic fasciitis is a rare autoimmune disease of uncertain etiology first described by Shulman¹ in 1974. It is similar in presentation and is perhaps related to scleroderma. Classic differentiating features include a peculiar peau d’orange appearance, peripheral eosinophilia, and lack of Raynaud phenomenon, thus it is regarded as a unique disease.² Despite the name of the disease, eosinophilia has been known to be absent in later stages of eosinophilic fasciitis.¹

Figure 1. Groove sign on the left forearm characteristic of eosinophilic fasciitis.

On physical examination, “prayer and groove signs” can sometimes be evident.³ Although it was not initially observed in our case, a groove sign was noted on the left forearm on a second inspection (Figure 1). In contrast with systemic sclerosis, visceral involvement rarely is seen with eosinophilic fasciitis. There are, however, 3 major exceptions to this rule. First, there can be widespread nerve deficits, esophageal dysmotility, and nonspecific electromyography findings (ie, denervation, reinnervation, fasciculations).⁴ There also can be a concomitant hematologic disorder or Hashimoto thyroiditis.⁵ Because eosinophilic fasciitis has been associated with monoclonal gammopathy, which our patient also demonstrated, it is important to conduct a workup with serum or urine protein electrophoresis. If the test is negative, it should be followed up with an immunofixation assay or serum light chain assays.

Some proposed risk factors for eosinophilic fasciitis include trauma, extensive exercise, and Borrelia burgdorferi infection, but many cases have none of these associations.⁸ Although not firmly proven in the literature, there have been reports of eosinophilic fasciitis after isolated trauma.⁵ A causal link could not be established between our patient’s car accident and eosinophilic fasciitis, but the coincidence was notable.

The treatment of eosinophilic fasciitis is similar to scleroderma. Corticosteroids are effective in most cases and recovery often occurs with monotherapy.⁵ Case series have demonstrated efficacy in adding methotrexate, azathioprine, colchicine, and hydroxychloroquine in refractory patients.^2,9 Our patient demonstrated a good response with a combination of prednisone and methotrexate. Relapses have been known to occur.²

A punch biopsy obtained from the right arm showed thickened acellular collagen bundles throughout the dermis and extending into the underlying subcutis. There also was obliteration of adnexal structures, loss of perieccrine fat, and sparse perivascular and interstitial lymphoplasmacytic infiltrate (Figure 2), consistent with a sclerosing disorder such as scleroderma or eosinophilic fasciitis.

Figure 2. A punch biopsy from the right arm showed thickened acellular collagen bundles throughout the dermis and extending into the underlying subcutis. There also was obliteration of adnexal structures, loss of perieccrine fat, and sparse perivascular and interstitial lymphoplasmacytic infiltrate (H&amp;E, original magnification ×10).

A complete blood cell count revealed eosinophil levels of 12.5% (reference range, 2.7%). Rheumatologic workup was negative for antinuclear antibody, double-stranded DNA, thyroid-stimulating hormone, anticentromere antibodies, and Scl-70 autoantibodies. Computed tomography of the chest and pelvis revealed a thickened patulous esophagus. Endoscopy showed dysmotility of the lower esophagus. At this point the differential diagnosis included scleredema versus eosinophilic fasciitis, and the patient was started on oral prednisone 60 mg daily. She showed rapid improvement in sclerosis, joint mobility, and ability to swallow. Magnetic resonance imaging was then performed and revealed thickening and contrast enhancement of the forearm fascia, particularly along the distal aspect, confirming a diagnosis of eosinophilic fasciitis. Further workup including immunofixation assay and serum light chain assays were performed, revealing IgG λ hypergammaglobulinemia. She was then additionally treated with oral methotrexate 15 mg weekly. Due to the rapid improvement of symptoms on oral prednisone over 2 weeks, the peripheral eosinophilia, the magnetic resonance imaging findings, and the results of skin biopsy, a diagnosis of eosinophilic fasciitis was heavily favored over scleroderma and scleredema.

A 43-year-old woman presented with pain and paresthesia of the bilateral legs of 3 months’ duration with skin tightness and discoloration, which she attributed to a car accident that occurred 7 months prior. She also reported abdominal pain, shortness of breath, fever, double vision, dysphagia, voice changes, temperature sensitivity, and hair loss. The patient underwent outpatient steroid injections with limited symptomatic relief. She denied any antecedent exposure to vinyl chloride, rapeseed oil, or L-tryptophan. Physical examination revealed thickened skin on the bilateral legs (top), reddish discoloration of the feet, decreased sensation to light touch, and edema of the ankles and wrists, as well as a peau d’orange appearance of the skin on the arms (bottom), legs, and abdomen.

The Diagnosis: Eosinophilic Fasciitis

Eosinophilic fasciitis is a rare autoimmune disease of uncertain etiology first described by Shulman¹ in 1974. It is similar in presentation and is perhaps related to scleroderma. Classic differentiating features include a peculiar peau d’orange appearance, peripheral eosinophilia, and lack of Raynaud phenomenon, thus it is regarded as a unique disease.² Despite the name of the disease, eosinophilia has been known to be absent in later stages of eosinophilic fasciitis.¹

Figure 1. Groove sign on the left forearm characteristic of eosinophilic fasciitis.

On physical examination, “prayer and groove signs” can sometimes be evident.³ Although it was not initially observed in our case, a groove sign was noted on the left forearm on a second inspection (Figure 1). In contrast with systemic sclerosis, visceral involvement rarely is seen with eosinophilic fasciitis. There are, however, 3 major exceptions to this rule. First, there can be widespread nerve deficits, esophageal dysmotility, and nonspecific electromyography findings (ie, denervation, reinnervation, fasciculations).⁴ There also can be a concomitant hematologic disorder or Hashimoto thyroiditis.⁵ Because eosinophilic fasciitis has been associated with monoclonal gammopathy, which our patient also demonstrated, it is important to conduct a workup with serum or urine protein electrophoresis. If the test is negative, it should be followed up with an immunofixation assay or serum light chain assays.

Some proposed risk factors for eosinophilic fasciitis include trauma, extensive exercise, and Borrelia burgdorferi infection, but many cases have none of these associations.⁸ Although not firmly proven in the literature, there have been reports of eosinophilic fasciitis after isolated trauma.⁵ A causal link could not be established between our patient’s car accident and eosinophilic fasciitis, but the coincidence was notable.

The treatment of eosinophilic fasciitis is similar to scleroderma. Corticosteroids are effective in most cases and recovery often occurs with monotherapy.⁵ Case series have demonstrated efficacy in adding methotrexate, azathioprine, colchicine, and hydroxychloroquine in refractory patients.^2,9 Our patient demonstrated a good response with a combination of prednisone and methotrexate. Relapses have been known to occur.²

A punch biopsy obtained from the right arm showed thickened acellular collagen bundles throughout the dermis and extending into the underlying subcutis. There also was obliteration of adnexal structures, loss of perieccrine fat, and sparse perivascular and interstitial lymphoplasmacytic infiltrate (Figure 2), consistent with a sclerosing disorder such as scleroderma or eosinophilic fasciitis.

Figure 2. A punch biopsy from the right arm showed thickened acellular collagen bundles throughout the dermis and extending into the underlying subcutis. There also was obliteration of adnexal structures, loss of perieccrine fat, and sparse perivascular and interstitial lymphoplasmacytic infiltrate (H&amp;E, original magnification ×10).

A complete blood cell count revealed eosinophil levels of 12.5% (reference range, 2.7%). Rheumatologic workup was negative for antinuclear antibody, double-stranded DNA, thyroid-stimulating hormone, anticentromere antibodies, and Scl-70 autoantibodies. Computed tomography of the chest and pelvis revealed a thickened patulous esophagus. Endoscopy showed dysmotility of the lower esophagus. At this point the differential diagnosis included scleredema versus eosinophilic fasciitis, and the patient was started on oral prednisone 60 mg daily. She showed rapid improvement in sclerosis, joint mobility, and ability to swallow. Magnetic resonance imaging was then performed and revealed thickening and contrast enhancement of the forearm fascia, particularly along the distal aspect, confirming a diagnosis of eosinophilic fasciitis. Further workup including immunofixation assay and serum light chain assays were performed, revealing IgG λ hypergammaglobulinemia. She was then additionally treated with oral methotrexate 15 mg weekly. Due to the rapid improvement of symptoms on oral prednisone over 2 weeks, the peripheral eosinophilia, the magnetic resonance imaging findings, and the results of skin biopsy, a diagnosis of eosinophilic fasciitis was heavily favored over scleroderma and scleredema.

Clinical question: Is trimethoprim-sulfamethoxazole equivalent to vancomycin for the treatment of severe infections caused by methicillin-resistant Staphyloccus aureus?

Bottom line: Trimethoprim-sulfamethoxazole (TMP-SMX) did not achieve noninferiority as compared with vancomycin for the treatment of severe methicillin-resistant Staphyloccus aureus (MRSA) infections in hospitalized patients, and it may lead to increased mortality in the subset of patients with bacteremia. (LOE = 1b)

Reference: Paul M, Bishara J, Yahav D, et al. Trimethoprim-sulfamethoxazole versus vancomycin for severe infections caused by meticillin-resistant Staphylococcus aureus. BMJ 2015;350:h2219.

Study design: Randomized controlled trial (nonblinded)

Funding source: Foundation

Allocation: Concealed

Setting: Inpatient (any location)

Synopsis

Although TMP-SMX can be used to treat uncomplicated skin and soft-tissue infections caused by MRSA, it is not currently recommended for more serious MRSA infections such as bacteremia or pneumonia. In this study, investigators tested whether TMP-SMX is noninferior to vancomycin for the treatment of hospitalized patients with severe MRSA infections. Patients included in the study (N = 252) had microbiologically documented MRSA infections, including complicated skin and soft-tissue infections, bone or joint infections, pneumonia, or primary bacteremia. Patients with MRSA isolates resistant to TMP-SMX or vancomycin were excluded.

Using concealed allocation, the investigators randomized the patients to receive either high-dose TMP-SMX (320 mg trimethoprim/1600 mg sulfamethoxazole intravenously twice daily) or vancomycin (1 mg intravenously twice daily) for at least 7 days. In the TMP-SMX group, treatment could be transitioned to an oral regimen of an equivalent dose at the clinician's discretion. The 2 groups had similar baseline characteristics with a mean age of 66 years and similar comorbidities, though the vancomycin group had a higher percentage of patients with bacteremia than the TMP-SMX group (30% vs 43%; P = .042). The primary outcome was treatment failure at 7 days, defined as a composite of death, persistent fever or hypotension, stable or worsening Sequential Organ Failure Assessment score, or persistent bacteremia. There was no statistically significant difference detected between the 2 groups for this outcome (38% treatment failure with TMP-SMX vs 27% with vancomycin; absolute difference 10.4%, 95% CI -1.2% to 21.5%).

However, since the 95% confidence interval for the absolute difference fell outside the predefined lower limit of noninferiority of 15%, the authors concluded that TMP-SMX failed to achieve noninferiority as compared with vancomycin. Additionally, in the subgroup of patients with bacteremia, patients were more likely to die in the TMP-SMX group as compared with the vancomycin group, although this difference again was not statistically significant (34% with TMP-SMX vs 18% with vancomycin; relative risk 1.90, 0.92-3.93).

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

Clinical question: Is trimethoprim-sulfamethoxazole equivalent to vancomycin for the treatment of severe infections caused by methicillin-resistant Staphyloccus aureus?

Bottom line: Trimethoprim-sulfamethoxazole (TMP-SMX) did not achieve noninferiority as compared with vancomycin for the treatment of severe methicillin-resistant Staphyloccus aureus (MRSA) infections in hospitalized patients, and it may lead to increased mortality in the subset of patients with bacteremia. (LOE = 1b)

Reference: Paul M, Bishara J, Yahav D, et al. Trimethoprim-sulfamethoxazole versus vancomycin for severe infections caused by meticillin-resistant Staphylococcus aureus. BMJ 2015;350:h2219.

Study design: Randomized controlled trial (nonblinded)

Funding source: Foundation

Allocation: Concealed

Setting: Inpatient (any location)

Synopsis

Although TMP-SMX can be used to treat uncomplicated skin and soft-tissue infections caused by MRSA, it is not currently recommended for more serious MRSA infections such as bacteremia or pneumonia. In this study, investigators tested whether TMP-SMX is noninferior to vancomycin for the treatment of hospitalized patients with severe MRSA infections. Patients included in the study (N = 252) had microbiologically documented MRSA infections, including complicated skin and soft-tissue infections, bone or joint infections, pneumonia, or primary bacteremia. Patients with MRSA isolates resistant to TMP-SMX or vancomycin were excluded.

Using concealed allocation, the investigators randomized the patients to receive either high-dose TMP-SMX (320 mg trimethoprim/1600 mg sulfamethoxazole intravenously twice daily) or vancomycin (1 mg intravenously twice daily) for at least 7 days. In the TMP-SMX group, treatment could be transitioned to an oral regimen of an equivalent dose at the clinician's discretion. The 2 groups had similar baseline characteristics with a mean age of 66 years and similar comorbidities, though the vancomycin group had a higher percentage of patients with bacteremia than the TMP-SMX group (30% vs 43%; P = .042). The primary outcome was treatment failure at 7 days, defined as a composite of death, persistent fever or hypotension, stable or worsening Sequential Organ Failure Assessment score, or persistent bacteremia. There was no statistically significant difference detected between the 2 groups for this outcome (38% treatment failure with TMP-SMX vs 27% with vancomycin; absolute difference 10.4%, 95% CI -1.2% to 21.5%).

However, since the 95% confidence interval for the absolute difference fell outside the predefined lower limit of noninferiority of 15%, the authors concluded that TMP-SMX failed to achieve noninferiority as compared with vancomycin. Additionally, in the subgroup of patients with bacteremia, patients were more likely to die in the TMP-SMX group as compared with the vancomycin group, although this difference again was not statistically significant (34% with TMP-SMX vs 18% with vancomycin; relative risk 1.90, 0.92-3.93).

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

Clinical question: Is trimethoprim-sulfamethoxazole equivalent to vancomycin for the treatment of severe infections caused by methicillin-resistant Staphyloccus aureus?

Bottom line: Trimethoprim-sulfamethoxazole (TMP-SMX) did not achieve noninferiority as compared with vancomycin for the treatment of severe methicillin-resistant Staphyloccus aureus (MRSA) infections in hospitalized patients, and it may lead to increased mortality in the subset of patients with bacteremia. (LOE = 1b)

Reference: Paul M, Bishara J, Yahav D, et al. Trimethoprim-sulfamethoxazole versus vancomycin for severe infections caused by meticillin-resistant Staphylococcus aureus. BMJ 2015;350:h2219.

Study design: Randomized controlled trial (nonblinded)

Funding source: Foundation

Allocation: Concealed

Setting: Inpatient (any location)

Synopsis

Although TMP-SMX can be used to treat uncomplicated skin and soft-tissue infections caused by MRSA, it is not currently recommended for more serious MRSA infections such as bacteremia or pneumonia. In this study, investigators tested whether TMP-SMX is noninferior to vancomycin for the treatment of hospitalized patients with severe MRSA infections. Patients included in the study (N = 252) had microbiologically documented MRSA infections, including complicated skin and soft-tissue infections, bone or joint infections, pneumonia, or primary bacteremia. Patients with MRSA isolates resistant to TMP-SMX or vancomycin were excluded.

Using concealed allocation, the investigators randomized the patients to receive either high-dose TMP-SMX (320 mg trimethoprim/1600 mg sulfamethoxazole intravenously twice daily) or vancomycin (1 mg intravenously twice daily) for at least 7 days. In the TMP-SMX group, treatment could be transitioned to an oral regimen of an equivalent dose at the clinician's discretion. The 2 groups had similar baseline characteristics with a mean age of 66 years and similar comorbidities, though the vancomycin group had a higher percentage of patients with bacteremia than the TMP-SMX group (30% vs 43%; P = .042). The primary outcome was treatment failure at 7 days, defined as a composite of death, persistent fever or hypotension, stable or worsening Sequential Organ Failure Assessment score, or persistent bacteremia. There was no statistically significant difference detected between the 2 groups for this outcome (38% treatment failure with TMP-SMX vs 27% with vancomycin; absolute difference 10.4%, 95% CI -1.2% to 21.5%).

However, since the 95% confidence interval for the absolute difference fell outside the predefined lower limit of noninferiority of 15%, the authors concluded that TMP-SMX failed to achieve noninferiority as compared with vancomycin. Additionally, in the subgroup of patients with bacteremia, patients were more likely to die in the TMP-SMX group as compared with the vancomycin group, although this difference again was not statistically significant (34% with TMP-SMX vs 18% with vancomycin; relative risk 1.90, 0.92-3.93).

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

Acne during pregnancy and lactation is common and poses a considerable treatment challenge for dermatologists. It is a disease that often is trivialized, viewed by the ill informed as cosmetic in nature. Combined with fetal and neonatal health concerns plus a healthy dose of medicolegal overlay, treatment of acne in this patient population may be complicated.

Pregnant and lactating women have been summarily orphaned from advances in drug therapy. Due to, in no small part, the pervasive litigious atmosphere surrounding birth defects in pregnancy, many health care providers have defaulted to avoiding all medications in this patient population to be “on the safe side,” and many have convinced pregnant women that taking medication to relieve pain and discomfort while pregnant is selfish and vain, especially where acne is concerned. However, erring on the safe side is not always safe. Drug avoidance can lead to increased physical and psychiatric morbidity.

Numerous studies have shown that acne is not trivial or inconsequential and may even be associated with suicidal ideations.^1,2 In one study, female gender and acne were both jointly and independently associated with the risk for major depression and suicide.³ The traditional notion that pregnancy is a time of joy and emotional well-being is not supported by data. There is a marked increase of mood instability during pregnancy. According to the American Psychological Association, the incidence of true clinical postpartum depression in the United States is 1 in 7 pregnancies but is likely much higher, as it often remains undiagnosed.⁴ These women may consider suicide and may even harm their children. Therefore, “first, do no harm” might indeed involve aggressive therapy in this patient population; at the very least, it warrants a thorough consideration of the risks and benefits rather than a knee-jerk “wait until you stop breastfeeding” default. Without adequate knowledge of true drug risks and with the stakes so high, we find ourselves in medicolegal quicksand. As clinicians, we understand the concept of weighing risks and benefits, but the balance of the scale cannot be determined when no evidence exists regarding the relative weight of the risk side.

Most drug risks in pregnancy are noted after market approval and are obtained from published case reports and retrospective birth defect registries. Reported problems likely represent a small fraction of actual cases. The absence of direct information regarding drug use during pregnancy is exacerbated by the knowledge that there are large gender differences in drug pharmacokinetics. This dichotomy would be expected to be especially pronounced between men and pregnant women in whom drug absorption, distribution, and elimination are all notably altered. A poorly publicized aberration in the drug approval process is that gender information is not required from generic medication bioequivalence studies. Although studies for drugs indicated for both sexes need to include male and female participants, resulting data showing gender differences are not required to be disclosed, which means that it is theoretically possible for a generic drug to be approved based on results in men only.

The pregnancy categories for drugs (A, B, C, D, and X), which were initially defined in 1979, have been our only aid in risk assessment but have little clinical relevance beyond defining the level of medicolegal risk. Furthermore, these drug categories are poised to disappear before the publication of this editorial, as new guidelines for labeling human prescription drugs are mandated to begin on June 30, 2015.⁵ Although guaranteed to be confusing at first, it seems the new labeling guidelines will be much more helpful for clinicians. One of the most important changes is the inclusion of the following statement in pregnancy and lactation subsections on drug labels: “All pregnancies have a background risk of birth defect, loss, or other adverse outcome regardless of drug exposure. The fetal risk summary below describes (name of drug)’s potential to increase the risk of developmental abnormalities above the background risk.”⁵ In the absence of concerning human data, efforts will be made to put positive animal data into perspective. In the absence of systemic exposure the label will state: “(Name of drug) is not absorbed systemically from (part of body) and cannot be detected in the blood. Maternal use is not expected to result in fetal exposure to the drug.”⁵ This final rule includes virtually all topical acne products, including topical retinoids.

As weak as the evidence-based risk information is for drugs in pregnancy, it is worse for lactation. It is a commonly mistaken belief among practitioners that the safety, or lack thereof, of medications during pregnancy indicates safety during lactation. In actuality, decisions should instead be based on safety data on the drug during the neonatal period. Levels of neonatal drug exposure through breast milk is 5- to 10-fold less than fetal exposure in utero.⁶ Therefore, it generally is safer for women to take drugs during lactation than during pregnancy. For the most part, medications enter the breast milk by passive diffusion from the maternal bloodstream. Several hours after a medication is taken, maternal blood levels fall and drug from the breast milk flows back along the concentration gradient into the maternal circulation. Therefore, safety is maximized by administering maternal medications immediately after the last feed and just prior to the longest sleep period of the child, usually at night.

In the lactation section of the new labeling guidelines ruling, the verbiage is completely different and highly clinically relevant. If the data demonstrate that a drug does not affect the quantity and/or quality of human breast milk, the product label must state: “The use of (name of drug) is compatible with breastfeeding.”⁵ If the drug is not systemically absorbed, the label will state simply and clearly, “Breastfeeding is not expected to result in fetal exposure to the drug.” Therefore, if these labeling guidelines are followed, it appears that all topical acne medications will be interpreted as safe during lactation under the new guidelines.

Dermatologists have taken an oath to “first, do no harm,” but in the case of acne in pregnancy and especially in lactation, we may need to treat aggressively and push the envelope beyond our current category B medications. Erring on the side of caution may be the wrong approach, especially in lactation where psychological consequences are high and neonatal exposure is minimal. The new US Food and Drug Administration guidelines should be helpful in the process of risk assessment and aid us in discussing rational, thoughtful, practical approaches with our patients.

Acne during pregnancy and lactation is common and poses a considerable treatment challenge for dermatologists. It is a disease that often is trivialized, viewed by the ill informed as cosmetic in nature. Combined with fetal and neonatal health concerns plus a healthy dose of medicolegal overlay, treatment of acne in this patient population may be complicated.

Pregnant and lactating women have been summarily orphaned from advances in drug therapy. Due to, in no small part, the pervasive litigious atmosphere surrounding birth defects in pregnancy, many health care providers have defaulted to avoiding all medications in this patient population to be “on the safe side,” and many have convinced pregnant women that taking medication to relieve pain and discomfort while pregnant is selfish and vain, especially where acne is concerned. However, erring on the safe side is not always safe. Drug avoidance can lead to increased physical and psychiatric morbidity.

Numerous studies have shown that acne is not trivial or inconsequential and may even be associated with suicidal ideations.^1,2 In one study, female gender and acne were both jointly and independently associated with the risk for major depression and suicide.³ The traditional notion that pregnancy is a time of joy and emotional well-being is not supported by data. There is a marked increase of mood instability during pregnancy. According to the American Psychological Association, the incidence of true clinical postpartum depression in the United States is 1 in 7 pregnancies but is likely much higher, as it often remains undiagnosed.⁴ These women may consider suicide and may even harm their children. Therefore, “first, do no harm” might indeed involve aggressive therapy in this patient population; at the very least, it warrants a thorough consideration of the risks and benefits rather than a knee-jerk “wait until you stop breastfeeding” default. Without adequate knowledge of true drug risks and with the stakes so high, we find ourselves in medicolegal quicksand. As clinicians, we understand the concept of weighing risks and benefits, but the balance of the scale cannot be determined when no evidence exists regarding the relative weight of the risk side.

Most drug risks in pregnancy are noted after market approval and are obtained from published case reports and retrospective birth defect registries. Reported problems likely represent a small fraction of actual cases. The absence of direct information regarding drug use during pregnancy is exacerbated by the knowledge that there are large gender differences in drug pharmacokinetics. This dichotomy would be expected to be especially pronounced between men and pregnant women in whom drug absorption, distribution, and elimination are all notably altered. A poorly publicized aberration in the drug approval process is that gender information is not required from generic medication bioequivalence studies. Although studies for drugs indicated for both sexes need to include male and female participants, resulting data showing gender differences are not required to be disclosed, which means that it is theoretically possible for a generic drug to be approved based on results in men only.

The pregnancy categories for drugs (A, B, C, D, and X), which were initially defined in 1979, have been our only aid in risk assessment but have little clinical relevance beyond defining the level of medicolegal risk. Furthermore, these drug categories are poised to disappear before the publication of this editorial, as new guidelines for labeling human prescription drugs are mandated to begin on June 30, 2015.⁵ Although guaranteed to be confusing at first, it seems the new labeling guidelines will be much more helpful for clinicians. One of the most important changes is the inclusion of the following statement in pregnancy and lactation subsections on drug labels: “All pregnancies have a background risk of birth defect, loss, or other adverse outcome regardless of drug exposure. The fetal risk summary below describes (name of drug)’s potential to increase the risk of developmental abnormalities above the background risk.”⁵ In the absence of concerning human data, efforts will be made to put positive animal data into perspective. In the absence of systemic exposure the label will state: “(Name of drug) is not absorbed systemically from (part of body) and cannot be detected in the blood. Maternal use is not expected to result in fetal exposure to the drug.”⁵ This final rule includes virtually all topical acne products, including topical retinoids.

As weak as the evidence-based risk information is for drugs in pregnancy, it is worse for lactation. It is a commonly mistaken belief among practitioners that the safety, or lack thereof, of medications during pregnancy indicates safety during lactation. In actuality, decisions should instead be based on safety data on the drug during the neonatal period. Levels of neonatal drug exposure through breast milk is 5- to 10-fold less than fetal exposure in utero.⁶ Therefore, it generally is safer for women to take drugs during lactation than during pregnancy. For the most part, medications enter the breast milk by passive diffusion from the maternal bloodstream. Several hours after a medication is taken, maternal blood levels fall and drug from the breast milk flows back along the concentration gradient into the maternal circulation. Therefore, safety is maximized by administering maternal medications immediately after the last feed and just prior to the longest sleep period of the child, usually at night.

In the lactation section of the new labeling guidelines ruling, the verbiage is completely different and highly clinically relevant. If the data demonstrate that a drug does not affect the quantity and/or quality of human breast milk, the product label must state: “The use of (name of drug) is compatible with breastfeeding.”⁵ If the drug is not systemically absorbed, the label will state simply and clearly, “Breastfeeding is not expected to result in fetal exposure to the drug.” Therefore, if these labeling guidelines are followed, it appears that all topical acne medications will be interpreted as safe during lactation under the new guidelines.

Dermatologists have taken an oath to “first, do no harm,” but in the case of acne in pregnancy and especially in lactation, we may need to treat aggressively and push the envelope beyond our current category B medications. Erring on the side of caution may be the wrong approach, especially in lactation where psychological consequences are high and neonatal exposure is minimal. The new US Food and Drug Administration guidelines should be helpful in the process of risk assessment and aid us in discussing rational, thoughtful, practical approaches with our patients.

Acne during pregnancy and lactation is common and poses a considerable treatment challenge for dermatologists. It is a disease that often is trivialized, viewed by the ill informed as cosmetic in nature. Combined with fetal and neonatal health concerns plus a healthy dose of medicolegal overlay, treatment of acne in this patient population may be complicated.

Pregnant and lactating women have been summarily orphaned from advances in drug therapy. Due to, in no small part, the pervasive litigious atmosphere surrounding birth defects in pregnancy, many health care providers have defaulted to avoiding all medications in this patient population to be “on the safe side,” and many have convinced pregnant women that taking medication to relieve pain and discomfort while pregnant is selfish and vain, especially where acne is concerned. However, erring on the safe side is not always safe. Drug avoidance can lead to increased physical and psychiatric morbidity.

Numerous studies have shown that acne is not trivial or inconsequential and may even be associated with suicidal ideations.^1,2 In one study, female gender and acne were both jointly and independently associated with the risk for major depression and suicide.³ The traditional notion that pregnancy is a time of joy and emotional well-being is not supported by data. There is a marked increase of mood instability during pregnancy. According to the American Psychological Association, the incidence of true clinical postpartum depression in the United States is 1 in 7 pregnancies but is likely much higher, as it often remains undiagnosed.⁴ These women may consider suicide and may even harm their children. Therefore, “first, do no harm” might indeed involve aggressive therapy in this patient population; at the very least, it warrants a thorough consideration of the risks and benefits rather than a knee-jerk “wait until you stop breastfeeding” default. Without adequate knowledge of true drug risks and with the stakes so high, we find ourselves in medicolegal quicksand. As clinicians, we understand the concept of weighing risks and benefits, but the balance of the scale cannot be determined when no evidence exists regarding the relative weight of the risk side.

Most drug risks in pregnancy are noted after market approval and are obtained from published case reports and retrospective birth defect registries. Reported problems likely represent a small fraction of actual cases. The absence of direct information regarding drug use during pregnancy is exacerbated by the knowledge that there are large gender differences in drug pharmacokinetics. This dichotomy would be expected to be especially pronounced between men and pregnant women in whom drug absorption, distribution, and elimination are all notably altered. A poorly publicized aberration in the drug approval process is that gender information is not required from generic medication bioequivalence studies. Although studies for drugs indicated for both sexes need to include male and female participants, resulting data showing gender differences are not required to be disclosed, which means that it is theoretically possible for a generic drug to be approved based on results in men only.

The pregnancy categories for drugs (A, B, C, D, and X), which were initially defined in 1979, have been our only aid in risk assessment but have little clinical relevance beyond defining the level of medicolegal risk. Furthermore, these drug categories are poised to disappear before the publication of this editorial, as new guidelines for labeling human prescription drugs are mandated to begin on June 30, 2015.⁵ Although guaranteed to be confusing at first, it seems the new labeling guidelines will be much more helpful for clinicians. One of the most important changes is the inclusion of the following statement in pregnancy and lactation subsections on drug labels: “All pregnancies have a background risk of birth defect, loss, or other adverse outcome regardless of drug exposure. The fetal risk summary below describes (name of drug)’s potential to increase the risk of developmental abnormalities above the background risk.”⁵ In the absence of concerning human data, efforts will be made to put positive animal data into perspective. In the absence of systemic exposure the label will state: “(Name of drug) is not absorbed systemically from (part of body) and cannot be detected in the blood. Maternal use is not expected to result in fetal exposure to the drug.”⁵ This final rule includes virtually all topical acne products, including topical retinoids.

As weak as the evidence-based risk information is for drugs in pregnancy, it is worse for lactation. It is a commonly mistaken belief among practitioners that the safety, or lack thereof, of medications during pregnancy indicates safety during lactation. In actuality, decisions should instead be based on safety data on the drug during the neonatal period. Levels of neonatal drug exposure through breast milk is 5- to 10-fold less than fetal exposure in utero.⁶ Therefore, it generally is safer for women to take drugs during lactation than during pregnancy. For the most part, medications enter the breast milk by passive diffusion from the maternal bloodstream. Several hours after a medication is taken, maternal blood levels fall and drug from the breast milk flows back along the concentration gradient into the maternal circulation. Therefore, safety is maximized by administering maternal medications immediately after the last feed and just prior to the longest sleep period of the child, usually at night.

In the lactation section of the new labeling guidelines ruling, the verbiage is completely different and highly clinically relevant. If the data demonstrate that a drug does not affect the quantity and/or quality of human breast milk, the product label must state: “The use of (name of drug) is compatible with breastfeeding.”⁵ If the drug is not systemically absorbed, the label will state simply and clearly, “Breastfeeding is not expected to result in fetal exposure to the drug.” Therefore, if these labeling guidelines are followed, it appears that all topical acne medications will be interpreted as safe during lactation under the new guidelines.

Dermatologists have taken an oath to “first, do no harm,” but in the case of acne in pregnancy and especially in lactation, we may need to treat aggressively and push the envelope beyond our current category B medications. Erring on the side of caution may be the wrong approach, especially in lactation where psychological consequences are high and neonatal exposure is minimal. The new US Food and Drug Administration guidelines should be helpful in the process of risk assessment and aid us in discussing rational, thoughtful, practical approaches with our patients.

A 56-year-old woman presents with hypertension. Her blood pressures have been about 160/100 mm Hg. Past medical history includes depression, GERD, and hypothyroidism, and the patient has an allergy to sulfamethoxazole (rash).

She receives a prescription for hydrochlorothiazide. The pharmacist calls later to report that the pharmacy did not fill the prescription because the patient has a sulfa allergy.

What would you recommend?

A. Call in a prescription for a calcium channel blocker.

B. Call in a prescription for an ACE inhibitor.

C. Call in a prescription for a beta-blocker.

D. Call and ask the pharmacist to fill the hydrochlorothiazide prescription.

I have received this call from pharmacies many times. The patients are usually very frustrated because they could not pick up their medications. Is this the right call from the pharmacist? Does the fact that the patient has a sulfa allergy make prescribing hydrochlorothiazide wrong?

Allergies to sulfonamide antibiotics occur in about 3% of patients who are prescribed the drugs. Sulfa-containing antibiotics contain a five- or six-member nitrogen-containing ring attached to the N1 nitrogen of the sulfonamide group and an arylamine group (H₂N) at the N4 position of the sulfonamide group (Pharmacotherapy 2004;24:856-70). Sulfa-containing nonantibiotics – including thiazides and loop diuretics, as well as COX-2 inhibitors – do not contain these same features.

There has always been concern that there is a possibility of increased risk of drug reactions in patients who receive a sulfa nonantibiotic, and frequently prescriptions for these medicines are not filled by pharmacies without directly confirming the intent by speaking with the prescriber.

Brian Hemstreet, Pharm.D., and Robert Page II, Pharm.D., did a prospective, observational study of patients admitted to a hospital with a history of sulfa allergy (Pharmacotherapy 2006;26:551-7). A total of 94 patients were studied who had a reported sulfa allergy. Forty of these patients were taking a sulfonamide nonantibiotic at the time of admission (most commonly furosemide). Nine of the patients received a sulfonamide nonantibiotic during their hospitalization. None of the patients had a drug reaction, either while receiving a sulfonamide nonantibiotic in the hospital, or previously while receiving one as an outpatient.

Dr. Pilar Tornero and colleagues used patch testing and control oral challenge in patients with previous fixed drug eruptions to trimethoprim-sulfamethoxazole or an unknown sulfonamide (Contact Dermatitis 2004;51:57-62). All patients received low doses of oral sulfonamide antibiotics (trimethoprim-sulfamethoxazole, sulfadiazine, or sulfamethizole). All patients also received furosemide.

Every patient with previous known sulfa reaction had a positive oral challenge test when given sulfamethoxazole. There was cross reactivity with other sulfa antibiotics: Seven of 18 patients with prior sulfamethoxazole allergy reacted to oral challenge with sulfadiazine, and 4 of 9 patients with prior allergy with sulfamethoxazole reacted to challenge with sulfamethazine. All 28 patients in the study were challenged with furosemide (a sulfa nonantibiotic) with no allergic reactions.

Dr. Brian Strom and colleagues conducted a retrospective cohort study using general practice research database, looking at risk of allergic reactions within 30 days of receipt of a sulfonamide nonantibiotic (N. Engl. J. Med. 2003;349:1628-35).

Patients who had a history of prior hypersensitivity to a sulfonamide antibiotic were compared with those with no previous history of allergy. Analyses were also performed in patients with a prior penicillin allergy. A total of 969 patients who had an allergic reaction after a sulfonamide antibiotic were evaluated.

Of those patients, 9.1% had an allergic reaction after receiving a sulfonamide nonantibiotic. In those patients without a sulfa antibiotic allergy, only 1.6% had a reaction to a sulfa nonantibiotic. Interestingly, in patients with a prior history of penicillin reaction, 14.6% had an allergic reaction when receiving a sulfa nonantibiotic.

Patients with a history of sulfa allergy to a sulfa antibiotic are more likely to have a reaction to a sulfa nonantibiotic than are those without a previous allergy history. But this appears to be due to overall increased reactiveness and not a cross reactivity, because those with history of penicillin allergy had an even higher allergy rate to sulfa nonantibiotics than did patients with a prior sulfa allergy.

Dr. Paauw is professor of medicine in the division of general internal medicine at the University of Washington, Seattle, and he serves as third-year medical student clerkship director at the University of Washington. Contact Dr. Paauw at [email protected].

A 56-year-old woman presents with hypertension. Her blood pressures have been about 160/100 mm Hg. Past medical history includes depression, GERD, and hypothyroidism, and the patient has an allergy to sulfamethoxazole (rash).

She receives a prescription for hydrochlorothiazide. The pharmacist calls later to report that the pharmacy did not fill the prescription because the patient has a sulfa allergy.

What would you recommend?

A. Call in a prescription for a calcium channel blocker.

B. Call in a prescription for an ACE inhibitor.

C. Call in a prescription for a beta-blocker.

D. Call and ask the pharmacist to fill the hydrochlorothiazide prescription.

I have received this call from pharmacies many times. The patients are usually very frustrated because they could not pick up their medications. Is this the right call from the pharmacist? Does the fact that the patient has a sulfa allergy make prescribing hydrochlorothiazide wrong?

Allergies to sulfonamide antibiotics occur in about 3% of patients who are prescribed the drugs. Sulfa-containing antibiotics contain a five- or six-member nitrogen-containing ring attached to the N1 nitrogen of the sulfonamide group and an arylamine group (H₂N) at the N4 position of the sulfonamide group (Pharmacotherapy 2004;24:856-70). Sulfa-containing nonantibiotics – including thiazides and loop diuretics, as well as COX-2 inhibitors – do not contain these same features.

There has always been concern that there is a possibility of increased risk of drug reactions in patients who receive a sulfa nonantibiotic, and frequently prescriptions for these medicines are not filled by pharmacies without directly confirming the intent by speaking with the prescriber.

Brian Hemstreet, Pharm.D., and Robert Page II, Pharm.D., did a prospective, observational study of patients admitted to a hospital with a history of sulfa allergy (Pharmacotherapy 2006;26:551-7). A total of 94 patients were studied who had a reported sulfa allergy. Forty of these patients were taking a sulfonamide nonantibiotic at the time of admission (most commonly furosemide). Nine of the patients received a sulfonamide nonantibiotic during their hospitalization. None of the patients had a drug reaction, either while receiving a sulfonamide nonantibiotic in the hospital, or previously while receiving one as an outpatient.

Dr. Pilar Tornero and colleagues used patch testing and control oral challenge in patients with previous fixed drug eruptions to trimethoprim-sulfamethoxazole or an unknown sulfonamide (Contact Dermatitis 2004;51:57-62). All patients received low doses of oral sulfonamide antibiotics (trimethoprim-sulfamethoxazole, sulfadiazine, or sulfamethizole). All patients also received furosemide.

Every patient with previous known sulfa reaction had a positive oral challenge test when given sulfamethoxazole. There was cross reactivity with other sulfa antibiotics: Seven of 18 patients with prior sulfamethoxazole allergy reacted to oral challenge with sulfadiazine, and 4 of 9 patients with prior allergy with sulfamethoxazole reacted to challenge with sulfamethazine. All 28 patients in the study were challenged with furosemide (a sulfa nonantibiotic) with no allergic reactions.

Dr. Brian Strom and colleagues conducted a retrospective cohort study using general practice research database, looking at risk of allergic reactions within 30 days of receipt of a sulfonamide nonantibiotic (N. Engl. J. Med. 2003;349:1628-35).

Patients who had a history of prior hypersensitivity to a sulfonamide antibiotic were compared with those with no previous history of allergy. Analyses were also performed in patients with a prior penicillin allergy. A total of 969 patients who had an allergic reaction after a sulfonamide antibiotic were evaluated.

Of those patients, 9.1% had an allergic reaction after receiving a sulfonamide nonantibiotic. In those patients without a sulfa antibiotic allergy, only 1.6% had a reaction to a sulfa nonantibiotic. Interestingly, in patients with a prior history of penicillin reaction, 14.6% had an allergic reaction when receiving a sulfa nonantibiotic.

Patients with a history of sulfa allergy to a sulfa antibiotic are more likely to have a reaction to a sulfa nonantibiotic than are those without a previous allergy history. But this appears to be due to overall increased reactiveness and not a cross reactivity, because those with history of penicillin allergy had an even higher allergy rate to sulfa nonantibiotics than did patients with a prior sulfa allergy.

Dr. Paauw is professor of medicine in the division of general internal medicine at the University of Washington, Seattle, and he serves as third-year medical student clerkship director at the University of Washington. Contact Dr. Paauw at [email protected].

A 56-year-old woman presents with hypertension. Her blood pressures have been about 160/100 mm Hg. Past medical history includes depression, GERD, and hypothyroidism, and the patient has an allergy to sulfamethoxazole (rash).

She receives a prescription for hydrochlorothiazide. The pharmacist calls later to report that the pharmacy did not fill the prescription because the patient has a sulfa allergy.

What would you recommend?

A. Call in a prescription for a calcium channel blocker.

B. Call in a prescription for an ACE inhibitor.

C. Call in a prescription for a beta-blocker.

D. Call and ask the pharmacist to fill the hydrochlorothiazide prescription.

I have received this call from pharmacies many times. The patients are usually very frustrated because they could not pick up their medications. Is this the right call from the pharmacist? Does the fact that the patient has a sulfa allergy make prescribing hydrochlorothiazide wrong?

Allergies to sulfonamide antibiotics occur in about 3% of patients who are prescribed the drugs. Sulfa-containing antibiotics contain a five- or six-member nitrogen-containing ring attached to the N1 nitrogen of the sulfonamide group and an arylamine group (H₂N) at the N4 position of the sulfonamide group (Pharmacotherapy 2004;24:856-70). Sulfa-containing nonantibiotics – including thiazides and loop diuretics, as well as COX-2 inhibitors – do not contain these same features.

There has always been concern that there is a possibility of increased risk of drug reactions in patients who receive a sulfa nonantibiotic, and frequently prescriptions for these medicines are not filled by pharmacies without directly confirming the intent by speaking with the prescriber.

Brian Hemstreet, Pharm.D., and Robert Page II, Pharm.D., did a prospective, observational study of patients admitted to a hospital with a history of sulfa allergy (Pharmacotherapy 2006;26:551-7). A total of 94 patients were studied who had a reported sulfa allergy. Forty of these patients were taking a sulfonamide nonantibiotic at the time of admission (most commonly furosemide). Nine of the patients received a sulfonamide nonantibiotic during their hospitalization. None of the patients had a drug reaction, either while receiving a sulfonamide nonantibiotic in the hospital, or previously while receiving one as an outpatient.

Dr. Pilar Tornero and colleagues used patch testing and control oral challenge in patients with previous fixed drug eruptions to trimethoprim-sulfamethoxazole or an unknown sulfonamide (Contact Dermatitis 2004;51:57-62). All patients received low doses of oral sulfonamide antibiotics (trimethoprim-sulfamethoxazole, sulfadiazine, or sulfamethizole). All patients also received furosemide.

Every patient with previous known sulfa reaction had a positive oral challenge test when given sulfamethoxazole. There was cross reactivity with other sulfa antibiotics: Seven of 18 patients with prior sulfamethoxazole allergy reacted to oral challenge with sulfadiazine, and 4 of 9 patients with prior allergy with sulfamethoxazole reacted to challenge with sulfamethazine. All 28 patients in the study were challenged with furosemide (a sulfa nonantibiotic) with no allergic reactions.

Dr. Brian Strom and colleagues conducted a retrospective cohort study using general practice research database, looking at risk of allergic reactions within 30 days of receipt of a sulfonamide nonantibiotic (N. Engl. J. Med. 2003;349:1628-35).

Patients who had a history of prior hypersensitivity to a sulfonamide antibiotic were compared with those with no previous history of allergy. Analyses were also performed in patients with a prior penicillin allergy. A total of 969 patients who had an allergic reaction after a sulfonamide antibiotic were evaluated.

Of those patients, 9.1% had an allergic reaction after receiving a sulfonamide nonantibiotic. In those patients without a sulfa antibiotic allergy, only 1.6% had a reaction to a sulfa nonantibiotic. Interestingly, in patients with a prior history of penicillin reaction, 14.6% had an allergic reaction when receiving a sulfa nonantibiotic.

Patients with a history of sulfa allergy to a sulfa antibiotic are more likely to have a reaction to a sulfa nonantibiotic than are those without a previous allergy history. But this appears to be due to overall increased reactiveness and not a cross reactivity, because those with history of penicillin allergy had an even higher allergy rate to sulfa nonantibiotics than did patients with a prior sulfa allergy.

Dr. Paauw is professor of medicine in the division of general internal medicine at the University of Washington, Seattle, and he serves as third-year medical student clerkship director at the University of Washington. Contact Dr. Paauw at [email protected].