Clinical question

Did the 2011 Accreditation Council for Graduate Medical Education resident work hour reforms affect patient outcomes?

Bottom line

Resident work hour reforms were proposed by the Accreditation Council for Graduate Medical Education (ACGME) to reduce resident fatigue (and thus potentially reduce the risk of medical errors), but implementation of the work hour changes also led to concerns over patient safety because of increased handoffs in care. This study shows that work hour reforms had no impact, either positive or negative, on the important patient outcomes of mortality and readmission rates. Other outcomes such as length of stay and number of intensive care unit transfers may need to be examined in future studies to detect more subtle differences. (LOE = 2b)

Reference

Patel MS, Volpp KG, Small DS, et al. Association of the 2011 ACGME resident duty hour reforms with mortality and readmissions among hospitalized Medicare patients. JAMA 2014;312(22):2364-2373.

Study design: Cohort (retrospective)

Funding source: Government

Allocation: Uncertain

Setting: Inpatient (any location)

Synopsis

In 2011, the ACGME instituted work hour reforms for residents that reduced the work hour limit from 30 consecutive hours to 16 hours for first-year residents and 24 hours for all other residents. Investigators in this study evaluated the effect of the 2011 ACGME reforms on 30-day all-location mortality and 30-day all-cause readmissions. Patients included in the study were Medicare patients who were admitted to acute care US hospitals from 2009 to 2012 with acute myocardial infarction, stroke, gastrointestinal bleeding, or congestive heart failure, or those admitted for general, orthopedic, or vascular surgery. Hospitals were classified by their level of teaching intensity using a resident-to-bed ratio defined as the number of residents divided by the number of staffed beds.

In an analysis that adjusted for demographics, co-morbidities, and the presence of surgical complications, the implementation of work hour reforms did not affect 30-day mortality or readmissions in more-intensive teaching hospitals relative to less-intensive teaching hospitals during the postreform year as compared with 2 years before the reform. Multiple factors beyond the implementation of work hour reforms, may have contributed to this lack of effect. First, adherence to the new reforms by residency programs in the first year is unclear. Second, concurrent initiatives to improve patient outcomes during this time may have affected all hospitals, teaching and nonteaching. Finally, the authors suggest that the greater emphasis on resident supervision with the new reforms may have counterbalanced any negative effects of increased resident handoffs.

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

Clinical question

Did the 2011 Accreditation Council for Graduate Medical Education resident work hour reforms affect patient outcomes?

Bottom line

Resident work hour reforms were proposed by the Accreditation Council for Graduate Medical Education (ACGME) to reduce resident fatigue (and thus potentially reduce the risk of medical errors), but implementation of the work hour changes also led to concerns over patient safety because of increased handoffs in care. This study shows that work hour reforms had no impact, either positive or negative, on the important patient outcomes of mortality and readmission rates. Other outcomes such as length of stay and number of intensive care unit transfers may need to be examined in future studies to detect more subtle differences. (LOE = 2b)

Reference

Patel MS, Volpp KG, Small DS, et al. Association of the 2011 ACGME resident duty hour reforms with mortality and readmissions among hospitalized Medicare patients. JAMA 2014;312(22):2364-2373.

Study design: Cohort (retrospective)

Funding source: Government

Allocation: Uncertain

Setting: Inpatient (any location)

Synopsis

In 2011, the ACGME instituted work hour reforms for residents that reduced the work hour limit from 30 consecutive hours to 16 hours for first-year residents and 24 hours for all other residents. Investigators in this study evaluated the effect of the 2011 ACGME reforms on 30-day all-location mortality and 30-day all-cause readmissions. Patients included in the study were Medicare patients who were admitted to acute care US hospitals from 2009 to 2012 with acute myocardial infarction, stroke, gastrointestinal bleeding, or congestive heart failure, or those admitted for general, orthopedic, or vascular surgery. Hospitals were classified by their level of teaching intensity using a resident-to-bed ratio defined as the number of residents divided by the number of staffed beds.

In an analysis that adjusted for demographics, co-morbidities, and the presence of surgical complications, the implementation of work hour reforms did not affect 30-day mortality or readmissions in more-intensive teaching hospitals relative to less-intensive teaching hospitals during the postreform year as compared with 2 years before the reform. Multiple factors beyond the implementation of work hour reforms, may have contributed to this lack of effect. First, adherence to the new reforms by residency programs in the first year is unclear. Second, concurrent initiatives to improve patient outcomes during this time may have affected all hospitals, teaching and nonteaching. Finally, the authors suggest that the greater emphasis on resident supervision with the new reforms may have counterbalanced any negative effects of increased resident handoffs.

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

Clinical question

Did the 2011 Accreditation Council for Graduate Medical Education resident work hour reforms affect patient outcomes?

Bottom line

Resident work hour reforms were proposed by the Accreditation Council for Graduate Medical Education (ACGME) to reduce resident fatigue (and thus potentially reduce the risk of medical errors), but implementation of the work hour changes also led to concerns over patient safety because of increased handoffs in care. This study shows that work hour reforms had no impact, either positive or negative, on the important patient outcomes of mortality and readmission rates. Other outcomes such as length of stay and number of intensive care unit transfers may need to be examined in future studies to detect more subtle differences. (LOE = 2b)

Reference

Patel MS, Volpp KG, Small DS, et al. Association of the 2011 ACGME resident duty hour reforms with mortality and readmissions among hospitalized Medicare patients. JAMA 2014;312(22):2364-2373.

Study design: Cohort (retrospective)

Funding source: Government

Allocation: Uncertain

Setting: Inpatient (any location)

Synopsis

In 2011, the ACGME instituted work hour reforms for residents that reduced the work hour limit from 30 consecutive hours to 16 hours for first-year residents and 24 hours for all other residents. Investigators in this study evaluated the effect of the 2011 ACGME reforms on 30-day all-location mortality and 30-day all-cause readmissions. Patients included in the study were Medicare patients who were admitted to acute care US hospitals from 2009 to 2012 with acute myocardial infarction, stroke, gastrointestinal bleeding, or congestive heart failure, or those admitted for general, orthopedic, or vascular surgery. Hospitals were classified by their level of teaching intensity using a resident-to-bed ratio defined as the number of residents divided by the number of staffed beds.

In an analysis that adjusted for demographics, co-morbidities, and the presence of surgical complications, the implementation of work hour reforms did not affect 30-day mortality or readmissions in more-intensive teaching hospitals relative to less-intensive teaching hospitals during the postreform year as compared with 2 years before the reform. Multiple factors beyond the implementation of work hour reforms, may have contributed to this lack of effect. First, adherence to the new reforms by residency programs in the first year is unclear. Second, concurrent initiatives to improve patient outcomes during this time may have affected all hospitals, teaching and nonteaching. Finally, the authors suggest that the greater emphasis on resident supervision with the new reforms may have counterbalanced any negative effects of increased resident handoffs.

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

Clinical question: For critically ill patients, does daily bathing with chlorhexidine reduce health care–associated infections?

Bottom line

These results show that daily chlorhexidine bathing does not significantly affect the incidence of health care–associated infections. These data conflict with data from prior research, suggesting that more investigation is needed before incorporating chlorhexidine bathing into routine practice, especially given the increased cost with its use and the possibility of the development of chlorhexidine resistance. (LOE = 1b)

Reference: Noto MJ, Domenico HJ, Byrne DW, et al. Chlorhexidine bathing and health care-associated infections. JAMA 2015;313(4):369-378.

Study design: Cross-over trial (randomized)

Funding source: Government

Allocation: Concealed

Setting: Inpatient (ICU only)

Synopsis

Previous studies have shown benefit of daily chlorhexidine bathing in patients at high risk of nosocomial blood stream infections (Daily POEM 7-31-2013; Daily POEM 4-26-2013). In this study, investigators randomized 5 intensive care units at a tertiary care hospital to provide daily bathing of all patients with either 2% chlorhexidine-impregnated cloths or with nonantimicrobial cloths. Each unit followed the assigned protocol for 10 weeks, followed by a 2-week washout period, and then crossed over to the alternate protocol for another 10 weeks. All units crossed over 3 times during the study. Almost 10,000 patients were included in the study. The primary outcome was a composite of health-care associated infections, including central-line associated bloodstream infections, catheter-associated urinary tract infections, ventilator-associated pneumonia, and Clostridium difficile infections. There was no significant difference detected in the rate of the primary outcome between the chlorhexidine group and the control group with approximately 3 infections per 1000 patient-days in both groups. Adjusting for factors including demographics, co-morbidities, and the unit of admission also did not reveal a difference.

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

Clinical question: For critically ill patients, does daily bathing with chlorhexidine reduce health care–associated infections?

Bottom line

These results show that daily chlorhexidine bathing does not significantly affect the incidence of health care–associated infections. These data conflict with data from prior research, suggesting that more investigation is needed before incorporating chlorhexidine bathing into routine practice, especially given the increased cost with its use and the possibility of the development of chlorhexidine resistance. (LOE = 1b)

Reference: Noto MJ, Domenico HJ, Byrne DW, et al. Chlorhexidine bathing and health care-associated infections. JAMA 2015;313(4):369-378.

Study design: Cross-over trial (randomized)

Funding source: Government

Allocation: Concealed

Setting: Inpatient (ICU only)

Synopsis

Previous studies have shown benefit of daily chlorhexidine bathing in patients at high risk of nosocomial blood stream infections (Daily POEM 7-31-2013; Daily POEM 4-26-2013). In this study, investigators randomized 5 intensive care units at a tertiary care hospital to provide daily bathing of all patients with either 2% chlorhexidine-impregnated cloths or with nonantimicrobial cloths. Each unit followed the assigned protocol for 10 weeks, followed by a 2-week washout period, and then crossed over to the alternate protocol for another 10 weeks. All units crossed over 3 times during the study. Almost 10,000 patients were included in the study. The primary outcome was a composite of health-care associated infections, including central-line associated bloodstream infections, catheter-associated urinary tract infections, ventilator-associated pneumonia, and Clostridium difficile infections. There was no significant difference detected in the rate of the primary outcome between the chlorhexidine group and the control group with approximately 3 infections per 1000 patient-days in both groups. Adjusting for factors including demographics, co-morbidities, and the unit of admission also did not reveal a difference.

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

Clinical question: For critically ill patients, does daily bathing with chlorhexidine reduce health care–associated infections?

Bottom line

These results show that daily chlorhexidine bathing does not significantly affect the incidence of health care–associated infections. These data conflict with data from prior research, suggesting that more investigation is needed before incorporating chlorhexidine bathing into routine practice, especially given the increased cost with its use and the possibility of the development of chlorhexidine resistance. (LOE = 1b)

Reference: Noto MJ, Domenico HJ, Byrne DW, et al. Chlorhexidine bathing and health care-associated infections. JAMA 2015;313(4):369-378.

Study design: Cross-over trial (randomized)

Funding source: Government

Allocation: Concealed

Setting: Inpatient (ICU only)

Synopsis

Previous studies have shown benefit of daily chlorhexidine bathing in patients at high risk of nosocomial blood stream infections (Daily POEM 7-31-2013; Daily POEM 4-26-2013). In this study, investigators randomized 5 intensive care units at a tertiary care hospital to provide daily bathing of all patients with either 2% chlorhexidine-impregnated cloths or with nonantimicrobial cloths. Each unit followed the assigned protocol for 10 weeks, followed by a 2-week washout period, and then crossed over to the alternate protocol for another 10 weeks. All units crossed over 3 times during the study. Almost 10,000 patients were included in the study. The primary outcome was a composite of health-care associated infections, including central-line associated bloodstream infections, catheter-associated urinary tract infections, ventilator-associated pneumonia, and Clostridium difficile infections. There was no significant difference detected in the rate of the primary outcome between the chlorhexidine group and the control group with approximately 3 infections per 1000 patient-days in both groups. Adjusting for factors including demographics, co-morbidities, and the unit of admission also did not reveal a difference.

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

Sleeping infant

Photo by Vera Kratochvil

Infants who have acute lymphoblastic leukemia (ALL) with MLL rearrangements have few other mutations, according to new research.

The findings suggest that targeting MLL rearrangements in these patients is likely the key to improving their survival.

“We frequently associate a cancer’s aggressiveness with its mutation rate, but this work indicates that the two don’t always go hand-in-hand,” said Richard K. Wilson, PhD, of the Washington University School of Medicine in St Louis, Missouri.

“Still, our findings provide a new direction for developing more effective treatments for these very young patients.”

Dr Wilson and his colleagues reported their findings in Nature Genetics.

The researchers performed whole-genome, exome, RNA, and targeted DNA sequencing to identify genetic alterations in 65 infants with ALL, including 47 with the MLL rearrangement.

The team was surprised to find that, despite being an aggressive leukemia, the MLL-rearranged subtype had among the lowest mutation rates reported for any cancer. The predominant leukemic clone carried a mean of 1.3 non-silent mutations.

“These results show that, to improve survival for patients with this aggressive leukemia, we need to develop drugs that target the abnormal proteins produced by the MLL fusion gene or that interact with the abnormal MLL fusion protein to shut down the cellular machinery that drives their tumors,” said James R. Downing, MD, of St Jude Research Hospital in Memphis, Tennessee. “That will not be easy, but this study found no obvious cooperating mutations to target.”

Almost half of infants with MLL-rearranged ALL (47%) had activating mutations in the kinase-PI3K-RAS signaling pathway. But the mutations were often present in only some of the leukemic cells.

Furthermore, the researchers analyzed leukemia cells in infants whose cancer returned after treatment and found that, at the time of relapse, the cells lacked these mutations.

“The fact that the mutations were often lost at relapse suggests that patients are unlikely to benefit from therapeutically targeting these mutations at diagnosis,” Dr Downing said.

The researchers also found that older children with MLL-rearranged leukemia had significantly more mutations than infants—a mean of 6.5 mutations per case (P=7.15 × 10⁻⁵).

Furthermore, 45% of the older children had mutations in genes that encode epigenetic regulatory proteins. And, aside from MLL, epigenetic regulators were rarely mutated in infants with MLL-rearranged ALL.

“While MLL belongs to a family of genes that encode epigenetic regulatory proteins, there was a striking difference between infants and older children regarding the frequency of mutations in other epigenetic regulatory genes,” said Anna Andersson, PhD, of Lund University in Sweden.

“This observation raises the possibility of a fundamental difference in the cell targeted for transformation in infants versus older patients,” said Tanja Gruber, MD, PhD, of St Jude.

“Our working hypothesis is that, in infants, the MLL rearrangement occurs in a developing blood cell, a prenatal progenitor cell, which requires fewer additional mutations to fully transform into leukemia. In contrast, in older patients, the MLL rearrangement isn’t enough on its own.”

Sleeping infant

Photo by Vera Kratochvil

Infants who have acute lymphoblastic leukemia (ALL) with MLL rearrangements have few other mutations, according to new research.

The findings suggest that targeting MLL rearrangements in these patients is likely the key to improving their survival.

“We frequently associate a cancer’s aggressiveness with its mutation rate, but this work indicates that the two don’t always go hand-in-hand,” said Richard K. Wilson, PhD, of the Washington University School of Medicine in St Louis, Missouri.

“Still, our findings provide a new direction for developing more effective treatments for these very young patients.”

Dr Wilson and his colleagues reported their findings in Nature Genetics.

The researchers performed whole-genome, exome, RNA, and targeted DNA sequencing to identify genetic alterations in 65 infants with ALL, including 47 with the MLL rearrangement.

The team was surprised to find that, despite being an aggressive leukemia, the MLL-rearranged subtype had among the lowest mutation rates reported for any cancer. The predominant leukemic clone carried a mean of 1.3 non-silent mutations.

“These results show that, to improve survival for patients with this aggressive leukemia, we need to develop drugs that target the abnormal proteins produced by the MLL fusion gene or that interact with the abnormal MLL fusion protein to shut down the cellular machinery that drives their tumors,” said James R. Downing, MD, of St Jude Research Hospital in Memphis, Tennessee. “That will not be easy, but this study found no obvious cooperating mutations to target.”

Almost half of infants with MLL-rearranged ALL (47%) had activating mutations in the kinase-PI3K-RAS signaling pathway. But the mutations were often present in only some of the leukemic cells.

Furthermore, the researchers analyzed leukemia cells in infants whose cancer returned after treatment and found that, at the time of relapse, the cells lacked these mutations.

“The fact that the mutations were often lost at relapse suggests that patients are unlikely to benefit from therapeutically targeting these mutations at diagnosis,” Dr Downing said.

The researchers also found that older children with MLL-rearranged leukemia had significantly more mutations than infants—a mean of 6.5 mutations per case (P=7.15 × 10⁻⁵).

Furthermore, 45% of the older children had mutations in genes that encode epigenetic regulatory proteins. And, aside from MLL, epigenetic regulators were rarely mutated in infants with MLL-rearranged ALL.

“While MLL belongs to a family of genes that encode epigenetic regulatory proteins, there was a striking difference between infants and older children regarding the frequency of mutations in other epigenetic regulatory genes,” said Anna Andersson, PhD, of Lund University in Sweden.

“This observation raises the possibility of a fundamental difference in the cell targeted for transformation in infants versus older patients,” said Tanja Gruber, MD, PhD, of St Jude.

“Our working hypothesis is that, in infants, the MLL rearrangement occurs in a developing blood cell, a prenatal progenitor cell, which requires fewer additional mutations to fully transform into leukemia. In contrast, in older patients, the MLL rearrangement isn’t enough on its own.”

Sleeping infant

Photo by Vera Kratochvil

Infants who have acute lymphoblastic leukemia (ALL) with MLL rearrangements have few other mutations, according to new research.

The findings suggest that targeting MLL rearrangements in these patients is likely the key to improving their survival.

“We frequently associate a cancer’s aggressiveness with its mutation rate, but this work indicates that the two don’t always go hand-in-hand,” said Richard K. Wilson, PhD, of the Washington University School of Medicine in St Louis, Missouri.

“Still, our findings provide a new direction for developing more effective treatments for these very young patients.”

Dr Wilson and his colleagues reported their findings in Nature Genetics.

The researchers performed whole-genome, exome, RNA, and targeted DNA sequencing to identify genetic alterations in 65 infants with ALL, including 47 with the MLL rearrangement.

The team was surprised to find that, despite being an aggressive leukemia, the MLL-rearranged subtype had among the lowest mutation rates reported for any cancer. The predominant leukemic clone carried a mean of 1.3 non-silent mutations.

“These results show that, to improve survival for patients with this aggressive leukemia, we need to develop drugs that target the abnormal proteins produced by the MLL fusion gene or that interact with the abnormal MLL fusion protein to shut down the cellular machinery that drives their tumors,” said James R. Downing, MD, of St Jude Research Hospital in Memphis, Tennessee. “That will not be easy, but this study found no obvious cooperating mutations to target.”

Almost half of infants with MLL-rearranged ALL (47%) had activating mutations in the kinase-PI3K-RAS signaling pathway. But the mutations were often present in only some of the leukemic cells.

Furthermore, the researchers analyzed leukemia cells in infants whose cancer returned after treatment and found that, at the time of relapse, the cells lacked these mutations.

“The fact that the mutations were often lost at relapse suggests that patients are unlikely to benefit from therapeutically targeting these mutations at diagnosis,” Dr Downing said.

The researchers also found that older children with MLL-rearranged leukemia had significantly more mutations than infants—a mean of 6.5 mutations per case (P=7.15 × 10⁻⁵).

Furthermore, 45% of the older children had mutations in genes that encode epigenetic regulatory proteins. And, aside from MLL, epigenetic regulators were rarely mutated in infants with MLL-rearranged ALL.

“While MLL belongs to a family of genes that encode epigenetic regulatory proteins, there was a striking difference between infants and older children regarding the frequency of mutations in other epigenetic regulatory genes,” said Anna Andersson, PhD, of Lund University in Sweden.

“This observation raises the possibility of a fundamental difference in the cell targeted for transformation in infants versus older patients,” said Tanja Gruber, MD, PhD, of St Jude.

“Our working hypothesis is that, in infants, the MLL rearrangement occurs in a developing blood cell, a prenatal progenitor cell, which requires fewer additional mutations to fully transform into leukemia. In contrast, in older patients, the MLL rearrangement isn’t enough on its own.”

The US Food and Drug Administration (FDA) has approved the leukocyte growth factor Zarxio (filgrastim-sndz), the first biosimilar product to be approved in the US.

A biosimilar product is approved based on data showing that it is highly similar to an already-approved biological product.

Sandoz Inc’s Zarxio is biosimilar to Amgen Inc’s Neupogen (filgrastim), which was originally licensed in 1991. Zarxio is now approved for the same indications as Neupogen.

Zarxio can be prescribed for:

• patients with cancer receiving myelosuppressive chemotherapy
• patients with acute myeloid leukemia receiving induction or consolidation chemotherapy
• patients with cancer undergoing bone marrow transplant
• patients undergoing autologous peripheral blood progenitor cell collection and therapy
• patients with severe chronic neutropenia.

Zarxio is marketed as Zarzio outside the US. The biosimilar is available in more than 60 countries worldwide.

“Biosimilars will provide access to important therapies for patients who need them,” said FDA Commissioner Margaret A. Hamburg, MD.

“Patients and the healthcare community can be confident that biosimilar products approved by the FDA meet the agency’s rigorous safety, efficacy, and quality standards.”

Zarxio data

The FDA’s approval of Zarxio is based on a review of evidence that included structural and functional characterization, in vivo data, human pharmacokinetic and pharmacodynamics data, clinical immunogenicity data, and other clinical safety and effectiveness data that demonstrates Zarxio is biosimilar to Neupogen.

The PIONEER study was the final piece of data the FDA used to approve Zarxio as biosimilar to Neupogen. The data was sufficient to allow extrapolation of the use of Zarxio to all indications of Neupogen.

In the PIONEER study, Zarxio and Neupogen both produced the expected reduction in the duration of severe neutropenia in cancer patients undergoing myelosuppressive chemotherapy—1.17 and 1.20 days, respectively.

The mean time to absolute neutrophil count recovery in cycle 1 was also similar—1.8 ± 0.97 days in the Zarxio arm and 1.7 ± 0.81 days in the Neupogen arm. No immunogenicity or antibodies against rhG-CSF were detected throughout the study.

The most common side effects of Zarxio are aching in the bones or muscles and redness, swelling, or itching at the injection site. Serious side effects may include spleen rupture; serious allergic reactions that may cause rash, shortness of breath, wheezing and/or swelling around the mouth and eyes; fast pulse and sweating; and acute respiratory distress syndrome.

About biosimilar approval

The Biologics Price Competition and Innovation Act of 2009 (BPCI Act) was passed as part of the Affordable Care Act that President Barack Obama signed into law in March 2010. The BPCI Act created an abbreviated licensure pathway for biological products shown to be “biosimilar” to or “interchangeable” with an FDA-licensed biological product, known as the reference product.

This abbreviated licensure pathway under section 351(k) of the Public Health Service Act permits reliance on certain existing scientific knowledge about the safety and effectiveness of the reference product, and it enables a biosimilar biological product to be licensed based on less than a full complement of product-specific preclinical and clinical data.

A biosimilar product can only be approved by the FDA if it has the same mechanism(s) of action, route(s) of administration, dosage form(s) and strength(s) as the reference product, and only for the indication(s) and condition(s) of use that have been approved for the reference product. The facilities where biosimilars are manufactured must also meet the FDA’s standards.

There must be no clinically meaningful differences between the biosimilar and the reference product in terms of safety and effectiveness. Only minor differences in clinically inactive components are allowable.

Zarxio has been approved as a biosimilar, not an interchangeable product. Under the BPCI Act, a biological product that has been approved as “interchangeable” may be substituted for the reference product without the intervention of the healthcare provider who prescribed the reference product.

For Zarxio’s approval, the FDA has designated a placeholder nonproprietary name for this product as “filgrastim-sndz.” The provision of a placeholder nonproprietary name should not be viewed as reflective of the agency’s decision on a comprehensive naming policy for biosimilars and other biological products.

While the FDA has not yet issued draft guidance on how current and future biological products marketed in the US should be named, the agency intends to do so in the near future.

For more details on Zarxio, see the full prescribing information.

The US Food and Drug Administration (FDA) has approved the leukocyte growth factor Zarxio (filgrastim-sndz), the first biosimilar product to be approved in the US.

A biosimilar product is approved based on data showing that it is highly similar to an already-approved biological product.

Sandoz Inc’s Zarxio is biosimilar to Amgen Inc’s Neupogen (filgrastim), which was originally licensed in 1991. Zarxio is now approved for the same indications as Neupogen.

Zarxio can be prescribed for:

• patients with cancer receiving myelosuppressive chemotherapy
• patients with acute myeloid leukemia receiving induction or consolidation chemotherapy
• patients with cancer undergoing bone marrow transplant
• patients undergoing autologous peripheral blood progenitor cell collection and therapy
• patients with severe chronic neutropenia.

Zarxio is marketed as Zarzio outside the US. The biosimilar is available in more than 60 countries worldwide.

“Biosimilars will provide access to important therapies for patients who need them,” said FDA Commissioner Margaret A. Hamburg, MD.

“Patients and the healthcare community can be confident that biosimilar products approved by the FDA meet the agency’s rigorous safety, efficacy, and quality standards.”

Zarxio data

The FDA’s approval of Zarxio is based on a review of evidence that included structural and functional characterization, in vivo data, human pharmacokinetic and pharmacodynamics data, clinical immunogenicity data, and other clinical safety and effectiveness data that demonstrates Zarxio is biosimilar to Neupogen.

The PIONEER study was the final piece of data the FDA used to approve Zarxio as biosimilar to Neupogen. The data was sufficient to allow extrapolation of the use of Zarxio to all indications of Neupogen.

In the PIONEER study, Zarxio and Neupogen both produced the expected reduction in the duration of severe neutropenia in cancer patients undergoing myelosuppressive chemotherapy—1.17 and 1.20 days, respectively.

The mean time to absolute neutrophil count recovery in cycle 1 was also similar—1.8 ± 0.97 days in the Zarxio arm and 1.7 ± 0.81 days in the Neupogen arm. No immunogenicity or antibodies against rhG-CSF were detected throughout the study.

The most common side effects of Zarxio are aching in the bones or muscles and redness, swelling, or itching at the injection site. Serious side effects may include spleen rupture; serious allergic reactions that may cause rash, shortness of breath, wheezing and/or swelling around the mouth and eyes; fast pulse and sweating; and acute respiratory distress syndrome.

About biosimilar approval

The Biologics Price Competition and Innovation Act of 2009 (BPCI Act) was passed as part of the Affordable Care Act that President Barack Obama signed into law in March 2010. The BPCI Act created an abbreviated licensure pathway for biological products shown to be “biosimilar” to or “interchangeable” with an FDA-licensed biological product, known as the reference product.

This abbreviated licensure pathway under section 351(k) of the Public Health Service Act permits reliance on certain existing scientific knowledge about the safety and effectiveness of the reference product, and it enables a biosimilar biological product to be licensed based on less than a full complement of product-specific preclinical and clinical data.

A biosimilar product can only be approved by the FDA if it has the same mechanism(s) of action, route(s) of administration, dosage form(s) and strength(s) as the reference product, and only for the indication(s) and condition(s) of use that have been approved for the reference product. The facilities where biosimilars are manufactured must also meet the FDA’s standards.

There must be no clinically meaningful differences between the biosimilar and the reference product in terms of safety and effectiveness. Only minor differences in clinically inactive components are allowable.

Zarxio has been approved as a biosimilar, not an interchangeable product. Under the BPCI Act, a biological product that has been approved as “interchangeable” may be substituted for the reference product without the intervention of the healthcare provider who prescribed the reference product.

For Zarxio’s approval, the FDA has designated a placeholder nonproprietary name for this product as “filgrastim-sndz.” The provision of a placeholder nonproprietary name should not be viewed as reflective of the agency’s decision on a comprehensive naming policy for biosimilars and other biological products.

While the FDA has not yet issued draft guidance on how current and future biological products marketed in the US should be named, the agency intends to do so in the near future.

For more details on Zarxio, see the full prescribing information.

The US Food and Drug Administration (FDA) has approved the leukocyte growth factor Zarxio (filgrastim-sndz), the first biosimilar product to be approved in the US.

A biosimilar product is approved based on data showing that it is highly similar to an already-approved biological product.

Sandoz Inc’s Zarxio is biosimilar to Amgen Inc’s Neupogen (filgrastim), which was originally licensed in 1991. Zarxio is now approved for the same indications as Neupogen.

Zarxio can be prescribed for:

• patients with cancer receiving myelosuppressive chemotherapy
• patients with acute myeloid leukemia receiving induction or consolidation chemotherapy
• patients with cancer undergoing bone marrow transplant
• patients undergoing autologous peripheral blood progenitor cell collection and therapy
• patients with severe chronic neutropenia.

Zarxio is marketed as Zarzio outside the US. The biosimilar is available in more than 60 countries worldwide.

“Biosimilars will provide access to important therapies for patients who need them,” said FDA Commissioner Margaret A. Hamburg, MD.

“Patients and the healthcare community can be confident that biosimilar products approved by the FDA meet the agency’s rigorous safety, efficacy, and quality standards.”

Zarxio data

The FDA’s approval of Zarxio is based on a review of evidence that included structural and functional characterization, in vivo data, human pharmacokinetic and pharmacodynamics data, clinical immunogenicity data, and other clinical safety and effectiveness data that demonstrates Zarxio is biosimilar to Neupogen.

The PIONEER study was the final piece of data the FDA used to approve Zarxio as biosimilar to Neupogen. The data was sufficient to allow extrapolation of the use of Zarxio to all indications of Neupogen.

In the PIONEER study, Zarxio and Neupogen both produced the expected reduction in the duration of severe neutropenia in cancer patients undergoing myelosuppressive chemotherapy—1.17 and 1.20 days, respectively.

The mean time to absolute neutrophil count recovery in cycle 1 was also similar—1.8 ± 0.97 days in the Zarxio arm and 1.7 ± 0.81 days in the Neupogen arm. No immunogenicity or antibodies against rhG-CSF were detected throughout the study.

The most common side effects of Zarxio are aching in the bones or muscles and redness, swelling, or itching at the injection site. Serious side effects may include spleen rupture; serious allergic reactions that may cause rash, shortness of breath, wheezing and/or swelling around the mouth and eyes; fast pulse and sweating; and acute respiratory distress syndrome.

About biosimilar approval

The Biologics Price Competition and Innovation Act of 2009 (BPCI Act) was passed as part of the Affordable Care Act that President Barack Obama signed into law in March 2010. The BPCI Act created an abbreviated licensure pathway for biological products shown to be “biosimilar” to or “interchangeable” with an FDA-licensed biological product, known as the reference product.

This abbreviated licensure pathway under section 351(k) of the Public Health Service Act permits reliance on certain existing scientific knowledge about the safety and effectiveness of the reference product, and it enables a biosimilar biological product to be licensed based on less than a full complement of product-specific preclinical and clinical data.

A biosimilar product can only be approved by the FDA if it has the same mechanism(s) of action, route(s) of administration, dosage form(s) and strength(s) as the reference product, and only for the indication(s) and condition(s) of use that have been approved for the reference product. The facilities where biosimilars are manufactured must also meet the FDA’s standards.

There must be no clinically meaningful differences between the biosimilar and the reference product in terms of safety and effectiveness. Only minor differences in clinically inactive components are allowable.

Zarxio has been approved as a biosimilar, not an interchangeable product. Under the BPCI Act, a biological product that has been approved as “interchangeable” may be substituted for the reference product without the intervention of the healthcare provider who prescribed the reference product.

For Zarxio’s approval, the FDA has designated a placeholder nonproprietary name for this product as “filgrastim-sndz.” The provision of a placeholder nonproprietary name should not be viewed as reflective of the agency’s decision on a comprehensive naming policy for biosimilars and other biological products.

While the FDA has not yet issued draft guidance on how current and future biological products marketed in the US should be named, the agency intends to do so in the near future.

For more details on Zarxio, see the full prescribing information.

Thrombus

Image by Andre E.X. Brown

The UK’s National Institute for Health and Care Excellence (NICE) has issued a draft guidance recommending the anticoagulant apixaban (Eliquis) as an option for treating and preventing venous thromboembolism (VTE) in adults.

A NICE committee concluded that apixaban is clinically and cost-effective for this indication.

The draft guidance is now with consultees, who can appeal against it. Once NICE issues its final guidance on a technology, it replaces local recommendations.

“Apixaban, like the other newer oral anticoagulants already recommended by NICE for the treatment and secondary prevention of VTE, does not require frequent blood tests to monitor treatment and so represents a potential benefit for many people who have had a VTE,” said Carole Longson, NICE Health Technology Evaluation Centre Director.

“The committee also heard that apixaban is the only oral anticoagulant for which the licensed dose is lower for secondary prevention than for initial treatment of VTE. This could also be of potential benefit in terms of reducing the risk of bleeding where treatment is continued and therefore increase the chance that a person would take apixaban long-term.”

Clinical effectiveness

The NICE committee assessed the clinical effectiveness of apixaban based on results of the AMPLIFY and AMPLIFY-EXT studies.

Results of the AMPLIFY study indicated that apixaban is noninferior to standard treatment for recurrent VTE—initial parenteral enoxaparin overlapped with warfarin. Apixaban was comparable in efficacy to standard therapy and induced significantly less bleeding.

In AMPLIFY-EXT, researchers compared 12 months of treatment with apixaban at 2 doses—2.5 mg and 5 mg—to placebo in patients who had previously received anticoagulant therapy for 6 to 12 months to treat a prior VTE.

Both doses of apixaban effectively prevented VTE, VTE-related events, and death. And the incidence of bleeding events was low in all treatment arms.

The NICE committee noted that there were limited data in these trials pertaining to patients who needed less than 6 months of treatment and for patients still at high risk of recurrent VTE after 6 months of treatment.

However, the committee concluded that, despite these limitations, the AMPLIFY trials were the pivotal trials that informed the marketing authorization for apixaban. As such, they were sufficient to inform a recommendation for the whole population covered by the marketing authorization.

The committee did point out that there were no head-to-head trials evaluating the relative effectiveness of apixaban compared with rivaroxaban and dabigatran etexilate for treating and preventing VTE.

In addition, there were insufficient data to assess the effectiveness and safety of apixaban in patients with active cancer who had VTE, so it was not possible to make a specific recommendation for this group.

Cost-effectiveness

The recommended dose of apixaban as VTE treatment is 10 mg twice a day for the first 7 days, followed by 5 mg twice a day for at least 3 months. To prevent recurrent VTE, patients who have completed 6 months of VTE treatment should take apixaban at 2.5 mg twice a day.

The cost of apixaban is £1.10 per tablet for either the 2.5 mg or 5 mg dose (excluding tax). The daily cost of apixaban is £2.20. (Costs may vary in different settings because of negotiated procurement discounts.)

Analyses suggested that the incremental cost-effectiveness ratio of apixaban was less than £20,000 per quality-adjusted life-year gained for either 6 months or life-long treatment. Therefore, NICE concluded that apixaban is a cost-effective use of National Health Service resources. 

Thrombus

Image by Andre E.X. Brown

The UK’s National Institute for Health and Care Excellence (NICE) has issued a draft guidance recommending the anticoagulant apixaban (Eliquis) as an option for treating and preventing venous thromboembolism (VTE) in adults.

A NICE committee concluded that apixaban is clinically and cost-effective for this indication.

The draft guidance is now with consultees, who can appeal against it. Once NICE issues its final guidance on a technology, it replaces local recommendations.

“Apixaban, like the other newer oral anticoagulants already recommended by NICE for the treatment and secondary prevention of VTE, does not require frequent blood tests to monitor treatment and so represents a potential benefit for many people who have had a VTE,” said Carole Longson, NICE Health Technology Evaluation Centre Director.

“The committee also heard that apixaban is the only oral anticoagulant for which the licensed dose is lower for secondary prevention than for initial treatment of VTE. This could also be of potential benefit in terms of reducing the risk of bleeding where treatment is continued and therefore increase the chance that a person would take apixaban long-term.”

Clinical effectiveness

The NICE committee assessed the clinical effectiveness of apixaban based on results of the AMPLIFY and AMPLIFY-EXT studies.

Results of the AMPLIFY study indicated that apixaban is noninferior to standard treatment for recurrent VTE—initial parenteral enoxaparin overlapped with warfarin. Apixaban was comparable in efficacy to standard therapy and induced significantly less bleeding.

In AMPLIFY-EXT, researchers compared 12 months of treatment with apixaban at 2 doses—2.5 mg and 5 mg—to placebo in patients who had previously received anticoagulant therapy for 6 to 12 months to treat a prior VTE.

Both doses of apixaban effectively prevented VTE, VTE-related events, and death. And the incidence of bleeding events was low in all treatment arms.

The NICE committee noted that there were limited data in these trials pertaining to patients who needed less than 6 months of treatment and for patients still at high risk of recurrent VTE after 6 months of treatment.

However, the committee concluded that, despite these limitations, the AMPLIFY trials were the pivotal trials that informed the marketing authorization for apixaban. As such, they were sufficient to inform a recommendation for the whole population covered by the marketing authorization.

The committee did point out that there were no head-to-head trials evaluating the relative effectiveness of apixaban compared with rivaroxaban and dabigatran etexilate for treating and preventing VTE.

In addition, there were insufficient data to assess the effectiveness and safety of apixaban in patients with active cancer who had VTE, so it was not possible to make a specific recommendation for this group.

Cost-effectiveness

The recommended dose of apixaban as VTE treatment is 10 mg twice a day for the first 7 days, followed by 5 mg twice a day for at least 3 months. To prevent recurrent VTE, patients who have completed 6 months of VTE treatment should take apixaban at 2.5 mg twice a day.

The cost of apixaban is £1.10 per tablet for either the 2.5 mg or 5 mg dose (excluding tax). The daily cost of apixaban is £2.20. (Costs may vary in different settings because of negotiated procurement discounts.)

Analyses suggested that the incremental cost-effectiveness ratio of apixaban was less than £20,000 per quality-adjusted life-year gained for either 6 months or life-long treatment. Therefore, NICE concluded that apixaban is a cost-effective use of National Health Service resources. 

Thrombus

Image by Andre E.X. Brown

The UK’s National Institute for Health and Care Excellence (NICE) has issued a draft guidance recommending the anticoagulant apixaban (Eliquis) as an option for treating and preventing venous thromboembolism (VTE) in adults.

A NICE committee concluded that apixaban is clinically and cost-effective for this indication.

The draft guidance is now with consultees, who can appeal against it. Once NICE issues its final guidance on a technology, it replaces local recommendations.

“Apixaban, like the other newer oral anticoagulants already recommended by NICE for the treatment and secondary prevention of VTE, does not require frequent blood tests to monitor treatment and so represents a potential benefit for many people who have had a VTE,” said Carole Longson, NICE Health Technology Evaluation Centre Director.

“The committee also heard that apixaban is the only oral anticoagulant for which the licensed dose is lower for secondary prevention than for initial treatment of VTE. This could also be of potential benefit in terms of reducing the risk of bleeding where treatment is continued and therefore increase the chance that a person would take apixaban long-term.”

Clinical effectiveness

The NICE committee assessed the clinical effectiveness of apixaban based on results of the AMPLIFY and AMPLIFY-EXT studies.

Results of the AMPLIFY study indicated that apixaban is noninferior to standard treatment for recurrent VTE—initial parenteral enoxaparin overlapped with warfarin. Apixaban was comparable in efficacy to standard therapy and induced significantly less bleeding.

In AMPLIFY-EXT, researchers compared 12 months of treatment with apixaban at 2 doses—2.5 mg and 5 mg—to placebo in patients who had previously received anticoagulant therapy for 6 to 12 months to treat a prior VTE.

Both doses of apixaban effectively prevented VTE, VTE-related events, and death. And the incidence of bleeding events was low in all treatment arms.

The NICE committee noted that there were limited data in these trials pertaining to patients who needed less than 6 months of treatment and for patients still at high risk of recurrent VTE after 6 months of treatment.

However, the committee concluded that, despite these limitations, the AMPLIFY trials were the pivotal trials that informed the marketing authorization for apixaban. As such, they were sufficient to inform a recommendation for the whole population covered by the marketing authorization.

The committee did point out that there were no head-to-head trials evaluating the relative effectiveness of apixaban compared with rivaroxaban and dabigatran etexilate for treating and preventing VTE.

In addition, there were insufficient data to assess the effectiveness and safety of apixaban in patients with active cancer who had VTE, so it was not possible to make a specific recommendation for this group.

Cost-effectiveness

The recommended dose of apixaban as VTE treatment is 10 mg twice a day for the first 7 days, followed by 5 mg twice a day for at least 3 months. To prevent recurrent VTE, patients who have completed 6 months of VTE treatment should take apixaban at 2.5 mg twice a day.

The cost of apixaban is £1.10 per tablet for either the 2.5 mg or 5 mg dose (excluding tax). The daily cost of apixaban is £2.20. (Costs may vary in different settings because of negotiated procurement discounts.)

Analyses suggested that the incremental cost-effectiveness ratio of apixaban was less than £20,000 per quality-adjusted life-year gained for either 6 months or life-long treatment. Therefore, NICE concluded that apixaban is a cost-effective use of National Health Service resources. 

Aspergillosis

The US Food and Drug Administration (FDA) has approved isavuconazonium sulfate (Cresemba) to treat adults with invasive aspergillosis and invasive mucormycosis, life-threatening fungal infections that predominantly occur in immunocompromised patients.

Isavuconazonium sulfate is an azole antifungal agent that works by targeting the cell wall of a fungus. The drug is available in oral and intravenous formulations.

“[The] approval provides a new treatment option for patients with serious fungal infections and underscores the importance of having available safe and effective antifungal drugs,” said Edward Cox, MD, director of the Office of Antimicrobial Products in the FDA’s Center for Drug Evaluation and Research.

Clinical trials

The FDA approved isavuconazonium sulfate to treat invasive aspergillosis based on results of the phase 3 SECURE trial. The study included 516 adults with invasive aspergillosis who were randomized to receive isavuconazonium sulfate or voriconazole.

Isavuconazonium sulfate demonstrated non-inferiority to voriconazole on the primary endpoint of all-cause mortality. All-cause mortality through day 42 was 18.6% in the isavuconazonium sulfate arm and 20.2% in the voriconazole arm.

In addition, isavuconazonium sulfate demonstrated similar rates of mortality and non-fatal adverse events as voriconazole

The FDA approved isavuconazonium sulfate to treat invasive mucormycosis based on results of the phase 3 VITAL trial. This single-arm study included 37 patients with invasive mucormycosis who received isavuconazonium sulfate.

All-cause mortality in these patients was 38%. The efficacy of isavuconazonium sulfate as a treatment for invasive mucormycosis has not been evaluated in concurrent, controlled clinical trials.

The most frequent adverse events for patients treated with isavuconazonium sulfate in clinical trials were nausea (26%), vomiting (25%), diarrhea (22%), headache (17%), elevated liver chemistry tests (17%), hypokalemia (14%), constipation (13%), dyspnea (12%), cough (12%), peripheral edema (11%), and back pain (10%).

QIDP status

Isavuconazonium sulfate is the sixth approved antifungal/antibacterial drug product designated as a qualified infectious disease product (QIDP). This designation is given to antibacterial or antifungal products that treat serious or life-threatening infections.

As part of its QIDP designation, isavuconazonium sulfate was given priority review. The QIDP designation also qualifies the drug for an additional 5 years of marketing exclusivity to be added to certain exclusivity periods already provided by the Food, Drug, and Cosmetic Act.

As invasive aspergillosis and mucormycosis are rare, the FDA also granted isavuconazonium sulfate orphan drug designations to treat these infections.

Isavuconazonium sulfate is marketed as Cresemba by Astellas Pharma US, Inc., which is based in Northbrook, Illinois. For more information on the drug, see the full prescribing information.

Aspergillosis

The US Food and Drug Administration (FDA) has approved isavuconazonium sulfate (Cresemba) to treat adults with invasive aspergillosis and invasive mucormycosis, life-threatening fungal infections that predominantly occur in immunocompromised patients.

Isavuconazonium sulfate is an azole antifungal agent that works by targeting the cell wall of a fungus. The drug is available in oral and intravenous formulations.

“[The] approval provides a new treatment option for patients with serious fungal infections and underscores the importance of having available safe and effective antifungal drugs,” said Edward Cox, MD, director of the Office of Antimicrobial Products in the FDA’s Center for Drug Evaluation and Research.

Clinical trials

The FDA approved isavuconazonium sulfate to treat invasive aspergillosis based on results of the phase 3 SECURE trial. The study included 516 adults with invasive aspergillosis who were randomized to receive isavuconazonium sulfate or voriconazole.

Isavuconazonium sulfate demonstrated non-inferiority to voriconazole on the primary endpoint of all-cause mortality. All-cause mortality through day 42 was 18.6% in the isavuconazonium sulfate arm and 20.2% in the voriconazole arm.

In addition, isavuconazonium sulfate demonstrated similar rates of mortality and non-fatal adverse events as voriconazole

The FDA approved isavuconazonium sulfate to treat invasive mucormycosis based on results of the phase 3 VITAL trial. This single-arm study included 37 patients with invasive mucormycosis who received isavuconazonium sulfate.

All-cause mortality in these patients was 38%. The efficacy of isavuconazonium sulfate as a treatment for invasive mucormycosis has not been evaluated in concurrent, controlled clinical trials.

The most frequent adverse events for patients treated with isavuconazonium sulfate in clinical trials were nausea (26%), vomiting (25%), diarrhea (22%), headache (17%), elevated liver chemistry tests (17%), hypokalemia (14%), constipation (13%), dyspnea (12%), cough (12%), peripheral edema (11%), and back pain (10%).

QIDP status

Isavuconazonium sulfate is the sixth approved antifungal/antibacterial drug product designated as a qualified infectious disease product (QIDP). This designation is given to antibacterial or antifungal products that treat serious or life-threatening infections.

As part of its QIDP designation, isavuconazonium sulfate was given priority review. The QIDP designation also qualifies the drug for an additional 5 years of marketing exclusivity to be added to certain exclusivity periods already provided by the Food, Drug, and Cosmetic Act.

As invasive aspergillosis and mucormycosis are rare, the FDA also granted isavuconazonium sulfate orphan drug designations to treat these infections.

Isavuconazonium sulfate is marketed as Cresemba by Astellas Pharma US, Inc., which is based in Northbrook, Illinois. For more information on the drug, see the full prescribing information.

Aspergillosis

The US Food and Drug Administration (FDA) has approved isavuconazonium sulfate (Cresemba) to treat adults with invasive aspergillosis and invasive mucormycosis, life-threatening fungal infections that predominantly occur in immunocompromised patients.

Isavuconazonium sulfate is an azole antifungal agent that works by targeting the cell wall of a fungus. The drug is available in oral and intravenous formulations.

“[The] approval provides a new treatment option for patients with serious fungal infections and underscores the importance of having available safe and effective antifungal drugs,” said Edward Cox, MD, director of the Office of Antimicrobial Products in the FDA’s Center for Drug Evaluation and Research.

Clinical trials

The FDA approved isavuconazonium sulfate to treat invasive aspergillosis based on results of the phase 3 SECURE trial. The study included 516 adults with invasive aspergillosis who were randomized to receive isavuconazonium sulfate or voriconazole.

Isavuconazonium sulfate demonstrated non-inferiority to voriconazole on the primary endpoint of all-cause mortality. All-cause mortality through day 42 was 18.6% in the isavuconazonium sulfate arm and 20.2% in the voriconazole arm.

In addition, isavuconazonium sulfate demonstrated similar rates of mortality and non-fatal adverse events as voriconazole

The FDA approved isavuconazonium sulfate to treat invasive mucormycosis based on results of the phase 3 VITAL trial. This single-arm study included 37 patients with invasive mucormycosis who received isavuconazonium sulfate.

All-cause mortality in these patients was 38%. The efficacy of isavuconazonium sulfate as a treatment for invasive mucormycosis has not been evaluated in concurrent, controlled clinical trials.

The most frequent adverse events for patients treated with isavuconazonium sulfate in clinical trials were nausea (26%), vomiting (25%), diarrhea (22%), headache (17%), elevated liver chemistry tests (17%), hypokalemia (14%), constipation (13%), dyspnea (12%), cough (12%), peripheral edema (11%), and back pain (10%).

QIDP status

Isavuconazonium sulfate is the sixth approved antifungal/antibacterial drug product designated as a qualified infectious disease product (QIDP). This designation is given to antibacterial or antifungal products that treat serious or life-threatening infections.

As part of its QIDP designation, isavuconazonium sulfate was given priority review. The QIDP designation also qualifies the drug for an additional 5 years of marketing exclusivity to be added to certain exclusivity periods already provided by the Food, Drug, and Cosmetic Act.

As invasive aspergillosis and mucormycosis are rare, the FDA also granted isavuconazonium sulfate orphan drug designations to treat these infections.

Isavuconazonium sulfate is marketed as Cresemba by Astellas Pharma US, Inc., which is based in Northbrook, Illinois. For more information on the drug, see the full prescribing information.

They say you can’t have it all, and they’re right. But you can have most of it. By that I mean you can achieve a work-life balance that will enable you to thrive in your career while you raise your dream family. While this goal may never be easy, and you may always feel like you want to do more, give more, and reach more, that’s just the nature of the beast. We are all overachievers. That’s how we’re programmed; it’s in our DNA. Why else would we have taken on so much debt and sacrificed so many years for a career? And while many of us specifically chose hospital medicine so we could offset our stressful, hectic work life with plenty of time off for self and family, our reality is still replete with everyday challenges and, frequently, burnout.

We eagerly seek out best practices to optimize patient care, but how often do we seek advice from trusted colleagues on their “best practices” for balancing work and home? While talking with some of my female colleagues recently, I expressed my dismay that my dishwasher had broken and I frequently found myself washing dinner dishes as I juggled homework for my two 6-year-olds and responded to a seemingly incessant pager. One laughed as she recalled the pains she went through to have not one, but two dishwashers installed in her kitchen during her remodel. Washing dishes by hand simply wasn’t realistic for her. Her two little boys demanded whatever physical and emotional energy she had left after a stressful day at the hospital.

It is okay to admit that you don’t have all the answers, and it is cathartic to accept that you may never be the homemaker your mother was and forget about matching your grandmothers’ skillsets. At some Alcoholics Anonymous meetings, new members stand up and introduce themselves by saying, “Hello, my name is ___, and I am an alcoholic.” I personally felt like a huge weight had been lifted from my shoulders when one day, I finally acknowledged I didn’t have all the answers and I could never follow all of the parenting experts’ advice. After all, experts come and go, and with it, their expert recommendations. I don’t even want to abide by the “no more than 30 minutes of screen time per day” mantra. My parents raised five children on rerun after rerun of “The Andy Griffith Show,” “The Brady Bunch,” and other sitcoms, not to mention movies and musicals, and every one of us has a terminal degree, and still remember how much fun we had as children. My parents set high expectations, and they taught us how to reach them, plain and simple. We worked hard and we got to play hard, too.

The bottom line is that different techniques work for different people. Find out which ones work for you and your family and pursue them, regardless of what others may think. And above all, don’t let guilt get the best of you, because it will eat away at you and potentially destroy all you want to accomplish. You know, the guilt of missing a soccer game or a school play, or even the guilt of stopping for fast food when you are just too tired to cook a nutritious meal. Give yourself a break. The realistic goal is to optimize your work-life balance; the elusive one is to perfect it.

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].

They say you can’t have it all, and they’re right. But you can have most of it. By that I mean you can achieve a work-life balance that will enable you to thrive in your career while you raise your dream family. While this goal may never be easy, and you may always feel like you want to do more, give more, and reach more, that’s just the nature of the beast. We are all overachievers. That’s how we’re programmed; it’s in our DNA. Why else would we have taken on so much debt and sacrificed so many years for a career? And while many of us specifically chose hospital medicine so we could offset our stressful, hectic work life with plenty of time off for self and family, our reality is still replete with everyday challenges and, frequently, burnout.

We eagerly seek out best practices to optimize patient care, but how often do we seek advice from trusted colleagues on their “best practices” for balancing work and home? While talking with some of my female colleagues recently, I expressed my dismay that my dishwasher had broken and I frequently found myself washing dinner dishes as I juggled homework for my two 6-year-olds and responded to a seemingly incessant pager. One laughed as she recalled the pains she went through to have not one, but two dishwashers installed in her kitchen during her remodel. Washing dishes by hand simply wasn’t realistic for her. Her two little boys demanded whatever physical and emotional energy she had left after a stressful day at the hospital.

It is okay to admit that you don’t have all the answers, and it is cathartic to accept that you may never be the homemaker your mother was and forget about matching your grandmothers’ skillsets. At some Alcoholics Anonymous meetings, new members stand up and introduce themselves by saying, “Hello, my name is ___, and I am an alcoholic.” I personally felt like a huge weight had been lifted from my shoulders when one day, I finally acknowledged I didn’t have all the answers and I could never follow all of the parenting experts’ advice. After all, experts come and go, and with it, their expert recommendations. I don’t even want to abide by the “no more than 30 minutes of screen time per day” mantra. My parents raised five children on rerun after rerun of “The Andy Griffith Show,” “The Brady Bunch,” and other sitcoms, not to mention movies and musicals, and every one of us has a terminal degree, and still remember how much fun we had as children. My parents set high expectations, and they taught us how to reach them, plain and simple. We worked hard and we got to play hard, too.

The bottom line is that different techniques work for different people. Find out which ones work for you and your family and pursue them, regardless of what others may think. And above all, don’t let guilt get the best of you, because it will eat away at you and potentially destroy all you want to accomplish. You know, the guilt of missing a soccer game or a school play, or even the guilt of stopping for fast food when you are just too tired to cook a nutritious meal. Give yourself a break. The realistic goal is to optimize your work-life balance; the elusive one is to perfect it.

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].

They say you can’t have it all, and they’re right. But you can have most of it. By that I mean you can achieve a work-life balance that will enable you to thrive in your career while you raise your dream family. While this goal may never be easy, and you may always feel like you want to do more, give more, and reach more, that’s just the nature of the beast. We are all overachievers. That’s how we’re programmed; it’s in our DNA. Why else would we have taken on so much debt and sacrificed so many years for a career? And while many of us specifically chose hospital medicine so we could offset our stressful, hectic work life with plenty of time off for self and family, our reality is still replete with everyday challenges and, frequently, burnout.

We eagerly seek out best practices to optimize patient care, but how often do we seek advice from trusted colleagues on their “best practices” for balancing work and home? While talking with some of my female colleagues recently, I expressed my dismay that my dishwasher had broken and I frequently found myself washing dinner dishes as I juggled homework for my two 6-year-olds and responded to a seemingly incessant pager. One laughed as she recalled the pains she went through to have not one, but two dishwashers installed in her kitchen during her remodel. Washing dishes by hand simply wasn’t realistic for her. Her two little boys demanded whatever physical and emotional energy she had left after a stressful day at the hospital.

It is okay to admit that you don’t have all the answers, and it is cathartic to accept that you may never be the homemaker your mother was and forget about matching your grandmothers’ skillsets. At some Alcoholics Anonymous meetings, new members stand up and introduce themselves by saying, “Hello, my name is ___, and I am an alcoholic.” I personally felt like a huge weight had been lifted from my shoulders when one day, I finally acknowledged I didn’t have all the answers and I could never follow all of the parenting experts’ advice. After all, experts come and go, and with it, their expert recommendations. I don’t even want to abide by the “no more than 30 minutes of screen time per day” mantra. My parents raised five children on rerun after rerun of “The Andy Griffith Show,” “The Brady Bunch,” and other sitcoms, not to mention movies and musicals, and every one of us has a terminal degree, and still remember how much fun we had as children. My parents set high expectations, and they taught us how to reach them, plain and simple. We worked hard and we got to play hard, too.

The bottom line is that different techniques work for different people. Find out which ones work for you and your family and pursue them, regardless of what others may think. And above all, don’t let guilt get the best of you, because it will eat away at you and potentially destroy all you want to accomplish. You know, the guilt of missing a soccer game or a school play, or even the guilt of stopping for fast food when you are just too tired to cook a nutritious meal. Give yourself a break. The realistic goal is to optimize your work-life balance; the elusive one is to perfect it.

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].

To the Editor:

Pemphigus vulgaris is an uncommon autoimmune blistering dermatosis characterized by painful mucocutaneous erosions. It can be a life-threatening condition if left untreated. The autoimmune process is mediated by autoantibodies against the keratinocyte surface antigens desmoglein 1 and 3.¹ Therapy is directed at lowering autoantibody levels with systemic corticosteroids and immunosuppressive agents. Use of these agents often is limited by collateral adverse effects.² Refractory disease may occur despite the use of high-dose corticosteroids or a combination of other immunosuppressants. The level of these pathogenic autoantibodies generally parallels the extent of disease activity, and removing them with plasmapheresis followed by immunosuppression should result in therapeutic response.³ We report a case of refractory pemphigus vulgaris that was controlled with plasmapheresis used in synchrony with pulse cyclophosphamide.

A 48-year-old Chinese man first presented with mucocutaneous erosions 2 years ago, and a diagnosis of pemphigus vulgaris was confirmed based on typical histologic and immunofluorescence features. Histologic features included suprabasal acantholysis with an intraepidermal blister as well as basal keratinocytes attached to the dermal papillae and present along the entire dermoepidermal junction (Figure 1). Direct immunofluorescence demonstrated intercellular deposits of IgG and complements in the lower epidermis, and indirect immunofluorescence showed the presence of the pathogenic pemphigus autoantibodies. The patient was initially treated with prednisolone (up to 1 mg/kg daily) and mycophenolate mofetil (1 g twice daily) for 6 months with moderate disease response. Two months later he experienced a disease flare that was triggered by sun exposure and concomitant herpes simplex virus infection. He achieved moderate disease control with acyclovir, 3 days of intravenous immunoglobulin, and combination prednisolone and azathioprine. There was no other relevant medical history. For the last year, the patient received continuous prednisolone (varying doses 0.5–1 mg/kg daily), concomitant azathioprine (up to 3 mg/kg daily), and long-term prophylactic acyclovir, but he continued to have residual crusted erosions over the scalp and face (best score of 25 points based on the autoimmune bullous skin disorder intensity score [ABSIS] ranging from 0–150 points⁴). He was admitted at the current presentation with another, more severe disease flare with extensive painful erosions over the trunk, arms, legs, face, and scalp (80% body surface area involvement and ABSIS score of 120 points)(Figure 2)⁴ that occurred after azathioprine was temporarily ceased for 1 week due to transaminitis, and despite a temporary increment in prednisolone dose. There was, however, no significant oral mucosal involvement. The desmoglein 1 and 3 antibody levels were elevated at more than 300 U/mL and 186 U/mL, respectively (>20 U/mL indicates positivity). A 3-day course of pulse intravenous methylprednisolone (10 mg/kg) failed to achieve clinical improvement or reduction of antibody titers. The use of various immunosuppressive agents was limited by persistent transaminitis and transient leukopenia.

Figure 1. Histologic features of pemphigus vulgaris including suprabasal acantholysis with an intraepidermal blister as well as basal keratinocytes attached to the dermal papillae and present along the entire dermoepidermal junction (H&E, original magnification ×40). Figure 2. Acute flare of pemphigus vulgaris with extensive erosions of the trunk and arms (80% body surface area involvement). Figure 3. Clinical improvement of pemphigus vulgaris after 9 sessions of plasmapheresis synchronized with pulse intravenous cyclophosphamide over a 3-week period. The erosions were almost completely reepithelialized.

Because of remarkable morbidity, the patient underwent interim plasmapheresis for rapid disease control. Plasmapheresis was carried out through a pheresible central venous catheter. One plasma volume exchange was done each session, which was 5 L for the patient’s body weight and hematocrit. Equal volume of colloid comprising 2.5 L of fresh frozen plasma and 2.5 L of 5% albumin was used for replacement. Plasma exchange was performed with a cell separator by discontinuous flow centrifugation with 4% acid citrate dextrose as an anticoagulant. For each session of plasmapheresis, 16 cycles of exchange (each processing approximately 300 mL of blood) was carried out, the entire process lasting for 4 hours. The coagulation and biochemical profile was checked after each session of plasmapheresis and corrected when necessary. The patient underwent 9 sessions of plasmapheresis over a 3-week period, synchronized with pulse intravenous cyclophosphamide (15 mg/kg) immediately after completion of the plasmapheresis sessions, resulting in a remarkable decrease in pathogenic antibody titers to near undetectable levels and clinical improvement (Figure 3). The extensive erosions gradually healed with good reepithelialization, and there was a notable reduction in the ABSIS score to 12 points. He received 3 more monthly treatments with pulse intravenous cyclophosphamide (15 mg/kg) and is currently maintained on oral cyclophosphamide (2 mg/kg daily) and low-dose prednisolone (0.3 mg/kg daily). There was no subsequent disease relapse at 6-month follow-up, with the ABSIS score maintained at 5 points, and no increase in pathogenic autoantibody titers. The patient subsequently was lost to follow-up.

Patients with severe disease or refractory cases of pemphigus vulgaris that have been maintained on unacceptably high doses of corticosteroids or immunosuppressants that cannot be tapered without a disease flare may develop remarkable adverse effects, both from medications and from long-term immunosuppression.² Our case illustrates the short-term benefit of plasmapheresis combined with immunosuppressants resulting in rapid disease control.

Plasmapheresis involves the selective removal of pathogenic materials from the circulation to achieve therapeutic effect, followed by appropriate replacement fluids. Treating pemphigus vulgaris with plasmapheresis was introduced in 1978 based on the rationale of removing pathogenic autoantibodies from the circulation.^3,5 Using desmoglein enzyme-linked immunosorbent assay, it has been shown that one centrifugal plasmapheresis procedure eliminates approximately 15% of the IgG autoantibodies from the whole body.⁶ An average of 5 plasmapheresis sessions on alternate days usually is required to deplete the levels of pathogenic autoantibodies to near undetectable levels.⁷ Our case required 9 plasmapheresis sessions over 3 weeks to achieve good therapeutic response.

It seems that using plasmapheresis to treat pemphigus vulgaris has fallen out of favor due to its inability to prevent the antibody rebound occurring during weeks 1 and 2 posttreatment. Because of a feedback mechanism, a massive antibody depletion by plasmapheresis triggers a rebound synthesis of more autoantibodies by pathogenic B cells to titers comparable to or higher than those before plasmapheresis.⁸ The use of plasmapheresis should be supported by immunosuppressive therapy to prevent antibody feedback rebound. Due to the advent of available immunosuppressive agents in recent years, there is a resurgence in the successful use of this old treatment modality combined with immunosuppressive therapy in managing refractory pemphigus vulgaris.^7,8 At present there is no clear data to support the use of one immunosuppressant versus another, but our case supports the use of pulse intravenous cyclophosphamide, as documented in other reports.^7,9 The success of immunosuppressive agents at reducing antibody levels depends on the timing (immediately after plasmapheresis) as well as individual responsiveness to the immunosuppressant.⁷

Our armamentarium of therapies for refractory pemphigus vulgaris continues to evolve. A more selective method of removing antibodies by extracorporeal immunoadsorption has the benefit of higher removal rates and reduced inadvertent loss of other plasma components.¹⁰ The combination of protein A immunoadsorption with rituximab, a monoclonal anti-CD20 antibody that induces B-cell depletion, also has been shown to induce rapid and durable remission in refractory cases.¹¹

Our case shows that plasmapheresis can be a useful alternative or adjunctive intervention in pemphigus vulgaris that is not responding to conventional therapy or in cases when steroids or immunosuppressants are contraindicated. There is a definite role for such therapeutic plasma exchanges in the rapid control of potentially life-threatening disease. Its benefits are optimized when used in synchrony with immunosuppressants immediately following plasmapheresis to prevent rebound effect of antibody depletion.

To the Editor:

Pemphigus vulgaris is an uncommon autoimmune blistering dermatosis characterized by painful mucocutaneous erosions. It can be a life-threatening condition if left untreated. The autoimmune process is mediated by autoantibodies against the keratinocyte surface antigens desmoglein 1 and 3.¹ Therapy is directed at lowering autoantibody levels with systemic corticosteroids and immunosuppressive agents. Use of these agents often is limited by collateral adverse effects.² Refractory disease may occur despite the use of high-dose corticosteroids or a combination of other immunosuppressants. The level of these pathogenic autoantibodies generally parallels the extent of disease activity, and removing them with plasmapheresis followed by immunosuppression should result in therapeutic response.³ We report a case of refractory pemphigus vulgaris that was controlled with plasmapheresis used in synchrony with pulse cyclophosphamide.

A 48-year-old Chinese man first presented with mucocutaneous erosions 2 years ago, and a diagnosis of pemphigus vulgaris was confirmed based on typical histologic and immunofluorescence features. Histologic features included suprabasal acantholysis with an intraepidermal blister as well as basal keratinocytes attached to the dermal papillae and present along the entire dermoepidermal junction (Figure 1). Direct immunofluorescence demonstrated intercellular deposits of IgG and complements in the lower epidermis, and indirect immunofluorescence showed the presence of the pathogenic pemphigus autoantibodies. The patient was initially treated with prednisolone (up to 1 mg/kg daily) and mycophenolate mofetil (1 g twice daily) for 6 months with moderate disease response. Two months later he experienced a disease flare that was triggered by sun exposure and concomitant herpes simplex virus infection. He achieved moderate disease control with acyclovir, 3 days of intravenous immunoglobulin, and combination prednisolone and azathioprine. There was no other relevant medical history. For the last year, the patient received continuous prednisolone (varying doses 0.5–1 mg/kg daily), concomitant azathioprine (up to 3 mg/kg daily), and long-term prophylactic acyclovir, but he continued to have residual crusted erosions over the scalp and face (best score of 25 points based on the autoimmune bullous skin disorder intensity score [ABSIS] ranging from 0–150 points⁴). He was admitted at the current presentation with another, more severe disease flare with extensive painful erosions over the trunk, arms, legs, face, and scalp (80% body surface area involvement and ABSIS score of 120 points)(Figure 2)⁴ that occurred after azathioprine was temporarily ceased for 1 week due to transaminitis, and despite a temporary increment in prednisolone dose. There was, however, no significant oral mucosal involvement. The desmoglein 1 and 3 antibody levels were elevated at more than 300 U/mL and 186 U/mL, respectively (>20 U/mL indicates positivity). A 3-day course of pulse intravenous methylprednisolone (10 mg/kg) failed to achieve clinical improvement or reduction of antibody titers. The use of various immunosuppressive agents was limited by persistent transaminitis and transient leukopenia.

Figure 1. Histologic features of pemphigus vulgaris including suprabasal acantholysis with an intraepidermal blister as well as basal keratinocytes attached to the dermal papillae and present along the entire dermoepidermal junction (H&E, original magnification ×40). Figure 2. Acute flare of pemphigus vulgaris with extensive erosions of the trunk and arms (80% body surface area involvement). Figure 3. Clinical improvement of pemphigus vulgaris after 9 sessions of plasmapheresis synchronized with pulse intravenous cyclophosphamide over a 3-week period. The erosions were almost completely reepithelialized.

Because of remarkable morbidity, the patient underwent interim plasmapheresis for rapid disease control. Plasmapheresis was carried out through a pheresible central venous catheter. One plasma volume exchange was done each session, which was 5 L for the patient’s body weight and hematocrit. Equal volume of colloid comprising 2.5 L of fresh frozen plasma and 2.5 L of 5% albumin was used for replacement. Plasma exchange was performed with a cell separator by discontinuous flow centrifugation with 4% acid citrate dextrose as an anticoagulant. For each session of plasmapheresis, 16 cycles of exchange (each processing approximately 300 mL of blood) was carried out, the entire process lasting for 4 hours. The coagulation and biochemical profile was checked after each session of plasmapheresis and corrected when necessary. The patient underwent 9 sessions of plasmapheresis over a 3-week period, synchronized with pulse intravenous cyclophosphamide (15 mg/kg) immediately after completion of the plasmapheresis sessions, resulting in a remarkable decrease in pathogenic antibody titers to near undetectable levels and clinical improvement (Figure 3). The extensive erosions gradually healed with good reepithelialization, and there was a notable reduction in the ABSIS score to 12 points. He received 3 more monthly treatments with pulse intravenous cyclophosphamide (15 mg/kg) and is currently maintained on oral cyclophosphamide (2 mg/kg daily) and low-dose prednisolone (0.3 mg/kg daily). There was no subsequent disease relapse at 6-month follow-up, with the ABSIS score maintained at 5 points, and no increase in pathogenic autoantibody titers. The patient subsequently was lost to follow-up.

Patients with severe disease or refractory cases of pemphigus vulgaris that have been maintained on unacceptably high doses of corticosteroids or immunosuppressants that cannot be tapered without a disease flare may develop remarkable adverse effects, both from medications and from long-term immunosuppression.² Our case illustrates the short-term benefit of plasmapheresis combined with immunosuppressants resulting in rapid disease control.

Plasmapheresis involves the selective removal of pathogenic materials from the circulation to achieve therapeutic effect, followed by appropriate replacement fluids. Treating pemphigus vulgaris with plasmapheresis was introduced in 1978 based on the rationale of removing pathogenic autoantibodies from the circulation.^3,5 Using desmoglein enzyme-linked immunosorbent assay, it has been shown that one centrifugal plasmapheresis procedure eliminates approximately 15% of the IgG autoantibodies from the whole body.⁶ An average of 5 plasmapheresis sessions on alternate days usually is required to deplete the levels of pathogenic autoantibodies to near undetectable levels.⁷ Our case required 9 plasmapheresis sessions over 3 weeks to achieve good therapeutic response.

It seems that using plasmapheresis to treat pemphigus vulgaris has fallen out of favor due to its inability to prevent the antibody rebound occurring during weeks 1 and 2 posttreatment. Because of a feedback mechanism, a massive antibody depletion by plasmapheresis triggers a rebound synthesis of more autoantibodies by pathogenic B cells to titers comparable to or higher than those before plasmapheresis.⁸ The use of plasmapheresis should be supported by immunosuppressive therapy to prevent antibody feedback rebound. Due to the advent of available immunosuppressive agents in recent years, there is a resurgence in the successful use of this old treatment modality combined with immunosuppressive therapy in managing refractory pemphigus vulgaris.^7,8 At present there is no clear data to support the use of one immunosuppressant versus another, but our case supports the use of pulse intravenous cyclophosphamide, as documented in other reports.^7,9 The success of immunosuppressive agents at reducing antibody levels depends on the timing (immediately after plasmapheresis) as well as individual responsiveness to the immunosuppressant.⁷

Our armamentarium of therapies for refractory pemphigus vulgaris continues to evolve. A more selective method of removing antibodies by extracorporeal immunoadsorption has the benefit of higher removal rates and reduced inadvertent loss of other plasma components.¹⁰ The combination of protein A immunoadsorption with rituximab, a monoclonal anti-CD20 antibody that induces B-cell depletion, also has been shown to induce rapid and durable remission in refractory cases.¹¹

Our case shows that plasmapheresis can be a useful alternative or adjunctive intervention in pemphigus vulgaris that is not responding to conventional therapy or in cases when steroids or immunosuppressants are contraindicated. There is a definite role for such therapeutic plasma exchanges in the rapid control of potentially life-threatening disease. Its benefits are optimized when used in synchrony with immunosuppressants immediately following plasmapheresis to prevent rebound effect of antibody depletion.

To the Editor:

Pemphigus vulgaris is an uncommon autoimmune blistering dermatosis characterized by painful mucocutaneous erosions. It can be a life-threatening condition if left untreated. The autoimmune process is mediated by autoantibodies against the keratinocyte surface antigens desmoglein 1 and 3.¹ Therapy is directed at lowering autoantibody levels with systemic corticosteroids and immunosuppressive agents. Use of these agents often is limited by collateral adverse effects.² Refractory disease may occur despite the use of high-dose corticosteroids or a combination of other immunosuppressants. The level of these pathogenic autoantibodies generally parallels the extent of disease activity, and removing them with plasmapheresis followed by immunosuppression should result in therapeutic response.³ We report a case of refractory pemphigus vulgaris that was controlled with plasmapheresis used in synchrony with pulse cyclophosphamide.

A 48-year-old Chinese man first presented with mucocutaneous erosions 2 years ago, and a diagnosis of pemphigus vulgaris was confirmed based on typical histologic and immunofluorescence features. Histologic features included suprabasal acantholysis with an intraepidermal blister as well as basal keratinocytes attached to the dermal papillae and present along the entire dermoepidermal junction (Figure 1). Direct immunofluorescence demonstrated intercellular deposits of IgG and complements in the lower epidermis, and indirect immunofluorescence showed the presence of the pathogenic pemphigus autoantibodies. The patient was initially treated with prednisolone (up to 1 mg/kg daily) and mycophenolate mofetil (1 g twice daily) for 6 months with moderate disease response. Two months later he experienced a disease flare that was triggered by sun exposure and concomitant herpes simplex virus infection. He achieved moderate disease control with acyclovir, 3 days of intravenous immunoglobulin, and combination prednisolone and azathioprine. There was no other relevant medical history. For the last year, the patient received continuous prednisolone (varying doses 0.5–1 mg/kg daily), concomitant azathioprine (up to 3 mg/kg daily), and long-term prophylactic acyclovir, but he continued to have residual crusted erosions over the scalp and face (best score of 25 points based on the autoimmune bullous skin disorder intensity score [ABSIS] ranging from 0–150 points⁴). He was admitted at the current presentation with another, more severe disease flare with extensive painful erosions over the trunk, arms, legs, face, and scalp (80% body surface area involvement and ABSIS score of 120 points)(Figure 2)⁴ that occurred after azathioprine was temporarily ceased for 1 week due to transaminitis, and despite a temporary increment in prednisolone dose. There was, however, no significant oral mucosal involvement. The desmoglein 1 and 3 antibody levels were elevated at more than 300 U/mL and 186 U/mL, respectively (>20 U/mL indicates positivity). A 3-day course of pulse intravenous methylprednisolone (10 mg/kg) failed to achieve clinical improvement or reduction of antibody titers. The use of various immunosuppressive agents was limited by persistent transaminitis and transient leukopenia.

Figure 1. Histologic features of pemphigus vulgaris including suprabasal acantholysis with an intraepidermal blister as well as basal keratinocytes attached to the dermal papillae and present along the entire dermoepidermal junction (H&E, original magnification ×40). Figure 2. Acute flare of pemphigus vulgaris with extensive erosions of the trunk and arms (80% body surface area involvement). Figure 3. Clinical improvement of pemphigus vulgaris after 9 sessions of plasmapheresis synchronized with pulse intravenous cyclophosphamide over a 3-week period. The erosions were almost completely reepithelialized.

Because of remarkable morbidity, the patient underwent interim plasmapheresis for rapid disease control. Plasmapheresis was carried out through a pheresible central venous catheter. One plasma volume exchange was done each session, which was 5 L for the patient’s body weight and hematocrit. Equal volume of colloid comprising 2.5 L of fresh frozen plasma and 2.5 L of 5% albumin was used for replacement. Plasma exchange was performed with a cell separator by discontinuous flow centrifugation with 4% acid citrate dextrose as an anticoagulant. For each session of plasmapheresis, 16 cycles of exchange (each processing approximately 300 mL of blood) was carried out, the entire process lasting for 4 hours. The coagulation and biochemical profile was checked after each session of plasmapheresis and corrected when necessary. The patient underwent 9 sessions of plasmapheresis over a 3-week period, synchronized with pulse intravenous cyclophosphamide (15 mg/kg) immediately after completion of the plasmapheresis sessions, resulting in a remarkable decrease in pathogenic antibody titers to near undetectable levels and clinical improvement (Figure 3). The extensive erosions gradually healed with good reepithelialization, and there was a notable reduction in the ABSIS score to 12 points. He received 3 more monthly treatments with pulse intravenous cyclophosphamide (15 mg/kg) and is currently maintained on oral cyclophosphamide (2 mg/kg daily) and low-dose prednisolone (0.3 mg/kg daily). There was no subsequent disease relapse at 6-month follow-up, with the ABSIS score maintained at 5 points, and no increase in pathogenic autoantibody titers. The patient subsequently was lost to follow-up.

Patients with severe disease or refractory cases of pemphigus vulgaris that have been maintained on unacceptably high doses of corticosteroids or immunosuppressants that cannot be tapered without a disease flare may develop remarkable adverse effects, both from medications and from long-term immunosuppression.² Our case illustrates the short-term benefit of plasmapheresis combined with immunosuppressants resulting in rapid disease control.

Plasmapheresis involves the selective removal of pathogenic materials from the circulation to achieve therapeutic effect, followed by appropriate replacement fluids. Treating pemphigus vulgaris with plasmapheresis was introduced in 1978 based on the rationale of removing pathogenic autoantibodies from the circulation.^3,5 Using desmoglein enzyme-linked immunosorbent assay, it has been shown that one centrifugal plasmapheresis procedure eliminates approximately 15% of the IgG autoantibodies from the whole body.⁶ An average of 5 plasmapheresis sessions on alternate days usually is required to deplete the levels of pathogenic autoantibodies to near undetectable levels.⁷ Our case required 9 plasmapheresis sessions over 3 weeks to achieve good therapeutic response.

It seems that using plasmapheresis to treat pemphigus vulgaris has fallen out of favor due to its inability to prevent the antibody rebound occurring during weeks 1 and 2 posttreatment. Because of a feedback mechanism, a massive antibody depletion by plasmapheresis triggers a rebound synthesis of more autoantibodies by pathogenic B cells to titers comparable to or higher than those before plasmapheresis.⁸ The use of plasmapheresis should be supported by immunosuppressive therapy to prevent antibody feedback rebound. Due to the advent of available immunosuppressive agents in recent years, there is a resurgence in the successful use of this old treatment modality combined with immunosuppressive therapy in managing refractory pemphigus vulgaris.^7,8 At present there is no clear data to support the use of one immunosuppressant versus another, but our case supports the use of pulse intravenous cyclophosphamide, as documented in other reports.^7,9 The success of immunosuppressive agents at reducing antibody levels depends on the timing (immediately after plasmapheresis) as well as individual responsiveness to the immunosuppressant.⁷

Our armamentarium of therapies for refractory pemphigus vulgaris continues to evolve. A more selective method of removing antibodies by extracorporeal immunoadsorption has the benefit of higher removal rates and reduced inadvertent loss of other plasma components.¹⁰ The combination of protein A immunoadsorption with rituximab, a monoclonal anti-CD20 antibody that induces B-cell depletion, also has been shown to induce rapid and durable remission in refractory cases.¹¹

Our case shows that plasmapheresis can be a useful alternative or adjunctive intervention in pemphigus vulgaris that is not responding to conventional therapy or in cases when steroids or immunosuppressants are contraindicated. There is a definite role for such therapeutic plasma exchanges in the rapid control of potentially life-threatening disease. Its benefits are optimized when used in synchrony with immunosuppressants immediately following plasmapheresis to prevent rebound effect of antibody depletion.