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Toward better treatment of CML
Credit: UC San Diego
In vitro experiments have revealed new insight into tyrosine kinase inhibitor (TKI) resistance among patients with chronic myeloid leukemia (CML).
Though it’s now possible to overcome TKI resistance resulting from single BCR-ABL1 mutants, targeting compound mutants remains a challenge.
So researchers tested several TKIs on various BCR-ABL1 compound mutants to determine which drug, if any, would be most effective for each combination.
The results appear in Cancer Cell.
Thomas O’Hare, PhD, of the Huntsman Cancer Institute at the University of Utah, and his colleagues first took an inventory of clinical BCR-ABL1 compound mutations associated with TKI resistance that had been reported in the literature.
The team identified 12 kinase domain positions that account for most clinical BCR-ABL1 TKI resistance—M244, G250, Q252, Y253, E255, V299, F311, T315, F317, M351, F359, and H396.
All of the clinically reported compound mutations include at least 1 of the 12 key positions, and most (65%) include 2. Each position has been implicated in resistance to 1 or more TKIs, including imatinib, nilotinib, dasatinib, bosutinib, rebastinib, and ponatinib.
The researchers found that some of the compound mutations they studied conferred resistance several-fold higher than that of either contributing mutation alone.
“We were able to sequence about 100 clinical samples, which gave us a very large body of data to shed light on the number of compound mutations and how they develop,” said Michael Deininger, MD, PhD, also of the Huntsman Cancer Institute.
“One key finding was that compound mutations containing an already known mutation called T315I tend to confer complete resistance to all available TKIs.”
The researchers had focused their testing on ponatinib, as the drug has proven effective against resistant CML, particularly cases with the T315I mutation. Unfortunately, ponatinib was often no match for compound mutations including T315I.
Tests did suggest that a 30 mg/day dose of ponatinib would maintain efficacy against 7 of the 8 non-T315I compound mutants tested, though the Y253H/E255V mutant proved resistant.
The researchers also found that a 15 mg/day dose of ponatinib could pre-empt outgrowth of 5 of the 8 non-T315I compound mutants, though Y253H/E255V, E255V/V299L, and F317L/F359V might be problematic.
But ponatinib proved substantially less effective against T315I-inclusive compound mutants. Nine of 10 T315I-inclusive compound mutants showed little or no sensitivity to ponatinib or any of the other TKIs tested. M244V/T315I was the only compound mutant not resistant to ponatinib.
The researchers noted that because ponatinib has proven effective against the T315I mutant in isolation, many patients treated with ponatinib are likely to have this mutation.
So it may be necessary to perform more sensitive screening on these patients to determine whether they might have T315I-inclusive compound mutants that could confer resistance.
“Fortunately, the problems we are studying affect a minority of CML patients,” Dr O’Hare said. “[S]till, this leaves some patients with no good treatment option at all. Our goal is to have a TKI option for every patient.”
According to Dr O’Hare, it’s only a matter of time until analogous compound mutations emerge in many other cancers, including acute myeloid leukemia and non-small cell lung cancer.
“Our findings in CML will provide a blueprint for contending with resistance in these highly aggressive diseases as well,” he concluded. 
Credit: UC San Diego
In vitro experiments have revealed new insight into tyrosine kinase inhibitor (TKI) resistance among patients with chronic myeloid leukemia (CML).
Though it’s now possible to overcome TKI resistance resulting from single BCR-ABL1 mutants, targeting compound mutants remains a challenge.
So researchers tested several TKIs on various BCR-ABL1 compound mutants to determine which drug, if any, would be most effective for each combination.
The results appear in Cancer Cell.
Thomas O’Hare, PhD, of the Huntsman Cancer Institute at the University of Utah, and his colleagues first took an inventory of clinical BCR-ABL1 compound mutations associated with TKI resistance that had been reported in the literature.
The team identified 12 kinase domain positions that account for most clinical BCR-ABL1 TKI resistance—M244, G250, Q252, Y253, E255, V299, F311, T315, F317, M351, F359, and H396.
All of the clinically reported compound mutations include at least 1 of the 12 key positions, and most (65%) include 2. Each position has been implicated in resistance to 1 or more TKIs, including imatinib, nilotinib, dasatinib, bosutinib, rebastinib, and ponatinib.
The researchers found that some of the compound mutations they studied conferred resistance several-fold higher than that of either contributing mutation alone.
“We were able to sequence about 100 clinical samples, which gave us a very large body of data to shed light on the number of compound mutations and how they develop,” said Michael Deininger, MD, PhD, also of the Huntsman Cancer Institute.
“One key finding was that compound mutations containing an already known mutation called T315I tend to confer complete resistance to all available TKIs.”
The researchers had focused their testing on ponatinib, as the drug has proven effective against resistant CML, particularly cases with the T315I mutation. Unfortunately, ponatinib was often no match for compound mutations including T315I.
Tests did suggest that a 30 mg/day dose of ponatinib would maintain efficacy against 7 of the 8 non-T315I compound mutants tested, though the Y253H/E255V mutant proved resistant.
The researchers also found that a 15 mg/day dose of ponatinib could pre-empt outgrowth of 5 of the 8 non-T315I compound mutants, though Y253H/E255V, E255V/V299L, and F317L/F359V might be problematic.
But ponatinib proved substantially less effective against T315I-inclusive compound mutants. Nine of 10 T315I-inclusive compound mutants showed little or no sensitivity to ponatinib or any of the other TKIs tested. M244V/T315I was the only compound mutant not resistant to ponatinib.
The researchers noted that because ponatinib has proven effective against the T315I mutant in isolation, many patients treated with ponatinib are likely to have this mutation.
So it may be necessary to perform more sensitive screening on these patients to determine whether they might have T315I-inclusive compound mutants that could confer resistance.
“Fortunately, the problems we are studying affect a minority of CML patients,” Dr O’Hare said. “[S]till, this leaves some patients with no good treatment option at all. Our goal is to have a TKI option for every patient.”
According to Dr O’Hare, it’s only a matter of time until analogous compound mutations emerge in many other cancers, including acute myeloid leukemia and non-small cell lung cancer.
“Our findings in CML will provide a blueprint for contending with resistance in these highly aggressive diseases as well,” he concluded.
Credit: UC San Diego
In vitro experiments have revealed new insight into tyrosine kinase inhibitor (TKI) resistance among patients with chronic myeloid leukemia (CML).
Though it’s now possible to overcome TKI resistance resulting from single BCR-ABL1 mutants, targeting compound mutants remains a challenge.
So researchers tested several TKIs on various BCR-ABL1 compound mutants to determine which drug, if any, would be most effective for each combination.
The results appear in Cancer Cell.
Thomas O’Hare, PhD, of the Huntsman Cancer Institute at the University of Utah, and his colleagues first took an inventory of clinical BCR-ABL1 compound mutations associated with TKI resistance that had been reported in the literature.
The team identified 12 kinase domain positions that account for most clinical BCR-ABL1 TKI resistance—M244, G250, Q252, Y253, E255, V299, F311, T315, F317, M351, F359, and H396.
All of the clinically reported compound mutations include at least 1 of the 12 key positions, and most (65%) include 2. Each position has been implicated in resistance to 1 or more TKIs, including imatinib, nilotinib, dasatinib, bosutinib, rebastinib, and ponatinib.
The researchers found that some of the compound mutations they studied conferred resistance several-fold higher than that of either contributing mutation alone.
“We were able to sequence about 100 clinical samples, which gave us a very large body of data to shed light on the number of compound mutations and how they develop,” said Michael Deininger, MD, PhD, also of the Huntsman Cancer Institute.
“One key finding was that compound mutations containing an already known mutation called T315I tend to confer complete resistance to all available TKIs.”
The researchers had focused their testing on ponatinib, as the drug has proven effective against resistant CML, particularly cases with the T315I mutation. Unfortunately, ponatinib was often no match for compound mutations including T315I.
Tests did suggest that a 30 mg/day dose of ponatinib would maintain efficacy against 7 of the 8 non-T315I compound mutants tested, though the Y253H/E255V mutant proved resistant.
The researchers also found that a 15 mg/day dose of ponatinib could pre-empt outgrowth of 5 of the 8 non-T315I compound mutants, though Y253H/E255V, E255V/V299L, and F317L/F359V might be problematic.
But ponatinib proved substantially less effective against T315I-inclusive compound mutants. Nine of 10 T315I-inclusive compound mutants showed little or no sensitivity to ponatinib or any of the other TKIs tested. M244V/T315I was the only compound mutant not resistant to ponatinib.
The researchers noted that because ponatinib has proven effective against the T315I mutant in isolation, many patients treated with ponatinib are likely to have this mutation.
So it may be necessary to perform more sensitive screening on these patients to determine whether they might have T315I-inclusive compound mutants that could confer resistance.
“Fortunately, the problems we are studying affect a minority of CML patients,” Dr O’Hare said. “[S]till, this leaves some patients with no good treatment option at all. Our goal is to have a TKI option for every patient.”
According to Dr O’Hare, it’s only a matter of time until analogous compound mutations emerge in many other cancers, including acute myeloid leukemia and non-small cell lung cancer.
“Our findings in CML will provide a blueprint for contending with resistance in these highly aggressive diseases as well,” he concluded.
Path to drug development often not straightforward, study shows
Credit: Rhoda Baer
An analysis of university discoveries licensed to biotechnology firms has revealed early bottlenecks in the drug development process.
Typically, universities do most of the basic research and then license a discovery to a small biotech firm that advances the research. The small firm will then sublicense the discovery to a large firm that can run clinical trials.
But an analysis published in Science Translational Medicine suggests the process rarely follows this straightforward path.
Instead, it often zigzags across biotech firms and between research areas before a drug is finally commercialized.
“The timeline for commercialization is much longer than most people think,” said study author Jerry Thursby, PhD, of the Georgia Institute of Technology in Atlanta.
To study the path of drug development, Dr Thursby and his colleagues built a database of 835 patents in 342 university licenses with biotech firms.
They then traced the path of patents to document whether the inventions were sublicensed to another firm for testing in a new disease category or whether the sublicense was to a large firm for clinical trials or marketing.
In all, 27% of inventions appeared in a second license (sublicense). The average time between invention and first license was 5.5 years, and the average time between first and second license was 3.5 years.
This time span is substantial, the researchers said, given that the average time from discovery to drug approval in the US is 13 years.
The team also found that sublicensing often resets the development timeline because a drug must be tested for an entirely new indication or several new indications.
The disease categories in the licenses analyzed spanned 20 distinct indications, and individual licenses included up to 5 indications. But the categories were very broad, such as “cancer” or “infectious diseases.”
Nevertheless, the researchers saw substantial changes in disease indications from the first license to the second. Only 19% of the inventions remained completely unchanged between the first and second license.
For 44% of inventions, none of the first-license indications remained in the second license. Twenty-eight percent of inventions had indications added between the first and second license, and 9% had indications subtracted.
The researchers said these results suggest a need for policies and initiatives that enhance early translation by more efficiently driving more inventions into multiple disease pipelines.
One option might be the formation of an open-source translational research database that complements clinicaltrials.gov, where patents and licenses for biomedical research thought to be destined for eventual therapeutic use would be logged and shared.
Credit: Rhoda Baer
An analysis of university discoveries licensed to biotechnology firms has revealed early bottlenecks in the drug development process.
Typically, universities do most of the basic research and then license a discovery to a small biotech firm that advances the research. The small firm will then sublicense the discovery to a large firm that can run clinical trials.
But an analysis published in Science Translational Medicine suggests the process rarely follows this straightforward path.
Instead, it often zigzags across biotech firms and between research areas before a drug is finally commercialized.
“The timeline for commercialization is much longer than most people think,” said study author Jerry Thursby, PhD, of the Georgia Institute of Technology in Atlanta.
To study the path of drug development, Dr Thursby and his colleagues built a database of 835 patents in 342 university licenses with biotech firms.
They then traced the path of patents to document whether the inventions were sublicensed to another firm for testing in a new disease category or whether the sublicense was to a large firm for clinical trials or marketing.
In all, 27% of inventions appeared in a second license (sublicense). The average time between invention and first license was 5.5 years, and the average time between first and second license was 3.5 years.
This time span is substantial, the researchers said, given that the average time from discovery to drug approval in the US is 13 years.
The team also found that sublicensing often resets the development timeline because a drug must be tested for an entirely new indication or several new indications.
The disease categories in the licenses analyzed spanned 20 distinct indications, and individual licenses included up to 5 indications. But the categories were very broad, such as “cancer” or “infectious diseases.”
Nevertheless, the researchers saw substantial changes in disease indications from the first license to the second. Only 19% of the inventions remained completely unchanged between the first and second license.
For 44% of inventions, none of the first-license indications remained in the second license. Twenty-eight percent of inventions had indications added between the first and second license, and 9% had indications subtracted.
The researchers said these results suggest a need for policies and initiatives that enhance early translation by more efficiently driving more inventions into multiple disease pipelines.
One option might be the formation of an open-source translational research database that complements clinicaltrials.gov, where patents and licenses for biomedical research thought to be destined for eventual therapeutic use would be logged and shared.
Credit: Rhoda Baer
An analysis of university discoveries licensed to biotechnology firms has revealed early bottlenecks in the drug development process.
Typically, universities do most of the basic research and then license a discovery to a small biotech firm that advances the research. The small firm will then sublicense the discovery to a large firm that can run clinical trials.
But an analysis published in Science Translational Medicine suggests the process rarely follows this straightforward path.
Instead, it often zigzags across biotech firms and between research areas before a drug is finally commercialized.
“The timeline for commercialization is much longer than most people think,” said study author Jerry Thursby, PhD, of the Georgia Institute of Technology in Atlanta.
To study the path of drug development, Dr Thursby and his colleagues built a database of 835 patents in 342 university licenses with biotech firms.
They then traced the path of patents to document whether the inventions were sublicensed to another firm for testing in a new disease category or whether the sublicense was to a large firm for clinical trials or marketing.
In all, 27% of inventions appeared in a second license (sublicense). The average time between invention and first license was 5.5 years, and the average time between first and second license was 3.5 years.
This time span is substantial, the researchers said, given that the average time from discovery to drug approval in the US is 13 years.
The team also found that sublicensing often resets the development timeline because a drug must be tested for an entirely new indication or several new indications.
The disease categories in the licenses analyzed spanned 20 distinct indications, and individual licenses included up to 5 indications. But the categories were very broad, such as “cancer” or “infectious diseases.”
Nevertheless, the researchers saw substantial changes in disease indications from the first license to the second. Only 19% of the inventions remained completely unchanged between the first and second license.
For 44% of inventions, none of the first-license indications remained in the second license. Twenty-eight percent of inventions had indications added between the first and second license, and 9% had indications subtracted.
The researchers said these results suggest a need for policies and initiatives that enhance early translation by more efficiently driving more inventions into multiple disease pipelines.
One option might be the formation of an open-source translational research database that complements clinicaltrials.gov, where patents and licenses for biomedical research thought to be destined for eventual therapeutic use would be logged and shared.
New pipette can move single cells
Credit: Rhoda Baer
Researchers say they have developed a pipette that can transfer a single cell at a time.
The device, called the handheld single-cell pipette (hSCP), has 2 plungers. The first is used to wash and capture a single cell, and the second can release the cell in the desired location.
Lidong Qin, PhD, of Houston Methodist Research Institute in Texas, and his colleagues described the hSCP and reported preliminary results with the device in the Journal of the American Chemical Society.
“Studying single cells and their unique functions has become a frontier in current biomedical research,” Dr Qin said. “One of the biggest challenges for single-cell research is picking out only one cell from a collection of millions of cells.”
He noted that current techniques for withdrawing single cells from a tube or Petri dish can be cumbersome, expensive, and time-consuming.
“Some old and clumsy methods are used to capture single cells,” he explained. “Some researchers use their mouths at one end of the pipette, driven by their own mouth force, to try to ensure only a minimum amount of cell suspension collected. The sample is then checked with a microscope to find out the number of cells captured. The opportunity to get only one cell is hit-or-miss and a bit troublesome.”
“One company provides a million-dollar machine that can help biologists transfer single cells to 96-well plates. Each run costs an additional $1000 to purchase the plate. Such technology will not be widely accessible to biologists.”
With that in mind, Dr Qin and his colleagues developed their 2-plunger hSCP. The first plunger withdraws fluid from a suspension of cells.
Fluid travels through canals on either side of a nanoscopic, laser-sculpted “hook” that is just big enough to trap a single cell. This hook can be altered depending on the size and type of cells a researcher is using.
The first plunger is also used to wash and separate the captured cell from other cells that may have been extracted. The second plunger pushes the captured cell out of the pipette into growth medium or onto a slide or welled plate for study.
Dr Qin said one of his goals is to make the technology cost $10 or less per run. And future designs of the hSCP will be developed with mass production in mind.
Dr Qin said his group can also produce hSCPs that pick up virtually any small number of cells, depending on a scientist’s needs, by etching more hooks during the pipette’s construction.
Credit: Rhoda Baer
Researchers say they have developed a pipette that can transfer a single cell at a time.
The device, called the handheld single-cell pipette (hSCP), has 2 plungers. The first is used to wash and capture a single cell, and the second can release the cell in the desired location.
Lidong Qin, PhD, of Houston Methodist Research Institute in Texas, and his colleagues described the hSCP and reported preliminary results with the device in the Journal of the American Chemical Society.
“Studying single cells and their unique functions has become a frontier in current biomedical research,” Dr Qin said. “One of the biggest challenges for single-cell research is picking out only one cell from a collection of millions of cells.”
He noted that current techniques for withdrawing single cells from a tube or Petri dish can be cumbersome, expensive, and time-consuming.
“Some old and clumsy methods are used to capture single cells,” he explained. “Some researchers use their mouths at one end of the pipette, driven by their own mouth force, to try to ensure only a minimum amount of cell suspension collected. The sample is then checked with a microscope to find out the number of cells captured. The opportunity to get only one cell is hit-or-miss and a bit troublesome.”
“One company provides a million-dollar machine that can help biologists transfer single cells to 96-well plates. Each run costs an additional $1000 to purchase the plate. Such technology will not be widely accessible to biologists.”
With that in mind, Dr Qin and his colleagues developed their 2-plunger hSCP. The first plunger withdraws fluid from a suspension of cells.
Fluid travels through canals on either side of a nanoscopic, laser-sculpted “hook” that is just big enough to trap a single cell. This hook can be altered depending on the size and type of cells a researcher is using.
The first plunger is also used to wash and separate the captured cell from other cells that may have been extracted. The second plunger pushes the captured cell out of the pipette into growth medium or onto a slide or welled plate for study.
Dr Qin said one of his goals is to make the technology cost $10 or less per run. And future designs of the hSCP will be developed with mass production in mind.
Dr Qin said his group can also produce hSCPs that pick up virtually any small number of cells, depending on a scientist’s needs, by etching more hooks during the pipette’s construction.
Credit: Rhoda Baer
Researchers say they have developed a pipette that can transfer a single cell at a time.
The device, called the handheld single-cell pipette (hSCP), has 2 plungers. The first is used to wash and capture a single cell, and the second can release the cell in the desired location.
Lidong Qin, PhD, of Houston Methodist Research Institute in Texas, and his colleagues described the hSCP and reported preliminary results with the device in the Journal of the American Chemical Society.
“Studying single cells and their unique functions has become a frontier in current biomedical research,” Dr Qin said. “One of the biggest challenges for single-cell research is picking out only one cell from a collection of millions of cells.”
He noted that current techniques for withdrawing single cells from a tube or Petri dish can be cumbersome, expensive, and time-consuming.
“Some old and clumsy methods are used to capture single cells,” he explained. “Some researchers use their mouths at one end of the pipette, driven by their own mouth force, to try to ensure only a minimum amount of cell suspension collected. The sample is then checked with a microscope to find out the number of cells captured. The opportunity to get only one cell is hit-or-miss and a bit troublesome.”
“One company provides a million-dollar machine that can help biologists transfer single cells to 96-well plates. Each run costs an additional $1000 to purchase the plate. Such technology will not be widely accessible to biologists.”
With that in mind, Dr Qin and his colleagues developed their 2-plunger hSCP. The first plunger withdraws fluid from a suspension of cells.
Fluid travels through canals on either side of a nanoscopic, laser-sculpted “hook” that is just big enough to trap a single cell. This hook can be altered depending on the size and type of cells a researcher is using.
The first plunger is also used to wash and separate the captured cell from other cells that may have been extracted. The second plunger pushes the captured cell out of the pipette into growth medium or onto a slide or welled plate for study.
Dr Qin said one of his goals is to make the technology cost $10 or less per run. And future designs of the hSCP will be developed with mass production in mind.
Dr Qin said his group can also produce hSCPs that pick up virtually any small number of cells, depending on a scientist’s needs, by etching more hooks during the pipette’s construction.
FDA expands indication for apixaban
Credit: Kevin MacKenzie
The US Food and Drug Administration (FDA) has approved apixaban (Eliquis) to treat venous thromboembolism (VTE) and prevent recurrent VTE after initial therapy.
Apixaban is an oral selective factor Xa inhibitor that is already FDA approved to reduce the risk of stroke and systemic embolism in patients with nonvalvular atrial fibrillation and to prevent VTE in patients who have undergone hip or knee replacement surgery.
Apixaban’s latest FDA approval was based on results of the AMPLIFY and AMPLIFY-EXT studies.
The AMPLIFY trial
AMPLIFY included 5395 patients with confirmed, symptomatic deep vein thrombosis (DVT) or pulmonary embolism (PE) who required treatment for 6 months. They had a mean age of 56.9 years, and 89.8% of randomized patients had unprovoked VTE.
About half of patients (n=2691) were randomized to receive apixaban at 10 mg twice daily for 7 days, followed by 5 mg twice daily for 6 months.
The other half (n=2704) were randomized to the standard of care—enoxaparin at 1 mg/kg twice daily for at least 5 days until they had an INR ≥ 2 and warfarin (target INR range 2.0-3.0) for 6 months.
Apixaban proved noninferior to standard therapy in the combined primary endpoint of recurrent, symptomatic VTE (nonfatal DVT or PE) or VTE-related death. This outcome occurred in 2.3% of patients in the apixaban arm and 2.7% of patients in the standard-therapy arm (P<0.0001 for noninferiority).
Apixaban also proved superior to standard therapy with regard to bleeding. The composite endpoint of major bleeding and clinically relevant, nonmajor bleeding occurred in 4.3% of patients in the apixaban arm and 9.7% of patients in the standard-therapy arm (P<0.001).
The AMPLIFY-EXT trial
AMPLIFY-EXT included 2486 patients who had completed 6 to 12 months of anticoagulation treatment for DVT or PE. Their mean age was 56.7 years, and 91.7% of randomized patients had unprovoked VTE.
Patients were randomized to receive apixaban at 2.5 mg (n=842), apixaban at 5 mg (n=815), or placebo (n=829).
Both apixaban doses were significantly superior to placebo (P<0.001) with regard to the primary efficacy endpoint, which was recurrent VTE or all-cause death.
During the 12-month active study period, these events occurred in 3.8% of patients in the 2.5 mg arm, 4.2% of patients in the 5 mg arm, and 11.6% of patients in the placebo arm.
The primary safety endpoint was the incidence of major bleeding, and there was no significant difference among the treatment arms. Major bleeding occurred in 0.2% of patients in the 2.5 mg arm, 0.1% of patients in the 5 mg arm, and 0.5% of patients in the placebo arm.
Nevertheless, apixaban has been shown to increase the risk of bleeding and can cause serious, potentially fatal, bleeding.
Apixaban’s label includes boxed warnings detailing the increased risk of thrombotic events in patients who prematurely discontinue the drug, as well as the increased risk of epidural or spinal hematoma, which may cause long-term or permanent paralysis, in patients undergoing spinal epidural anesthesia or spinal puncture.
For more information, visit eliquis.com. The drug is under joint development by Pfizer and Bristol-Myers Squibb.
Credit: Kevin MacKenzie
The US Food and Drug Administration (FDA) has approved apixaban (Eliquis) to treat venous thromboembolism (VTE) and prevent recurrent VTE after initial therapy.
Apixaban is an oral selective factor Xa inhibitor that is already FDA approved to reduce the risk of stroke and systemic embolism in patients with nonvalvular atrial fibrillation and to prevent VTE in patients who have undergone hip or knee replacement surgery.
Apixaban’s latest FDA approval was based on results of the AMPLIFY and AMPLIFY-EXT studies.
The AMPLIFY trial
AMPLIFY included 5395 patients with confirmed, symptomatic deep vein thrombosis (DVT) or pulmonary embolism (PE) who required treatment for 6 months. They had a mean age of 56.9 years, and 89.8% of randomized patients had unprovoked VTE.
About half of patients (n=2691) were randomized to receive apixaban at 10 mg twice daily for 7 days, followed by 5 mg twice daily for 6 months.
The other half (n=2704) were randomized to the standard of care—enoxaparin at 1 mg/kg twice daily for at least 5 days until they had an INR ≥ 2 and warfarin (target INR range 2.0-3.0) for 6 months.
Apixaban proved noninferior to standard therapy in the combined primary endpoint of recurrent, symptomatic VTE (nonfatal DVT or PE) or VTE-related death. This outcome occurred in 2.3% of patients in the apixaban arm and 2.7% of patients in the standard-therapy arm (P<0.0001 for noninferiority).
Apixaban also proved superior to standard therapy with regard to bleeding. The composite endpoint of major bleeding and clinically relevant, nonmajor bleeding occurred in 4.3% of patients in the apixaban arm and 9.7% of patients in the standard-therapy arm (P<0.001).
The AMPLIFY-EXT trial
AMPLIFY-EXT included 2486 patients who had completed 6 to 12 months of anticoagulation treatment for DVT or PE. Their mean age was 56.7 years, and 91.7% of randomized patients had unprovoked VTE.
Patients were randomized to receive apixaban at 2.5 mg (n=842), apixaban at 5 mg (n=815), or placebo (n=829).
Both apixaban doses were significantly superior to placebo (P<0.001) with regard to the primary efficacy endpoint, which was recurrent VTE or all-cause death.
During the 12-month active study period, these events occurred in 3.8% of patients in the 2.5 mg arm, 4.2% of patients in the 5 mg arm, and 11.6% of patients in the placebo arm.
The primary safety endpoint was the incidence of major bleeding, and there was no significant difference among the treatment arms. Major bleeding occurred in 0.2% of patients in the 2.5 mg arm, 0.1% of patients in the 5 mg arm, and 0.5% of patients in the placebo arm.
Nevertheless, apixaban has been shown to increase the risk of bleeding and can cause serious, potentially fatal, bleeding.
Apixaban’s label includes boxed warnings detailing the increased risk of thrombotic events in patients who prematurely discontinue the drug, as well as the increased risk of epidural or spinal hematoma, which may cause long-term or permanent paralysis, in patients undergoing spinal epidural anesthesia or spinal puncture.
For more information, visit eliquis.com. The drug is under joint development by Pfizer and Bristol-Myers Squibb.
Credit: Kevin MacKenzie
The US Food and Drug Administration (FDA) has approved apixaban (Eliquis) to treat venous thromboembolism (VTE) and prevent recurrent VTE after initial therapy.
Apixaban is an oral selective factor Xa inhibitor that is already FDA approved to reduce the risk of stroke and systemic embolism in patients with nonvalvular atrial fibrillation and to prevent VTE in patients who have undergone hip or knee replacement surgery.
Apixaban’s latest FDA approval was based on results of the AMPLIFY and AMPLIFY-EXT studies.
The AMPLIFY trial
AMPLIFY included 5395 patients with confirmed, symptomatic deep vein thrombosis (DVT) or pulmonary embolism (PE) who required treatment for 6 months. They had a mean age of 56.9 years, and 89.8% of randomized patients had unprovoked VTE.
About half of patients (n=2691) were randomized to receive apixaban at 10 mg twice daily for 7 days, followed by 5 mg twice daily for 6 months.
The other half (n=2704) were randomized to the standard of care—enoxaparin at 1 mg/kg twice daily for at least 5 days until they had an INR ≥ 2 and warfarin (target INR range 2.0-3.0) for 6 months.
Apixaban proved noninferior to standard therapy in the combined primary endpoint of recurrent, symptomatic VTE (nonfatal DVT or PE) or VTE-related death. This outcome occurred in 2.3% of patients in the apixaban arm and 2.7% of patients in the standard-therapy arm (P<0.0001 for noninferiority).
Apixaban also proved superior to standard therapy with regard to bleeding. The composite endpoint of major bleeding and clinically relevant, nonmajor bleeding occurred in 4.3% of patients in the apixaban arm and 9.7% of patients in the standard-therapy arm (P<0.001).
The AMPLIFY-EXT trial
AMPLIFY-EXT included 2486 patients who had completed 6 to 12 months of anticoagulation treatment for DVT or PE. Their mean age was 56.7 years, and 91.7% of randomized patients had unprovoked VTE.
Patients were randomized to receive apixaban at 2.5 mg (n=842), apixaban at 5 mg (n=815), or placebo (n=829).
Both apixaban doses were significantly superior to placebo (P<0.001) with regard to the primary efficacy endpoint, which was recurrent VTE or all-cause death.
During the 12-month active study period, these events occurred in 3.8% of patients in the 2.5 mg arm, 4.2% of patients in the 5 mg arm, and 11.6% of patients in the placebo arm.
The primary safety endpoint was the incidence of major bleeding, and there was no significant difference among the treatment arms. Major bleeding occurred in 0.2% of patients in the 2.5 mg arm, 0.1% of patients in the 5 mg arm, and 0.5% of patients in the placebo arm.
Nevertheless, apixaban has been shown to increase the risk of bleeding and can cause serious, potentially fatal, bleeding.
Apixaban’s label includes boxed warnings detailing the increased risk of thrombotic events in patients who prematurely discontinue the drug, as well as the increased risk of epidural or spinal hematoma, which may cause long-term or permanent paralysis, in patients undergoing spinal epidural anesthesia or spinal puncture.
For more information, visit eliquis.com. The drug is under joint development by Pfizer and Bristol-Myers Squibb.
Apixaban approved for treating DVT, pulmonary embolism and reducing risk of recurrence
The oral factor Xa inhibitor apixaban is now approved for the treatment of deep vein thrombosis and pulmonary embolism, and for reducing the risk of recurrent DVT and PE following initial treatment, the manufacturers have announced.
This approval is based on the results of the AMPLIFY and AMPLIFY-EXT studies, according to the statement issued by Bristol-Myers Squibb and Pfizer Aug. 21.
Apixaban, initially approved in 2012 and marketed as Eliquis, is already approved for reducing the risk of stroke and systemic embolism in patients with nonvalvular atrial fibrillation and for the prophylaxis of DVT, "which may lead to PE," after hip or knee surgery. The recommended dose for the treatment of DVT and PE is 10 mg twice a day for 7 days, followed by 5 mg twice a day. The recommended dose for reducing the risk for recurrent DVT and PE, after initial therapy, is 2.5 mg twice a day.
AMPLIFY was a noninferiority study of about 5,200 patients with symptomatic DVT or PE. It compared apixaban (10 mg twice a day for 1 week, followed by 5 mg twice a day for 6 months) with standard care using enoxaparin (1 mg/kg administered subcutaneously twice a day for at least 5 days [until the international normalized ratio was at least 2], followed by warfarin for at least 5 days [target INR range of 2.0-3.0] for 6 months). The primary efficacy endpoint, a composite of recurrent symptomatic VTE or VTE-related death over 6 months, was comparable in the two groups: 2.3% among those on apixaban and 2.7% among those on enoxaparin/warfarin, according to the prescribing information.
The primary safety endpoint, major bleeding, was 0.6% among those on apixaban vs. 1.8% among those on enoxaparin/warfarin, a statistically significant difference. Rates of clinically relevant nonmajor bleeding, a secondary safety endpoint, was 3.9% among those on apixaban vs. 8% among those on enoxaparin/warfarin.
In Amplify-EXT, almost 2,500 patients who had received anticoagulant therapy for DVT and/or PE for 6-12 months and had not had a recurrent event were randomized to treatment with apixaban 2.5 or 5 mg twice a day, or placebo, followed for a mean of almost 1 year. The rate of recurrent VTE or all-cause death was 3.8% among those on 2.5 mg twice daily and 4.2% among those on 5 mg twice daily, vs. 11.6% among those on placebo; the effects of both doses were significantly more effective in reducing risk than was placebo.
In this study, the rate of bleeding-related adverse reactions was 13.3% among those on apixaban vs. 8.7% among those on placebo. The rate of major bleeding was 0.2% among those on the 2.5 mg twice-daily dose and 0.1% among those on the 5 mg twice-daily dose, vs. 0.5% among those on placebo.
The apixaban label includes a boxed warning about an increased risk of spinal/epidural hematoma in patients undergoing neuraxial anesthesia or spinal puncture while on the drug.
Serious adverse events associated with apixaban should be reported to the FDA’s MedWatch program.
The oral factor Xa inhibitor apixaban is now approved for the treatment of deep vein thrombosis and pulmonary embolism, and for reducing the risk of recurrent DVT and PE following initial treatment, the manufacturers have announced.
This approval is based on the results of the AMPLIFY and AMPLIFY-EXT studies, according to the statement issued by Bristol-Myers Squibb and Pfizer Aug. 21.
Apixaban, initially approved in 2012 and marketed as Eliquis, is already approved for reducing the risk of stroke and systemic embolism in patients with nonvalvular atrial fibrillation and for the prophylaxis of DVT, "which may lead to PE," after hip or knee surgery. The recommended dose for the treatment of DVT and PE is 10 mg twice a day for 7 days, followed by 5 mg twice a day. The recommended dose for reducing the risk for recurrent DVT and PE, after initial therapy, is 2.5 mg twice a day.
AMPLIFY was a noninferiority study of about 5,200 patients with symptomatic DVT or PE. It compared apixaban (10 mg twice a day for 1 week, followed by 5 mg twice a day for 6 months) with standard care using enoxaparin (1 mg/kg administered subcutaneously twice a day for at least 5 days [until the international normalized ratio was at least 2], followed by warfarin for at least 5 days [target INR range of 2.0-3.0] for 6 months). The primary efficacy endpoint, a composite of recurrent symptomatic VTE or VTE-related death over 6 months, was comparable in the two groups: 2.3% among those on apixaban and 2.7% among those on enoxaparin/warfarin, according to the prescribing information.
The primary safety endpoint, major bleeding, was 0.6% among those on apixaban vs. 1.8% among those on enoxaparin/warfarin, a statistically significant difference. Rates of clinically relevant nonmajor bleeding, a secondary safety endpoint, was 3.9% among those on apixaban vs. 8% among those on enoxaparin/warfarin.
In Amplify-EXT, almost 2,500 patients who had received anticoagulant therapy for DVT and/or PE for 6-12 months and had not had a recurrent event were randomized to treatment with apixaban 2.5 or 5 mg twice a day, or placebo, followed for a mean of almost 1 year. The rate of recurrent VTE or all-cause death was 3.8% among those on 2.5 mg twice daily and 4.2% among those on 5 mg twice daily, vs. 11.6% among those on placebo; the effects of both doses were significantly more effective in reducing risk than was placebo.
In this study, the rate of bleeding-related adverse reactions was 13.3% among those on apixaban vs. 8.7% among those on placebo. The rate of major bleeding was 0.2% among those on the 2.5 mg twice-daily dose and 0.1% among those on the 5 mg twice-daily dose, vs. 0.5% among those on placebo.
The apixaban label includes a boxed warning about an increased risk of spinal/epidural hematoma in patients undergoing neuraxial anesthesia or spinal puncture while on the drug.
Serious adverse events associated with apixaban should be reported to the FDA’s MedWatch program.
The oral factor Xa inhibitor apixaban is now approved for the treatment of deep vein thrombosis and pulmonary embolism, and for reducing the risk of recurrent DVT and PE following initial treatment, the manufacturers have announced.
This approval is based on the results of the AMPLIFY and AMPLIFY-EXT studies, according to the statement issued by Bristol-Myers Squibb and Pfizer Aug. 21.
Apixaban, initially approved in 2012 and marketed as Eliquis, is already approved for reducing the risk of stroke and systemic embolism in patients with nonvalvular atrial fibrillation and for the prophylaxis of DVT, "which may lead to PE," after hip or knee surgery. The recommended dose for the treatment of DVT and PE is 10 mg twice a day for 7 days, followed by 5 mg twice a day. The recommended dose for reducing the risk for recurrent DVT and PE, after initial therapy, is 2.5 mg twice a day.
AMPLIFY was a noninferiority study of about 5,200 patients with symptomatic DVT or PE. It compared apixaban (10 mg twice a day for 1 week, followed by 5 mg twice a day for 6 months) with standard care using enoxaparin (1 mg/kg administered subcutaneously twice a day for at least 5 days [until the international normalized ratio was at least 2], followed by warfarin for at least 5 days [target INR range of 2.0-3.0] for 6 months). The primary efficacy endpoint, a composite of recurrent symptomatic VTE or VTE-related death over 6 months, was comparable in the two groups: 2.3% among those on apixaban and 2.7% among those on enoxaparin/warfarin, according to the prescribing information.
The primary safety endpoint, major bleeding, was 0.6% among those on apixaban vs. 1.8% among those on enoxaparin/warfarin, a statistically significant difference. Rates of clinically relevant nonmajor bleeding, a secondary safety endpoint, was 3.9% among those on apixaban vs. 8% among those on enoxaparin/warfarin.
In Amplify-EXT, almost 2,500 patients who had received anticoagulant therapy for DVT and/or PE for 6-12 months and had not had a recurrent event were randomized to treatment with apixaban 2.5 or 5 mg twice a day, or placebo, followed for a mean of almost 1 year. The rate of recurrent VTE or all-cause death was 3.8% among those on 2.5 mg twice daily and 4.2% among those on 5 mg twice daily, vs. 11.6% among those on placebo; the effects of both doses were significantly more effective in reducing risk than was placebo.
In this study, the rate of bleeding-related adverse reactions was 13.3% among those on apixaban vs. 8.7% among those on placebo. The rate of major bleeding was 0.2% among those on the 2.5 mg twice-daily dose and 0.1% among those on the 5 mg twice-daily dose, vs. 0.5% among those on placebo.
The apixaban label includes a boxed warning about an increased risk of spinal/epidural hematoma in patients undergoing neuraxial anesthesia or spinal puncture while on the drug.
Serious adverse events associated with apixaban should be reported to the FDA’s MedWatch program.
Questionable Benefit of Oral Chlorhexidine in Mechanically Ventilated Patients
Clinical question
For patients receiving mechanical ventilation, does routine oral care with chlorhexidine improve outcomes?
Bottom line
Oral care with chlorhexidine decreases the incidence of respiratory tract infections in mechanically ventilated cardiac surgery patients, but not in noncardiac surgery patients. Additionally, the use of chlorhexidine does not have a statistically significant effect on mortality, length of stay (LOS), or duration of mechanical ventilation in either population. Further research is needed to determine the benefit and safety of this common intervention in different patient populations. (LOE = 1a)
Reference
Study design
Meta-analysis (randomized controlled trials)
Funding source
Unknown/not stated
Allocation
Uncertain
Setting
Inpatient (ICU only)
Synopsis
Previous meta-analyses demonstrated the effectiveness of chlorhexidine in the intensive care unit (ICU) for the prevention of ventilator-associated pneumonia, but did not distinguish between cardiac surgery and noncardiac surgery populations. These investigators searched multiple databases including PubMed and Embase, as well as reviewed reference lists of retrieved articles, to find randomized controlled trials that evaluated oral care with chlorhexidine versus oral care with placebo in mechanically ventilated patients for the prevention of nosocomial pneumonia, mortality, LOS, duration of mechanical ventilation, and antibiotic exposure. Two authors independently assessed the studies for inclusion and abstraction of data. The included studies were then rated for quality based on randomization strategy, allocation concealment, blinding, and completeness of follow-up. Of the 16 studies included in the review, 7 took place in combined medical–surgical units, 3 were in cardiac surgery units, and the rest were in other surgical or medical units. The presence of double-blinding in a study correlated with a higher quality rating. Data from the 3 studies of cardiac surgery patients showed fewer respiratory infections in patients receiving chlorhexidine (relative risk [RR] = 0.56; 95% CI, 0.41-0.77), but no association with mortality. The 13 studies involving noncardiac surgery patients, all of which focused specifically on ventilator-associated pneumonia, showed no significant difference in risk, even when the data was limited to the higher quality double-blind studies. However, there was a nonsignificant trend toward higher mortality with chlorhexidine use in this group of trials (RR = 1.13; 0.99-1.29). No significant differences were noted for the duration of mechanical ventilation, ICU LOS, hospital LOS, or antibiotic exposure, though data was limited for the latter 2 outcomes. The authors note that decreased exposure to an endotracheal tube in cardiac surgery patients, as compared with noncardiac surgery patients, may account for the decreased risk of pneumonia seen in this population. The potential increase in mortality in noncardiac surgery patients is harder to explain, but the authors postulate that this may be due to aspiration of chlorhexidine leading to acute lung injury.
Dr. Kulkarni is an assistant professor of hospital medicine at Northwestern University in Chicago.
Clinical question
For patients receiving mechanical ventilation, does routine oral care with chlorhexidine improve outcomes?
Bottom line
Oral care with chlorhexidine decreases the incidence of respiratory tract infections in mechanically ventilated cardiac surgery patients, but not in noncardiac surgery patients. Additionally, the use of chlorhexidine does not have a statistically significant effect on mortality, length of stay (LOS), or duration of mechanical ventilation in either population. Further research is needed to determine the benefit and safety of this common intervention in different patient populations. (LOE = 1a)
Reference
Study design
Meta-analysis (randomized controlled trials)
Funding source
Unknown/not stated
Allocation
Uncertain
Setting
Inpatient (ICU only)
Synopsis
Previous meta-analyses demonstrated the effectiveness of chlorhexidine in the intensive care unit (ICU) for the prevention of ventilator-associated pneumonia, but did not distinguish between cardiac surgery and noncardiac surgery populations. These investigators searched multiple databases including PubMed and Embase, as well as reviewed reference lists of retrieved articles, to find randomized controlled trials that evaluated oral care with chlorhexidine versus oral care with placebo in mechanically ventilated patients for the prevention of nosocomial pneumonia, mortality, LOS, duration of mechanical ventilation, and antibiotic exposure. Two authors independently assessed the studies for inclusion and abstraction of data. The included studies were then rated for quality based on randomization strategy, allocation concealment, blinding, and completeness of follow-up. Of the 16 studies included in the review, 7 took place in combined medical–surgical units, 3 were in cardiac surgery units, and the rest were in other surgical or medical units. The presence of double-blinding in a study correlated with a higher quality rating. Data from the 3 studies of cardiac surgery patients showed fewer respiratory infections in patients receiving chlorhexidine (relative risk [RR] = 0.56; 95% CI, 0.41-0.77), but no association with mortality. The 13 studies involving noncardiac surgery patients, all of which focused specifically on ventilator-associated pneumonia, showed no significant difference in risk, even when the data was limited to the higher quality double-blind studies. However, there was a nonsignificant trend toward higher mortality with chlorhexidine use in this group of trials (RR = 1.13; 0.99-1.29). No significant differences were noted for the duration of mechanical ventilation, ICU LOS, hospital LOS, or antibiotic exposure, though data was limited for the latter 2 outcomes. The authors note that decreased exposure to an endotracheal tube in cardiac surgery patients, as compared with noncardiac surgery patients, may account for the decreased risk of pneumonia seen in this population. The potential increase in mortality in noncardiac surgery patients is harder to explain, but the authors postulate that this may be due to aspiration of chlorhexidine leading to acute lung injury.
Dr. Kulkarni is an assistant professor of hospital medicine at Northwestern University in Chicago.
Clinical question
For patients receiving mechanical ventilation, does routine oral care with chlorhexidine improve outcomes?
Bottom line
Oral care with chlorhexidine decreases the incidence of respiratory tract infections in mechanically ventilated cardiac surgery patients, but not in noncardiac surgery patients. Additionally, the use of chlorhexidine does not have a statistically significant effect on mortality, length of stay (LOS), or duration of mechanical ventilation in either population. Further research is needed to determine the benefit and safety of this common intervention in different patient populations. (LOE = 1a)
Reference
Study design
Meta-analysis (randomized controlled trials)
Funding source
Unknown/not stated
Allocation
Uncertain
Setting
Inpatient (ICU only)
Synopsis
Previous meta-analyses demonstrated the effectiveness of chlorhexidine in the intensive care unit (ICU) for the prevention of ventilator-associated pneumonia, but did not distinguish between cardiac surgery and noncardiac surgery populations. These investigators searched multiple databases including PubMed and Embase, as well as reviewed reference lists of retrieved articles, to find randomized controlled trials that evaluated oral care with chlorhexidine versus oral care with placebo in mechanically ventilated patients for the prevention of nosocomial pneumonia, mortality, LOS, duration of mechanical ventilation, and antibiotic exposure. Two authors independently assessed the studies for inclusion and abstraction of data. The included studies were then rated for quality based on randomization strategy, allocation concealment, blinding, and completeness of follow-up. Of the 16 studies included in the review, 7 took place in combined medical–surgical units, 3 were in cardiac surgery units, and the rest were in other surgical or medical units. The presence of double-blinding in a study correlated with a higher quality rating. Data from the 3 studies of cardiac surgery patients showed fewer respiratory infections in patients receiving chlorhexidine (relative risk [RR] = 0.56; 95% CI, 0.41-0.77), but no association with mortality. The 13 studies involving noncardiac surgery patients, all of which focused specifically on ventilator-associated pneumonia, showed no significant difference in risk, even when the data was limited to the higher quality double-blind studies. However, there was a nonsignificant trend toward higher mortality with chlorhexidine use in this group of trials (RR = 1.13; 0.99-1.29). No significant differences were noted for the duration of mechanical ventilation, ICU LOS, hospital LOS, or antibiotic exposure, though data was limited for the latter 2 outcomes. The authors note that decreased exposure to an endotracheal tube in cardiac surgery patients, as compared with noncardiac surgery patients, may account for the decreased risk of pneumonia seen in this population. The potential increase in mortality in noncardiac surgery patients is harder to explain, but the authors postulate that this may be due to aspiration of chlorhexidine leading to acute lung injury.
Dr. Kulkarni is an assistant professor of hospital medicine at Northwestern University in Chicago.
Net Benefit With Azithromycin Use in Elderly Hospitalized Patients With Pneumonia
Clinical question
Is the use of azithromycin for older patients hospitalized with pneumonia associated with increased mortality or an increased risk of cardiovascular events?
Bottom line
For older patients hospitalized with pneumonia, the use of combination antibiotic therapy including azithromycin is associated with decreased mortality but increased risk of myocardial infarction (MI). You would need to treat 21 patients with azithromycin to prevent 1 death within 90 days; you would need to treat 144 patients to cause 1 MI. This results in a net benefit of 7 deaths prevented for 1 nonfatal MI induced with the use of azithromycin. (LOE = 2b)
Reference
Study design
Cohort (retrospective)
Funding source
Government
Allocation
Uncertain
Setting
Inpatient (any location)
Synopsis
Using data from the Veterans Administration health care system, these authors examined the association of azithromycin with death and cardiovascular outcomes in older patients who were hospitalized with pneumonia. Patients included in the study were those aged at least 65 years who received antibiotic therapy per guidelines from the Infectious Diseases Society of America and American Thoracic Society for the treatment of community-acquired pneumonia. Primary outcomes were death at 30 days and 90 days, as well as cardiovascular events within 90 days. The cohort was divided into those who received combination therapy (which included azithromycin) and those who received other guideline-concordant antibiotics. Subsequently, propensity scores were used to match patients based on potential confounders -- such as age, intensive care unit (ICU) admission, and history of prior cardiac disease -- that could affect the severity of illness or outcomes. Almost 64,000 patients were included in the propensity-matched analysis. Patients had a mean age of 78 years, 16% were admitted to the ICU, and 5% received invasive mechanical ventilation. In this cohort, 90-day mortality was lower for azithromycin users (17% vs 22%; odds ratio [OR] = 0.76; 95% CI, 0.73-0.80). Although azithromycin users had more MIs (5.1% vs 4.4%; OR = 1.17; 1.08-1.25), there were no statistically significant differences in overall cardiac events, cardiac arrhythmias, or heart failure.
Dr. Kulkarni is an assistant professor of hospital medicine at Northwestern University in Chicago.
Clinical question
Is the use of azithromycin for older patients hospitalized with pneumonia associated with increased mortality or an increased risk of cardiovascular events?
Bottom line
For older patients hospitalized with pneumonia, the use of combination antibiotic therapy including azithromycin is associated with decreased mortality but increased risk of myocardial infarction (MI). You would need to treat 21 patients with azithromycin to prevent 1 death within 90 days; you would need to treat 144 patients to cause 1 MI. This results in a net benefit of 7 deaths prevented for 1 nonfatal MI induced with the use of azithromycin. (LOE = 2b)
Reference
Study design
Cohort (retrospective)
Funding source
Government
Allocation
Uncertain
Setting
Inpatient (any location)
Synopsis
Using data from the Veterans Administration health care system, these authors examined the association of azithromycin with death and cardiovascular outcomes in older patients who were hospitalized with pneumonia. Patients included in the study were those aged at least 65 years who received antibiotic therapy per guidelines from the Infectious Diseases Society of America and American Thoracic Society for the treatment of community-acquired pneumonia. Primary outcomes were death at 30 days and 90 days, as well as cardiovascular events within 90 days. The cohort was divided into those who received combination therapy (which included azithromycin) and those who received other guideline-concordant antibiotics. Subsequently, propensity scores were used to match patients based on potential confounders -- such as age, intensive care unit (ICU) admission, and history of prior cardiac disease -- that could affect the severity of illness or outcomes. Almost 64,000 patients were included in the propensity-matched analysis. Patients had a mean age of 78 years, 16% were admitted to the ICU, and 5% received invasive mechanical ventilation. In this cohort, 90-day mortality was lower for azithromycin users (17% vs 22%; odds ratio [OR] = 0.76; 95% CI, 0.73-0.80). Although azithromycin users had more MIs (5.1% vs 4.4%; OR = 1.17; 1.08-1.25), there were no statistically significant differences in overall cardiac events, cardiac arrhythmias, or heart failure.
Dr. Kulkarni is an assistant professor of hospital medicine at Northwestern University in Chicago.
Clinical question
Is the use of azithromycin for older patients hospitalized with pneumonia associated with increased mortality or an increased risk of cardiovascular events?
Bottom line
For older patients hospitalized with pneumonia, the use of combination antibiotic therapy including azithromycin is associated with decreased mortality but increased risk of myocardial infarction (MI). You would need to treat 21 patients with azithromycin to prevent 1 death within 90 days; you would need to treat 144 patients to cause 1 MI. This results in a net benefit of 7 deaths prevented for 1 nonfatal MI induced with the use of azithromycin. (LOE = 2b)
Reference
Study design
Cohort (retrospective)
Funding source
Government
Allocation
Uncertain
Setting
Inpatient (any location)
Synopsis
Using data from the Veterans Administration health care system, these authors examined the association of azithromycin with death and cardiovascular outcomes in older patients who were hospitalized with pneumonia. Patients included in the study were those aged at least 65 years who received antibiotic therapy per guidelines from the Infectious Diseases Society of America and American Thoracic Society for the treatment of community-acquired pneumonia. Primary outcomes were death at 30 days and 90 days, as well as cardiovascular events within 90 days. The cohort was divided into those who received combination therapy (which included azithromycin) and those who received other guideline-concordant antibiotics. Subsequently, propensity scores were used to match patients based on potential confounders -- such as age, intensive care unit (ICU) admission, and history of prior cardiac disease -- that could affect the severity of illness or outcomes. Almost 64,000 patients were included in the propensity-matched analysis. Patients had a mean age of 78 years, 16% were admitted to the ICU, and 5% received invasive mechanical ventilation. In this cohort, 90-day mortality was lower for azithromycin users (17% vs 22%; odds ratio [OR] = 0.76; 95% CI, 0.73-0.80). Although azithromycin users had more MIs (5.1% vs 4.4%; OR = 1.17; 1.08-1.25), there were no statistically significant differences in overall cardiac events, cardiac arrhythmias, or heart failure.
Dr. Kulkarni is an assistant professor of hospital medicine at Northwestern University in Chicago.
American College of Rheumatology guidelines for screening, treatment, and management of lupus nephritis
Renal Biopsy and Histology
The Task Force Panel recommended that all patients with clinical evidence of active lupus nephritis (LN), previously untreated, undergo renal biopsy (unless strongly contraindicated) so that glomerular disease can be classified by current International Society of Nephrology/Renal Pathology Society (ISN/RPS) classification (level C evidence) (see Table 1 in the original guideline document for ISN/RPS classification of LN). In addition, disease can be evaluated for activity and chronicity and for tubular and vascular changes. Finally, biopsies may identify additional or alternative causes of renal disease, such as tubular necrosis related to medications, hypovolemia, or hypotension. Biopsy is most highly recommended in patients with the characteristics indicated in the following table.
Table. Indications for Renal Biopsy in Patients with Systemic Lupus Erythematosus
| Level of Evidence | |
|---|---|
| Increasing serum creatinine without compelling alternative causes (such as sepsis, hypovolemia, or medication) | C |
| Confirmed proteinuria of ≥1.0 gm per 24 hours (either 24-hour urine specimens or spot protein/creatinine ratios are acceptable) | C |
Combinations of the following, assuming the findings are confirmed in at least two tests done within a short period of time and in the absence of alternative causes:
| C |
RBCs = red blood cells; hpf = high-power field.
The Task Force Panel recommended that treatment be based in large part on the classification of type of LN by these ISN/RPS criteria. As a result, the following recommendations are presented according to the histologic classification of nephritis. The Task Force Panel agreed that class I (minimal mesangial immune deposits on immunofluorescence with normal light microscopy) and class II (mesangial hypercellularity or matrix expansion on light microscopy with immune deposits confined to mesangium on immunofluorescence) generally do not require immunosuppressive treatment (level C evidence). In general, patients with class III (subendothelial immune deposits and proliferative changes in <50% of glomeruli) and class IV (subendothelial deposits and proliferative glomerular changes involving ≥50% of glomeruli) require aggressive therapy with glucocorticoids and immunosuppressive agents. Class V (subepithelial immune deposits and membranous thickening of glomerular capillaries) when combined with class III or IV should be treated in the same manner as class III or IV. Class V alone ("pure membranous LN") may be approached somewhat differently, as indicated below under "Recommendations for Induction of Improvement in Patients with Class V 'Pure Membranous' LN". Histologic class VI (sclerosis of ≥90% of glomeruli) generally requires preparation for renal replacement therapy rather than immunosuppression. The designations "A" and "C" indicate whether active or chronic changes are present; the higher the chronicity the less likely that the nephritis will respond to immunosuppression. However, A or C classifications were not included in the entry criteria for clinical trials in LN published to date, and therefore they are not considered in the recommendations.
Adjunctive Treatments
The Task Force Panel recommended that all systemic lupus erythematosus (SLE) patients with nephritis be treated with a background of hydroxychloroquine (HCQ; level C evidence), unless there is a contraindication.
All LN patients with proteinuria ≥0.5 gm per 24 hours (or equivalent by protein/creatinine ratios on spot urine samples) should have blockade of the renin–angiotensin system, which drives intraglomerular pressure (level A evidence for nondiabetic chronic renal disease). Treatment with either angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs) reduces proteinuria by approximately 30%, and significantly delays doubling of serum creatinine and progression to end-stage renal disease in patients with nondiabetic chronic renal disease. These classes of medications are contraindicated in pregnancy. The use of combination ACE inhibitors/ARB therapies is controversial. ACE inhibitors or ARB treatments are superior to calcium-channel blockers and diuretics alone in preserving renal function in chronic kidney disease.
The Task Force Panel recommended that careful attention be paid to control of hypertension, with a target of ≤130/80 mm Hg (level A evidence for nondiabetic chronic renal disease). The Task Force Panel also recommended that statin therapy be introduced in patients with low-density lipoprotein cholesterol >100 mg/dl (level C evidence). Note that a glomerular filtration rate <60 ml/minute/1.73 m2 (equivalent to a serum creatinine level >1.5 mg/dl or 133 µmoles/liter) is a risk factor for accelerated atherosclerosis. SLE itself is also an independent risk factor for accelerated atherosclerosis.
Finally, the Task Force Panel recommended that women of child-bearing potential with active or prior LN receive counseling regarding pregnancy risks conferred by the disease and its treatments (level C evidence).
Recommendations for Induction of Improvement in Patients with ISN Class III/IV Lupus Glomerulonephritis
The Task Force Panel recommended mycophenolate mofetil (MMF) (2–3 gm total daily orally) or intravenous (IV) cyclophosphamide (CYC) along with glucocorticoids (level A evidence) (see Figure 2 in the original guideline document). MMF and CYC are considered equivalent based on recent high-quality studies, a meta-analysis, and expert opinion. Long-term studies with MMF are not as abundant as those with CYC; data show good results for induction therapy with MMF of 3 gm total dose daily for 6 months, followed by maintenance with lower doses of MMF for 3 years. MMF has been similar in efficacy in all races studied to date (whites, Asians, African Americans, and Latin/Hispanic Americans). The Aspreva Lupus Management Study (ALMS) trial comparing response rates of LN to MMF plus glucocorticoids showed similar improvement in whites, Asians, and other races (primarily African Americans and Hispanics). However, The Task Force Panel voted that Asians compared to non-Asians might require lower doses of MMF for similar efficacy (level C evidence). Therefore, the physician might aim for 3 gm per day total daily highest dose in non-Asians and 2 gm per day in Asians. There is evidence that African Americans and Hispanics with LN respond less well to IV CYC than do patients of white or Asian races. MMF/mycophenolic acid (MPA) may be an initial choice more likely to induce improvement in patients who are African American or Hispanic.
The exact suggested dose of MMF varied based on the clinical scenario: for those with class III/IV without cellular crescents and for those with proteinuria and a stable creatinine for whom a renal biopsy sample cannot be obtained, both 2 gm and 3 gm total daily doses were acceptable to the Task Force Panel, while a dose of 3 gm daily was favored for those with class III/IV and crescents and for those with proteinuria and a recent significant rise in creatinine.
Some evidence suggests that MPA and enteric-coated mycophenolate sodium are less likely than MMF to cause nausea and diarrhea, but this is controversial, and the exact equivalency of the preparations is not firmly established. The Core Expert Panel recommended that MMF and MPA are likely to be equivalent in inducing improvement of LN, with 1,440–2,160 mg total daily dose of MPA roughly equivalent to 2,000–3,000 mg total daily dose of MMF. Some investigators have suggested that serum levels of MPA, the active metabolite of MMF, should be measured at the trough or peak (1 hour after a dose), and treatment of SLE should be guided by these levels. However, there are not enough data at this time to make recommendations for monitoring of drug levels.
There are two regimens of IV CYC recommended by the Task Force Panel: 1) low-dose "Euro-Lupus" CYC (500 mg IV once every 2 weeks for a total of 6 doses), followed by maintenance therapy with daily oral azathioprine (AZA) or daily oral MMF (level B evidence), and 2) high-dose CYC (500–1,000 mg/m2 IV once a month for 6 doses), followed by maintenance treatment with MMF or AZA (level A evidence) (see Figure 2 in the original guideline document). If CYC is being considered for treatment, the Core Expert Panel recommended IV CYC at the low "Euro-Lupus" dose for white patients with Western European or Southern European racial/ethnic backgrounds (level B evidence). In European study patients, the low- and high-dose regimens were equivalent in efficacy, and serious infections were less frequent with the lower doses. The low- and high-dose regimens have not been compared in nonwhite racial groups. Ten years of followup comparing low- and high-dose regimens showed similar rates of LN flares, end-stage renal disease, and doubling of the serum creatinine.
Pulse IV glucocorticoids (500–1,000 mg methylprednisolone daily for 3 doses) in combination with immunosuppressive therapy is recommended by the Task Force Panel, followed by daily oral glucocorticoids (0.5–1 mg/kg/day), followed by a taper to the minimal amount necessary to control disease (level C evidence). There are insufficient data to recommend a specific steroid taper because the nephritis and extrarenal manifestations vary from patient to patient. There was no consensus reached regarding the use of monthly IV methylprednisolone with monthly IV CYC.
Although AZA has been used to treat LN, the Task Force Panel did not recommend it as one of the first choices for induction therapy.
The panel recommends that most patients be followed for 6 months after initiation of induction treatment with either CYC or MMF before making major changes in treatment other than alteration of glucocorticoid doses, unless there is clear evidence of worsening at 3 months (50% or more worsening of proteinuria or serum creatinine; level A evidence).
Fertility issues are often a concern for young SLE patients with nephritis. In a discussion, the Task Force Panel recommended that MMF was preferable to CYC for patients who express a major concern with fertility preservation, since high-dose CYC can cause permanent infertility in both women and men (level A evidence of gonadal toxicity). Six months of high-dose IV CYC was associated with approximately 10% sustained infertility in young women, and higher rates in older women. If 6 months of CYC were followed by quarterly doses, there was a higher rate of infertility. The Task Force Panel did not reach a consensus on the use of leuprolide in patients with SLE receiving CYC as a means to preserve fertility. They also noted that MMF is teratogenic (class D in US Food and Drug Administration [FDA] ranking). Therefore, the physician should be sure that a patient is not pregnant before prescribing MMF or MPA, and the medications should be stopped for at least 6 weeks before pregnancy is attempted.
Recommendations for Induction of Improvement in Patients with Class IV or IV/V Plus Cellular Crescents
The Task Force Panel recommended either CYC or MMF for induction of improvement in this type of LN (level C evidence), along with IV pulses of high-dose glucocorticoid and initiation of oral glucocorticoids at the higher-range dosage, 1 mg/kg/day orally (see Figure 2 in the original guideline document). For the purpose of these recommendations statements, the presence of any crescents on a renal biopsy sample was considered crescentic LN. Until recently, experts have favored high-dose IV CYC for treatment of LN with cellular crescents. In general, the presence of crescents indicates a poorer prognosis, even with appropriate treatment. Further recommendations for a pregnant patient with crescentic glomerulonephritis are provided in the section on "Treatment of LN in Patients Who Are Pregnant," below.
Recommendations for Induction of Improvement in Patients with Class V "Pure Membranous" LN
The Task Force Panel recommends that patients with pure class V LN and with nephrotic range proteinuria be started on prednisone (0.5 mg/kg/day) plus MMF 2–3 gm total daily dose (level A evidence) (see Figure 3 in the original guideline document).
Other therapies for membranous LN have been reported; however, the Task Force Panel did not reach consensus on a recommendation regarding those therapies.
Recommendations for Maintaining Improvement in Patients Who Respond to Induction Therapy
The Task Force Panel recommended that either AZA or MMF be used for maintenance therapy (level A evidence) (see Figure 2 in the original guideline document). The Task Force Panel did not vote on the rate of medication taper during the maintenance phase; to date, there are no adequate data to inform the physician regarding how rapidly AZA or MMF can be tapered or withdrawn.
Recommendations for Changing Therapies in Patients Who Do Not Respond Adequately to Induction Therapy
In patients who fail to respond after 6 months of treatment (based on the treating physician's clinical impression) with glucocorticoids plus MMF or CYC, the Task Force Panel recommends a switch of the immunosuppressive agent from either CYC to MMF, or from MMF to CYC, with these changes accompanied by IV pulses of glucocorticoids for 3 days (level C evidence) (see Figure 2 in the original guideline document). For CYC, either low dose or high dose can be used in white individuals, as discussed above in the section on "Recommendations for Induction of Improvement in Patients with ISN Class III/IV Lupus Glomerulonephritis," above. Evidence to support these opinions is not as strong as evidence for the efficacy of initial induction therapy. The panel also voted that in some cases rituximab can be used in patients whose nephritis fails to improve or worsens after 6 months of one induction therapy, or after the patient has failed both CYC and MMF treatments (level C evidence). The Task Force Panel did not reach consensus regarding the use of calcineurin inhibitors in this setting; however, there is evidence for their efficacy as an induction agent and in refractory disease.
There is evidence in open-label trials that LN may respond to rituximab treatment. Prospective, randomized, placebo-controlled trials did not show a significant difference between rituximab and placebo (on a background of MMF and glucocorticoids) after 1 year of treatment.
Evidence to support the use of cyclosporine or tacrolimus in LN is from open trials and recent prospective clinical trials; additional prospective trials are in progress. In a recent prospective trial, tacrolimus was equivalent to high-dose IV CYC in inducing complete and partial remissions of LN over a 6-month period. In another 4-year–long prospective trial, cyclosporine was similar to AZA in preventing renal flares in patients receiving maintenance therapy.
If nephritis is worsening in patients treated for 3 months with glucocorticoids plus CYC or MMF, the Task Force Panel recommended that the clinician can choose any of the alternative treatments discussed (level C evidence). Although combinations of MMF and calcineurin inhibitors and of rituximab and MMF are being studied and might be considered for those who have failed the recommended induction therapies, data are not robust enough at this time to include them for voting scenarios.
The FDA has approved belimumab for use in seropositive patients with SLE who have active disease in spite of prior therapies.
Identification of Vascular Disease in Patients with SLE and Renal Abnormalities
Several types of vascular involvement can occur in renal tissue of SLE, including vasculitis, fibrinoid necrosis with narrowing of small arteries/arterioles ("bland" vasculopathy), thrombotic microangiopathy, and renal vein thrombosis. In general, vasculitis is treated similarly to the more common forms of LN discussed above. Bland vasculopathy is highly associated with hypertension; it is not clear which comes first, SLE or hypertension. Thrombotic microangiopathy can be associated with a thrombotic thrombocytopenia–like picture. The Task Force Panel recommended that thrombotic microangiopathy be treated primarily with plasma exchange therapy (level C evidence)
Treatment of LN in Patients Who Are Pregnant
The Task Force Panel recommended several approaches for management of LN in women who are pregnant (all level C evidence) (see Figure 4 in the original guideline document). In patients with prior LN but no current evidence of systemic or renal disease activity, no nephritis medications are necessary. Patients with mild systemic activity may be treated with HCQ; this probably reduces activity of SLE during pregnancy. If clinically active nephritis is present, or there is substantial extrarenal disease activity, the clinician may prescribe glucocorticoids at doses necessary to control disease activity, and if necessary AZA can be added. High-dose glucocorticoid therapy in patients with SLE is associated with a high risk of maternal complications such as hypertension and diabetes mellitus. MMF, CYC, and methotrexate should be avoided because they are teratogenic in humans. Although AZA is listed as pregnancy category D in Micromedex, cross-sectional studies have shown that the risk of fetal abnormalities is low. The dose of AZA should not exceed 2 mg/kg in a pregnant woman. For patients with a persistently active nephritis with documented or suspected class III or IV with crescents, consideration of delivery after 28 weeks for a viable fetus is recommended.
Monitoring Activity of LN
Recommendations for monitoring LN are shown in the following table, and result from votes of the Task Force Panel (level C evidence).
Table. Recommended Monitoring of Lupus Nephritis*
| Blood Pressure | Urinalysis | Protein/Creatinine Ratio | Serum Creatinine | C3/C4 Levels | Anti-DNA | |
|---|---|---|---|---|---|---|
| Active nephritis at onset of treatment | 1 | 1 | 1 | 1 | 2† | 3 |
| Previous active nephritis, none currently | 3 | 3 | 3 | 3 | 3 | 6 |
| Pregnant with active GN at onset of treatment | 1 | 1 | 1 | 1 | 1 | 1 |
| Pregnant with previous nephritis, none currently | 1 | 1 | 3 | 3 | 3 | 3 |
| No prior or current nephritis | 3 | 6 | 6 | 6 | 6 | 6 |
*Values are the monthly intervals suggested as the minimum frequency at which the indicated laboratory tests should be measured in the systemic lupus erythematosus scenarios shown in the left-hand column. GN = glomerulonephritis.
†Opinion of authors based on a study published after the Task Force Panel had voted.
Definitions:
Level of Evidence
- Level of Evidence A: Data derived from multiple randomized clinical trials
- Level of Evidence B: Data derived from a single randomized trial, or nonrandomized studies
- Level of Evidence C: Only consensus opinion of experts, case studies, or standard-of-care
- Class III/IV induction therapy for lupus nephritis (LN)
- Treatment of class V LN without proliferative changes and with nephrotic range proteinuria (>3 gm/24 hours)
- Treatment of class III, IV, and V LN in patients who are pregnant
Renal Biopsy and Histology
The Task Force Panel recommended that all patients with clinical evidence of active lupus nephritis (LN), previously untreated, undergo renal biopsy (unless strongly contraindicated) so that glomerular disease can be classified by current International Society of Nephrology/Renal Pathology Society (ISN/RPS) classification (level C evidence) (see Table 1 in the original guideline document for ISN/RPS classification of LN). In addition, disease can be evaluated for activity and chronicity and for tubular and vascular changes. Finally, biopsies may identify additional or alternative causes of renal disease, such as tubular necrosis related to medications, hypovolemia, or hypotension. Biopsy is most highly recommended in patients with the characteristics indicated in the following table.
Table. Indications for Renal Biopsy in Patients with Systemic Lupus Erythematosus
| Level of Evidence | |
|---|---|
| Increasing serum creatinine without compelling alternative causes (such as sepsis, hypovolemia, or medication) | C |
| Confirmed proteinuria of ≥1.0 gm per 24 hours (either 24-hour urine specimens or spot protein/creatinine ratios are acceptable) | C |
Combinations of the following, assuming the findings are confirmed in at least two tests done within a short period of time and in the absence of alternative causes:
| C |
RBCs = red blood cells; hpf = high-power field.
The Task Force Panel recommended that treatment be based in large part on the classification of type of LN by these ISN/RPS criteria. As a result, the following recommendations are presented according to the histologic classification of nephritis. The Task Force Panel agreed that class I (minimal mesangial immune deposits on immunofluorescence with normal light microscopy) and class II (mesangial hypercellularity or matrix expansion on light microscopy with immune deposits confined to mesangium on immunofluorescence) generally do not require immunosuppressive treatment (level C evidence). In general, patients with class III (subendothelial immune deposits and proliferative changes in <50% of glomeruli) and class IV (subendothelial deposits and proliferative glomerular changes involving ≥50% of glomeruli) require aggressive therapy with glucocorticoids and immunosuppressive agents. Class V (subepithelial immune deposits and membranous thickening of glomerular capillaries) when combined with class III or IV should be treated in the same manner as class III or IV. Class V alone ("pure membranous LN") may be approached somewhat differently, as indicated below under "Recommendations for Induction of Improvement in Patients with Class V 'Pure Membranous' LN". Histologic class VI (sclerosis of ≥90% of glomeruli) generally requires preparation for renal replacement therapy rather than immunosuppression. The designations "A" and "C" indicate whether active or chronic changes are present; the higher the chronicity the less likely that the nephritis will respond to immunosuppression. However, A or C classifications were not included in the entry criteria for clinical trials in LN published to date, and therefore they are not considered in the recommendations.
Adjunctive Treatments
The Task Force Panel recommended that all systemic lupus erythematosus (SLE) patients with nephritis be treated with a background of hydroxychloroquine (HCQ; level C evidence), unless there is a contraindication.
All LN patients with proteinuria ≥0.5 gm per 24 hours (or equivalent by protein/creatinine ratios on spot urine samples) should have blockade of the renin–angiotensin system, which drives intraglomerular pressure (level A evidence for nondiabetic chronic renal disease). Treatment with either angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs) reduces proteinuria by approximately 30%, and significantly delays doubling of serum creatinine and progression to end-stage renal disease in patients with nondiabetic chronic renal disease. These classes of medications are contraindicated in pregnancy. The use of combination ACE inhibitors/ARB therapies is controversial. ACE inhibitors or ARB treatments are superior to calcium-channel blockers and diuretics alone in preserving renal function in chronic kidney disease.
The Task Force Panel recommended that careful attention be paid to control of hypertension, with a target of ≤130/80 mm Hg (level A evidence for nondiabetic chronic renal disease). The Task Force Panel also recommended that statin therapy be introduced in patients with low-density lipoprotein cholesterol >100 mg/dl (level C evidence). Note that a glomerular filtration rate <60 ml/minute/1.73 m2 (equivalent to a serum creatinine level >1.5 mg/dl or 133 µmoles/liter) is a risk factor for accelerated atherosclerosis. SLE itself is also an independent risk factor for accelerated atherosclerosis.
Finally, the Task Force Panel recommended that women of child-bearing potential with active or prior LN receive counseling regarding pregnancy risks conferred by the disease and its treatments (level C evidence).
Recommendations for Induction of Improvement in Patients with ISN Class III/IV Lupus Glomerulonephritis
The Task Force Panel recommended mycophenolate mofetil (MMF) (2–3 gm total daily orally) or intravenous (IV) cyclophosphamide (CYC) along with glucocorticoids (level A evidence) (see Figure 2 in the original guideline document). MMF and CYC are considered equivalent based on recent high-quality studies, a meta-analysis, and expert opinion. Long-term studies with MMF are not as abundant as those with CYC; data show good results for induction therapy with MMF of 3 gm total dose daily for 6 months, followed by maintenance with lower doses of MMF for 3 years. MMF has been similar in efficacy in all races studied to date (whites, Asians, African Americans, and Latin/Hispanic Americans). The Aspreva Lupus Management Study (ALMS) trial comparing response rates of LN to MMF plus glucocorticoids showed similar improvement in whites, Asians, and other races (primarily African Americans and Hispanics). However, The Task Force Panel voted that Asians compared to non-Asians might require lower doses of MMF for similar efficacy (level C evidence). Therefore, the physician might aim for 3 gm per day total daily highest dose in non-Asians and 2 gm per day in Asians. There is evidence that African Americans and Hispanics with LN respond less well to IV CYC than do patients of white or Asian races. MMF/mycophenolic acid (MPA) may be an initial choice more likely to induce improvement in patients who are African American or Hispanic.
The exact suggested dose of MMF varied based on the clinical scenario: for those with class III/IV without cellular crescents and for those with proteinuria and a stable creatinine for whom a renal biopsy sample cannot be obtained, both 2 gm and 3 gm total daily doses were acceptable to the Task Force Panel, while a dose of 3 gm daily was favored for those with class III/IV and crescents and for those with proteinuria and a recent significant rise in creatinine.
Some evidence suggests that MPA and enteric-coated mycophenolate sodium are less likely than MMF to cause nausea and diarrhea, but this is controversial, and the exact equivalency of the preparations is not firmly established. The Core Expert Panel recommended that MMF and MPA are likely to be equivalent in inducing improvement of LN, with 1,440–2,160 mg total daily dose of MPA roughly equivalent to 2,000–3,000 mg total daily dose of MMF. Some investigators have suggested that serum levels of MPA, the active metabolite of MMF, should be measured at the trough or peak (1 hour after a dose), and treatment of SLE should be guided by these levels. However, there are not enough data at this time to make recommendations for monitoring of drug levels.
There are two regimens of IV CYC recommended by the Task Force Panel: 1) low-dose "Euro-Lupus" CYC (500 mg IV once every 2 weeks for a total of 6 doses), followed by maintenance therapy with daily oral azathioprine (AZA) or daily oral MMF (level B evidence), and 2) high-dose CYC (500–1,000 mg/m2 IV once a month for 6 doses), followed by maintenance treatment with MMF or AZA (level A evidence) (see Figure 2 in the original guideline document). If CYC is being considered for treatment, the Core Expert Panel recommended IV CYC at the low "Euro-Lupus" dose for white patients with Western European or Southern European racial/ethnic backgrounds (level B evidence). In European study patients, the low- and high-dose regimens were equivalent in efficacy, and serious infections were less frequent with the lower doses. The low- and high-dose regimens have not been compared in nonwhite racial groups. Ten years of followup comparing low- and high-dose regimens showed similar rates of LN flares, end-stage renal disease, and doubling of the serum creatinine.
Pulse IV glucocorticoids (500–1,000 mg methylprednisolone daily for 3 doses) in combination with immunosuppressive therapy is recommended by the Task Force Panel, followed by daily oral glucocorticoids (0.5–1 mg/kg/day), followed by a taper to the minimal amount necessary to control disease (level C evidence). There are insufficient data to recommend a specific steroid taper because the nephritis and extrarenal manifestations vary from patient to patient. There was no consensus reached regarding the use of monthly IV methylprednisolone with monthly IV CYC.
Although AZA has been used to treat LN, the Task Force Panel did not recommend it as one of the first choices for induction therapy.
The panel recommends that most patients be followed for 6 months after initiation of induction treatment with either CYC or MMF before making major changes in treatment other than alteration of glucocorticoid doses, unless there is clear evidence of worsening at 3 months (50% or more worsening of proteinuria or serum creatinine; level A evidence).
Fertility issues are often a concern for young SLE patients with nephritis. In a discussion, the Task Force Panel recommended that MMF was preferable to CYC for patients who express a major concern with fertility preservation, since high-dose CYC can cause permanent infertility in both women and men (level A evidence of gonadal toxicity). Six months of high-dose IV CYC was associated with approximately 10% sustained infertility in young women, and higher rates in older women. If 6 months of CYC were followed by quarterly doses, there was a higher rate of infertility. The Task Force Panel did not reach a consensus on the use of leuprolide in patients with SLE receiving CYC as a means to preserve fertility. They also noted that MMF is teratogenic (class D in US Food and Drug Administration [FDA] ranking). Therefore, the physician should be sure that a patient is not pregnant before prescribing MMF or MPA, and the medications should be stopped for at least 6 weeks before pregnancy is attempted.
Recommendations for Induction of Improvement in Patients with Class IV or IV/V Plus Cellular Crescents
The Task Force Panel recommended either CYC or MMF for induction of improvement in this type of LN (level C evidence), along with IV pulses of high-dose glucocorticoid and initiation of oral glucocorticoids at the higher-range dosage, 1 mg/kg/day orally (see Figure 2 in the original guideline document). For the purpose of these recommendations statements, the presence of any crescents on a renal biopsy sample was considered crescentic LN. Until recently, experts have favored high-dose IV CYC for treatment of LN with cellular crescents. In general, the presence of crescents indicates a poorer prognosis, even with appropriate treatment. Further recommendations for a pregnant patient with crescentic glomerulonephritis are provided in the section on "Treatment of LN in Patients Who Are Pregnant," below.
Recommendations for Induction of Improvement in Patients with Class V "Pure Membranous" LN
The Task Force Panel recommends that patients with pure class V LN and with nephrotic range proteinuria be started on prednisone (0.5 mg/kg/day) plus MMF 2–3 gm total daily dose (level A evidence) (see Figure 3 in the original guideline document).
Other therapies for membranous LN have been reported; however, the Task Force Panel did not reach consensus on a recommendation regarding those therapies.
Recommendations for Maintaining Improvement in Patients Who Respond to Induction Therapy
The Task Force Panel recommended that either AZA or MMF be used for maintenance therapy (level A evidence) (see Figure 2 in the original guideline document). The Task Force Panel did not vote on the rate of medication taper during the maintenance phase; to date, there are no adequate data to inform the physician regarding how rapidly AZA or MMF can be tapered or withdrawn.
Recommendations for Changing Therapies in Patients Who Do Not Respond Adequately to Induction Therapy
In patients who fail to respond after 6 months of treatment (based on the treating physician's clinical impression) with glucocorticoids plus MMF or CYC, the Task Force Panel recommends a switch of the immunosuppressive agent from either CYC to MMF, or from MMF to CYC, with these changes accompanied by IV pulses of glucocorticoids for 3 days (level C evidence) (see Figure 2 in the original guideline document). For CYC, either low dose or high dose can be used in white individuals, as discussed above in the section on "Recommendations for Induction of Improvement in Patients with ISN Class III/IV Lupus Glomerulonephritis," above. Evidence to support these opinions is not as strong as evidence for the efficacy of initial induction therapy. The panel also voted that in some cases rituximab can be used in patients whose nephritis fails to improve or worsens after 6 months of one induction therapy, or after the patient has failed both CYC and MMF treatments (level C evidence). The Task Force Panel did not reach consensus regarding the use of calcineurin inhibitors in this setting; however, there is evidence for their efficacy as an induction agent and in refractory disease.
There is evidence in open-label trials that LN may respond to rituximab treatment. Prospective, randomized, placebo-controlled trials did not show a significant difference between rituximab and placebo (on a background of MMF and glucocorticoids) after 1 year of treatment.
Evidence to support the use of cyclosporine or tacrolimus in LN is from open trials and recent prospective clinical trials; additional prospective trials are in progress. In a recent prospective trial, tacrolimus was equivalent to high-dose IV CYC in inducing complete and partial remissions of LN over a 6-month period. In another 4-year–long prospective trial, cyclosporine was similar to AZA in preventing renal flares in patients receiving maintenance therapy.
If nephritis is worsening in patients treated for 3 months with glucocorticoids plus CYC or MMF, the Task Force Panel recommended that the clinician can choose any of the alternative treatments discussed (level C evidence). Although combinations of MMF and calcineurin inhibitors and of rituximab and MMF are being studied and might be considered for those who have failed the recommended induction therapies, data are not robust enough at this time to include them for voting scenarios.
The FDA has approved belimumab for use in seropositive patients with SLE who have active disease in spite of prior therapies.
Identification of Vascular Disease in Patients with SLE and Renal Abnormalities
Several types of vascular involvement can occur in renal tissue of SLE, including vasculitis, fibrinoid necrosis with narrowing of small arteries/arterioles ("bland" vasculopathy), thrombotic microangiopathy, and renal vein thrombosis. In general, vasculitis is treated similarly to the more common forms of LN discussed above. Bland vasculopathy is highly associated with hypertension; it is not clear which comes first, SLE or hypertension. Thrombotic microangiopathy can be associated with a thrombotic thrombocytopenia–like picture. The Task Force Panel recommended that thrombotic microangiopathy be treated primarily with plasma exchange therapy (level C evidence)
Treatment of LN in Patients Who Are Pregnant
The Task Force Panel recommended several approaches for management of LN in women who are pregnant (all level C evidence) (see Figure 4 in the original guideline document). In patients with prior LN but no current evidence of systemic or renal disease activity, no nephritis medications are necessary. Patients with mild systemic activity may be treated with HCQ; this probably reduces activity of SLE during pregnancy. If clinically active nephritis is present, or there is substantial extrarenal disease activity, the clinician may prescribe glucocorticoids at doses necessary to control disease activity, and if necessary AZA can be added. High-dose glucocorticoid therapy in patients with SLE is associated with a high risk of maternal complications such as hypertension and diabetes mellitus. MMF, CYC, and methotrexate should be avoided because they are teratogenic in humans. Although AZA is listed as pregnancy category D in Micromedex, cross-sectional studies have shown that the risk of fetal abnormalities is low. The dose of AZA should not exceed 2 mg/kg in a pregnant woman. For patients with a persistently active nephritis with documented or suspected class III or IV with crescents, consideration of delivery after 28 weeks for a viable fetus is recommended.
Monitoring Activity of LN
Recommendations for monitoring LN are shown in the following table, and result from votes of the Task Force Panel (level C evidence).
Table. Recommended Monitoring of Lupus Nephritis*
| Blood Pressure | Urinalysis | Protein/Creatinine Ratio | Serum Creatinine | C3/C4 Levels | Anti-DNA | |
|---|---|---|---|---|---|---|
| Active nephritis at onset of treatment | 1 | 1 | 1 | 1 | 2† | 3 |
| Previous active nephritis, none currently | 3 | 3 | 3 | 3 | 3 | 6 |
| Pregnant with active GN at onset of treatment | 1 | 1 | 1 | 1 | 1 | 1 |
| Pregnant with previous nephritis, none currently | 1 | 1 | 3 | 3 | 3 | 3 |
| No prior or current nephritis | 3 | 6 | 6 | 6 | 6 | 6 |
*Values are the monthly intervals suggested as the minimum frequency at which the indicated laboratory tests should be measured in the systemic lupus erythematosus scenarios shown in the left-hand column. GN = glomerulonephritis.
†Opinion of authors based on a study published after the Task Force Panel had voted.
Definitions:
Level of Evidence
- Level of Evidence A: Data derived from multiple randomized clinical trials
- Level of Evidence B: Data derived from a single randomized trial, or nonrandomized studies
- Level of Evidence C: Only consensus opinion of experts, case studies, or standard-of-care
- Class III/IV induction therapy for lupus nephritis (LN)
- Treatment of class V LN without proliferative changes and with nephrotic range proteinuria (>3 gm/24 hours)
- Treatment of class III, IV, and V LN in patients who are pregnant
Renal Biopsy and Histology
The Task Force Panel recommended that all patients with clinical evidence of active lupus nephritis (LN), previously untreated, undergo renal biopsy (unless strongly contraindicated) so that glomerular disease can be classified by current International Society of Nephrology/Renal Pathology Society (ISN/RPS) classification (level C evidence) (see Table 1 in the original guideline document for ISN/RPS classification of LN). In addition, disease can be evaluated for activity and chronicity and for tubular and vascular changes. Finally, biopsies may identify additional or alternative causes of renal disease, such as tubular necrosis related to medications, hypovolemia, or hypotension. Biopsy is most highly recommended in patients with the characteristics indicated in the following table.
Table. Indications for Renal Biopsy in Patients with Systemic Lupus Erythematosus
| Level of Evidence | |
|---|---|
| Increasing serum creatinine without compelling alternative causes (such as sepsis, hypovolemia, or medication) | C |
| Confirmed proteinuria of ≥1.0 gm per 24 hours (either 24-hour urine specimens or spot protein/creatinine ratios are acceptable) | C |
Combinations of the following, assuming the findings are confirmed in at least two tests done within a short period of time and in the absence of alternative causes:
| C |
RBCs = red blood cells; hpf = high-power field.
The Task Force Panel recommended that treatment be based in large part on the classification of type of LN by these ISN/RPS criteria. As a result, the following recommendations are presented according to the histologic classification of nephritis. The Task Force Panel agreed that class I (minimal mesangial immune deposits on immunofluorescence with normal light microscopy) and class II (mesangial hypercellularity or matrix expansion on light microscopy with immune deposits confined to mesangium on immunofluorescence) generally do not require immunosuppressive treatment (level C evidence). In general, patients with class III (subendothelial immune deposits and proliferative changes in <50% of glomeruli) and class IV (subendothelial deposits and proliferative glomerular changes involving ≥50% of glomeruli) require aggressive therapy with glucocorticoids and immunosuppressive agents. Class V (subepithelial immune deposits and membranous thickening of glomerular capillaries) when combined with class III or IV should be treated in the same manner as class III or IV. Class V alone ("pure membranous LN") may be approached somewhat differently, as indicated below under "Recommendations for Induction of Improvement in Patients with Class V 'Pure Membranous' LN". Histologic class VI (sclerosis of ≥90% of glomeruli) generally requires preparation for renal replacement therapy rather than immunosuppression. The designations "A" and "C" indicate whether active or chronic changes are present; the higher the chronicity the less likely that the nephritis will respond to immunosuppression. However, A or C classifications were not included in the entry criteria for clinical trials in LN published to date, and therefore they are not considered in the recommendations.
Adjunctive Treatments
The Task Force Panel recommended that all systemic lupus erythematosus (SLE) patients with nephritis be treated with a background of hydroxychloroquine (HCQ; level C evidence), unless there is a contraindication.
All LN patients with proteinuria ≥0.5 gm per 24 hours (or equivalent by protein/creatinine ratios on spot urine samples) should have blockade of the renin–angiotensin system, which drives intraglomerular pressure (level A evidence for nondiabetic chronic renal disease). Treatment with either angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs) reduces proteinuria by approximately 30%, and significantly delays doubling of serum creatinine and progression to end-stage renal disease in patients with nondiabetic chronic renal disease. These classes of medications are contraindicated in pregnancy. The use of combination ACE inhibitors/ARB therapies is controversial. ACE inhibitors or ARB treatments are superior to calcium-channel blockers and diuretics alone in preserving renal function in chronic kidney disease.
The Task Force Panel recommended that careful attention be paid to control of hypertension, with a target of ≤130/80 mm Hg (level A evidence for nondiabetic chronic renal disease). The Task Force Panel also recommended that statin therapy be introduced in patients with low-density lipoprotein cholesterol >100 mg/dl (level C evidence). Note that a glomerular filtration rate <60 ml/minute/1.73 m2 (equivalent to a serum creatinine level >1.5 mg/dl or 133 µmoles/liter) is a risk factor for accelerated atherosclerosis. SLE itself is also an independent risk factor for accelerated atherosclerosis.
Finally, the Task Force Panel recommended that women of child-bearing potential with active or prior LN receive counseling regarding pregnancy risks conferred by the disease and its treatments (level C evidence).
Recommendations for Induction of Improvement in Patients with ISN Class III/IV Lupus Glomerulonephritis
The Task Force Panel recommended mycophenolate mofetil (MMF) (2–3 gm total daily orally) or intravenous (IV) cyclophosphamide (CYC) along with glucocorticoids (level A evidence) (see Figure 2 in the original guideline document). MMF and CYC are considered equivalent based on recent high-quality studies, a meta-analysis, and expert opinion. Long-term studies with MMF are not as abundant as those with CYC; data show good results for induction therapy with MMF of 3 gm total dose daily for 6 months, followed by maintenance with lower doses of MMF for 3 years. MMF has been similar in efficacy in all races studied to date (whites, Asians, African Americans, and Latin/Hispanic Americans). The Aspreva Lupus Management Study (ALMS) trial comparing response rates of LN to MMF plus glucocorticoids showed similar improvement in whites, Asians, and other races (primarily African Americans and Hispanics). However, The Task Force Panel voted that Asians compared to non-Asians might require lower doses of MMF for similar efficacy (level C evidence). Therefore, the physician might aim for 3 gm per day total daily highest dose in non-Asians and 2 gm per day in Asians. There is evidence that African Americans and Hispanics with LN respond less well to IV CYC than do patients of white or Asian races. MMF/mycophenolic acid (MPA) may be an initial choice more likely to induce improvement in patients who are African American or Hispanic.
The exact suggested dose of MMF varied based on the clinical scenario: for those with class III/IV without cellular crescents and for those with proteinuria and a stable creatinine for whom a renal biopsy sample cannot be obtained, both 2 gm and 3 gm total daily doses were acceptable to the Task Force Panel, while a dose of 3 gm daily was favored for those with class III/IV and crescents and for those with proteinuria and a recent significant rise in creatinine.
Some evidence suggests that MPA and enteric-coated mycophenolate sodium are less likely than MMF to cause nausea and diarrhea, but this is controversial, and the exact equivalency of the preparations is not firmly established. The Core Expert Panel recommended that MMF and MPA are likely to be equivalent in inducing improvement of LN, with 1,440–2,160 mg total daily dose of MPA roughly equivalent to 2,000–3,000 mg total daily dose of MMF. Some investigators have suggested that serum levels of MPA, the active metabolite of MMF, should be measured at the trough or peak (1 hour after a dose), and treatment of SLE should be guided by these levels. However, there are not enough data at this time to make recommendations for monitoring of drug levels.
There are two regimens of IV CYC recommended by the Task Force Panel: 1) low-dose "Euro-Lupus" CYC (500 mg IV once every 2 weeks for a total of 6 doses), followed by maintenance therapy with daily oral azathioprine (AZA) or daily oral MMF (level B evidence), and 2) high-dose CYC (500–1,000 mg/m2 IV once a month for 6 doses), followed by maintenance treatment with MMF or AZA (level A evidence) (see Figure 2 in the original guideline document). If CYC is being considered for treatment, the Core Expert Panel recommended IV CYC at the low "Euro-Lupus" dose for white patients with Western European or Southern European racial/ethnic backgrounds (level B evidence). In European study patients, the low- and high-dose regimens were equivalent in efficacy, and serious infections were less frequent with the lower doses. The low- and high-dose regimens have not been compared in nonwhite racial groups. Ten years of followup comparing low- and high-dose regimens showed similar rates of LN flares, end-stage renal disease, and doubling of the serum creatinine.
Pulse IV glucocorticoids (500–1,000 mg methylprednisolone daily for 3 doses) in combination with immunosuppressive therapy is recommended by the Task Force Panel, followed by daily oral glucocorticoids (0.5–1 mg/kg/day), followed by a taper to the minimal amount necessary to control disease (level C evidence). There are insufficient data to recommend a specific steroid taper because the nephritis and extrarenal manifestations vary from patient to patient. There was no consensus reached regarding the use of monthly IV methylprednisolone with monthly IV CYC.
Although AZA has been used to treat LN, the Task Force Panel did not recommend it as one of the first choices for induction therapy.
The panel recommends that most patients be followed for 6 months after initiation of induction treatment with either CYC or MMF before making major changes in treatment other than alteration of glucocorticoid doses, unless there is clear evidence of worsening at 3 months (50% or more worsening of proteinuria or serum creatinine; level A evidence).
Fertility issues are often a concern for young SLE patients with nephritis. In a discussion, the Task Force Panel recommended that MMF was preferable to CYC for patients who express a major concern with fertility preservation, since high-dose CYC can cause permanent infertility in both women and men (level A evidence of gonadal toxicity). Six months of high-dose IV CYC was associated with approximately 10% sustained infertility in young women, and higher rates in older women. If 6 months of CYC were followed by quarterly doses, there was a higher rate of infertility. The Task Force Panel did not reach a consensus on the use of leuprolide in patients with SLE receiving CYC as a means to preserve fertility. They also noted that MMF is teratogenic (class D in US Food and Drug Administration [FDA] ranking). Therefore, the physician should be sure that a patient is not pregnant before prescribing MMF or MPA, and the medications should be stopped for at least 6 weeks before pregnancy is attempted.
Recommendations for Induction of Improvement in Patients with Class IV or IV/V Plus Cellular Crescents
The Task Force Panel recommended either CYC or MMF for induction of improvement in this type of LN (level C evidence), along with IV pulses of high-dose glucocorticoid and initiation of oral glucocorticoids at the higher-range dosage, 1 mg/kg/day orally (see Figure 2 in the original guideline document). For the purpose of these recommendations statements, the presence of any crescents on a renal biopsy sample was considered crescentic LN. Until recently, experts have favored high-dose IV CYC for treatment of LN with cellular crescents. In general, the presence of crescents indicates a poorer prognosis, even with appropriate treatment. Further recommendations for a pregnant patient with crescentic glomerulonephritis are provided in the section on "Treatment of LN in Patients Who Are Pregnant," below.
Recommendations for Induction of Improvement in Patients with Class V "Pure Membranous" LN
The Task Force Panel recommends that patients with pure class V LN and with nephrotic range proteinuria be started on prednisone (0.5 mg/kg/day) plus MMF 2–3 gm total daily dose (level A evidence) (see Figure 3 in the original guideline document).
Other therapies for membranous LN have been reported; however, the Task Force Panel did not reach consensus on a recommendation regarding those therapies.
Recommendations for Maintaining Improvement in Patients Who Respond to Induction Therapy
The Task Force Panel recommended that either AZA or MMF be used for maintenance therapy (level A evidence) (see Figure 2 in the original guideline document). The Task Force Panel did not vote on the rate of medication taper during the maintenance phase; to date, there are no adequate data to inform the physician regarding how rapidly AZA or MMF can be tapered or withdrawn.
Recommendations for Changing Therapies in Patients Who Do Not Respond Adequately to Induction Therapy
In patients who fail to respond after 6 months of treatment (based on the treating physician's clinical impression) with glucocorticoids plus MMF or CYC, the Task Force Panel recommends a switch of the immunosuppressive agent from either CYC to MMF, or from MMF to CYC, with these changes accompanied by IV pulses of glucocorticoids for 3 days (level C evidence) (see Figure 2 in the original guideline document). For CYC, either low dose or high dose can be used in white individuals, as discussed above in the section on "Recommendations for Induction of Improvement in Patients with ISN Class III/IV Lupus Glomerulonephritis," above. Evidence to support these opinions is not as strong as evidence for the efficacy of initial induction therapy. The panel also voted that in some cases rituximab can be used in patients whose nephritis fails to improve or worsens after 6 months of one induction therapy, or after the patient has failed both CYC and MMF treatments (level C evidence). The Task Force Panel did not reach consensus regarding the use of calcineurin inhibitors in this setting; however, there is evidence for their efficacy as an induction agent and in refractory disease.
There is evidence in open-label trials that LN may respond to rituximab treatment. Prospective, randomized, placebo-controlled trials did not show a significant difference between rituximab and placebo (on a background of MMF and glucocorticoids) after 1 year of treatment.
Evidence to support the use of cyclosporine or tacrolimus in LN is from open trials and recent prospective clinical trials; additional prospective trials are in progress. In a recent prospective trial, tacrolimus was equivalent to high-dose IV CYC in inducing complete and partial remissions of LN over a 6-month period. In another 4-year–long prospective trial, cyclosporine was similar to AZA in preventing renal flares in patients receiving maintenance therapy.
If nephritis is worsening in patients treated for 3 months with glucocorticoids plus CYC or MMF, the Task Force Panel recommended that the clinician can choose any of the alternative treatments discussed (level C evidence). Although combinations of MMF and calcineurin inhibitors and of rituximab and MMF are being studied and might be considered for those who have failed the recommended induction therapies, data are not robust enough at this time to include them for voting scenarios.
The FDA has approved belimumab for use in seropositive patients with SLE who have active disease in spite of prior therapies.
Identification of Vascular Disease in Patients with SLE and Renal Abnormalities
Several types of vascular involvement can occur in renal tissue of SLE, including vasculitis, fibrinoid necrosis with narrowing of small arteries/arterioles ("bland" vasculopathy), thrombotic microangiopathy, and renal vein thrombosis. In general, vasculitis is treated similarly to the more common forms of LN discussed above. Bland vasculopathy is highly associated with hypertension; it is not clear which comes first, SLE or hypertension. Thrombotic microangiopathy can be associated with a thrombotic thrombocytopenia–like picture. The Task Force Panel recommended that thrombotic microangiopathy be treated primarily with plasma exchange therapy (level C evidence)
Treatment of LN in Patients Who Are Pregnant
The Task Force Panel recommended several approaches for management of LN in women who are pregnant (all level C evidence) (see Figure 4 in the original guideline document). In patients with prior LN but no current evidence of systemic or renal disease activity, no nephritis medications are necessary. Patients with mild systemic activity may be treated with HCQ; this probably reduces activity of SLE during pregnancy. If clinically active nephritis is present, or there is substantial extrarenal disease activity, the clinician may prescribe glucocorticoids at doses necessary to control disease activity, and if necessary AZA can be added. High-dose glucocorticoid therapy in patients with SLE is associated with a high risk of maternal complications such as hypertension and diabetes mellitus. MMF, CYC, and methotrexate should be avoided because they are teratogenic in humans. Although AZA is listed as pregnancy category D in Micromedex, cross-sectional studies have shown that the risk of fetal abnormalities is low. The dose of AZA should not exceed 2 mg/kg in a pregnant woman. For patients with a persistently active nephritis with documented or suspected class III or IV with crescents, consideration of delivery after 28 weeks for a viable fetus is recommended.
Monitoring Activity of LN
Recommendations for monitoring LN are shown in the following table, and result from votes of the Task Force Panel (level C evidence).
Table. Recommended Monitoring of Lupus Nephritis*
| Blood Pressure | Urinalysis | Protein/Creatinine Ratio | Serum Creatinine | C3/C4 Levels | Anti-DNA | |
|---|---|---|---|---|---|---|
| Active nephritis at onset of treatment | 1 | 1 | 1 | 1 | 2† | 3 |
| Previous active nephritis, none currently | 3 | 3 | 3 | 3 | 3 | 6 |
| Pregnant with active GN at onset of treatment | 1 | 1 | 1 | 1 | 1 | 1 |
| Pregnant with previous nephritis, none currently | 1 | 1 | 3 | 3 | 3 | 3 |
| No prior or current nephritis | 3 | 6 | 6 | 6 | 6 | 6 |
*Values are the monthly intervals suggested as the minimum frequency at which the indicated laboratory tests should be measured in the systemic lupus erythematosus scenarios shown in the left-hand column. GN = glomerulonephritis.
†Opinion of authors based on a study published after the Task Force Panel had voted.
Definitions:
Level of Evidence
- Level of Evidence A: Data derived from multiple randomized clinical trials
- Level of Evidence B: Data derived from a single randomized trial, or nonrandomized studies
- Level of Evidence C: Only consensus opinion of experts, case studies, or standard-of-care
- Class III/IV induction therapy for lupus nephritis (LN)
- Treatment of class V LN without proliferative changes and with nephrotic range proteinuria (>3 gm/24 hours)
- Treatment of class III, IV, and V LN in patients who are pregnant
OBJECTIVE: To provide a new set of management recommendations for lupus nephritis (LN) for adults with lupus nephritis (LN), particularly to those receiving care in the United States.
Guidelines are copyright © 2012 American College of Rheumatology. All rights reserved. The summary is provided by the Agency for Healthcare Research and Quality.
New Developments in Chronic Lymphocytic Leukemia Treatment
Recently, Federal Practitioner talked with Sanjai Sharma, MD, about how signaling pathways in chronic lymphocytic leukemia (CLL) is critical to the development of therapeutic agents to treat this disease. Ibrutinib and idelalisib are therapeutic agents that block signaling pathways and, therefore, inhibit the growth of CLL cells.
For more information about CLL, read "Signaling Pathways and Novel Inhibitors in Chronic Lymphocytic Leukemia," in our August 2014 issue.
Dr. Sharma is a physician at the West Los Angeles VA Medical Center and associate professor in the Department of Medicine, Hematology/Oncology at UCLA, both in California.
Recently, Federal Practitioner talked with Sanjai Sharma, MD, about how signaling pathways in chronic lymphocytic leukemia (CLL) is critical to the development of therapeutic agents to treat this disease. Ibrutinib and idelalisib are therapeutic agents that block signaling pathways and, therefore, inhibit the growth of CLL cells.
For more information about CLL, read "Signaling Pathways and Novel Inhibitors in Chronic Lymphocytic Leukemia," in our August 2014 issue.
Dr. Sharma is a physician at the West Los Angeles VA Medical Center and associate professor in the Department of Medicine, Hematology/Oncology at UCLA, both in California.
Recently, Federal Practitioner talked with Sanjai Sharma, MD, about how signaling pathways in chronic lymphocytic leukemia (CLL) is critical to the development of therapeutic agents to treat this disease. Ibrutinib and idelalisib are therapeutic agents that block signaling pathways and, therefore, inhibit the growth of CLL cells.
For more information about CLL, read "Signaling Pathways and Novel Inhibitors in Chronic Lymphocytic Leukemia," in our August 2014 issue.
Dr. Sharma is a physician at the West Los Angeles VA Medical Center and associate professor in the Department of Medicine, Hematology/Oncology at UCLA, both in California.
Monthly transfusions may prevent stroke recurrence in SCD
Credit: St Jude Children’s
Research Hospital
Monthly blood transfusions can reduce the risk of silent or overt stroke among children with sickle cell disease (SCD) who previously had a silent stroke, according to a study published in The New England Journal of Medicine.
Children with evidence of silent cerebral infarcts who received monthly blood transfusions for 3 years had a 58% lower risk of suffering repeat silent or overt
strokes than children who did not receive transfusions.
In fact, researchers said the actual benefit of transfusion therapy may be even higher, as 15% of the children who were assigned to receive transfusions either did not receive them or only received them for a brief period.
“The results of our study show that blood transfusions can play a critical role in preventing this insidious and potentially devastating condition,” said study author James F. Casella, MD, of the Johns Hopkins Children’s Center in Baltimore, Maryland.
“They also highlight the importance of intervening early to preclude ongoing or further brain injury among these youngsters. Most importantly, our findings suggest a much-needed treatment option for clinicians and families of children with sickle cell disease who have had silent strokes.”
Previous studies have suggested that blood transfusions may help prevent stroke in patients with SCD by increasing the number of normal red blood cells and decreasing the likelihood of blocked blood vessels.
But Dr Casella and his colleagues wanted to determine if monthly blood transfusions would help prevent stroke in children with SCD who had evidence of a previous silent cerebral infarct, as well as whether the benefits of transfusion outweigh the risks.
The researchers analyzed 196 children, ages 5 to 15 years, who were diagnosed with SCD and had infarct-like lesions on their MRI scans. The children were randomized to an observation arm or to receive blood transfusions every month for 3 years.
Six percent (6/99) of children who received regular transfusions suffered another silent or overt stroke. One of the patients had a stroke, and 5 had new or enlarged silent cerebral infarcts.
In comparison, 14% (14/97) of children in the observation arm experienced a silent or overt stroke. Seven had a stroke, and 7 had new or enlarged silent cerebral infarcts.
So children who did not receive transfusions were more than twice as likely as their peers to have repeat strokes.
Children who did not receive transfusions were also more likely to suffer a range of other SCD-related problems, such as episodes of extreme pain. There were 295 pain episodes among children who did not receive transfusions and 126 episodes among transfused patients.
An unexpected result, according to the researchers, was that intelligence measures were not different between the 2 treatment arms. Previous studies suggested that silent strokes are associated with a 5-point reduction in IQ. The researchers said they plan to explore this finding further.
Nevertheless, this study provides “clear evidence” that transfusions can decrease the progression of silent strokes in children with SCD, said study author Michael R. DeBaun, MD, of Vanderbilt University in Nashville, Tennessee.
“These results suggest that children who have this disease should be screened early for silent strokes, at least by the time they begin elementary school, to help them manage the disease and to ensure minimal impact on school performance,” he added.
Dr DeBaun and his colleagues said children with SCD should have a surveillance MRI, preferably without sedation, at a young age. Most children with SCD who are at risk for a silent stroke will have one by age 6 years.
The researchers also noted that healthcare providers should discuss treatment options with families to determine if transfusion therapy is appropriate, as there is a risk of transfusion reactions and iron overload.
The decision to transfuse should be made by factoring in each child’s overall health, medical history, and the ability to take time from school for monthly procedures.
The researchers said further study is needed to identify which children with a history of silent strokes are at greatest risk for recurrence so transfusion therapy can be targeted to them.
An editorial related to this study also calls for additional research to determine if the findings can be translated to clinical practice.
Credit: St Jude Children’s
Research Hospital
Monthly blood transfusions can reduce the risk of silent or overt stroke among children with sickle cell disease (SCD) who previously had a silent stroke, according to a study published in The New England Journal of Medicine.
Children with evidence of silent cerebral infarcts who received monthly blood transfusions for 3 years had a 58% lower risk of suffering repeat silent or overt
strokes than children who did not receive transfusions.
In fact, researchers said the actual benefit of transfusion therapy may be even higher, as 15% of the children who were assigned to receive transfusions either did not receive them or only received them for a brief period.
“The results of our study show that blood transfusions can play a critical role in preventing this insidious and potentially devastating condition,” said study author James F. Casella, MD, of the Johns Hopkins Children’s Center in Baltimore, Maryland.
“They also highlight the importance of intervening early to preclude ongoing or further brain injury among these youngsters. Most importantly, our findings suggest a much-needed treatment option for clinicians and families of children with sickle cell disease who have had silent strokes.”
Previous studies have suggested that blood transfusions may help prevent stroke in patients with SCD by increasing the number of normal red blood cells and decreasing the likelihood of blocked blood vessels.
But Dr Casella and his colleagues wanted to determine if monthly blood transfusions would help prevent stroke in children with SCD who had evidence of a previous silent cerebral infarct, as well as whether the benefits of transfusion outweigh the risks.
The researchers analyzed 196 children, ages 5 to 15 years, who were diagnosed with SCD and had infarct-like lesions on their MRI scans. The children were randomized to an observation arm or to receive blood transfusions every month for 3 years.
Six percent (6/99) of children who received regular transfusions suffered another silent or overt stroke. One of the patients had a stroke, and 5 had new or enlarged silent cerebral infarcts.
In comparison, 14% (14/97) of children in the observation arm experienced a silent or overt stroke. Seven had a stroke, and 7 had new or enlarged silent cerebral infarcts.
So children who did not receive transfusions were more than twice as likely as their peers to have repeat strokes.
Children who did not receive transfusions were also more likely to suffer a range of other SCD-related problems, such as episodes of extreme pain. There were 295 pain episodes among children who did not receive transfusions and 126 episodes among transfused patients.
An unexpected result, according to the researchers, was that intelligence measures were not different between the 2 treatment arms. Previous studies suggested that silent strokes are associated with a 5-point reduction in IQ. The researchers said they plan to explore this finding further.
Nevertheless, this study provides “clear evidence” that transfusions can decrease the progression of silent strokes in children with SCD, said study author Michael R. DeBaun, MD, of Vanderbilt University in Nashville, Tennessee.
“These results suggest that children who have this disease should be screened early for silent strokes, at least by the time they begin elementary school, to help them manage the disease and to ensure minimal impact on school performance,” he added.
Dr DeBaun and his colleagues said children with SCD should have a surveillance MRI, preferably without sedation, at a young age. Most children with SCD who are at risk for a silent stroke will have one by age 6 years.
The researchers also noted that healthcare providers should discuss treatment options with families to determine if transfusion therapy is appropriate, as there is a risk of transfusion reactions and iron overload.
The decision to transfuse should be made by factoring in each child’s overall health, medical history, and the ability to take time from school for monthly procedures.
The researchers said further study is needed to identify which children with a history of silent strokes are at greatest risk for recurrence so transfusion therapy can be targeted to them.
An editorial related to this study also calls for additional research to determine if the findings can be translated to clinical practice.
Credit: St Jude Children’s
Research Hospital
Monthly blood transfusions can reduce the risk of silent or overt stroke among children with sickle cell disease (SCD) who previously had a silent stroke, according to a study published in The New England Journal of Medicine.
Children with evidence of silent cerebral infarcts who received monthly blood transfusions for 3 years had a 58% lower risk of suffering repeat silent or overt
strokes than children who did not receive transfusions.
In fact, researchers said the actual benefit of transfusion therapy may be even higher, as 15% of the children who were assigned to receive transfusions either did not receive them or only received them for a brief period.
“The results of our study show that blood transfusions can play a critical role in preventing this insidious and potentially devastating condition,” said study author James F. Casella, MD, of the Johns Hopkins Children’s Center in Baltimore, Maryland.
“They also highlight the importance of intervening early to preclude ongoing or further brain injury among these youngsters. Most importantly, our findings suggest a much-needed treatment option for clinicians and families of children with sickle cell disease who have had silent strokes.”
Previous studies have suggested that blood transfusions may help prevent stroke in patients with SCD by increasing the number of normal red blood cells and decreasing the likelihood of blocked blood vessels.
But Dr Casella and his colleagues wanted to determine if monthly blood transfusions would help prevent stroke in children with SCD who had evidence of a previous silent cerebral infarct, as well as whether the benefits of transfusion outweigh the risks.
The researchers analyzed 196 children, ages 5 to 15 years, who were diagnosed with SCD and had infarct-like lesions on their MRI scans. The children were randomized to an observation arm or to receive blood transfusions every month for 3 years.
Six percent (6/99) of children who received regular transfusions suffered another silent or overt stroke. One of the patients had a stroke, and 5 had new or enlarged silent cerebral infarcts.
In comparison, 14% (14/97) of children in the observation arm experienced a silent or overt stroke. Seven had a stroke, and 7 had new or enlarged silent cerebral infarcts.
So children who did not receive transfusions were more than twice as likely as their peers to have repeat strokes.
Children who did not receive transfusions were also more likely to suffer a range of other SCD-related problems, such as episodes of extreme pain. There were 295 pain episodes among children who did not receive transfusions and 126 episodes among transfused patients.
An unexpected result, according to the researchers, was that intelligence measures were not different between the 2 treatment arms. Previous studies suggested that silent strokes are associated with a 5-point reduction in IQ. The researchers said they plan to explore this finding further.
Nevertheless, this study provides “clear evidence” that transfusions can decrease the progression of silent strokes in children with SCD, said study author Michael R. DeBaun, MD, of Vanderbilt University in Nashville, Tennessee.
“These results suggest that children who have this disease should be screened early for silent strokes, at least by the time they begin elementary school, to help them manage the disease and to ensure minimal impact on school performance,” he added.
Dr DeBaun and his colleagues said children with SCD should have a surveillance MRI, preferably without sedation, at a young age. Most children with SCD who are at risk for a silent stroke will have one by age 6 years.
The researchers also noted that healthcare providers should discuss treatment options with families to determine if transfusion therapy is appropriate, as there is a risk of transfusion reactions and iron overload.
The decision to transfuse should be made by factoring in each child’s overall health, medical history, and the ability to take time from school for monthly procedures.
The researchers said further study is needed to identify which children with a history of silent strokes are at greatest risk for recurrence so transfusion therapy can be targeted to them.
An editorial related to this study also calls for additional research to determine if the findings can be translated to clinical practice.