Guidelines

A new draft guideline for the diagnosis and management of thrombocytopenic purpura (TTP) was recently released by the International Society on Thrombosis and Hemostasis (ISTH).

Svisio/Thinkstock

According to the panel of experts involved, the ISTH guideline takes into account the latest TTP findings, offering a more up-to-date resource for clinicians than the two previously published guidelines in 2012 from the British Committee for Standards in Haematology and in 2017 from the TTP group of Japan’s Blood Coagulation Abnormalities Research Team.

“Since the publication of these guidelines, there have been significant developments in the diagnosis and treatment of TTP, and an increase in published data on how management strategies affect objective health outcomes,” the panel members wrote in the guideline, which is available at ISTH.org.

Despite these advancements, TTP remains a challenging condition for both clinicians and patients for a variety of reasons, the panel noted, which was led by clinical cochair X. Long Zheng, MD, PhD, of the University of Alabama in Birmingham and method cochair Sara K. Vesely, PhD, of the University of Oklahoma, Oklahoma City.

The ISTH guideline provides recommendations for adult patients with either immune or hereditary TTP, from acute events through remission, including diagnostic steps to determine if a case of thrombotic microangiopathy is in fact TTP.

Nearly all the recommendations are based on very-low-certainty evidence. Some of the key treatment recommendations include the following:

• For patients with immune TTP experiencing a first acute event, add corticosteroids to therapeutic plasma exchange (TPE), rather than treating with TPE alone. This is a strong recommendation.
• For patients with immune TTP experiencing a first acute event, add rituximab to corticosteroids and TPE, rather than corticosteroids and TPE alone. This is a conditional recommendation.
• For patients with immune TTP experiencing a relapse, add corticosteroids to TPE, rather than TPE alone. This is a strong recommendation.
• For patients with immune TTP experiencing a relapse, add rituximab to corticosteroids and TPE, rather than steroids and TPE alone. This is a conditional recommendation.
• For patients with immune TTP experiencing an acute event – either a first event or a relapse – use caplacizumab. This is a conditional recommendation based on moderate-certainty evidence.
• For patients with immune TTP who are in remission and have low plasma ADAMTS13 activity but no other symptoms of TMA, use rituximab for prophylaxis. This is a conditional recommendation.
• For patients with hereditary TTP who are in remission, plasma infusion or a watch-and-wait strategy is recommended. This is a conditional recommendation.
• For patients with hereditary TTP who are in remission, do not use factor VIII concentrate infusions. A watch-and-wait strategy is advised. This is a conditional recommendation.
• For patients with immune TTP who are pregnant and have decreased plasma ADAMTS13 activity but no symptoms of TMA, use prophylactic treatment. This is a strong recommendation.
• For patients with hereditary TTP who are pregnant, use prophylactic treatment. This is a strong recommendation. The panel further recommended treatment with plasma infusion rather than factor VIII products, which was a conditional recommendation.

The multidisciplinary expert panel included hematologists and pathologists with expertise in TTP, neurologists, nephrologists, intensive care specialists, and patient representatives. The panel followed the GRADE approach and the Population, Intervention, Comparison, Outcome (PICO) framework, and adhered to standards set forth by the Health and Medicine Division (HMD) of the National Academies of Sciences, Engineering, and Medicine and the GIN-McMaster Guideline Development Checklist.

Even with an experienced group of physicians and a structured plan, however, the creation of guidelines for rare diseases like TTP presents a unique set of obstacles, according to the panel members. Challenges include a small body of relevant evidence that is often inconsistent and lacking in high certainty and studies that do not address outcomes important to patients. These shortcomings can make it difficult for guideline developers to issue strong recommendations.

“However, well-developed clinical practice guidelines are vital in rare diseases; these conditions are, by their nature, encountered very infrequently by individual clinicians, who may feel unprepared to address their diagnosis and treatment,” the panelists wrote. “Well-synthesized evidence and clear recommendations play an important role in supporting clinical decision making. Systematically created guidelines can also highlight areas where evidence is uncertain, clinical judgement is required, and future research in the area is warranted.”

The guideline was supported by ISTH. Fifty percent of the panel members had no or minimal conflict of interest; those with conflicts of interest abstained from voting on recommendations relevant to their conflicts.

A new draft guideline for the diagnosis and management of thrombocytopenic purpura (TTP) was recently released by the International Society on Thrombosis and Hemostasis (ISTH).

Svisio/Thinkstock

According to the panel of experts involved, the ISTH guideline takes into account the latest TTP findings, offering a more up-to-date resource for clinicians than the two previously published guidelines in 2012 from the British Committee for Standards in Haematology and in 2017 from the TTP group of Japan’s Blood Coagulation Abnormalities Research Team.

“Since the publication of these guidelines, there have been significant developments in the diagnosis and treatment of TTP, and an increase in published data on how management strategies affect objective health outcomes,” the panel members wrote in the guideline, which is available at ISTH.org.

Despite these advancements, TTP remains a challenging condition for both clinicians and patients for a variety of reasons, the panel noted, which was led by clinical cochair X. Long Zheng, MD, PhD, of the University of Alabama in Birmingham and method cochair Sara K. Vesely, PhD, of the University of Oklahoma, Oklahoma City.

The ISTH guideline provides recommendations for adult patients with either immune or hereditary TTP, from acute events through remission, including diagnostic steps to determine if a case of thrombotic microangiopathy is in fact TTP.

Nearly all the recommendations are based on very-low-certainty evidence. Some of the key treatment recommendations include the following:

• For patients with immune TTP experiencing a first acute event, add corticosteroids to therapeutic plasma exchange (TPE), rather than treating with TPE alone. This is a strong recommendation.
• For patients with immune TTP experiencing a first acute event, add rituximab to corticosteroids and TPE, rather than corticosteroids and TPE alone. This is a conditional recommendation.
• For patients with immune TTP experiencing a relapse, add corticosteroids to TPE, rather than TPE alone. This is a strong recommendation.
• For patients with immune TTP experiencing a relapse, add rituximab to corticosteroids and TPE, rather than steroids and TPE alone. This is a conditional recommendation.
• For patients with immune TTP experiencing an acute event – either a first event or a relapse – use caplacizumab. This is a conditional recommendation based on moderate-certainty evidence.
• For patients with immune TTP who are in remission and have low plasma ADAMTS13 activity but no other symptoms of TMA, use rituximab for prophylaxis. This is a conditional recommendation.
• For patients with hereditary TTP who are in remission, plasma infusion or a watch-and-wait strategy is recommended. This is a conditional recommendation.
• For patients with hereditary TTP who are in remission, do not use factor VIII concentrate infusions. A watch-and-wait strategy is advised. This is a conditional recommendation.
• For patients with immune TTP who are pregnant and have decreased plasma ADAMTS13 activity but no symptoms of TMA, use prophylactic treatment. This is a strong recommendation.
• For patients with hereditary TTP who are pregnant, use prophylactic treatment. This is a strong recommendation. The panel further recommended treatment with plasma infusion rather than factor VIII products, which was a conditional recommendation.

The multidisciplinary expert panel included hematologists and pathologists with expertise in TTP, neurologists, nephrologists, intensive care specialists, and patient representatives. The panel followed the GRADE approach and the Population, Intervention, Comparison, Outcome (PICO) framework, and adhered to standards set forth by the Health and Medicine Division (HMD) of the National Academies of Sciences, Engineering, and Medicine and the GIN-McMaster Guideline Development Checklist.

Even with an experienced group of physicians and a structured plan, however, the creation of guidelines for rare diseases like TTP presents a unique set of obstacles, according to the panel members. Challenges include a small body of relevant evidence that is often inconsistent and lacking in high certainty and studies that do not address outcomes important to patients. These shortcomings can make it difficult for guideline developers to issue strong recommendations.

“However, well-developed clinical practice guidelines are vital in rare diseases; these conditions are, by their nature, encountered very infrequently by individual clinicians, who may feel unprepared to address their diagnosis and treatment,” the panelists wrote. “Well-synthesized evidence and clear recommendations play an important role in supporting clinical decision making. Systematically created guidelines can also highlight areas where evidence is uncertain, clinical judgement is required, and future research in the area is warranted.”

The guideline was supported by ISTH. Fifty percent of the panel members had no or minimal conflict of interest; those with conflicts of interest abstained from voting on recommendations relevant to their conflicts.

A new draft guideline for the diagnosis and management of thrombocytopenic purpura (TTP) was recently released by the International Society on Thrombosis and Hemostasis (ISTH).

Svisio/Thinkstock

According to the panel of experts involved, the ISTH guideline takes into account the latest TTP findings, offering a more up-to-date resource for clinicians than the two previously published guidelines in 2012 from the British Committee for Standards in Haematology and in 2017 from the TTP group of Japan’s Blood Coagulation Abnormalities Research Team.

“Since the publication of these guidelines, there have been significant developments in the diagnosis and treatment of TTP, and an increase in published data on how management strategies affect objective health outcomes,” the panel members wrote in the guideline, which is available at ISTH.org.

Despite these advancements, TTP remains a challenging condition for both clinicians and patients for a variety of reasons, the panel noted, which was led by clinical cochair X. Long Zheng, MD, PhD, of the University of Alabama in Birmingham and method cochair Sara K. Vesely, PhD, of the University of Oklahoma, Oklahoma City.

The ISTH guideline provides recommendations for adult patients with either immune or hereditary TTP, from acute events through remission, including diagnostic steps to determine if a case of thrombotic microangiopathy is in fact TTP.

Nearly all the recommendations are based on very-low-certainty evidence. Some of the key treatment recommendations include the following:

• For patients with immune TTP experiencing a first acute event, add corticosteroids to therapeutic plasma exchange (TPE), rather than treating with TPE alone. This is a strong recommendation.
• For patients with immune TTP experiencing a first acute event, add rituximab to corticosteroids and TPE, rather than corticosteroids and TPE alone. This is a conditional recommendation.
• For patients with immune TTP experiencing a relapse, add corticosteroids to TPE, rather than TPE alone. This is a strong recommendation.
• For patients with immune TTP experiencing a relapse, add rituximab to corticosteroids and TPE, rather than steroids and TPE alone. This is a conditional recommendation.
• For patients with immune TTP experiencing an acute event – either a first event or a relapse – use caplacizumab. This is a conditional recommendation based on moderate-certainty evidence.
• For patients with immune TTP who are in remission and have low plasma ADAMTS13 activity but no other symptoms of TMA, use rituximab for prophylaxis. This is a conditional recommendation.
• For patients with hereditary TTP who are in remission, plasma infusion or a watch-and-wait strategy is recommended. This is a conditional recommendation.
• For patients with hereditary TTP who are in remission, do not use factor VIII concentrate infusions. A watch-and-wait strategy is advised. This is a conditional recommendation.
• For patients with immune TTP who are pregnant and have decreased plasma ADAMTS13 activity but no symptoms of TMA, use prophylactic treatment. This is a strong recommendation.
• For patients with hereditary TTP who are pregnant, use prophylactic treatment. This is a strong recommendation. The panel further recommended treatment with plasma infusion rather than factor VIII products, which was a conditional recommendation.

The multidisciplinary expert panel included hematologists and pathologists with expertise in TTP, neurologists, nephrologists, intensive care specialists, and patient representatives. The panel followed the GRADE approach and the Population, Intervention, Comparison, Outcome (PICO) framework, and adhered to standards set forth by the Health and Medicine Division (HMD) of the National Academies of Sciences, Engineering, and Medicine and the GIN-McMaster Guideline Development Checklist.

Even with an experienced group of physicians and a structured plan, however, the creation of guidelines for rare diseases like TTP presents a unique set of obstacles, according to the panel members. Challenges include a small body of relevant evidence that is often inconsistent and lacking in high certainty and studies that do not address outcomes important to patients. These shortcomings can make it difficult for guideline developers to issue strong recommendations.

“However, well-developed clinical practice guidelines are vital in rare diseases; these conditions are, by their nature, encountered very infrequently by individual clinicians, who may feel unprepared to address their diagnosis and treatment,” the panelists wrote. “Well-synthesized evidence and clear recommendations play an important role in supporting clinical decision making. Systematically created guidelines can also highlight areas where evidence is uncertain, clinical judgement is required, and future research in the area is warranted.”

The guideline was supported by ISTH. Fifty percent of the panel members had no or minimal conflict of interest; those with conflicts of interest abstained from voting on recommendations relevant to their conflicts.

An international panel of neurologists has drafted a consensus statement on the diagnosis, prognosis, and treatment of stridor in patients with multiple system atrophy (MSA). The statement was published Oct. 1 in Neurology. In addition to reviewing the literature on the topic and providing recommendations, the authors described several areas for future research.

MSA is a rare neurodegenerative disorder that entails autonomic failure, cerebellar ataxia, and parkinsonism. Laryngeal stridor has a high positive predictive value in the diagnosis of MSA, but consensus about its definition and clinical implications had not been established previously. The Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) delle Scienze Neurologiche di Bologna (Italy) convened a consensus conference of experts in 2017 to determine diagnostic criteria for stridor in MSA, define its prognostic value, suggest treatment options, and indicate subjects for future research. The neurologists reviewed studies of any design that reported original data. They based their statements on 34 published articles, most of which were class III or IV.

The authors defined stridor in MSA as “a strained, high-pitched, harsh respiratory sound, mainly inspiratory, caused by laryngeal dysfunction leading to narrowing of the rima glottidis.” Stridor may occur exclusively during sleep or during sleep and wakefulness. It may be recognized during a clinical examination, through witness report, or through an audio recording. Neurologists may consider laryngoscopy to exclude mechanical lesions or functional vocal cord abnormalities related to other neurologic conditions, wrote the authors. Drug-induced sleep endoscopy and video polysomnography also may be considered.

Whether stridor, or certain features of stridor, affects survival in MSA is uncertain. “Stridor within 3 years of motor or autonomic symptom onset may shorten survival,” according to the statement. “However, identification of stridor onset may be difficult.” Moreover, stridor during wakefulness is considered to reflect a more advanced stage of disease, compared with stridor during sleep. Although stridor can be distressing for the patient and his or her caregivers, its influence on health-related quality of life has yet to be determined, according to the statement.

Continuous positive airway pressure (CPAP) during sleep can be a useful symptomatic treatment and should be considered a first-line therapy for stridor, wrote the authors. Tracheostomy, another effective symptomatic treatment, bypasses upper-airway obstruction at the larynx. “Persistent and severe stridor may require tracheostomy,” according to the statement. It is not certain whether CPAP improves survival in patients with MSA and stridor, and tracheostomy may improve survival. The literature contains insufficient evidence about whether minimally invasive procedures or botulinum toxin injections are effective symptomatic treatments for stridor, wrote the authors.

During their review of the literature, the authors identified what they considered to be several research gaps. The diagnosis of stridor remains challenging, and investigators should develop a questionnaire for detecting stridor, they wrote. A smartphone application also could be developed to recognize stridor automatically. “The relationship between stridor and other breathing disorders (i.e., central apneas and breathing rate abnormalities) and their respective contributions to disease prognosis and survival should be determined through a multicenter prospective study,” according to the statement. Finally, randomized controlled trials comparing CPAP and tracheostomy for various degrees of stridor could guide physicians’ choice of treatment.

The IRCCS funded the study. One of the authors is a section editor for Neurology, and other authors reported receiving honoraria from various companies such as Novartis, Sanofi, and UCB.

[email protected]

SOURCE: Cortelli P et al. Neurology. 2019;93(14):630-9.

An international panel of neurologists has drafted a consensus statement on the diagnosis, prognosis, and treatment of stridor in patients with multiple system atrophy (MSA). The statement was published Oct. 1 in Neurology. In addition to reviewing the literature on the topic and providing recommendations, the authors described several areas for future research.

MSA is a rare neurodegenerative disorder that entails autonomic failure, cerebellar ataxia, and parkinsonism. Laryngeal stridor has a high positive predictive value in the diagnosis of MSA, but consensus about its definition and clinical implications had not been established previously. The Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) delle Scienze Neurologiche di Bologna (Italy) convened a consensus conference of experts in 2017 to determine diagnostic criteria for stridor in MSA, define its prognostic value, suggest treatment options, and indicate subjects for future research. The neurologists reviewed studies of any design that reported original data. They based their statements on 34 published articles, most of which were class III or IV.

The authors defined stridor in MSA as “a strained, high-pitched, harsh respiratory sound, mainly inspiratory, caused by laryngeal dysfunction leading to narrowing of the rima glottidis.” Stridor may occur exclusively during sleep or during sleep and wakefulness. It may be recognized during a clinical examination, through witness report, or through an audio recording. Neurologists may consider laryngoscopy to exclude mechanical lesions or functional vocal cord abnormalities related to other neurologic conditions, wrote the authors. Drug-induced sleep endoscopy and video polysomnography also may be considered.

Whether stridor, or certain features of stridor, affects survival in MSA is uncertain. “Stridor within 3 years of motor or autonomic symptom onset may shorten survival,” according to the statement. “However, identification of stridor onset may be difficult.” Moreover, stridor during wakefulness is considered to reflect a more advanced stage of disease, compared with stridor during sleep. Although stridor can be distressing for the patient and his or her caregivers, its influence on health-related quality of life has yet to be determined, according to the statement.

Continuous positive airway pressure (CPAP) during sleep can be a useful symptomatic treatment and should be considered a first-line therapy for stridor, wrote the authors. Tracheostomy, another effective symptomatic treatment, bypasses upper-airway obstruction at the larynx. “Persistent and severe stridor may require tracheostomy,” according to the statement. It is not certain whether CPAP improves survival in patients with MSA and stridor, and tracheostomy may improve survival. The literature contains insufficient evidence about whether minimally invasive procedures or botulinum toxin injections are effective symptomatic treatments for stridor, wrote the authors.

During their review of the literature, the authors identified what they considered to be several research gaps. The diagnosis of stridor remains challenging, and investigators should develop a questionnaire for detecting stridor, they wrote. A smartphone application also could be developed to recognize stridor automatically. “The relationship between stridor and other breathing disorders (i.e., central apneas and breathing rate abnormalities) and their respective contributions to disease prognosis and survival should be determined through a multicenter prospective study,” according to the statement. Finally, randomized controlled trials comparing CPAP and tracheostomy for various degrees of stridor could guide physicians’ choice of treatment.

The IRCCS funded the study. One of the authors is a section editor for Neurology, and other authors reported receiving honoraria from various companies such as Novartis, Sanofi, and UCB.

[email protected]

SOURCE: Cortelli P et al. Neurology. 2019;93(14):630-9.

An international panel of neurologists has drafted a consensus statement on the diagnosis, prognosis, and treatment of stridor in patients with multiple system atrophy (MSA). The statement was published Oct. 1 in Neurology. In addition to reviewing the literature on the topic and providing recommendations, the authors described several areas for future research.

MSA is a rare neurodegenerative disorder that entails autonomic failure, cerebellar ataxia, and parkinsonism. Laryngeal stridor has a high positive predictive value in the diagnosis of MSA, but consensus about its definition and clinical implications had not been established previously. The Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) delle Scienze Neurologiche di Bologna (Italy) convened a consensus conference of experts in 2017 to determine diagnostic criteria for stridor in MSA, define its prognostic value, suggest treatment options, and indicate subjects for future research. The neurologists reviewed studies of any design that reported original data. They based their statements on 34 published articles, most of which were class III or IV.

The authors defined stridor in MSA as “a strained, high-pitched, harsh respiratory sound, mainly inspiratory, caused by laryngeal dysfunction leading to narrowing of the rima glottidis.” Stridor may occur exclusively during sleep or during sleep and wakefulness. It may be recognized during a clinical examination, through witness report, or through an audio recording. Neurologists may consider laryngoscopy to exclude mechanical lesions or functional vocal cord abnormalities related to other neurologic conditions, wrote the authors. Drug-induced sleep endoscopy and video polysomnography also may be considered.

Whether stridor, or certain features of stridor, affects survival in MSA is uncertain. “Stridor within 3 years of motor or autonomic symptom onset may shorten survival,” according to the statement. “However, identification of stridor onset may be difficult.” Moreover, stridor during wakefulness is considered to reflect a more advanced stage of disease, compared with stridor during sleep. Although stridor can be distressing for the patient and his or her caregivers, its influence on health-related quality of life has yet to be determined, according to the statement.

Continuous positive airway pressure (CPAP) during sleep can be a useful symptomatic treatment and should be considered a first-line therapy for stridor, wrote the authors. Tracheostomy, another effective symptomatic treatment, bypasses upper-airway obstruction at the larynx. “Persistent and severe stridor may require tracheostomy,” according to the statement. It is not certain whether CPAP improves survival in patients with MSA and stridor, and tracheostomy may improve survival. The literature contains insufficient evidence about whether minimally invasive procedures or botulinum toxin injections are effective symptomatic treatments for stridor, wrote the authors.

During their review of the literature, the authors identified what they considered to be several research gaps. The diagnosis of stridor remains challenging, and investigators should develop a questionnaire for detecting stridor, they wrote. A smartphone application also could be developed to recognize stridor automatically. “The relationship between stridor and other breathing disorders (i.e., central apneas and breathing rate abnormalities) and their respective contributions to disease prognosis and survival should be determined through a multicenter prospective study,” according to the statement. Finally, randomized controlled trials comparing CPAP and tracheostomy for various degrees of stridor could guide physicians’ choice of treatment.

The IRCCS funded the study. One of the authors is a section editor for Neurology, and other authors reported receiving honoraria from various companies such as Novartis, Sanofi, and UCB.

[email protected]

SOURCE: Cortelli P et al. Neurology. 2019;93(14):630-9.

New consensus statements, released by a group of 36 experts, provide specific recommendations related to monitoring bleeding and assessing efficacy of treatment in patients with acquired hemophilia.

Svisio/Thinkstock

A global survey was developed by a nine-member steering committee with expertise in the hemostatic management of patients with acquired hemophilia. The Delphi methodology was used to obtain consensus on a list of statements on the location-specific treatment of bleeding in acquired hemophilia.

“The initial survey was circulated via email for refinement and was formally corroborated at a face-to-face meeting,” wrote Andreas Tiede, MD, PhD, of Hannover (Germany) Medical School and fellow experts. The report is published in Haemophilia.

The key areas outlined include the initial management of bleeding, and management of location-specific bleeding, including urological, gastrointestinal, muscle, and pharyngeal bleeds, as well as intracranial and postpartum hemorrhage.

If an expert hematologist is not available, and the bleeding event is life‐threatening, the emergency physician should initiate treatment in accordance with local or national recommendations, according to the initial management guidelines.

With respect to urological bleeds, the best interval for evaluating successful achievement of hemostasis is every 6-12 hours. The experts also reported that, if first-line hemostatic therapy is not effective, more intensive treatment should be considered every 6-12 hours.

In the management of intracranial hemorrhage, the frequency of clinical evaluation is subject to the particular scenario, and it can vary from every 2 hours (for clinical assessment) to every 24 hours (for imaging studies), they wrote.

If initial hemostatic treatment is not effective, more intensive therapy should be considered every 6 hours, they recommended.

“The statement addressing optimal frequency for assessing hemostasis in intracranial bleeds was the subject of much deliberation among the steering committee regarding timing of assessment,” the experts acknowledged.

The geographic diversity and global representation of expert participants were major strengths of these recommendations. However, these statements did not consider socioeconomic parameters or geopolitical differences that could affect patient care. As a result, they may not be applicable to all patient populations.

The manuscript was funded by Novo Nordisk AG. The authors reported having financial affiliations with Novo Nordisk and several other companies.

SOURCE: Tiede A et al. Haemophilia. 2019 Sep 13. doi: 10.1111/hae.13844.

New consensus statements, released by a group of 36 experts, provide specific recommendations related to monitoring bleeding and assessing efficacy of treatment in patients with acquired hemophilia.

Svisio/Thinkstock

A global survey was developed by a nine-member steering committee with expertise in the hemostatic management of patients with acquired hemophilia. The Delphi methodology was used to obtain consensus on a list of statements on the location-specific treatment of bleeding in acquired hemophilia.

“The initial survey was circulated via email for refinement and was formally corroborated at a face-to-face meeting,” wrote Andreas Tiede, MD, PhD, of Hannover (Germany) Medical School and fellow experts. The report is published in Haemophilia.

The key areas outlined include the initial management of bleeding, and management of location-specific bleeding, including urological, gastrointestinal, muscle, and pharyngeal bleeds, as well as intracranial and postpartum hemorrhage.

If an expert hematologist is not available, and the bleeding event is life‐threatening, the emergency physician should initiate treatment in accordance with local or national recommendations, according to the initial management guidelines.

With respect to urological bleeds, the best interval for evaluating successful achievement of hemostasis is every 6-12 hours. The experts also reported that, if first-line hemostatic therapy is not effective, more intensive treatment should be considered every 6-12 hours.

In the management of intracranial hemorrhage, the frequency of clinical evaluation is subject to the particular scenario, and it can vary from every 2 hours (for clinical assessment) to every 24 hours (for imaging studies), they wrote.

If initial hemostatic treatment is not effective, more intensive therapy should be considered every 6 hours, they recommended.

“The statement addressing optimal frequency for assessing hemostasis in intracranial bleeds was the subject of much deliberation among the steering committee regarding timing of assessment,” the experts acknowledged.

The geographic diversity and global representation of expert participants were major strengths of these recommendations. However, these statements did not consider socioeconomic parameters or geopolitical differences that could affect patient care. As a result, they may not be applicable to all patient populations.

The manuscript was funded by Novo Nordisk AG. The authors reported having financial affiliations with Novo Nordisk and several other companies.

SOURCE: Tiede A et al. Haemophilia. 2019 Sep 13. doi: 10.1111/hae.13844.

New consensus statements, released by a group of 36 experts, provide specific recommendations related to monitoring bleeding and assessing efficacy of treatment in patients with acquired hemophilia.

Svisio/Thinkstock

A global survey was developed by a nine-member steering committee with expertise in the hemostatic management of patients with acquired hemophilia. The Delphi methodology was used to obtain consensus on a list of statements on the location-specific treatment of bleeding in acquired hemophilia.

“The initial survey was circulated via email for refinement and was formally corroborated at a face-to-face meeting,” wrote Andreas Tiede, MD, PhD, of Hannover (Germany) Medical School and fellow experts. The report is published in Haemophilia.

The key areas outlined include the initial management of bleeding, and management of location-specific bleeding, including urological, gastrointestinal, muscle, and pharyngeal bleeds, as well as intracranial and postpartum hemorrhage.

If an expert hematologist is not available, and the bleeding event is life‐threatening, the emergency physician should initiate treatment in accordance with local or national recommendations, according to the initial management guidelines.

With respect to urological bleeds, the best interval for evaluating successful achievement of hemostasis is every 6-12 hours. The experts also reported that, if first-line hemostatic therapy is not effective, more intensive treatment should be considered every 6-12 hours.

In the management of intracranial hemorrhage, the frequency of clinical evaluation is subject to the particular scenario, and it can vary from every 2 hours (for clinical assessment) to every 24 hours (for imaging studies), they wrote.

If initial hemostatic treatment is not effective, more intensive therapy should be considered every 6 hours, they recommended.

“The statement addressing optimal frequency for assessing hemostasis in intracranial bleeds was the subject of much deliberation among the steering committee regarding timing of assessment,” the experts acknowledged.

The geographic diversity and global representation of expert participants were major strengths of these recommendations. However, these statements did not consider socioeconomic parameters or geopolitical differences that could affect patient care. As a result, they may not be applicable to all patient populations.

The manuscript was funded by Novo Nordisk AG. The authors reported having financial affiliations with Novo Nordisk and several other companies.

SOURCE: Tiede A et al. Haemophilia. 2019 Sep 13. doi: 10.1111/hae.13844.

All adult patients with primary sclerosing cholangitis should be screened at least annually for cholangiocarcinoma and gallbladder cancer, particularly in the first year after their diagnosis, according to a clinical practice update published in Clinical Gastroenterology and Hepatology.

Individuals with primary sclerosing cholangitis have a 400-fold higher risk of cholangiocarcinoma, compared with the general population, and around one-third of cancers are detected within 1 year of the cholangitis diagnosis, Christopher L. Bowlus, MD, of the University of California, Davis, and coauthors wrote.

The clinical practice update from the American Gastroenterological Association was in response to the observation that, while there is significant evidence for an increasing incidence of cirrhosis, hepatic decompensation, hepatocellular carcinoma, and liver transplant listing among patients with primary sclerosing cholangitis, there is a lack of good evidence to guide cholangiocarcinoma surveillance in these patients.

“The low prevalence and long duration of PSC [primary sclerosing cholangitis] present substantial barriers to better understanding risk stratification, developing biomarkers, and measuring the impact surveillance has on clinical outcomes,” they wrote.

The first recommendation was that surveillance for cholangiocarcinoma and gallbladder cancer should be considered in all adult patients with primary sclerosing cholangitis, regardless of their disease stage. The authors especially emphasized the importance of surveillance in the first year after a diagnosis of primary sclerosing cholangitis, in patients who also have ulcerative colitis, and in those diagnosed at an older age.

They cited one study that found regular surveillance of patients with primary sclerosing cholangitis was associated with significantly higher 5-year survival rates, compared with those no regular screening (68% vs. 20%; P less than .0061).

In terms of surveillance modalities, the update suggested 6- to 12-monthly imaging of the biliary tree with ultrasound computed tomography, computed tomography, or magnetic resonance imaging – with or without serum carbohydrate antigen 19-9. However the authors wrote that MRI was often preferred to CT because of its superior sensitivity.

They advised against endoscopic retrograde cholangiopancreatography with brush cytology for routine surveillance because of procedural risks. On the other hand, they suggested this procedure, with or without fluorescence in situ hybridization analysis and/or cholangioscopy, could be used for investigation.

“In addition to ERCP [endoscopic retrograde cholangiopancreatography] with brushings, endoscopic ultrasound, intraductal ultrasonography, and cholangioscopy may be used to direct biopsy sampling,” they wrote. Symptoms such as increasing cholestatic biochemistry values, jaundice, fever, right upper quadrant pain, or pruritus should trigger evaluation for cholangiocarcinoma.

However the authors advised “great caution” with the use of fine-needle aspiration of perihilar biliary strictures in liver transplant candidates because of the risk of tumor seeding if the lesion turned out to be cholangiocarcinoma.

On the question of cholangiocarcinoma surveillance in pediatric patients and those with small-duct primary sclerosing cholangitis, the authors wrote that cholangiocarcinoma was so rare in these patients that routine cholangiocarcinoma surveillance was not required.

The clinical update also looked at the prevalence and risk factors for gallbladder cancer, which affects around 2% of individuals with primary sclerosing cholangitis. Two studies found gallbladder polyps in 10%-17% of patients, but the authors noted that “the optimal modality for diagnosis of gallbladder polyps in PSC remains unknown”.

“Because of the high risk of malignancy in gallbladder mass lesions and a 5-year survival rate of 5% to 10% for gallbladder cancer, patients should undergo annual US [ultrasound] screening,” they wrote.

They said the question of whether to perform a cholecystectomy in patients with gallbladder polyps should be guided by the size and growth of the polyps because there is an increased risk of gallbladder cancer in polyps larger than 8 mm and by the clinical status of the patient.

Finally, the update examined the issue of hepatocellular carcinoma in patients with primary sclerosing cholangitis, which – while rare – may increase with the presence of cirrhosis.

The authors advised that patients with primary sclerosing cholangitis and cirrhosis should undergo surveillance for hepatocellular carcinoma every 6 months with ultrasound, CT, or MRI.

“We anticipate that with the development of large patient cohorts, advances in uncovering genetic and other risk factors for cholangiocarcinoma, and development of effective treatments for PSC, further refinement of this practice update will be required.”

Two authors declared consultancies, grants and research contracts with the pharmaceutical sector. No other conflicts of interest were declared.

SOURCE: Bowlus C et al. Clin Gastroenterol Hepatol. 2019 Jul 12. doi 10.1016/j.cgh.2019.07.011.

All adult patients with primary sclerosing cholangitis should be screened at least annually for cholangiocarcinoma and gallbladder cancer, particularly in the first year after their diagnosis, according to a clinical practice update published in Clinical Gastroenterology and Hepatology.

Individuals with primary sclerosing cholangitis have a 400-fold higher risk of cholangiocarcinoma, compared with the general population, and around one-third of cancers are detected within 1 year of the cholangitis diagnosis, Christopher L. Bowlus, MD, of the University of California, Davis, and coauthors wrote.

The clinical practice update from the American Gastroenterological Association was in response to the observation that, while there is significant evidence for an increasing incidence of cirrhosis, hepatic decompensation, hepatocellular carcinoma, and liver transplant listing among patients with primary sclerosing cholangitis, there is a lack of good evidence to guide cholangiocarcinoma surveillance in these patients.

“The low prevalence and long duration of PSC [primary sclerosing cholangitis] present substantial barriers to better understanding risk stratification, developing biomarkers, and measuring the impact surveillance has on clinical outcomes,” they wrote.

The first recommendation was that surveillance for cholangiocarcinoma and gallbladder cancer should be considered in all adult patients with primary sclerosing cholangitis, regardless of their disease stage. The authors especially emphasized the importance of surveillance in the first year after a diagnosis of primary sclerosing cholangitis, in patients who also have ulcerative colitis, and in those diagnosed at an older age.

They cited one study that found regular surveillance of patients with primary sclerosing cholangitis was associated with significantly higher 5-year survival rates, compared with those no regular screening (68% vs. 20%; P less than .0061).

In terms of surveillance modalities, the update suggested 6- to 12-monthly imaging of the biliary tree with ultrasound computed tomography, computed tomography, or magnetic resonance imaging – with or without serum carbohydrate antigen 19-9. However the authors wrote that MRI was often preferred to CT because of its superior sensitivity.

They advised against endoscopic retrograde cholangiopancreatography with brush cytology for routine surveillance because of procedural risks. On the other hand, they suggested this procedure, with or without fluorescence in situ hybridization analysis and/or cholangioscopy, could be used for investigation.

“In addition to ERCP [endoscopic retrograde cholangiopancreatography] with brushings, endoscopic ultrasound, intraductal ultrasonography, and cholangioscopy may be used to direct biopsy sampling,” they wrote. Symptoms such as increasing cholestatic biochemistry values, jaundice, fever, right upper quadrant pain, or pruritus should trigger evaluation for cholangiocarcinoma.

However the authors advised “great caution” with the use of fine-needle aspiration of perihilar biliary strictures in liver transplant candidates because of the risk of tumor seeding if the lesion turned out to be cholangiocarcinoma.

On the question of cholangiocarcinoma surveillance in pediatric patients and those with small-duct primary sclerosing cholangitis, the authors wrote that cholangiocarcinoma was so rare in these patients that routine cholangiocarcinoma surveillance was not required.

The clinical update also looked at the prevalence and risk factors for gallbladder cancer, which affects around 2% of individuals with primary sclerosing cholangitis. Two studies found gallbladder polyps in 10%-17% of patients, but the authors noted that “the optimal modality for diagnosis of gallbladder polyps in PSC remains unknown”.

“Because of the high risk of malignancy in gallbladder mass lesions and a 5-year survival rate of 5% to 10% for gallbladder cancer, patients should undergo annual US [ultrasound] screening,” they wrote.

They said the question of whether to perform a cholecystectomy in patients with gallbladder polyps should be guided by the size and growth of the polyps because there is an increased risk of gallbladder cancer in polyps larger than 8 mm and by the clinical status of the patient.

Finally, the update examined the issue of hepatocellular carcinoma in patients with primary sclerosing cholangitis, which – while rare – may increase with the presence of cirrhosis.

The authors advised that patients with primary sclerosing cholangitis and cirrhosis should undergo surveillance for hepatocellular carcinoma every 6 months with ultrasound, CT, or MRI.

“We anticipate that with the development of large patient cohorts, advances in uncovering genetic and other risk factors for cholangiocarcinoma, and development of effective treatments for PSC, further refinement of this practice update will be required.”

Two authors declared consultancies, grants and research contracts with the pharmaceutical sector. No other conflicts of interest were declared.

SOURCE: Bowlus C et al. Clin Gastroenterol Hepatol. 2019 Jul 12. doi 10.1016/j.cgh.2019.07.011.

All adult patients with primary sclerosing cholangitis should be screened at least annually for cholangiocarcinoma and gallbladder cancer, particularly in the first year after their diagnosis, according to a clinical practice update published in Clinical Gastroenterology and Hepatology.

Individuals with primary sclerosing cholangitis have a 400-fold higher risk of cholangiocarcinoma, compared with the general population, and around one-third of cancers are detected within 1 year of the cholangitis diagnosis, Christopher L. Bowlus, MD, of the University of California, Davis, and coauthors wrote.

The clinical practice update from the American Gastroenterological Association was in response to the observation that, while there is significant evidence for an increasing incidence of cirrhosis, hepatic decompensation, hepatocellular carcinoma, and liver transplant listing among patients with primary sclerosing cholangitis, there is a lack of good evidence to guide cholangiocarcinoma surveillance in these patients.

“The low prevalence and long duration of PSC [primary sclerosing cholangitis] present substantial barriers to better understanding risk stratification, developing biomarkers, and measuring the impact surveillance has on clinical outcomes,” they wrote.

The first recommendation was that surveillance for cholangiocarcinoma and gallbladder cancer should be considered in all adult patients with primary sclerosing cholangitis, regardless of their disease stage. The authors especially emphasized the importance of surveillance in the first year after a diagnosis of primary sclerosing cholangitis, in patients who also have ulcerative colitis, and in those diagnosed at an older age.

They cited one study that found regular surveillance of patients with primary sclerosing cholangitis was associated with significantly higher 5-year survival rates, compared with those no regular screening (68% vs. 20%; P less than .0061).

In terms of surveillance modalities, the update suggested 6- to 12-monthly imaging of the biliary tree with ultrasound computed tomography, computed tomography, or magnetic resonance imaging – with or without serum carbohydrate antigen 19-9. However the authors wrote that MRI was often preferred to CT because of its superior sensitivity.

They advised against endoscopic retrograde cholangiopancreatography with brush cytology for routine surveillance because of procedural risks. On the other hand, they suggested this procedure, with or without fluorescence in situ hybridization analysis and/or cholangioscopy, could be used for investigation.

“In addition to ERCP [endoscopic retrograde cholangiopancreatography] with brushings, endoscopic ultrasound, intraductal ultrasonography, and cholangioscopy may be used to direct biopsy sampling,” they wrote. Symptoms such as increasing cholestatic biochemistry values, jaundice, fever, right upper quadrant pain, or pruritus should trigger evaluation for cholangiocarcinoma.

However the authors advised “great caution” with the use of fine-needle aspiration of perihilar biliary strictures in liver transplant candidates because of the risk of tumor seeding if the lesion turned out to be cholangiocarcinoma.

On the question of cholangiocarcinoma surveillance in pediatric patients and those with small-duct primary sclerosing cholangitis, the authors wrote that cholangiocarcinoma was so rare in these patients that routine cholangiocarcinoma surveillance was not required.

The clinical update also looked at the prevalence and risk factors for gallbladder cancer, which affects around 2% of individuals with primary sclerosing cholangitis. Two studies found gallbladder polyps in 10%-17% of patients, but the authors noted that “the optimal modality for diagnosis of gallbladder polyps in PSC remains unknown”.

“Because of the high risk of malignancy in gallbladder mass lesions and a 5-year survival rate of 5% to 10% for gallbladder cancer, patients should undergo annual US [ultrasound] screening,” they wrote.

They said the question of whether to perform a cholecystectomy in patients with gallbladder polyps should be guided by the size and growth of the polyps because there is an increased risk of gallbladder cancer in polyps larger than 8 mm and by the clinical status of the patient.

Finally, the update examined the issue of hepatocellular carcinoma in patients with primary sclerosing cholangitis, which – while rare – may increase with the presence of cirrhosis.

The authors advised that patients with primary sclerosing cholangitis and cirrhosis should undergo surveillance for hepatocellular carcinoma every 6 months with ultrasound, CT, or MRI.

“We anticipate that with the development of large patient cohorts, advances in uncovering genetic and other risk factors for cholangiocarcinoma, and development of effective treatments for PSC, further refinement of this practice update will be required.”

Two authors declared consultancies, grants and research contracts with the pharmaceutical sector. No other conflicts of interest were declared.

SOURCE: Bowlus C et al. Clin Gastroenterol Hepatol. 2019 Jul 12. doi 10.1016/j.cgh.2019.07.011.

Patients 50-79 years old with a demonstrably low risk of developing the disease within 15 years probably don’t need to be screened for colorectal cancer. But if their risk of disease is at least 3% over 15 years, patients should be screened, Lise M. Helsingen, MD, and colleagues wrote in BMJ (2019;367:l5515 doi: 10.1136/bmj.l5515).

For these patients, “We suggest screening with one of the four screening options: fecal immunochemical test (FIT) every year, FIT every 2 years, a single sigmoidoscopy, or a single colonoscopy,” wrote Dr. Helsingen of the University of Oslo, and her team.

She chaired a 22-member international panel that developed a collaborative effort from the MAGIC research and innovation program as a part of the BMJ Rapid Recommendations project. The team reviewed 12 research papers comprising almost 1.4 million patients from Denmark, Italy, the Netherlands, Norway, Poland, Spain, Sweden, the United Kingdom, and the United States. Follow-up ranged from 0 to 19.5 years for colorectal cancer incidence and up to 30 years for mortality.

Because of the dearth of relevant data in some studies, however, the projected outcomes had to be simulated, with benefits and harms calculations based on 100% screening adherence. However, the team noted, it’s impossible to achieve complete adherence. Most studies of colorectal screening don’t exceed a 50% adherence level.

“All the modeling data are of low certainty. It is a useful indication, but there is a high chance that new evidence will show a smaller or larger benefit, which in turn may alter these recommendations.”

Compared with no screening, all four screening models reduced the risk of colorectal cancer mortality to a similar level.

• FIT every year, 59%.
• FIT every 2 years, 50%.
• Single sigmoidoscopy, 52%.
• Single colonoscopy, 67%.

Screening had less of an impact on reducing the incidence of colorectal cancer:

• FIT every 2 years, 0.05%.
• FIT every year, 0.15%.
• Single sigmoidoscopy, 27%.
• Single colonoscopy, 34%.

The panel also assessed potential harms. Among almost 1 million patients, the colonoscopy-related mortality rate was 0.03 per 1,000 procedures. The perforation rate was 0.8 per 1,000 colonoscopies after a positive fecal test, and 1.4 per 1,000 screened with sigmoidoscopy. The bleeding rate was 1.9 per 1,000 colonoscopies performed after a positive fecal test, and 3-4 per 1,000 screened with sigmoidoscopy.

Successful implementation of these recommendations hinges on accurate risk assessment, however. The team recommended the QCancer platform as “one of the best performing models for both men and women.”

The calculator includes age, sex, ethnicity, smoking status, alcohol use, family history of gastrointestinal cancer, personal history of other cancers, diabetes, ulcerative colitis, colonic polyps, and body mass index.

“We suggest this model because it is available as an online calculator; includes only risk factors available in routine health care; has been validated in a population separate from the derivation population; has reasonable discriminatory ability; and has a good fit between predicted and observed outcomes. In addition, it is the only online risk calculator we know of that predicts risk over a 15-year time horizon.”

The team stressed that their recommendations can’t be applied to all patients. Because evidence for both screening recommendations was weak – largely because of the dearth of supporting data – patients and physicians should cocreate a personalized screening plan.

“Several factors influence individuals’ decisions whether to be screened, even when they are presented with the same information,” the authors said. These include variation in an individual’s values and preferences, a close balance of benefits versus harms and burdens, and personal preference.

“Some individuals may value a minimally invasive test such as FIT, and the possibility of invasive screening with colonoscopy might put them off screening altogether. Those who most value preventing colorectal cancer or avoiding repeated testing are likely to choose sigmoidoscopy or colonoscopy.”

The authors had no financial conflicts of interest.

SOURCE: BMJ 2019;367:l5515. doi: 10.1136/bmj.l5515.

Patients 50-79 years old with a demonstrably low risk of developing the disease within 15 years probably don’t need to be screened for colorectal cancer. But if their risk of disease is at least 3% over 15 years, patients should be screened, Lise M. Helsingen, MD, and colleagues wrote in BMJ (2019;367:l5515 doi: 10.1136/bmj.l5515).

For these patients, “We suggest screening with one of the four screening options: fecal immunochemical test (FIT) every year, FIT every 2 years, a single sigmoidoscopy, or a single colonoscopy,” wrote Dr. Helsingen of the University of Oslo, and her team.

She chaired a 22-member international panel that developed a collaborative effort from the MAGIC research and innovation program as a part of the BMJ Rapid Recommendations project. The team reviewed 12 research papers comprising almost 1.4 million patients from Denmark, Italy, the Netherlands, Norway, Poland, Spain, Sweden, the United Kingdom, and the United States. Follow-up ranged from 0 to 19.5 years for colorectal cancer incidence and up to 30 years for mortality.

Because of the dearth of relevant data in some studies, however, the projected outcomes had to be simulated, with benefits and harms calculations based on 100% screening adherence. However, the team noted, it’s impossible to achieve complete adherence. Most studies of colorectal screening don’t exceed a 50% adherence level.

“All the modeling data are of low certainty. It is a useful indication, but there is a high chance that new evidence will show a smaller or larger benefit, which in turn may alter these recommendations.”

Compared with no screening, all four screening models reduced the risk of colorectal cancer mortality to a similar level.

• FIT every year, 59%.
• FIT every 2 years, 50%.
• Single sigmoidoscopy, 52%.
• Single colonoscopy, 67%.

Screening had less of an impact on reducing the incidence of colorectal cancer:

• FIT every 2 years, 0.05%.
• FIT every year, 0.15%.
• Single sigmoidoscopy, 27%.
• Single colonoscopy, 34%.

The panel also assessed potential harms. Among almost 1 million patients, the colonoscopy-related mortality rate was 0.03 per 1,000 procedures. The perforation rate was 0.8 per 1,000 colonoscopies after a positive fecal test, and 1.4 per 1,000 screened with sigmoidoscopy. The bleeding rate was 1.9 per 1,000 colonoscopies performed after a positive fecal test, and 3-4 per 1,000 screened with sigmoidoscopy.

Successful implementation of these recommendations hinges on accurate risk assessment, however. The team recommended the QCancer platform as “one of the best performing models for both men and women.”

The calculator includes age, sex, ethnicity, smoking status, alcohol use, family history of gastrointestinal cancer, personal history of other cancers, diabetes, ulcerative colitis, colonic polyps, and body mass index.

“We suggest this model because it is available as an online calculator; includes only risk factors available in routine health care; has been validated in a population separate from the derivation population; has reasonable discriminatory ability; and has a good fit between predicted and observed outcomes. In addition, it is the only online risk calculator we know of that predicts risk over a 15-year time horizon.”

The team stressed that their recommendations can’t be applied to all patients. Because evidence for both screening recommendations was weak – largely because of the dearth of supporting data – patients and physicians should cocreate a personalized screening plan.

“Several factors influence individuals’ decisions whether to be screened, even when they are presented with the same information,” the authors said. These include variation in an individual’s values and preferences, a close balance of benefits versus harms and burdens, and personal preference.

“Some individuals may value a minimally invasive test such as FIT, and the possibility of invasive screening with colonoscopy might put them off screening altogether. Those who most value preventing colorectal cancer or avoiding repeated testing are likely to choose sigmoidoscopy or colonoscopy.”

The authors had no financial conflicts of interest.

SOURCE: BMJ 2019;367:l5515. doi: 10.1136/bmj.l5515.

Patients 50-79 years old with a demonstrably low risk of developing the disease within 15 years probably don’t need to be screened for colorectal cancer. But if their risk of disease is at least 3% over 15 years, patients should be screened, Lise M. Helsingen, MD, and colleagues wrote in BMJ (2019;367:l5515 doi: 10.1136/bmj.l5515).

For these patients, “We suggest screening with one of the four screening options: fecal immunochemical test (FIT) every year, FIT every 2 years, a single sigmoidoscopy, or a single colonoscopy,” wrote Dr. Helsingen of the University of Oslo, and her team.

She chaired a 22-member international panel that developed a collaborative effort from the MAGIC research and innovation program as a part of the BMJ Rapid Recommendations project. The team reviewed 12 research papers comprising almost 1.4 million patients from Denmark, Italy, the Netherlands, Norway, Poland, Spain, Sweden, the United Kingdom, and the United States. Follow-up ranged from 0 to 19.5 years for colorectal cancer incidence and up to 30 years for mortality.

Because of the dearth of relevant data in some studies, however, the projected outcomes had to be simulated, with benefits and harms calculations based on 100% screening adherence. However, the team noted, it’s impossible to achieve complete adherence. Most studies of colorectal screening don’t exceed a 50% adherence level.

“All the modeling data are of low certainty. It is a useful indication, but there is a high chance that new evidence will show a smaller or larger benefit, which in turn may alter these recommendations.”

Compared with no screening, all four screening models reduced the risk of colorectal cancer mortality to a similar level.

• FIT every year, 59%.
• FIT every 2 years, 50%.
• Single sigmoidoscopy, 52%.
• Single colonoscopy, 67%.

Screening had less of an impact on reducing the incidence of colorectal cancer:

• FIT every 2 years, 0.05%.
• FIT every year, 0.15%.
• Single sigmoidoscopy, 27%.
• Single colonoscopy, 34%.

The panel also assessed potential harms. Among almost 1 million patients, the colonoscopy-related mortality rate was 0.03 per 1,000 procedures. The perforation rate was 0.8 per 1,000 colonoscopies after a positive fecal test, and 1.4 per 1,000 screened with sigmoidoscopy. The bleeding rate was 1.9 per 1,000 colonoscopies performed after a positive fecal test, and 3-4 per 1,000 screened with sigmoidoscopy.

Successful implementation of these recommendations hinges on accurate risk assessment, however. The team recommended the QCancer platform as “one of the best performing models for both men and women.”

The calculator includes age, sex, ethnicity, smoking status, alcohol use, family history of gastrointestinal cancer, personal history of other cancers, diabetes, ulcerative colitis, colonic polyps, and body mass index.

“We suggest this model because it is available as an online calculator; includes only risk factors available in routine health care; has been validated in a population separate from the derivation population; has reasonable discriminatory ability; and has a good fit between predicted and observed outcomes. In addition, it is the only online risk calculator we know of that predicts risk over a 15-year time horizon.”

The team stressed that their recommendations can’t be applied to all patients. Because evidence for both screening recommendations was weak – largely because of the dearth of supporting data – patients and physicians should cocreate a personalized screening plan.

“Several factors influence individuals’ decisions whether to be screened, even when they are presented with the same information,” the authors said. These include variation in an individual’s values and preferences, a close balance of benefits versus harms and burdens, and personal preference.

“Some individuals may value a minimally invasive test such as FIT, and the possibility of invasive screening with colonoscopy might put them off screening altogether. Those who most value preventing colorectal cancer or avoiding repeated testing are likely to choose sigmoidoscopy or colonoscopy.”

The authors had no financial conflicts of interest.

SOURCE: BMJ 2019;367:l5515. doi: 10.1136/bmj.l5515.

Long-term home noninvasive ventilation (LTH-NIV) has conditional value for patients with chronic hypercapnic chronic obstructive pulmonary disease (COPD), according to a new guideline from a European Respiratory Society task force.

“Our recommendations, based on the best available evidence, can guide the management of chronic hypercapnic respiratory failure in COPD patients aimed at improving patient outcomes,” wrote Begum Ergan, MD, of Dokuz Eylul University, Izmir, Turkey, and coauthors. The guideline was published in the European Respiratory Journal.

To provide insight into the clinical application of LTH-NIV, the European Respiratory Society convened a task force of 20 clinicians, methodologists, and experts. Their four recommendations were developed based on the GRADE (Grading, Recommendation, Assessment, Development and Evaluation) methodology.

The first recommendation was to use LTH-NIV for patients with chronic stable hypercapnic COPD. Though an analysis of randomized, controlled trials showed little effect on mortality or hospitalizations, pooled analyses showed that NIV may decrease dyspnea scores (standardized mean difference, –0.51; 95% confidence interval, –0.06 to –0.95) and increase health-related quality of life (SMD, 0.49; 95% CI, –0.01 to 0.98).

The second was to use LTH-NIV in patients with COPD following a life-threatening episode of acute hypercapnic respiratory failure requiring acute NIV, if hypercapnia persists. Though it was not associated with a reduction in mortality (risk ratio, 0.92; 95% CI, 0.67-1.25), it was found to potentially reduce exacerbations (SMD, 0.19; 95% CI, –0.40 to 0.01) and hospitalizations (RR, 0.61; 95% CI, 0.30-1.24).

The third was to titrate LTH-NIV to normalize or reduce PaCO₂ levels in patients with COPD. While this recommendation was issued with a very low certainty of evidence, it was driven by the “minimal potential harms of targeted PaCO₂ reduction.”

The fourth was to use fixed pressure support mode as first-choice ventilator mode in patients with COPD using LTH-NIV. The six trials on this subject did not provide insight into long-term outcomes, nor were there significant improvements seen in health-related quality of life, sleep quality, or exercise tolerance. As such, it was also issued with a very low certainty of evidence.

The authors acknowledged all four recommendations as weak and conditional, “due to limitations in the certainty of the available evidence.” As such, they noted that their recommendations “require consideration of individual preferences, resource considerations, technical expertise, and clinical circumstances prior to implementation in clinical practice.”

The authors reported numerous disclosures, including receiving grants and personal fees from various medical supply companies.

SOURCE: Ergan B et al. Eur Respir J. 2019 Aug 29. doi: 10.1183/13993003.01003-2019.

Long-term home noninvasive ventilation (LTH-NIV) has conditional value for patients with chronic hypercapnic chronic obstructive pulmonary disease (COPD), according to a new guideline from a European Respiratory Society task force.

“Our recommendations, based on the best available evidence, can guide the management of chronic hypercapnic respiratory failure in COPD patients aimed at improving patient outcomes,” wrote Begum Ergan, MD, of Dokuz Eylul University, Izmir, Turkey, and coauthors. The guideline was published in the European Respiratory Journal.

To provide insight into the clinical application of LTH-NIV, the European Respiratory Society convened a task force of 20 clinicians, methodologists, and experts. Their four recommendations were developed based on the GRADE (Grading, Recommendation, Assessment, Development and Evaluation) methodology.

The first recommendation was to use LTH-NIV for patients with chronic stable hypercapnic COPD. Though an analysis of randomized, controlled trials showed little effect on mortality or hospitalizations, pooled analyses showed that NIV may decrease dyspnea scores (standardized mean difference, –0.51; 95% confidence interval, –0.06 to –0.95) and increase health-related quality of life (SMD, 0.49; 95% CI, –0.01 to 0.98).

The second was to use LTH-NIV in patients with COPD following a life-threatening episode of acute hypercapnic respiratory failure requiring acute NIV, if hypercapnia persists. Though it was not associated with a reduction in mortality (risk ratio, 0.92; 95% CI, 0.67-1.25), it was found to potentially reduce exacerbations (SMD, 0.19; 95% CI, –0.40 to 0.01) and hospitalizations (RR, 0.61; 95% CI, 0.30-1.24).

The third was to titrate LTH-NIV to normalize or reduce PaCO₂ levels in patients with COPD. While this recommendation was issued with a very low certainty of evidence, it was driven by the “minimal potential harms of targeted PaCO₂ reduction.”

The fourth was to use fixed pressure support mode as first-choice ventilator mode in patients with COPD using LTH-NIV. The six trials on this subject did not provide insight into long-term outcomes, nor were there significant improvements seen in health-related quality of life, sleep quality, or exercise tolerance. As such, it was also issued with a very low certainty of evidence.

The authors acknowledged all four recommendations as weak and conditional, “due to limitations in the certainty of the available evidence.” As such, they noted that their recommendations “require consideration of individual preferences, resource considerations, technical expertise, and clinical circumstances prior to implementation in clinical practice.”

The authors reported numerous disclosures, including receiving grants and personal fees from various medical supply companies.

SOURCE: Ergan B et al. Eur Respir J. 2019 Aug 29. doi: 10.1183/13993003.01003-2019.

Long-term home noninvasive ventilation (LTH-NIV) has conditional value for patients with chronic hypercapnic chronic obstructive pulmonary disease (COPD), according to a new guideline from a European Respiratory Society task force.

“Our recommendations, based on the best available evidence, can guide the management of chronic hypercapnic respiratory failure in COPD patients aimed at improving patient outcomes,” wrote Begum Ergan, MD, of Dokuz Eylul University, Izmir, Turkey, and coauthors. The guideline was published in the European Respiratory Journal.

To provide insight into the clinical application of LTH-NIV, the European Respiratory Society convened a task force of 20 clinicians, methodologists, and experts. Their four recommendations were developed based on the GRADE (Grading, Recommendation, Assessment, Development and Evaluation) methodology.

The first recommendation was to use LTH-NIV for patients with chronic stable hypercapnic COPD. Though an analysis of randomized, controlled trials showed little effect on mortality or hospitalizations, pooled analyses showed that NIV may decrease dyspnea scores (standardized mean difference, –0.51; 95% confidence interval, –0.06 to –0.95) and increase health-related quality of life (SMD, 0.49; 95% CI, –0.01 to 0.98).

The second was to use LTH-NIV in patients with COPD following a life-threatening episode of acute hypercapnic respiratory failure requiring acute NIV, if hypercapnia persists. Though it was not associated with a reduction in mortality (risk ratio, 0.92; 95% CI, 0.67-1.25), it was found to potentially reduce exacerbations (SMD, 0.19; 95% CI, –0.40 to 0.01) and hospitalizations (RR, 0.61; 95% CI, 0.30-1.24).

The third was to titrate LTH-NIV to normalize or reduce PaCO₂ levels in patients with COPD. While this recommendation was issued with a very low certainty of evidence, it was driven by the “minimal potential harms of targeted PaCO₂ reduction.”

The fourth was to use fixed pressure support mode as first-choice ventilator mode in patients with COPD using LTH-NIV. The six trials on this subject did not provide insight into long-term outcomes, nor were there significant improvements seen in health-related quality of life, sleep quality, or exercise tolerance. As such, it was also issued with a very low certainty of evidence.

The authors acknowledged all four recommendations as weak and conditional, “due to limitations in the certainty of the available evidence.” As such, they noted that their recommendations “require consideration of individual preferences, resource considerations, technical expertise, and clinical circumstances prior to implementation in clinical practice.”

The authors reported numerous disclosures, including receiving grants and personal fees from various medical supply companies.

SOURCE: Ergan B et al. Eur Respir J. 2019 Aug 29. doi: 10.1183/13993003.01003-2019.

A new international position statement on testosterone therapy for women concludes that a trial of testosterone is appropriate for postmenopausal women with hypoactive sexual desire dysfunction (HSDD) and that its use for any other condition, symptom, or reason is not supported by available evidence.

The seven-page position statement, developed by an international task force of experts from the Endocrine Society, the American College of Gynecologists and Obstetricians, and multiple other medical societies, also emphasized that blood concentrations of testosterone should approximate premenopausal physiological conditions.

“When testosterone therapy is given, the resultant blood levels should not be above those seen in healthy young women,” said lead author Susan Ruth Davis, PhD, MBBS, of Monash University in Melbourne, Australia, in a press release issued by the Endocrine Society. Dr. Davis is president of the International Menopause Society, which coordinated the panel.

The statement was published in the Journal of Clinical Endocrinology & Metabolism and three other medical journals.

Margaret E. Wierman, MD, who represented the Endocrine Society on the task force, said in an interview that there has been “growing concern about testosterone being prescribed for a variety of signs and symptoms without data to support” such use. At the same time, there is significant concern about the ongoing lack of approved formulations licensed specifically for women, she said.

In part, the statement is about a renewed “call to industry to make some [female-specific] formulations so that we can examine other potential roles of testosterone in women,” said Dr. Wierman, professor of medicine and physiology at the University of Colorado at Denver, Aurora, and chief of endocrinology at the Rocky Mountain Regional Veterans Affairs Medical Center in Aurora.

“Testosterone may be useful [for indications other than HSDD], but we don’t know. There may be no [breast or cardiovascular disease risk], but we don’t know,” she said. “And without a formulation to study potential benefits and risks, it’s good to be cautious. It’s good to really outline where we have data and where we don’t.”

The Endocrine Society’s 2014 clinical practice guideline on androgen therapy in women, for which Dr. Wierman was the lead author, also recommended against the off-label use of testosterone for sexual dysfunction other than HSDD or for any other reason, such as cognitive, cardiovascular, metabolic, or bone health. As with the new statement, the society’s position statement was guided by an international, multisociety task force, albeit a smaller one.

For the new global position statement, the task force’s review of evidence includes a recently published systematic review and meta-analysis of randomized controlled trial data – of at least 12 weeks’ duration – on the use of testosterone for sexual function, cardiometabolic variables, cognitive measures, and musculoskeletal health. Some of the data from the randomized controlled trials were unpublished.

The meta-analysis, led by Dr. Davis and published in July in the Lancet Diabetes & Endocrinology, found that, compared with placebo or a comparator (such as estrogen, with or without progesterone), testosterone in either oral or transdermal form significantly improved sexual function in postmenopausal women. However, data about the effects of testosterone for other indications, its long-term safety, and its use in premenopausal women, were insufficient for drawing any conclusions (Lancet Diabetes Endocrinol. 2019 Jul 25. doi: 10.1016/S2213-8587[19]30189-5).

In addition, testosterone administered orally – but not nonorally (patch or cream) – was associated with adverse lipid profiles, Dr. Davis and her colleagues reported.

Another systematic review and meta-analysis, published in Fertility and Sterility in 2017 and included in the task force’s evidence review, focused specifically on transdermal testosterone for menopausal women with HSDD, with or without estrogen and progestin therapy. It also showed short-term efficacy in terms of improvement in sexual function, as well as short-term safety (Fertil Steril. 2017;107(2):475-82).

The new position statement warns about the lack of long-term safety data, stating that “safety data for testosterone in physiologic doses are not available beyond 24 months of treatment.”

In the short term, testosterone therapy for postmenopausal women (in doses approximating testosterone concentrations for premenopausal women), is associated with mild increases in acne and body/facial hair growth in some women, but not with alopecia, clitoromegaly, or voice change. Short-term transdermal therapy also does not seem to affect breast cancer risk or have any significant effects on lipid profiles, the statement says.

The panel points out, however, that randomized controlled trials with testosterone therapy have excluded women who are at high risk of cardiometabolic disease, and that women with a previous diagnosis of breast cancer have also been excluded from randomized trials of testosterone in women with HSDD. This is a “big issue,” said Dr. Wierman, and means that recommendations regarding the effect of testosterone in postmenopausal women with HSDD may not be generalizable to possible at-risk subpopulations.

The panel endorsed testosterone therapy specifically for women with HSDD because most of the studies reporting on sexual function have recruited women with diagnosed HSDD. Demonstrated benefits of testosterone in these cases include improved sexual desire, arousal, orgasm, and pleasure, and reduced concerns and distress about sex. HSDD should be diagnosed after formal biopsychosocial assessment, the statement notes.

“We don’t completely understand the control of sexual function in women, but it’s very dependent on estrogen status. And it’s also dependent on psychosocial factors, emotional health, relationship issues, and physical issues,” Dr. Wierman said in the interview.

“In practice, we look at all these issues, and we first optimize estrogen status. Once that’s done, and we’ve looked at all the other components of sexual function, then we can consider off-label use of testosterone,” she said. “If there’s no response in 3-6 months, we stop it.”

Testosterone levels do not correlate with sexual dysfunction, Dr. Wierman emphasized, and direct assays for the measurement of total and free testosterone are unreliable. The statement acknowledges that but still recommends measurement of testosterone using direct assays, in cases in which liquid/gas chromatography and tandem mass spectrometry assay (which has “high accuracy and reproducibility”) are not available. This is “to exclude high baseline concentrations and also to exclude supraphysiological concentrations during treatment,” the panel said.

Most endocrinologists and other experts who prescribe testosterone therapy for women use an approved male formulation off label and adjust it – an approach that the panel says is reasonable as long as hormone concentrations are “maintained in the physiologic female range.”

Compounded “bioidentical” testosterone therapy “cannot be recommended for the treatment of HSDD because of the lack of evidence for safety and efficacy,” the statement says.

“A big concern of many endocrinologists,” Dr. Wierman added, “is the recent explosion of using pharmacological levels of both estrogen and testosterone in either [injections] or pellets.” The Endocrine Society and other societies have alerted the Food and Drug Administration to “this new cottage industry, which may have significant side effects and risks for our patients,” she said.
Dr. Wierman reported received funding from Corcept Therapeutics, Novartis, and the Cancer League of Colorado, and honoraria or consultation fees from Pfizer to review ASPIRE grant applications for studies of acromegaly as well as Endocrine Society honorarium for teaching in the Endocrine Board Review and Clinical Endocrine Update. Dr. Davis reported receiving funding from a National Health and Medical Research Council Project Grant, a National Breast Foundation accelerator grant, and the Grollo-Ruzenne Foundation, as well as honoraria from Besins and Pfizer Australia. She has been a consultant to Besins Healthcare, Mayne Pharmaceuticals, Lawley Pharmaceuticals, and Que Oncology. Disclosures for other authors of the position statement are listed with the statement.

SOURCE: Davis SR et al. J Clin Endocrinol Metab. 2019 Sep 2. doi: 10.1210/jc.2019-01603.
 

A new international position statement on testosterone therapy for women concludes that a trial of testosterone is appropriate for postmenopausal women with hypoactive sexual desire dysfunction (HSDD) and that its use for any other condition, symptom, or reason is not supported by available evidence.

The seven-page position statement, developed by an international task force of experts from the Endocrine Society, the American College of Gynecologists and Obstetricians, and multiple other medical societies, also emphasized that blood concentrations of testosterone should approximate premenopausal physiological conditions.

“When testosterone therapy is given, the resultant blood levels should not be above those seen in healthy young women,” said lead author Susan Ruth Davis, PhD, MBBS, of Monash University in Melbourne, Australia, in a press release issued by the Endocrine Society. Dr. Davis is president of the International Menopause Society, which coordinated the panel.

The statement was published in the Journal of Clinical Endocrinology & Metabolism and three other medical journals.

Margaret E. Wierman, MD, who represented the Endocrine Society on the task force, said in an interview that there has been “growing concern about testosterone being prescribed for a variety of signs and symptoms without data to support” such use. At the same time, there is significant concern about the ongoing lack of approved formulations licensed specifically for women, she said.

In part, the statement is about a renewed “call to industry to make some [female-specific] formulations so that we can examine other potential roles of testosterone in women,” said Dr. Wierman, professor of medicine and physiology at the University of Colorado at Denver, Aurora, and chief of endocrinology at the Rocky Mountain Regional Veterans Affairs Medical Center in Aurora.

“Testosterone may be useful [for indications other than HSDD], but we don’t know. There may be no [breast or cardiovascular disease risk], but we don’t know,” she said. “And without a formulation to study potential benefits and risks, it’s good to be cautious. It’s good to really outline where we have data and where we don’t.”

The Endocrine Society’s 2014 clinical practice guideline on androgen therapy in women, for which Dr. Wierman was the lead author, also recommended against the off-label use of testosterone for sexual dysfunction other than HSDD or for any other reason, such as cognitive, cardiovascular, metabolic, or bone health. As with the new statement, the society’s position statement was guided by an international, multisociety task force, albeit a smaller one.

For the new global position statement, the task force’s review of evidence includes a recently published systematic review and meta-analysis of randomized controlled trial data – of at least 12 weeks’ duration – on the use of testosterone for sexual function, cardiometabolic variables, cognitive measures, and musculoskeletal health. Some of the data from the randomized controlled trials were unpublished.

The meta-analysis, led by Dr. Davis and published in July in the Lancet Diabetes & Endocrinology, found that, compared with placebo or a comparator (such as estrogen, with or without progesterone), testosterone in either oral or transdermal form significantly improved sexual function in postmenopausal women. However, data about the effects of testosterone for other indications, its long-term safety, and its use in premenopausal women, were insufficient for drawing any conclusions (Lancet Diabetes Endocrinol. 2019 Jul 25. doi: 10.1016/S2213-8587[19]30189-5).

In addition, testosterone administered orally – but not nonorally (patch or cream) – was associated with adverse lipid profiles, Dr. Davis and her colleagues reported.

Another systematic review and meta-analysis, published in Fertility and Sterility in 2017 and included in the task force’s evidence review, focused specifically on transdermal testosterone for menopausal women with HSDD, with or without estrogen and progestin therapy. It also showed short-term efficacy in terms of improvement in sexual function, as well as short-term safety (Fertil Steril. 2017;107(2):475-82).

The new position statement warns about the lack of long-term safety data, stating that “safety data for testosterone in physiologic doses are not available beyond 24 months of treatment.”

In the short term, testosterone therapy for postmenopausal women (in doses approximating testosterone concentrations for premenopausal women), is associated with mild increases in acne and body/facial hair growth in some women, but not with alopecia, clitoromegaly, or voice change. Short-term transdermal therapy also does not seem to affect breast cancer risk or have any significant effects on lipid profiles, the statement says.

The panel points out, however, that randomized controlled trials with testosterone therapy have excluded women who are at high risk of cardiometabolic disease, and that women with a previous diagnosis of breast cancer have also been excluded from randomized trials of testosterone in women with HSDD. This is a “big issue,” said Dr. Wierman, and means that recommendations regarding the effect of testosterone in postmenopausal women with HSDD may not be generalizable to possible at-risk subpopulations.

The panel endorsed testosterone therapy specifically for women with HSDD because most of the studies reporting on sexual function have recruited women with diagnosed HSDD. Demonstrated benefits of testosterone in these cases include improved sexual desire, arousal, orgasm, and pleasure, and reduced concerns and distress about sex. HSDD should be diagnosed after formal biopsychosocial assessment, the statement notes.

“We don’t completely understand the control of sexual function in women, but it’s very dependent on estrogen status. And it’s also dependent on psychosocial factors, emotional health, relationship issues, and physical issues,” Dr. Wierman said in the interview.

“In practice, we look at all these issues, and we first optimize estrogen status. Once that’s done, and we’ve looked at all the other components of sexual function, then we can consider off-label use of testosterone,” she said. “If there’s no response in 3-6 months, we stop it.”

Testosterone levels do not correlate with sexual dysfunction, Dr. Wierman emphasized, and direct assays for the measurement of total and free testosterone are unreliable. The statement acknowledges that but still recommends measurement of testosterone using direct assays, in cases in which liquid/gas chromatography and tandem mass spectrometry assay (which has “high accuracy and reproducibility”) are not available. This is “to exclude high baseline concentrations and also to exclude supraphysiological concentrations during treatment,” the panel said.

Most endocrinologists and other experts who prescribe testosterone therapy for women use an approved male formulation off label and adjust it – an approach that the panel says is reasonable as long as hormone concentrations are “maintained in the physiologic female range.”

Compounded “bioidentical” testosterone therapy “cannot be recommended for the treatment of HSDD because of the lack of evidence for safety and efficacy,” the statement says.

“A big concern of many endocrinologists,” Dr. Wierman added, “is the recent explosion of using pharmacological levels of both estrogen and testosterone in either [injections] or pellets.” The Endocrine Society and other societies have alerted the Food and Drug Administration to “this new cottage industry, which may have significant side effects and risks for our patients,” she said.
Dr. Wierman reported received funding from Corcept Therapeutics, Novartis, and the Cancer League of Colorado, and honoraria or consultation fees from Pfizer to review ASPIRE grant applications for studies of acromegaly as well as Endocrine Society honorarium for teaching in the Endocrine Board Review and Clinical Endocrine Update. Dr. Davis reported receiving funding from a National Health and Medical Research Council Project Grant, a National Breast Foundation accelerator grant, and the Grollo-Ruzenne Foundation, as well as honoraria from Besins and Pfizer Australia. She has been a consultant to Besins Healthcare, Mayne Pharmaceuticals, Lawley Pharmaceuticals, and Que Oncology. Disclosures for other authors of the position statement are listed with the statement.

SOURCE: Davis SR et al. J Clin Endocrinol Metab. 2019 Sep 2. doi: 10.1210/jc.2019-01603.
 

A new international position statement on testosterone therapy for women concludes that a trial of testosterone is appropriate for postmenopausal women with hypoactive sexual desire dysfunction (HSDD) and that its use for any other condition, symptom, or reason is not supported by available evidence.

The seven-page position statement, developed by an international task force of experts from the Endocrine Society, the American College of Gynecologists and Obstetricians, and multiple other medical societies, also emphasized that blood concentrations of testosterone should approximate premenopausal physiological conditions.

“When testosterone therapy is given, the resultant blood levels should not be above those seen in healthy young women,” said lead author Susan Ruth Davis, PhD, MBBS, of Monash University in Melbourne, Australia, in a press release issued by the Endocrine Society. Dr. Davis is president of the International Menopause Society, which coordinated the panel.

The statement was published in the Journal of Clinical Endocrinology & Metabolism and three other medical journals.

Margaret E. Wierman, MD, who represented the Endocrine Society on the task force, said in an interview that there has been “growing concern about testosterone being prescribed for a variety of signs and symptoms without data to support” such use. At the same time, there is significant concern about the ongoing lack of approved formulations licensed specifically for women, she said.

In part, the statement is about a renewed “call to industry to make some [female-specific] formulations so that we can examine other potential roles of testosterone in women,” said Dr. Wierman, professor of medicine and physiology at the University of Colorado at Denver, Aurora, and chief of endocrinology at the Rocky Mountain Regional Veterans Affairs Medical Center in Aurora.

“Testosterone may be useful [for indications other than HSDD], but we don’t know. There may be no [breast or cardiovascular disease risk], but we don’t know,” she said. “And without a formulation to study potential benefits and risks, it’s good to be cautious. It’s good to really outline where we have data and where we don’t.”

The Endocrine Society’s 2014 clinical practice guideline on androgen therapy in women, for which Dr. Wierman was the lead author, also recommended against the off-label use of testosterone for sexual dysfunction other than HSDD or for any other reason, such as cognitive, cardiovascular, metabolic, or bone health. As with the new statement, the society’s position statement was guided by an international, multisociety task force, albeit a smaller one.

For the new global position statement, the task force’s review of evidence includes a recently published systematic review and meta-analysis of randomized controlled trial data – of at least 12 weeks’ duration – on the use of testosterone for sexual function, cardiometabolic variables, cognitive measures, and musculoskeletal health. Some of the data from the randomized controlled trials were unpublished.

The meta-analysis, led by Dr. Davis and published in July in the Lancet Diabetes & Endocrinology, found that, compared with placebo or a comparator (such as estrogen, with or without progesterone), testosterone in either oral or transdermal form significantly improved sexual function in postmenopausal women. However, data about the effects of testosterone for other indications, its long-term safety, and its use in premenopausal women, were insufficient for drawing any conclusions (Lancet Diabetes Endocrinol. 2019 Jul 25. doi: 10.1016/S2213-8587[19]30189-5).

In addition, testosterone administered orally – but not nonorally (patch or cream) – was associated with adverse lipid profiles, Dr. Davis and her colleagues reported.

Another systematic review and meta-analysis, published in Fertility and Sterility in 2017 and included in the task force’s evidence review, focused specifically on transdermal testosterone for menopausal women with HSDD, with or without estrogen and progestin therapy. It also showed short-term efficacy in terms of improvement in sexual function, as well as short-term safety (Fertil Steril. 2017;107(2):475-82).

The new position statement warns about the lack of long-term safety data, stating that “safety data for testosterone in physiologic doses are not available beyond 24 months of treatment.”

In the short term, testosterone therapy for postmenopausal women (in doses approximating testosterone concentrations for premenopausal women), is associated with mild increases in acne and body/facial hair growth in some women, but not with alopecia, clitoromegaly, or voice change. Short-term transdermal therapy also does not seem to affect breast cancer risk or have any significant effects on lipid profiles, the statement says.

The panel points out, however, that randomized controlled trials with testosterone therapy have excluded women who are at high risk of cardiometabolic disease, and that women with a previous diagnosis of breast cancer have also been excluded from randomized trials of testosterone in women with HSDD. This is a “big issue,” said Dr. Wierman, and means that recommendations regarding the effect of testosterone in postmenopausal women with HSDD may not be generalizable to possible at-risk subpopulations.

The panel endorsed testosterone therapy specifically for women with HSDD because most of the studies reporting on sexual function have recruited women with diagnosed HSDD. Demonstrated benefits of testosterone in these cases include improved sexual desire, arousal, orgasm, and pleasure, and reduced concerns and distress about sex. HSDD should be diagnosed after formal biopsychosocial assessment, the statement notes.

“We don’t completely understand the control of sexual function in women, but it’s very dependent on estrogen status. And it’s also dependent on psychosocial factors, emotional health, relationship issues, and physical issues,” Dr. Wierman said in the interview.

“In practice, we look at all these issues, and we first optimize estrogen status. Once that’s done, and we’ve looked at all the other components of sexual function, then we can consider off-label use of testosterone,” she said. “If there’s no response in 3-6 months, we stop it.”

Testosterone levels do not correlate with sexual dysfunction, Dr. Wierman emphasized, and direct assays for the measurement of total and free testosterone are unreliable. The statement acknowledges that but still recommends measurement of testosterone using direct assays, in cases in which liquid/gas chromatography and tandem mass spectrometry assay (which has “high accuracy and reproducibility”) are not available. This is “to exclude high baseline concentrations and also to exclude supraphysiological concentrations during treatment,” the panel said.

Most endocrinologists and other experts who prescribe testosterone therapy for women use an approved male formulation off label and adjust it – an approach that the panel says is reasonable as long as hormone concentrations are “maintained in the physiologic female range.”

Compounded “bioidentical” testosterone therapy “cannot be recommended for the treatment of HSDD because of the lack of evidence for safety and efficacy,” the statement says.

“A big concern of many endocrinologists,” Dr. Wierman added, “is the recent explosion of using pharmacological levels of both estrogen and testosterone in either [injections] or pellets.” The Endocrine Society and other societies have alerted the Food and Drug Administration to “this new cottage industry, which may have significant side effects and risks for our patients,” she said.
Dr. Wierman reported received funding from Corcept Therapeutics, Novartis, and the Cancer League of Colorado, and honoraria or consultation fees from Pfizer to review ASPIRE grant applications for studies of acromegaly as well as Endocrine Society honorarium for teaching in the Endocrine Board Review and Clinical Endocrine Update. Dr. Davis reported receiving funding from a National Health and Medical Research Council Project Grant, a National Breast Foundation accelerator grant, and the Grollo-Ruzenne Foundation, as well as honoraria from Besins and Pfizer Australia. She has been a consultant to Besins Healthcare, Mayne Pharmaceuticals, Lawley Pharmaceuticals, and Que Oncology. Disclosures for other authors of the position statement are listed with the statement.

SOURCE: Davis SR et al. J Clin Endocrinol Metab. 2019 Sep 2. doi: 10.1210/jc.2019-01603.
 

It is estimated that there are 1.1 million people in the United States living with HIV and that 15% of those people do not know they have HIV. Although the number of new cases reported each year is decreasing, there were still 38,281 new diagnoses in 2017. New cases might be decreasing overall, but the incidence of HIV is rising in some groups including people aged 25-29 years old and American Indian/Alaska Native and Asian populations. In addition, HIV disproportionately affects men who have sex with men, black/African American populations, and Hispanic/Latino populations, according to the USPSTF statement.

Given the prevalence of HIV and rising new cases in certain groups, it is thought that preexposure prophylaxis (PrEP) is being underutilized. The CDC reported that, in 2015, 1.2 million people were candidates for PrEP, but in 2017, only 100,282 people were using PrEP. The USPSTF performed a meta-analysis of 12 RCTs comparing rates of HIV infection in groups treated with PrEP versus those treated with placebo or no treatment and found a risk ratio of 0.46 (95% confidence interval, 0.33-0.66) and absolute risk reduction of –2% (95% CI, –2.8% to –1.2%) after 4 months and 4 years.

With this epidemiologic data and the meta-analysis, the USPSTF offered the following recommendations.
 

Screening

In order to decrease the rates of transmission and incidence of HIV infection, we must appropriately identify those who would be good candidates for PrEP. That begins with taking a complete and thorough sexual and injection drug use history in a manner that does not make patients feel stigmatized or discriminated against. The USPSTF recommends screening for HIV infection in patients aged 15-65 years old, in younger and older patients who have increased risk factors, and all pregnant patients. PrEP is not an appropriate choice in those who have HIV because it can lead to drug resistance.

When screening for HIV and considering starting PrEP, it is recommended that clinicians also test for kidney function, hepatitis B and C, other STIs, and pregnancy. The USPSTF suggests that the following groups be considered for PrEP given the increased risk of HIV infection:

• Men who have sex with men, are sexually active, and have one of these additional characteristics: a serodiscordant sex partner, inconsistent use of condoms during receptive or insertive anal sex, or infection with syphilis, gonorrhea, or chlamydia in the past 6 months.
• Heterosexual men or women who are sexually active with one or more of these additional characteristics: a serodiscordant sex partner, inconsistent use of condoms during sex with a partner whose HIV status is unknown and who is at high risk, and infection with syphilis or gonorrhea in the past 6 months.
• Patients who inject drugs with one or more of the following characteristics: shared use of drug injection equipment and risk of sexual acquisition (as in the categories above).

The USPSTF also notes that those who engage in transactional sex (for money, drugs, or housing) and transgender patients are at an increased risk of HIV infection.

Treatment

The only FDA approved treatment for the prevention HIV infection is once daily oral combined tenofovir disoproxil fumarate and emtricitabine; however, some studies have found that tenofovir disproxil fumarate monotherapy is also effective. Considering these trials, the CDC has suggested that tenofovir disoproxil fumarate monotherapy can be used as an alternative for men and women at high risk and those who inject drugs.

Tenofovir disoproxil fumarate/emtricitabine can also be used in pregnant patients, however the USPSTF notes that no PrEP trials included pregnant women. Additionally, tenofovir disoproxil fumarate/emtricitabine can be used in adolescents who weigh more than 35 kg. It is unknown how much time it takes to achieve protection against HIV infection after starting PrEP, and there is no clear timeline for how long patients should be on PrEP. Patients may discontinue medication because of preference, decreased risk of HIV exposure, or side effects.

Side effects include renal adverse events (serum creatinine rise), gastrointestinal adverse events (mostly nausea), and bone loss and increased fracture risk, although none were statistically significant when PrEP and placebo groups were compared. The USPSTF’s recommendations note that the effectiveness of PrEP is dependent on medication adherence.

While PrEP is an important part of preventing HIV, it is always important to counsel patients on other ways to reduce risk. The USPSTF notes that consistent condom use reduces the risk of HIV infection by around 80% in addition to reducing the risk of other STIs. All trials studied by the USPSTF for these recommendations included counseling on behavior, adherence, and condom use.
 

Bottom Line

It is estimated that 1.1 million Americans are living with HIV and 15% are unaware that they are positive for HIV. Overall cases of new HIV diagnoses are down, but they are rising in some groups. PrEP is an effective medication for reducing the risk of HIV infection, but is currently underutilized. Every patient should be screened for high-risk sexual behavior and drug use with a thorough history. Patients aged 15-65 years should be screened for HIV. If patients are negative for HIV, but participate in high-risk sexual behaviors and drug injection, they should be offered PrEP along with counseling on, medication adherence, condom use, and reduction of high-risk behaviors.
 

Dr. Skolnik is professor of family and community medicine at Jefferson Medical College, Philadelphia, and an associate director of the family medicine residency program at Abington (Pa.) Jefferson Health. Dr. Sprogell is a second-year resident in the Family Medicine Residency Program at Abington Jefferson Health

Reference

Owens DK et al. “Preexposure prophylaxis for the prevention of HIV infection: US Preventive Services Task Force recommendation statement.” JAMA. 2019 Jun 11;321(22):2203-13.

It is estimated that there are 1.1 million people in the United States living with HIV and that 15% of those people do not know they have HIV. Although the number of new cases reported each year is decreasing, there were still 38,281 new diagnoses in 2017. New cases might be decreasing overall, but the incidence of HIV is rising in some groups including people aged 25-29 years old and American Indian/Alaska Native and Asian populations. In addition, HIV disproportionately affects men who have sex with men, black/African American populations, and Hispanic/Latino populations, according to the USPSTF statement.

Given the prevalence of HIV and rising new cases in certain groups, it is thought that preexposure prophylaxis (PrEP) is being underutilized. The CDC reported that, in 2015, 1.2 million people were candidates for PrEP, but in 2017, only 100,282 people were using PrEP. The USPSTF performed a meta-analysis of 12 RCTs comparing rates of HIV infection in groups treated with PrEP versus those treated with placebo or no treatment and found a risk ratio of 0.46 (95% confidence interval, 0.33-0.66) and absolute risk reduction of –2% (95% CI, –2.8% to –1.2%) after 4 months and 4 years.

With this epidemiologic data and the meta-analysis, the USPSTF offered the following recommendations.
 

Screening

In order to decrease the rates of transmission and incidence of HIV infection, we must appropriately identify those who would be good candidates for PrEP. That begins with taking a complete and thorough sexual and injection drug use history in a manner that does not make patients feel stigmatized or discriminated against. The USPSTF recommends screening for HIV infection in patients aged 15-65 years old, in younger and older patients who have increased risk factors, and all pregnant patients. PrEP is not an appropriate choice in those who have HIV because it can lead to drug resistance.

When screening for HIV and considering starting PrEP, it is recommended that clinicians also test for kidney function, hepatitis B and C, other STIs, and pregnancy. The USPSTF suggests that the following groups be considered for PrEP given the increased risk of HIV infection:

• Men who have sex with men, are sexually active, and have one of these additional characteristics: a serodiscordant sex partner, inconsistent use of condoms during receptive or insertive anal sex, or infection with syphilis, gonorrhea, or chlamydia in the past 6 months.
• Heterosexual men or women who are sexually active with one or more of these additional characteristics: a serodiscordant sex partner, inconsistent use of condoms during sex with a partner whose HIV status is unknown and who is at high risk, and infection with syphilis or gonorrhea in the past 6 months.
• Patients who inject drugs with one or more of the following characteristics: shared use of drug injection equipment and risk of sexual acquisition (as in the categories above).

The USPSTF also notes that those who engage in transactional sex (for money, drugs, or housing) and transgender patients are at an increased risk of HIV infection.

Treatment

The only FDA approved treatment for the prevention HIV infection is once daily oral combined tenofovir disoproxil fumarate and emtricitabine; however, some studies have found that tenofovir disproxil fumarate monotherapy is also effective. Considering these trials, the CDC has suggested that tenofovir disoproxil fumarate monotherapy can be used as an alternative for men and women at high risk and those who inject drugs.

Tenofovir disoproxil fumarate/emtricitabine can also be used in pregnant patients, however the USPSTF notes that no PrEP trials included pregnant women. Additionally, tenofovir disoproxil fumarate/emtricitabine can be used in adolescents who weigh more than 35 kg. It is unknown how much time it takes to achieve protection against HIV infection after starting PrEP, and there is no clear timeline for how long patients should be on PrEP. Patients may discontinue medication because of preference, decreased risk of HIV exposure, or side effects.

Side effects include renal adverse events (serum creatinine rise), gastrointestinal adverse events (mostly nausea), and bone loss and increased fracture risk, although none were statistically significant when PrEP and placebo groups were compared. The USPSTF’s recommendations note that the effectiveness of PrEP is dependent on medication adherence.

While PrEP is an important part of preventing HIV, it is always important to counsel patients on other ways to reduce risk. The USPSTF notes that consistent condom use reduces the risk of HIV infection by around 80% in addition to reducing the risk of other STIs. All trials studied by the USPSTF for these recommendations included counseling on behavior, adherence, and condom use.
 

Bottom Line

It is estimated that 1.1 million Americans are living with HIV and 15% are unaware that they are positive for HIV. Overall cases of new HIV diagnoses are down, but they are rising in some groups. PrEP is an effective medication for reducing the risk of HIV infection, but is currently underutilized. Every patient should be screened for high-risk sexual behavior and drug use with a thorough history. Patients aged 15-65 years should be screened for HIV. If patients are negative for HIV, but participate in high-risk sexual behaviors and drug injection, they should be offered PrEP along with counseling on, medication adherence, condom use, and reduction of high-risk behaviors.
 

Dr. Skolnik is professor of family and community medicine at Jefferson Medical College, Philadelphia, and an associate director of the family medicine residency program at Abington (Pa.) Jefferson Health. Dr. Sprogell is a second-year resident in the Family Medicine Residency Program at Abington Jefferson Health

Reference

Owens DK et al. “Preexposure prophylaxis for the prevention of HIV infection: US Preventive Services Task Force recommendation statement.” JAMA. 2019 Jun 11;321(22):2203-13.

It is estimated that there are 1.1 million people in the United States living with HIV and that 15% of those people do not know they have HIV. Although the number of new cases reported each year is decreasing, there were still 38,281 new diagnoses in 2017. New cases might be decreasing overall, but the incidence of HIV is rising in some groups including people aged 25-29 years old and American Indian/Alaska Native and Asian populations. In addition, HIV disproportionately affects men who have sex with men, black/African American populations, and Hispanic/Latino populations, according to the USPSTF statement.

Given the prevalence of HIV and rising new cases in certain groups, it is thought that preexposure prophylaxis (PrEP) is being underutilized. The CDC reported that, in 2015, 1.2 million people were candidates for PrEP, but in 2017, only 100,282 people were using PrEP. The USPSTF performed a meta-analysis of 12 RCTs comparing rates of HIV infection in groups treated with PrEP versus those treated with placebo or no treatment and found a risk ratio of 0.46 (95% confidence interval, 0.33-0.66) and absolute risk reduction of –2% (95% CI, –2.8% to –1.2%) after 4 months and 4 years.

With this epidemiologic data and the meta-analysis, the USPSTF offered the following recommendations.
 

Screening

In order to decrease the rates of transmission and incidence of HIV infection, we must appropriately identify those who would be good candidates for PrEP. That begins with taking a complete and thorough sexual and injection drug use history in a manner that does not make patients feel stigmatized or discriminated against. The USPSTF recommends screening for HIV infection in patients aged 15-65 years old, in younger and older patients who have increased risk factors, and all pregnant patients. PrEP is not an appropriate choice in those who have HIV because it can lead to drug resistance.

When screening for HIV and considering starting PrEP, it is recommended that clinicians also test for kidney function, hepatitis B and C, other STIs, and pregnancy. The USPSTF suggests that the following groups be considered for PrEP given the increased risk of HIV infection:

• Men who have sex with men, are sexually active, and have one of these additional characteristics: a serodiscordant sex partner, inconsistent use of condoms during receptive or insertive anal sex, or infection with syphilis, gonorrhea, or chlamydia in the past 6 months.
• Heterosexual men or women who are sexually active with one or more of these additional characteristics: a serodiscordant sex partner, inconsistent use of condoms during sex with a partner whose HIV status is unknown and who is at high risk, and infection with syphilis or gonorrhea in the past 6 months.
• Patients who inject drugs with one or more of the following characteristics: shared use of drug injection equipment and risk of sexual acquisition (as in the categories above).

The USPSTF also notes that those who engage in transactional sex (for money, drugs, or housing) and transgender patients are at an increased risk of HIV infection.

Treatment

The only FDA approved treatment for the prevention HIV infection is once daily oral combined tenofovir disoproxil fumarate and emtricitabine; however, some studies have found that tenofovir disproxil fumarate monotherapy is also effective. Considering these trials, the CDC has suggested that tenofovir disoproxil fumarate monotherapy can be used as an alternative for men and women at high risk and those who inject drugs.

Tenofovir disoproxil fumarate/emtricitabine can also be used in pregnant patients, however the USPSTF notes that no PrEP trials included pregnant women. Additionally, tenofovir disoproxil fumarate/emtricitabine can be used in adolescents who weigh more than 35 kg. It is unknown how much time it takes to achieve protection against HIV infection after starting PrEP, and there is no clear timeline for how long patients should be on PrEP. Patients may discontinue medication because of preference, decreased risk of HIV exposure, or side effects.

Side effects include renal adverse events (serum creatinine rise), gastrointestinal adverse events (mostly nausea), and bone loss and increased fracture risk, although none were statistically significant when PrEP and placebo groups were compared. The USPSTF’s recommendations note that the effectiveness of PrEP is dependent on medication adherence.

While PrEP is an important part of preventing HIV, it is always important to counsel patients on other ways to reduce risk. The USPSTF notes that consistent condom use reduces the risk of HIV infection by around 80% in addition to reducing the risk of other STIs. All trials studied by the USPSTF for these recommendations included counseling on behavior, adherence, and condom use.
 

Bottom Line

It is estimated that 1.1 million Americans are living with HIV and 15% are unaware that they are positive for HIV. Overall cases of new HIV diagnoses are down, but they are rising in some groups. PrEP is an effective medication for reducing the risk of HIV infection, but is currently underutilized. Every patient should be screened for high-risk sexual behavior and drug use with a thorough history. Patients aged 15-65 years should be screened for HIV. If patients are negative for HIV, but participate in high-risk sexual behaviors and drug injection, they should be offered PrEP along with counseling on, medication adherence, condom use, and reduction of high-risk behaviors.
 

Dr. Skolnik is professor of family and community medicine at Jefferson Medical College, Philadelphia, and an associate director of the family medicine residency program at Abington (Pa.) Jefferson Health. Dr. Sprogell is a second-year resident in the Family Medicine Residency Program at Abington Jefferson Health

Reference

Owens DK et al. “Preexposure prophylaxis for the prevention of HIV infection: US Preventive Services Task Force recommendation statement.” JAMA. 2019 Jun 11;321(22):2203-13.

The American College of Rheumatology, Spondylitis Association of America, and Spondyloarthritis Research and Treatment Network have updated their guidelines on management of ankylosing spondylitis and nonradiographic axial spondyloarthritis.

These guidelines serve as an update to the previous guidelines that were first published in 2015 (Arthritis Care Res. 2016;68:151–66). While the new guidelines did not review all recommendations from the 2015 guidelines, 20 questions on pharmacologic treatment were re-reviewed in addition to 26 new questions and recommendations.

Michael M. Ward, MD, chief of the Clinical Trials and Outcomes Branch at the National Institute of Arthritis and Musculoskeletal and Skin Diseases, said in an interview that the availability of new medications to treat axial spondyloarthritis (axSpA) prompted the updated guidelines.

“We took the opportunity to revisit some previous recommendations for which substantial new evidence was available, and also included new recommendations on some other topics, such as imaging,” said Dr. Ward, who is also first author of the new guidelines.

The panel that developed the questions focused on scenarios that a clinician would likely encounter in clinical practice, or situations in which how to manage a case is not clear. “Given this perspective, there were many questions that had limited evidence, but recommendations were made for all questions. For those questions that had less evidence in the literature, we relied more on the expertise of the panel,” Dr. Ward said.

The questions and recommendations for ankylosing spondylitis (AS) and nonradiographic axSpA centered around use of interleukin-17 (IL-17) inhibitors, tofacitinib (Xeljanz), and biosimilars of tumor necrosis factor-alpha inhibitors (TNFi), as well as when to taper and discontinue these medications.

Strong recommendations for patients with AS included using NSAIDs (low level of evidence), using TNFi when active disease remains despite NSAID treatment (high level of evidence), and using secukinumab (Cosentyx) or ixekizumab (Taltz) when active disease remains despite NSAID treatment over no treatment (high level of evidence). The guidelines also strongly recommend the use of physical therapy for adults with stable AS over no physical therapy (low level of evidence), as well as total hip arthroplasty in cases of advanced hip arthritis. The writing panel also strongly advised that adults with AS-related comorbidities should receive treatment by an ophthalmologist in cases of acute iritis. Strong recommendations were made against switching to a biosimilar of a TNFi after receiving treatment with an originator TNFi (regardless of whether it is for active or stable AS), use of systemic glucocorticoids in adults with active AS, treatment with spinal manipulation in patients with spinal fusion or advanced spinal osteoporosis, and screening for cardiac conduction defects and valvular heart disease with electrocardiograms.

Strong recommendations for nonradiographic axSpA were similar to those made for patients with AS, and the panel made strong recommendations for use of NSAIDs in patients with active disease; for TNFi treatment when NSAIDs fail; against switching to a biosimilar of a TNFi after starting the originator TNFi; against using systemic glucocorticoids; and in favor of using physical therapy rather than not.

The panel also made a number of conditional recommendations for AS and nonradiographic axSpA patients with regard to biologic preference and imaging. TNFis were conditionally recommended over secukinumab or ixekizumab in patients with active disease despite NSAIDs treatment, and in cases where a patient is not responding to a first TNFi treatment, the panel conditionally recommended secukinumab or ixekizumab over a second TNFi (very low evidence for all). Secukinumab or ixekizumab were also conditionally recommended over tofacitinib (very low evidence). Sulfasalazine, methotrexate, and tofacitinib were conditionally recommended in cases where patients had prominent peripheral arthritis or when TNFis are not available (very low to moderate evidence). The panel recommended against adding sulfasalazine or methotrexate to existing TNFi treatment (very low evidence), and they also advised against tapering as a standard treatment approach or discontinuing the biologic (very low evidence). MRI of the spine or pelvis was conditionally recommended to examine disease activity in unclear cases, but the panel recommended against ordering MRI scans to monitor disease inactivity (very low evidence).

“Most of the recommendations are conditional, primarily because of the relatively low level of evidence in the literature that addressed many of the questions,” while stronger recommendations came from larger clinical trials, Dr. Ward said. “The need for this update demonstrates the rapid progress in treatment that is occurring in axial spondyloarthritis, but the low level of evidence for many questions indicates that much more research is needed.”

Nine authors reported personal and institutional relationships in the form of consultancies, educational advisory board memberships, and site investigator appointments for AbbVie, Amgen, Boehringer Ingelheim, Bristol-Myers Squibb, Celgene, Eli Lilly, GlaxoSmithKline, Galapagos, Janssen, Novartis, Pfizer, and UCB. The other authors reported no relevant conflicts of interest.

SOURCE: Ward MM et al. Arthritis Care Res. 2019 Aug 21. doi: 10.1002/acr.24025.

The American College of Rheumatology, Spondylitis Association of America, and Spondyloarthritis Research and Treatment Network have updated their guidelines on management of ankylosing spondylitis and nonradiographic axial spondyloarthritis.

These guidelines serve as an update to the previous guidelines that were first published in 2015 (Arthritis Care Res. 2016;68:151–66). While the new guidelines did not review all recommendations from the 2015 guidelines, 20 questions on pharmacologic treatment were re-reviewed in addition to 26 new questions and recommendations.

Michael M. Ward, MD, chief of the Clinical Trials and Outcomes Branch at the National Institute of Arthritis and Musculoskeletal and Skin Diseases, said in an interview that the availability of new medications to treat axial spondyloarthritis (axSpA) prompted the updated guidelines.

“We took the opportunity to revisit some previous recommendations for which substantial new evidence was available, and also included new recommendations on some other topics, such as imaging,” said Dr. Ward, who is also first author of the new guidelines.

The panel that developed the questions focused on scenarios that a clinician would likely encounter in clinical practice, or situations in which how to manage a case is not clear. “Given this perspective, there were many questions that had limited evidence, but recommendations were made for all questions. For those questions that had less evidence in the literature, we relied more on the expertise of the panel,” Dr. Ward said.

The questions and recommendations for ankylosing spondylitis (AS) and nonradiographic axSpA centered around use of interleukin-17 (IL-17) inhibitors, tofacitinib (Xeljanz), and biosimilars of tumor necrosis factor-alpha inhibitors (TNFi), as well as when to taper and discontinue these medications.

Strong recommendations for patients with AS included using NSAIDs (low level of evidence), using TNFi when active disease remains despite NSAID treatment (high level of evidence), and using secukinumab (Cosentyx) or ixekizumab (Taltz) when active disease remains despite NSAID treatment over no treatment (high level of evidence). The guidelines also strongly recommend the use of physical therapy for adults with stable AS over no physical therapy (low level of evidence), as well as total hip arthroplasty in cases of advanced hip arthritis. The writing panel also strongly advised that adults with AS-related comorbidities should receive treatment by an ophthalmologist in cases of acute iritis. Strong recommendations were made against switching to a biosimilar of a TNFi after receiving treatment with an originator TNFi (regardless of whether it is for active or stable AS), use of systemic glucocorticoids in adults with active AS, treatment with spinal manipulation in patients with spinal fusion or advanced spinal osteoporosis, and screening for cardiac conduction defects and valvular heart disease with electrocardiograms.

Strong recommendations for nonradiographic axSpA were similar to those made for patients with AS, and the panel made strong recommendations for use of NSAIDs in patients with active disease; for TNFi treatment when NSAIDs fail; against switching to a biosimilar of a TNFi after starting the originator TNFi; against using systemic glucocorticoids; and in favor of using physical therapy rather than not.

The panel also made a number of conditional recommendations for AS and nonradiographic axSpA patients with regard to biologic preference and imaging. TNFis were conditionally recommended over secukinumab or ixekizumab in patients with active disease despite NSAIDs treatment, and in cases where a patient is not responding to a first TNFi treatment, the panel conditionally recommended secukinumab or ixekizumab over a second TNFi (very low evidence for all). Secukinumab or ixekizumab were also conditionally recommended over tofacitinib (very low evidence). Sulfasalazine, methotrexate, and tofacitinib were conditionally recommended in cases where patients had prominent peripheral arthritis or when TNFis are not available (very low to moderate evidence). The panel recommended against adding sulfasalazine or methotrexate to existing TNFi treatment (very low evidence), and they also advised against tapering as a standard treatment approach or discontinuing the biologic (very low evidence). MRI of the spine or pelvis was conditionally recommended to examine disease activity in unclear cases, but the panel recommended against ordering MRI scans to monitor disease inactivity (very low evidence).

“Most of the recommendations are conditional, primarily because of the relatively low level of evidence in the literature that addressed many of the questions,” while stronger recommendations came from larger clinical trials, Dr. Ward said. “The need for this update demonstrates the rapid progress in treatment that is occurring in axial spondyloarthritis, but the low level of evidence for many questions indicates that much more research is needed.”

Nine authors reported personal and institutional relationships in the form of consultancies, educational advisory board memberships, and site investigator appointments for AbbVie, Amgen, Boehringer Ingelheim, Bristol-Myers Squibb, Celgene, Eli Lilly, GlaxoSmithKline, Galapagos, Janssen, Novartis, Pfizer, and UCB. The other authors reported no relevant conflicts of interest.

SOURCE: Ward MM et al. Arthritis Care Res. 2019 Aug 21. doi: 10.1002/acr.24025.

The American College of Rheumatology, Spondylitis Association of America, and Spondyloarthritis Research and Treatment Network have updated their guidelines on management of ankylosing spondylitis and nonradiographic axial spondyloarthritis.

These guidelines serve as an update to the previous guidelines that were first published in 2015 (Arthritis Care Res. 2016;68:151–66). While the new guidelines did not review all recommendations from the 2015 guidelines, 20 questions on pharmacologic treatment were re-reviewed in addition to 26 new questions and recommendations.

Michael M. Ward, MD, chief of the Clinical Trials and Outcomes Branch at the National Institute of Arthritis and Musculoskeletal and Skin Diseases, said in an interview that the availability of new medications to treat axial spondyloarthritis (axSpA) prompted the updated guidelines.

“We took the opportunity to revisit some previous recommendations for which substantial new evidence was available, and also included new recommendations on some other topics, such as imaging,” said Dr. Ward, who is also first author of the new guidelines.

The panel that developed the questions focused on scenarios that a clinician would likely encounter in clinical practice, or situations in which how to manage a case is not clear. “Given this perspective, there were many questions that had limited evidence, but recommendations were made for all questions. For those questions that had less evidence in the literature, we relied more on the expertise of the panel,” Dr. Ward said.

The questions and recommendations for ankylosing spondylitis (AS) and nonradiographic axSpA centered around use of interleukin-17 (IL-17) inhibitors, tofacitinib (Xeljanz), and biosimilars of tumor necrosis factor-alpha inhibitors (TNFi), as well as when to taper and discontinue these medications.

Strong recommendations for patients with AS included using NSAIDs (low level of evidence), using TNFi when active disease remains despite NSAID treatment (high level of evidence), and using secukinumab (Cosentyx) or ixekizumab (Taltz) when active disease remains despite NSAID treatment over no treatment (high level of evidence). The guidelines also strongly recommend the use of physical therapy for adults with stable AS over no physical therapy (low level of evidence), as well as total hip arthroplasty in cases of advanced hip arthritis. The writing panel also strongly advised that adults with AS-related comorbidities should receive treatment by an ophthalmologist in cases of acute iritis. Strong recommendations were made against switching to a biosimilar of a TNFi after receiving treatment with an originator TNFi (regardless of whether it is for active or stable AS), use of systemic glucocorticoids in adults with active AS, treatment with spinal manipulation in patients with spinal fusion or advanced spinal osteoporosis, and screening for cardiac conduction defects and valvular heart disease with electrocardiograms.

Strong recommendations for nonradiographic axSpA were similar to those made for patients with AS, and the panel made strong recommendations for use of NSAIDs in patients with active disease; for TNFi treatment when NSAIDs fail; against switching to a biosimilar of a TNFi after starting the originator TNFi; against using systemic glucocorticoids; and in favor of using physical therapy rather than not.

The panel also made a number of conditional recommendations for AS and nonradiographic axSpA patients with regard to biologic preference and imaging. TNFis were conditionally recommended over secukinumab or ixekizumab in patients with active disease despite NSAIDs treatment, and in cases where a patient is not responding to a first TNFi treatment, the panel conditionally recommended secukinumab or ixekizumab over a second TNFi (very low evidence for all). Secukinumab or ixekizumab were also conditionally recommended over tofacitinib (very low evidence). Sulfasalazine, methotrexate, and tofacitinib were conditionally recommended in cases where patients had prominent peripheral arthritis or when TNFis are not available (very low to moderate evidence). The panel recommended against adding sulfasalazine or methotrexate to existing TNFi treatment (very low evidence), and they also advised against tapering as a standard treatment approach or discontinuing the biologic (very low evidence). MRI of the spine or pelvis was conditionally recommended to examine disease activity in unclear cases, but the panel recommended against ordering MRI scans to monitor disease inactivity (very low evidence).

“Most of the recommendations are conditional, primarily because of the relatively low level of evidence in the literature that addressed many of the questions,” while stronger recommendations came from larger clinical trials, Dr. Ward said. “The need for this update demonstrates the rapid progress in treatment that is occurring in axial spondyloarthritis, but the low level of evidence for many questions indicates that much more research is needed.”

Nine authors reported personal and institutional relationships in the form of consultancies, educational advisory board memberships, and site investigator appointments for AbbVie, Amgen, Boehringer Ingelheim, Bristol-Myers Squibb, Celgene, Eli Lilly, GlaxoSmithKline, Galapagos, Janssen, Novartis, Pfizer, and UCB. The other authors reported no relevant conflicts of interest.

SOURCE: Ward MM et al. Arthritis Care Res. 2019 Aug 21. doi: 10.1002/acr.24025.

Patients with multiple sclerosis (MS) should follow local vaccine standards and receive the yearly influenza vaccine, unless there are specific contraindications, such as active treatment with immunosuppressive or immunomodulating agents, according to an American Academy of Neurology practice guideline.

itsmejust/Thinkstock

A summary of the guideline on vaccine-preventable infections and immunization in MS was published online Aug. 28 in Neurology. The new effort updates a 2002 guideline on this topic and incorporates new evidence, vaccines, and disease-modifying therapies (DMTs). The guideline was endorsed by the Consortium of Multiple Sclerosis Centers and by the Multiple Sclerosis Association of America.

To create the guideline, lead author Mauricio F. Farez, MD, of the Raúl Carrea Institute for Neurological Research (FLENI) in Buenos Aires and colleagues on the 17-member guideline panel performed a systematic review of the evidence and reached consensus on recommendations using a modified Delphi voting process. The review included randomized, controlled trials; cohort studies; and case-control studies published between 1990 and March 2018.

“Immunosuppressive or immunomodulating agents used to treat MS may suppress or modulate normal immune function. These drugs may increase susceptibility to infections and may reduce vaccine effectiveness because of a decreased ability to mount an immune response,” the authors said.

Based on its review of the evidence, principles of care, and inferences, the authors made the following eight recommendations:

• Clinicians should discuss with patients the evidence regarding immunization in MS (Level B). In addition, clinicians should examine patients’ opinions, preferences, and questions regarding immunizations (Level B).
• Clinicians should recommend that patients with MS follow all local vaccine standards in the absence of specific contraindications (Level B).
• Clinicians should consider local risks of vaccine-preventable diseases when counseling patients (Level B).
• Clinicians should recommend that patients with MS receive the influenza vaccination if there is no specific contraindication, such as a previous severe reaction (Level B).
• When treatment with an immunosuppressive or immunomodulating agent is considered, clinicians should counsel patients about infection risks associated with the specific medication and the treatment-specific vaccination guidance in the medication’s prescribing instructions (Level B). In addition, physicians should assess patients’ vaccination status before prescribing immunosuppressive or immunomodulating therapy and vaccinate patients according to local regulatory standards and treatment-specific infectious risks at least 4-6 weeks before initiating therapy, as advised by the prescribing information (Level B). Furthermore, clinicians may discuss the advantages of vaccination soon after MS diagnosis, regardless of initial therapeutic plans, to prevent delays should immunosuppressive or immunomodulating therapies be initiated in the future (Level C, based on variation in patient preferences).
• Clinicians must screen for certain infections (such as hepatitis, tuberculosis, and varicella zoster virus) according to a medication’s prescribing information before starting immunosuppressive or immunomodulating treatment (Level A) and should treat patients who have latent infections before MS treatment according to the medication prescribing information (Level B, based on feasibility and cost relative to benefit). Further, in high-risk populations or in countries with a high burden of infectious disease, clinicians must screen for latent infections before starting immunosuppressive or immunomodulating medications, even when such screening is not specifically mentioned in the prescribing information (Level A). Clinicians should consult infectious disease or other specialists about treating patients with latent infection before starting immunosuppressive or immunomodulating medications (Level B).
• Clinicians should recommend against live-attenuated vaccines in people with MS who receive immunosuppressive or immunomodulating therapies or have recently discontinued these therapies (Level B, based on importance of outcomes). When the risk of infection is high, clinicians may recommend live-attenuated vaccines if killed vaccines are unavailable (Level C, based on variation in patient preferences, benefit relative to harm, and importance of outcomes).
• If a patient with MS is experiencing a relapse, clinicians should delay vaccination until the relapse has clinically resolved or is no longer active, often many weeks after relapse onset (Level B).

Personal and population-level benefits

“There is no evidence that vaccination increases the risk of MS exacerbation, although the literature is sparse,” the authors said. “In addition to conferring personal benefits, vaccination of the MS patient population contributes to the well-established phenomenon of herd immunity for the communities in which patients with MS live,” the authors wrote.

Because influenza infection has known risks of exacerbation and morbidity, whereas influenza vaccine has no identified risks of exacerbation, “benefits of influenza vaccination outweigh the risks in most scenarios, although patients with MS receiving some [immunosuppressive or immunomodulating] treatments (fingolimod [Gilenya], glatiramer acetate [Copaxone], and mitoxantrone) may have a reduced response to influenza vaccination,” the authors said. Studies in patients with diseases other than MS suggest that rituximab (Rituxan) also may be associated with reduced influenza vaccine responsiveness.

Immunosuppressive or immunomodulatory medications including alemtuzumab (Lemtrada), dimethyl fumarate (Tecfidera), fingolimod, mitoxantrone, natalizumab (Tysabri), ocrelizumab (Ocrevus), rituximab, and teriflunomide (Aubagio) have been associated with severe occurrences or recurrences of vaccine-preventable infections, and many package inserts approved by the Food and Drug Administration provide guidance regarding immunization with live vaccines and treatment.

Prescribing information for alemtuzumab, fingolimod, ocrelizumab, and teriflunomide recommends against the use of live vaccines during and immediately preceding treatment. Furthermore, the prescribing information recommends waiting 2-6 months after treatment to immunize with live vaccines, depending on the half-life of the specific therapy.

“The guideline panel identified no evidence that vaccines increase the risk of relapse or worsen relapse severity, but studies are limited,” Dr. Farez and colleagues wrote. “Experts remain concerned that vaccines may worsen relapse severity if given to patients who are actively experiencing an MS relapse.” In addition, use of glucocorticoids may raise concerns about the safety of live-virus vaccines. “Immunization is not typically an urgent need and, in most cases, can be temporarily delayed without a marked increase in infection risk,” the guideline says.
 

Few high-quality studies

Data were lacking or insufficient to assess whether most vaccine-preventable diseases increase the risk of MS exacerbations. “It is probable that individuals with active MS exacerbations have higher odds of varicella zoster virus viral DNA present in peripheral blood mononuclear cells than individuals with MS in remission,” the guideline says.

Human papillomavirus, pertussis, and tetanus toxoid vaccinations probably are associated with a lower likelihood of a subsequent MS diagnosis, and smallpox vaccination is possibly associated with a lower likelihood of a subsequent MS diagnosis, the review found.

Studies included in the systematic review did not address whether live-attenuated vaccines are as effective in patients with MS as they are in the general population. With regard to the effectiveness of inactivated vaccines, patients with MS possibly are less likely to have a sufficient response to influenza vaccination, compared with controls.

The systematic review “found few high-quality studies to inform recommendations,” the authors said. “As more [immunosuppressive or immunomodulating] agents are developed to manage chronic diseases such as MS, long-term prospective cohort studies are required to evaluate both the safety and effectiveness of immunizations in MS.”

Dr. Farez has received funding for travel from Teva Argentina, Novartis Argentina, and Merck Serono Argentina and has received research support from Biogen. Coauthors’ disclosures included financial ties to pharmaceutical companies.

[email protected]

SOURCE: Farez M et al. Neurology. 2019 Aug 28. doi: 10.1212/WNL.0000000000008157.

Patients with multiple sclerosis (MS) should follow local vaccine standards and receive the yearly influenza vaccine, unless there are specific contraindications, such as active treatment with immunosuppressive or immunomodulating agents, according to an American Academy of Neurology practice guideline.

itsmejust/Thinkstock

A summary of the guideline on vaccine-preventable infections and immunization in MS was published online Aug. 28 in Neurology. The new effort updates a 2002 guideline on this topic and incorporates new evidence, vaccines, and disease-modifying therapies (DMTs). The guideline was endorsed by the Consortium of Multiple Sclerosis Centers and by the Multiple Sclerosis Association of America.

To create the guideline, lead author Mauricio F. Farez, MD, of the Raúl Carrea Institute for Neurological Research (FLENI) in Buenos Aires and colleagues on the 17-member guideline panel performed a systematic review of the evidence and reached consensus on recommendations using a modified Delphi voting process. The review included randomized, controlled trials; cohort studies; and case-control studies published between 1990 and March 2018.

“Immunosuppressive or immunomodulating agents used to treat MS may suppress or modulate normal immune function. These drugs may increase susceptibility to infections and may reduce vaccine effectiveness because of a decreased ability to mount an immune response,” the authors said.

Based on its review of the evidence, principles of care, and inferences, the authors made the following eight recommendations:

• Clinicians should discuss with patients the evidence regarding immunization in MS (Level B). In addition, clinicians should examine patients’ opinions, preferences, and questions regarding immunizations (Level B).
• Clinicians should recommend that patients with MS follow all local vaccine standards in the absence of specific contraindications (Level B).
• Clinicians should consider local risks of vaccine-preventable diseases when counseling patients (Level B).
• Clinicians should recommend that patients with MS receive the influenza vaccination if there is no specific contraindication, such as a previous severe reaction (Level B).
• When treatment with an immunosuppressive or immunomodulating agent is considered, clinicians should counsel patients about infection risks associated with the specific medication and the treatment-specific vaccination guidance in the medication’s prescribing instructions (Level B). In addition, physicians should assess patients’ vaccination status before prescribing immunosuppressive or immunomodulating therapy and vaccinate patients according to local regulatory standards and treatment-specific infectious risks at least 4-6 weeks before initiating therapy, as advised by the prescribing information (Level B). Furthermore, clinicians may discuss the advantages of vaccination soon after MS diagnosis, regardless of initial therapeutic plans, to prevent delays should immunosuppressive or immunomodulating therapies be initiated in the future (Level C, based on variation in patient preferences).
• Clinicians must screen for certain infections (such as hepatitis, tuberculosis, and varicella zoster virus) according to a medication’s prescribing information before starting immunosuppressive or immunomodulating treatment (Level A) and should treat patients who have latent infections before MS treatment according to the medication prescribing information (Level B, based on feasibility and cost relative to benefit). Further, in high-risk populations or in countries with a high burden of infectious disease, clinicians must screen for latent infections before starting immunosuppressive or immunomodulating medications, even when such screening is not specifically mentioned in the prescribing information (Level A). Clinicians should consult infectious disease or other specialists about treating patients with latent infection before starting immunosuppressive or immunomodulating medications (Level B).
• Clinicians should recommend against live-attenuated vaccines in people with MS who receive immunosuppressive or immunomodulating therapies or have recently discontinued these therapies (Level B, based on importance of outcomes). When the risk of infection is high, clinicians may recommend live-attenuated vaccines if killed vaccines are unavailable (Level C, based on variation in patient preferences, benefit relative to harm, and importance of outcomes).
• If a patient with MS is experiencing a relapse, clinicians should delay vaccination until the relapse has clinically resolved or is no longer active, often many weeks after relapse onset (Level B).

Personal and population-level benefits

“There is no evidence that vaccination increases the risk of MS exacerbation, although the literature is sparse,” the authors said. “In addition to conferring personal benefits, vaccination of the MS patient population contributes to the well-established phenomenon of herd immunity for the communities in which patients with MS live,” the authors wrote.

Because influenza infection has known risks of exacerbation and morbidity, whereas influenza vaccine has no identified risks of exacerbation, “benefits of influenza vaccination outweigh the risks in most scenarios, although patients with MS receiving some [immunosuppressive or immunomodulating] treatments (fingolimod [Gilenya], glatiramer acetate [Copaxone], and mitoxantrone) may have a reduced response to influenza vaccination,” the authors said. Studies in patients with diseases other than MS suggest that rituximab (Rituxan) also may be associated with reduced influenza vaccine responsiveness.

Immunosuppressive or immunomodulatory medications including alemtuzumab (Lemtrada), dimethyl fumarate (Tecfidera), fingolimod, mitoxantrone, natalizumab (Tysabri), ocrelizumab (Ocrevus), rituximab, and teriflunomide (Aubagio) have been associated with severe occurrences or recurrences of vaccine-preventable infections, and many package inserts approved by the Food and Drug Administration provide guidance regarding immunization with live vaccines and treatment.

Prescribing information for alemtuzumab, fingolimod, ocrelizumab, and teriflunomide recommends against the use of live vaccines during and immediately preceding treatment. Furthermore, the prescribing information recommends waiting 2-6 months after treatment to immunize with live vaccines, depending on the half-life of the specific therapy.

“The guideline panel identified no evidence that vaccines increase the risk of relapse or worsen relapse severity, but studies are limited,” Dr. Farez and colleagues wrote. “Experts remain concerned that vaccines may worsen relapse severity if given to patients who are actively experiencing an MS relapse.” In addition, use of glucocorticoids may raise concerns about the safety of live-virus vaccines. “Immunization is not typically an urgent need and, in most cases, can be temporarily delayed without a marked increase in infection risk,” the guideline says.
 

Few high-quality studies

Data were lacking or insufficient to assess whether most vaccine-preventable diseases increase the risk of MS exacerbations. “It is probable that individuals with active MS exacerbations have higher odds of varicella zoster virus viral DNA present in peripheral blood mononuclear cells than individuals with MS in remission,” the guideline says.

Human papillomavirus, pertussis, and tetanus toxoid vaccinations probably are associated with a lower likelihood of a subsequent MS diagnosis, and smallpox vaccination is possibly associated with a lower likelihood of a subsequent MS diagnosis, the review found.

Studies included in the systematic review did not address whether live-attenuated vaccines are as effective in patients with MS as they are in the general population. With regard to the effectiveness of inactivated vaccines, patients with MS possibly are less likely to have a sufficient response to influenza vaccination, compared with controls.

The systematic review “found few high-quality studies to inform recommendations,” the authors said. “As more [immunosuppressive or immunomodulating] agents are developed to manage chronic diseases such as MS, long-term prospective cohort studies are required to evaluate both the safety and effectiveness of immunizations in MS.”

Dr. Farez has received funding for travel from Teva Argentina, Novartis Argentina, and Merck Serono Argentina and has received research support from Biogen. Coauthors’ disclosures included financial ties to pharmaceutical companies.

[email protected]

SOURCE: Farez M et al. Neurology. 2019 Aug 28. doi: 10.1212/WNL.0000000000008157.

Patients with multiple sclerosis (MS) should follow local vaccine standards and receive the yearly influenza vaccine, unless there are specific contraindications, such as active treatment with immunosuppressive or immunomodulating agents, according to an American Academy of Neurology practice guideline.

itsmejust/Thinkstock

A summary of the guideline on vaccine-preventable infections and immunization in MS was published online Aug. 28 in Neurology. The new effort updates a 2002 guideline on this topic and incorporates new evidence, vaccines, and disease-modifying therapies (DMTs). The guideline was endorsed by the Consortium of Multiple Sclerosis Centers and by the Multiple Sclerosis Association of America.

To create the guideline, lead author Mauricio F. Farez, MD, of the Raúl Carrea Institute for Neurological Research (FLENI) in Buenos Aires and colleagues on the 17-member guideline panel performed a systematic review of the evidence and reached consensus on recommendations using a modified Delphi voting process. The review included randomized, controlled trials; cohort studies; and case-control studies published between 1990 and March 2018.

“Immunosuppressive or immunomodulating agents used to treat MS may suppress or modulate normal immune function. These drugs may increase susceptibility to infections and may reduce vaccine effectiveness because of a decreased ability to mount an immune response,” the authors said.

Based on its review of the evidence, principles of care, and inferences, the authors made the following eight recommendations:

• Clinicians should discuss with patients the evidence regarding immunization in MS (Level B). In addition, clinicians should examine patients’ opinions, preferences, and questions regarding immunizations (Level B).
• Clinicians should recommend that patients with MS follow all local vaccine standards in the absence of specific contraindications (Level B).
• Clinicians should consider local risks of vaccine-preventable diseases when counseling patients (Level B).
• Clinicians should recommend that patients with MS receive the influenza vaccination if there is no specific contraindication, such as a previous severe reaction (Level B).
• When treatment with an immunosuppressive or immunomodulating agent is considered, clinicians should counsel patients about infection risks associated with the specific medication and the treatment-specific vaccination guidance in the medication’s prescribing instructions (Level B). In addition, physicians should assess patients’ vaccination status before prescribing immunosuppressive or immunomodulating therapy and vaccinate patients according to local regulatory standards and treatment-specific infectious risks at least 4-6 weeks before initiating therapy, as advised by the prescribing information (Level B). Furthermore, clinicians may discuss the advantages of vaccination soon after MS diagnosis, regardless of initial therapeutic plans, to prevent delays should immunosuppressive or immunomodulating therapies be initiated in the future (Level C, based on variation in patient preferences).
• Clinicians must screen for certain infections (such as hepatitis, tuberculosis, and varicella zoster virus) according to a medication’s prescribing information before starting immunosuppressive or immunomodulating treatment (Level A) and should treat patients who have latent infections before MS treatment according to the medication prescribing information (Level B, based on feasibility and cost relative to benefit). Further, in high-risk populations or in countries with a high burden of infectious disease, clinicians must screen for latent infections before starting immunosuppressive or immunomodulating medications, even when such screening is not specifically mentioned in the prescribing information (Level A). Clinicians should consult infectious disease or other specialists about treating patients with latent infection before starting immunosuppressive or immunomodulating medications (Level B).
• Clinicians should recommend against live-attenuated vaccines in people with MS who receive immunosuppressive or immunomodulating therapies or have recently discontinued these therapies (Level B, based on importance of outcomes). When the risk of infection is high, clinicians may recommend live-attenuated vaccines if killed vaccines are unavailable (Level C, based on variation in patient preferences, benefit relative to harm, and importance of outcomes).
• If a patient with MS is experiencing a relapse, clinicians should delay vaccination until the relapse has clinically resolved or is no longer active, often many weeks after relapse onset (Level B).

Personal and population-level benefits

“There is no evidence that vaccination increases the risk of MS exacerbation, although the literature is sparse,” the authors said. “In addition to conferring personal benefits, vaccination of the MS patient population contributes to the well-established phenomenon of herd immunity for the communities in which patients with MS live,” the authors wrote.

Because influenza infection has known risks of exacerbation and morbidity, whereas influenza vaccine has no identified risks of exacerbation, “benefits of influenza vaccination outweigh the risks in most scenarios, although patients with MS receiving some [immunosuppressive or immunomodulating] treatments (fingolimod [Gilenya], glatiramer acetate [Copaxone], and mitoxantrone) may have a reduced response to influenza vaccination,” the authors said. Studies in patients with diseases other than MS suggest that rituximab (Rituxan) also may be associated with reduced influenza vaccine responsiveness.

Immunosuppressive or immunomodulatory medications including alemtuzumab (Lemtrada), dimethyl fumarate (Tecfidera), fingolimod, mitoxantrone, natalizumab (Tysabri), ocrelizumab (Ocrevus), rituximab, and teriflunomide (Aubagio) have been associated with severe occurrences or recurrences of vaccine-preventable infections, and many package inserts approved by the Food and Drug Administration provide guidance regarding immunization with live vaccines and treatment.

Prescribing information for alemtuzumab, fingolimod, ocrelizumab, and teriflunomide recommends against the use of live vaccines during and immediately preceding treatment. Furthermore, the prescribing information recommends waiting 2-6 months after treatment to immunize with live vaccines, depending on the half-life of the specific therapy.

“The guideline panel identified no evidence that vaccines increase the risk of relapse or worsen relapse severity, but studies are limited,” Dr. Farez and colleagues wrote. “Experts remain concerned that vaccines may worsen relapse severity if given to patients who are actively experiencing an MS relapse.” In addition, use of glucocorticoids may raise concerns about the safety of live-virus vaccines. “Immunization is not typically an urgent need and, in most cases, can be temporarily delayed without a marked increase in infection risk,” the guideline says.
 

Few high-quality studies

Data were lacking or insufficient to assess whether most vaccine-preventable diseases increase the risk of MS exacerbations. “It is probable that individuals with active MS exacerbations have higher odds of varicella zoster virus viral DNA present in peripheral blood mononuclear cells than individuals with MS in remission,” the guideline says.

Human papillomavirus, pertussis, and tetanus toxoid vaccinations probably are associated with a lower likelihood of a subsequent MS diagnosis, and smallpox vaccination is possibly associated with a lower likelihood of a subsequent MS diagnosis, the review found.

Studies included in the systematic review did not address whether live-attenuated vaccines are as effective in patients with MS as they are in the general population. With regard to the effectiveness of inactivated vaccines, patients with MS possibly are less likely to have a sufficient response to influenza vaccination, compared with controls.

The systematic review “found few high-quality studies to inform recommendations,” the authors said. “As more [immunosuppressive or immunomodulating] agents are developed to manage chronic diseases such as MS, long-term prospective cohort studies are required to evaluate both the safety and effectiveness of immunizations in MS.”

Dr. Farez has received funding for travel from Teva Argentina, Novartis Argentina, and Merck Serono Argentina and has received research support from Biogen. Coauthors’ disclosures included financial ties to pharmaceutical companies.

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SOURCE: Farez M et al. Neurology. 2019 Aug 28. doi: 10.1212/WNL.0000000000008157.