TOPLINE:

A data-driven subclassification of antineutrophil cytoplasmic antibody (ANCA)–associated vasculitis has identified five distinct clusters with varying degrees of kidney involvement and systemic inflammation, offering insights into improved patient stratification and treatment approaches.

METHODOLOGY:

• ANCA-associated vasculitis is a rare and complex autoimmune disease that is traditionally classified into granulomatosis with polyangiitis (GPA) and microscopic polyangiitis (MPA).
• Researchers employed advanced artificial intelligence and big data techniques to identify phenotypically distinct subgroups of ANCA-associated vasculitis and developed a classification system using real-world patient data from the Federated Vasculitis Registry consortium.
• They included 3868 patients diagnosed with ANCA-associated vasculitis between November 1, 1966, and March 1, 2023 (mean age at diagnosis, 57.2 years; 51.9% men), across six European vasculitis registries; while a majority of patients (62.9%) were diagnosed with GPA, the remaining 37.1% were diagnosed with MPA.
• Overall, 17 clinical and demographic variables such as the age at diagnosis, gender, serum creatinine and C-reactive protein levels, the type of ANCA, and the involvement of various organ systems were used to create a model for categorizing patients into different clusters.
• The median follow-up duration was 4.2 years.

TAKEAWAY:

• Five distinct clusters were identified in ANCA-associated vasculitis; three had significant kidney involvement (the severe kidney cluster, myeloperoxidase-ANCA-positive kidney cluster, and proteinase 3-ANCA-positive kidney cluster) and two had minimal kidney involvement (young respiratory cluster and inflammatory multisystem cluster).
• The clusters with significant kidney involvement were associated with poorer outcomes, including a higher risk for kidney failure and death. The severe kidney cluster had the poorest prognosis, with mortality and the rate of end-stage kidney failure being 30.5% and 41.6%, respectively.
• The young respiratory cluster, characterized by predominant ear-nose-throat involvement and low systemic inflammation, showed the best prognostic outcomes.
• This cluster membership model showed a greater predictive accuracy for patient and kidney survival than traditional methods based on clinical diagnosis or ANCA specificity.

IN PRACTICE:

“These findings highlight the necessity of recognizing severe kidney disease at the time of diagnosis as an indicator of poor outcome, thereby necessitating intensified treatment approaches,” experts from the Department of Internal Medicine IV (Nephrology and Hypertension), Medical University of Innsbruck, Austria, wrote in an accompanying editorial published online on August 22, 2024, in The Lancet Rheumatology.

SOURCE:

This study was led by Karl Gisslander, Department of Clinical Sciences, Lund University, Lund, Sweden, and was published online on August 22, 2024, in The Lancet Rheumatology.

LIMITATIONS:

Data on estimated glomerular filtration rate recovery in clusters with kidney disease were lacking. Populations from East Asia, where myeloperoxidase-ANCA positivity is more prevalent, were not included.

DISCLOSURES:

This study received funding from the European Union’s Horizon 2020 research and innovation program under the European Joint Programme on Rare Diseases. Some authors declared serving on advisory boards or receiving grants, contracts, travel support, consulting fees, payments, or honoraria from various pharmaceutical companies and other institutions.

This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article appeared on Medscape.com.

TOPLINE:

A data-driven subclassification of antineutrophil cytoplasmic antibody (ANCA)–associated vasculitis has identified five distinct clusters with varying degrees of kidney involvement and systemic inflammation, offering insights into improved patient stratification and treatment approaches.

METHODOLOGY:

• ANCA-associated vasculitis is a rare and complex autoimmune disease that is traditionally classified into granulomatosis with polyangiitis (GPA) and microscopic polyangiitis (MPA).
• Researchers employed advanced artificial intelligence and big data techniques to identify phenotypically distinct subgroups of ANCA-associated vasculitis and developed a classification system using real-world patient data from the Federated Vasculitis Registry consortium.
• They included 3868 patients diagnosed with ANCA-associated vasculitis between November 1, 1966, and March 1, 2023 (mean age at diagnosis, 57.2 years; 51.9% men), across six European vasculitis registries; while a majority of patients (62.9%) were diagnosed with GPA, the remaining 37.1% were diagnosed with MPA.
• Overall, 17 clinical and demographic variables such as the age at diagnosis, gender, serum creatinine and C-reactive protein levels, the type of ANCA, and the involvement of various organ systems were used to create a model for categorizing patients into different clusters.
• The median follow-up duration was 4.2 years.

TAKEAWAY:

• Five distinct clusters were identified in ANCA-associated vasculitis; three had significant kidney involvement (the severe kidney cluster, myeloperoxidase-ANCA-positive kidney cluster, and proteinase 3-ANCA-positive kidney cluster) and two had minimal kidney involvement (young respiratory cluster and inflammatory multisystem cluster).
• The clusters with significant kidney involvement were associated with poorer outcomes, including a higher risk for kidney failure and death. The severe kidney cluster had the poorest prognosis, with mortality and the rate of end-stage kidney failure being 30.5% and 41.6%, respectively.
• The young respiratory cluster, characterized by predominant ear-nose-throat involvement and low systemic inflammation, showed the best prognostic outcomes.
• This cluster membership model showed a greater predictive accuracy for patient and kidney survival than traditional methods based on clinical diagnosis or ANCA specificity.

IN PRACTICE:

“These findings highlight the necessity of recognizing severe kidney disease at the time of diagnosis as an indicator of poor outcome, thereby necessitating intensified treatment approaches,” experts from the Department of Internal Medicine IV (Nephrology and Hypertension), Medical University of Innsbruck, Austria, wrote in an accompanying editorial published online on August 22, 2024, in The Lancet Rheumatology.

SOURCE:

This study was led by Karl Gisslander, Department of Clinical Sciences, Lund University, Lund, Sweden, and was published online on August 22, 2024, in The Lancet Rheumatology.

LIMITATIONS:

Data on estimated glomerular filtration rate recovery in clusters with kidney disease were lacking. Populations from East Asia, where myeloperoxidase-ANCA positivity is more prevalent, were not included.

DISCLOSURES:

This study received funding from the European Union’s Horizon 2020 research and innovation program under the European Joint Programme on Rare Diseases. Some authors declared serving on advisory boards or receiving grants, contracts, travel support, consulting fees, payments, or honoraria from various pharmaceutical companies and other institutions.

This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article appeared on Medscape.com.

TOPLINE:

A data-driven subclassification of antineutrophil cytoplasmic antibody (ANCA)–associated vasculitis has identified five distinct clusters with varying degrees of kidney involvement and systemic inflammation, offering insights into improved patient stratification and treatment approaches.

METHODOLOGY:

• ANCA-associated vasculitis is a rare and complex autoimmune disease that is traditionally classified into granulomatosis with polyangiitis (GPA) and microscopic polyangiitis (MPA).
• Researchers employed advanced artificial intelligence and big data techniques to identify phenotypically distinct subgroups of ANCA-associated vasculitis and developed a classification system using real-world patient data from the Federated Vasculitis Registry consortium.
• They included 3868 patients diagnosed with ANCA-associated vasculitis between November 1, 1966, and March 1, 2023 (mean age at diagnosis, 57.2 years; 51.9% men), across six European vasculitis registries; while a majority of patients (62.9%) were diagnosed with GPA, the remaining 37.1% were diagnosed with MPA.
• Overall, 17 clinical and demographic variables such as the age at diagnosis, gender, serum creatinine and C-reactive protein levels, the type of ANCA, and the involvement of various organ systems were used to create a model for categorizing patients into different clusters.
• The median follow-up duration was 4.2 years.

TAKEAWAY:

• Five distinct clusters were identified in ANCA-associated vasculitis; three had significant kidney involvement (the severe kidney cluster, myeloperoxidase-ANCA-positive kidney cluster, and proteinase 3-ANCA-positive kidney cluster) and two had minimal kidney involvement (young respiratory cluster and inflammatory multisystem cluster).
• The clusters with significant kidney involvement were associated with poorer outcomes, including a higher risk for kidney failure and death. The severe kidney cluster had the poorest prognosis, with mortality and the rate of end-stage kidney failure being 30.5% and 41.6%, respectively.
• The young respiratory cluster, characterized by predominant ear-nose-throat involvement and low systemic inflammation, showed the best prognostic outcomes.
• This cluster membership model showed a greater predictive accuracy for patient and kidney survival than traditional methods based on clinical diagnosis or ANCA specificity.

IN PRACTICE:

“These findings highlight the necessity of recognizing severe kidney disease at the time of diagnosis as an indicator of poor outcome, thereby necessitating intensified treatment approaches,” experts from the Department of Internal Medicine IV (Nephrology and Hypertension), Medical University of Innsbruck, Austria, wrote in an accompanying editorial published online on August 22, 2024, in The Lancet Rheumatology.

SOURCE:

This study was led by Karl Gisslander, Department of Clinical Sciences, Lund University, Lund, Sweden, and was published online on August 22, 2024, in The Lancet Rheumatology.

LIMITATIONS:

Data on estimated glomerular filtration rate recovery in clusters with kidney disease were lacking. Populations from East Asia, where myeloperoxidase-ANCA positivity is more prevalent, were not included.

DISCLOSURES:

This study received funding from the European Union’s Horizon 2020 research and innovation program under the European Joint Programme on Rare Diseases. Some authors declared serving on advisory boards or receiving grants, contracts, travel support, consulting fees, payments, or honoraria from various pharmaceutical companies and other institutions.

This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article appeared on Medscape.com.

The term “reform school” is a bit outdated. It used to refer to institutions where young offenders were sent instead of prison. Some argue that pharmacy benefit managers (PBMs) should bypass reform school and go straight to prison. “PBM reform” has become a ubiquitous term, encompassing any legislative or regulatory efforts aimed at curbing PBMs’ bad behavior. When discussing PBM reform, it’s crucial to understand the various segments of the healthcare system affected by PBMs. This complexity often makes it challenging to determine what these reform packages would actually achieve and who they would benefit.

Pharmacists have long been vocal critics of PBMs, and while their issues are extremely important, it is essential to remember that the ultimate victims of PBM misconduct, in terms of access to care, are patients. At some point, we will all be patients, making this issue universally relevant. It has been quite challenging to follow federal legislation on this topic as these packages attempt to address a number of bad behaviors by PBMs affecting a variety of victims. This discussion will examine those reforms that would directly improve patient’s access to available and affordable medications.
 

Policy Categories of PBM Reform

There are five policy categories of PBM reform legislation overall, including three that have the greatest potential to directly address patient needs. The first is patient access to medications (utilization management, copay assistance, prior authorization, etc.), followed by delinking drug list prices from PBM income and pass-through of price concessions from the manufacturer. The remaining two categories involve transparency and pharmacy-facing reform, both of which are very important. However, this discussion will revolve around the first three categories. It should be noted that many of the legislation packages addressing the categories of patient access, delinking, and pass-through also include transparency issues, particularly as they relate to pharmacy-facing issues.

Patient Access to Medications — Step Therapy Legislation

One of the major obstacles to patient access to medications is the use of PBM utilization management tools such as step therapy (“fail first”), prior authorizations, nonmedical switching, and formulary exclusions. These tools dictate when patients can obtain necessary medications and for how long patients who are stable on their current treatments can remain on them.

While many states have enacted step therapy reforms to prevent stable patients from being whip-sawed between medications that maximize PBM profits (often labeled as “savings”), these state protections apply only to state-regulated health plans. These include fully insured health plans and those offered through the Affordable Care Act’s Health Insurance Marketplace. It also includes state employees, state corrections, and, in some cases, state labor unions. State legislation does not extend to patients covered by employer self-insured health plans, called ERISA plans for the federal law that governs employee benefit plans, the Employee Retirement Income Security Act. These ERISA plans include nearly 35 million people nationwide.

This is where the Safe Step Act (S.652/H.R.2630) becomes crucial, as it allows employees to request exceptions to harmful fail-first protocols. The bill has gained significant momentum, having been reported out of the Senate HELP Committee and discussed in House markups. The Safe Step Act would mandate that an exception to a step therapy protocol must be granted if:

• The required treatment has been ineffective
• The treatment is expected to be ineffective, and delaying effective treatment would lead to irreversible consequences
• The treatment will cause or is likely to cause an adverse reaction
• The treatment is expected to prevent the individual from performing daily activities or occupational responsibilities
• The individual is stable on their current prescription drugs
• There are other circumstances as determined by the Employee Benefits Security Administration

This legislation is vital for ensuring that patients have timely access to the medications they need without unnecessary delays or disruptions.
 

Patient Access to Medications — Prior Authorizations

Another significant issue affecting patient access to medications is prior authorizations (PAs). According to an American Medical Association survey, nearly one in four physicians (24%) report that a PA has led to a serious adverse event for a patient in their care. In rheumatology, PAs often result in delays in care (even for those initially approved) and a significant increase in steroid usage. In particular, PAs in Medicare Advantage (MA) plans are harmful to Medicare beneficiaries.

The Improving Seniors’ Timely Access to Care Act (H.R.8702 / S.4532) aims to reform PAs used in MA plans, making the process more efficient and transparent to improve access to care for seniors. Unfortunately, it does not cover Part D drugs and may only cover Part B drugs depending on the MA plan’s benefit package. Here are the key provisions of the act:

• Electronic PA: Implementing real-time decisions for routinely approved items and services.
• Transparency: Requiring annual publication of PA information, such as the percentage of requests approved and the average response time.
• Quality and Timeliness Standards: The Centers for Medicare & Medicaid Services (CMS) will set standards for the quality and timeliness of PA determinations.
• Streamlining Approvals: Simplifying the approval process and reducing the time allowed for health plans to consider PA requests.

This bill passed the House in September 2022 but stalled in the Senate because of an unfavorable Congressional Budget Office score. CMS has since finalized portions of this bill via regulation, zeroing out the CBO score and increasing the chances of its passage.
 

Delinking Drug Prices from PBM Income and Pass-Through of Price Concessions

Affordability is a crucial aspect of accessibility, especially when it comes to medications. Over the years, we’ve learned that PBMs often favor placing the highest list price drugs on formularies because the rebates and various fees they receive from manufacturers are based on a percentage of the list price. In other words, the higher the medication’s price, the more money the PBM makes.

This practice is evident in both commercial and government formularies, where brand-name drugs are often preferred, while lower-priced generics are either excluded or placed on higher tiers. As a result, while major PBMs benefit from these rebates and fees, patients continue to pay their cost share based on the list price of the medication.

To improve the affordability of medications, a key aspect of PBM reform should be to disincentivize PBMs from selecting higher-priced medications and/or require the pass-through of manufacturer price concessions to patients.

Several major PBM reform bills are currently being considered that address either the delinking of price concessions from the list price of the drug or some form of pass-through of these concessions. These reforms are essential to ensure that patients can access affordable medications without being burdened by inflated costs.

The legislation includes the Pharmacy Benefit Manager Reform Act (S.1339); the Modernizing & Ensuring PBM Accountability Act (S.2973); the Better Mental Health Care, Lower Cost Drugs, and Extenders Act (S.3430); the Protecting Patients Against PBM Abuses Act (H.R. 2880); the DRUG Act (S.2474 / H.R.6283); and the Share the Savings with Seniors Act (S.2474 / H.R.5376).

As with all legislation, there are limitations and compromises in each of these. However, these bills are a good first step in addressing PBM remuneration (rebates and fees) based on the list price of the drug and/or passing through to the patient the benefit of manufacturer price concessions. By focusing on key areas like utilization management, delinking drug prices from PBM income, and allowing patients to directly benefit from manufacturer price concessions, we can work toward a more equitable and efficient healthcare system. Reigning in PBM bad behavior is a challenge, but the potential benefits for patient care and access make it a crucial fight worth pursuing.

Please help in efforts to improve patients’ access to available and affordable medications by contacting your representatives in Congress to impart to them the importance of passing legislation. The CSRO’s legislative map tool can help to inform you of the latest information on these and other bills and assist you in engaging with your representatives on them.

Dr. Feldman is a rheumatologist in private practice with The Rheumatology Group in New Orleans. She is the CSRO’s vice president of Advocacy and Government Affairs and its immediate past president, as well as past chair of the Alliance for Safe Biologic Medicines and a past member of the American College of Rheumatology insurance subcommittee. She has no relevant conflicts of interest to disclose. You can reach her at [email protected].

The term “reform school” is a bit outdated. It used to refer to institutions where young offenders were sent instead of prison. Some argue that pharmacy benefit managers (PBMs) should bypass reform school and go straight to prison. “PBM reform” has become a ubiquitous term, encompassing any legislative or regulatory efforts aimed at curbing PBMs’ bad behavior. When discussing PBM reform, it’s crucial to understand the various segments of the healthcare system affected by PBMs. This complexity often makes it challenging to determine what these reform packages would actually achieve and who they would benefit.

Pharmacists have long been vocal critics of PBMs, and while their issues are extremely important, it is essential to remember that the ultimate victims of PBM misconduct, in terms of access to care, are patients. At some point, we will all be patients, making this issue universally relevant. It has been quite challenging to follow federal legislation on this topic as these packages attempt to address a number of bad behaviors by PBMs affecting a variety of victims. This discussion will examine those reforms that would directly improve patient’s access to available and affordable medications.
 

Policy Categories of PBM Reform

There are five policy categories of PBM reform legislation overall, including three that have the greatest potential to directly address patient needs. The first is patient access to medications (utilization management, copay assistance, prior authorization, etc.), followed by delinking drug list prices from PBM income and pass-through of price concessions from the manufacturer. The remaining two categories involve transparency and pharmacy-facing reform, both of which are very important. However, this discussion will revolve around the first three categories. It should be noted that many of the legislation packages addressing the categories of patient access, delinking, and pass-through also include transparency issues, particularly as they relate to pharmacy-facing issues.

Patient Access to Medications — Step Therapy Legislation

One of the major obstacles to patient access to medications is the use of PBM utilization management tools such as step therapy (“fail first”), prior authorizations, nonmedical switching, and formulary exclusions. These tools dictate when patients can obtain necessary medications and for how long patients who are stable on their current treatments can remain on them.

While many states have enacted step therapy reforms to prevent stable patients from being whip-sawed between medications that maximize PBM profits (often labeled as “savings”), these state protections apply only to state-regulated health plans. These include fully insured health plans and those offered through the Affordable Care Act’s Health Insurance Marketplace. It also includes state employees, state corrections, and, in some cases, state labor unions. State legislation does not extend to patients covered by employer self-insured health plans, called ERISA plans for the federal law that governs employee benefit plans, the Employee Retirement Income Security Act. These ERISA plans include nearly 35 million people nationwide.

This is where the Safe Step Act (S.652/H.R.2630) becomes crucial, as it allows employees to request exceptions to harmful fail-first protocols. The bill has gained significant momentum, having been reported out of the Senate HELP Committee and discussed in House markups. The Safe Step Act would mandate that an exception to a step therapy protocol must be granted if:

• The required treatment has been ineffective
• The treatment is expected to be ineffective, and delaying effective treatment would lead to irreversible consequences
• The treatment will cause or is likely to cause an adverse reaction
• The treatment is expected to prevent the individual from performing daily activities or occupational responsibilities
• The individual is stable on their current prescription drugs
• There are other circumstances as determined by the Employee Benefits Security Administration

This legislation is vital for ensuring that patients have timely access to the medications they need without unnecessary delays or disruptions.
 

Patient Access to Medications — Prior Authorizations

Another significant issue affecting patient access to medications is prior authorizations (PAs). According to an American Medical Association survey, nearly one in four physicians (24%) report that a PA has led to a serious adverse event for a patient in their care. In rheumatology, PAs often result in delays in care (even for those initially approved) and a significant increase in steroid usage. In particular, PAs in Medicare Advantage (MA) plans are harmful to Medicare beneficiaries.

The Improving Seniors’ Timely Access to Care Act (H.R.8702 / S.4532) aims to reform PAs used in MA plans, making the process more efficient and transparent to improve access to care for seniors. Unfortunately, it does not cover Part D drugs and may only cover Part B drugs depending on the MA plan’s benefit package. Here are the key provisions of the act:

• Electronic PA: Implementing real-time decisions for routinely approved items and services.
• Transparency: Requiring annual publication of PA information, such as the percentage of requests approved and the average response time.
• Quality and Timeliness Standards: The Centers for Medicare & Medicaid Services (CMS) will set standards for the quality and timeliness of PA determinations.
• Streamlining Approvals: Simplifying the approval process and reducing the time allowed for health plans to consider PA requests.

This bill passed the House in September 2022 but stalled in the Senate because of an unfavorable Congressional Budget Office score. CMS has since finalized portions of this bill via regulation, zeroing out the CBO score and increasing the chances of its passage.
 

Delinking Drug Prices from PBM Income and Pass-Through of Price Concessions

Affordability is a crucial aspect of accessibility, especially when it comes to medications. Over the years, we’ve learned that PBMs often favor placing the highest list price drugs on formularies because the rebates and various fees they receive from manufacturers are based on a percentage of the list price. In other words, the higher the medication’s price, the more money the PBM makes.

This practice is evident in both commercial and government formularies, where brand-name drugs are often preferred, while lower-priced generics are either excluded or placed on higher tiers. As a result, while major PBMs benefit from these rebates and fees, patients continue to pay their cost share based on the list price of the medication.

To improve the affordability of medications, a key aspect of PBM reform should be to disincentivize PBMs from selecting higher-priced medications and/or require the pass-through of manufacturer price concessions to patients.

Several major PBM reform bills are currently being considered that address either the delinking of price concessions from the list price of the drug or some form of pass-through of these concessions. These reforms are essential to ensure that patients can access affordable medications without being burdened by inflated costs.

The legislation includes the Pharmacy Benefit Manager Reform Act (S.1339); the Modernizing & Ensuring PBM Accountability Act (S.2973); the Better Mental Health Care, Lower Cost Drugs, and Extenders Act (S.3430); the Protecting Patients Against PBM Abuses Act (H.R. 2880); the DRUG Act (S.2474 / H.R.6283); and the Share the Savings with Seniors Act (S.2474 / H.R.5376).

As with all legislation, there are limitations and compromises in each of these. However, these bills are a good first step in addressing PBM remuneration (rebates and fees) based on the list price of the drug and/or passing through to the patient the benefit of manufacturer price concessions. By focusing on key areas like utilization management, delinking drug prices from PBM income, and allowing patients to directly benefit from manufacturer price concessions, we can work toward a more equitable and efficient healthcare system. Reigning in PBM bad behavior is a challenge, but the potential benefits for patient care and access make it a crucial fight worth pursuing.

Please help in efforts to improve patients’ access to available and affordable medications by contacting your representatives in Congress to impart to them the importance of passing legislation. The CSRO’s legislative map tool can help to inform you of the latest information on these and other bills and assist you in engaging with your representatives on them.

Dr. Feldman is a rheumatologist in private practice with The Rheumatology Group in New Orleans. She is the CSRO’s vice president of Advocacy and Government Affairs and its immediate past president, as well as past chair of the Alliance for Safe Biologic Medicines and a past member of the American College of Rheumatology insurance subcommittee. She has no relevant conflicts of interest to disclose. You can reach her at [email protected].

The term “reform school” is a bit outdated. It used to refer to institutions where young offenders were sent instead of prison. Some argue that pharmacy benefit managers (PBMs) should bypass reform school and go straight to prison. “PBM reform” has become a ubiquitous term, encompassing any legislative or regulatory efforts aimed at curbing PBMs’ bad behavior. When discussing PBM reform, it’s crucial to understand the various segments of the healthcare system affected by PBMs. This complexity often makes it challenging to determine what these reform packages would actually achieve and who they would benefit.

Pharmacists have long been vocal critics of PBMs, and while their issues are extremely important, it is essential to remember that the ultimate victims of PBM misconduct, in terms of access to care, are patients. At some point, we will all be patients, making this issue universally relevant. It has been quite challenging to follow federal legislation on this topic as these packages attempt to address a number of bad behaviors by PBMs affecting a variety of victims. This discussion will examine those reforms that would directly improve patient’s access to available and affordable medications.
 

Policy Categories of PBM Reform

There are five policy categories of PBM reform legislation overall, including three that have the greatest potential to directly address patient needs. The first is patient access to medications (utilization management, copay assistance, prior authorization, etc.), followed by delinking drug list prices from PBM income and pass-through of price concessions from the manufacturer. The remaining two categories involve transparency and pharmacy-facing reform, both of which are very important. However, this discussion will revolve around the first three categories. It should be noted that many of the legislation packages addressing the categories of patient access, delinking, and pass-through also include transparency issues, particularly as they relate to pharmacy-facing issues.

Patient Access to Medications — Step Therapy Legislation

One of the major obstacles to patient access to medications is the use of PBM utilization management tools such as step therapy (“fail first”), prior authorizations, nonmedical switching, and formulary exclusions. These tools dictate when patients can obtain necessary medications and for how long patients who are stable on their current treatments can remain on them.

While many states have enacted step therapy reforms to prevent stable patients from being whip-sawed between medications that maximize PBM profits (often labeled as “savings”), these state protections apply only to state-regulated health plans. These include fully insured health plans and those offered through the Affordable Care Act’s Health Insurance Marketplace. It also includes state employees, state corrections, and, in some cases, state labor unions. State legislation does not extend to patients covered by employer self-insured health plans, called ERISA plans for the federal law that governs employee benefit plans, the Employee Retirement Income Security Act. These ERISA plans include nearly 35 million people nationwide.

This is where the Safe Step Act (S.652/H.R.2630) becomes crucial, as it allows employees to request exceptions to harmful fail-first protocols. The bill has gained significant momentum, having been reported out of the Senate HELP Committee and discussed in House markups. The Safe Step Act would mandate that an exception to a step therapy protocol must be granted if:

• The required treatment has been ineffective
• The treatment is expected to be ineffective, and delaying effective treatment would lead to irreversible consequences
• The treatment will cause or is likely to cause an adverse reaction
• The treatment is expected to prevent the individual from performing daily activities or occupational responsibilities
• The individual is stable on their current prescription drugs
• There are other circumstances as determined by the Employee Benefits Security Administration

This legislation is vital for ensuring that patients have timely access to the medications they need without unnecessary delays or disruptions.
 

Patient Access to Medications — Prior Authorizations

Another significant issue affecting patient access to medications is prior authorizations (PAs). According to an American Medical Association survey, nearly one in four physicians (24%) report that a PA has led to a serious adverse event for a patient in their care. In rheumatology, PAs often result in delays in care (even for those initially approved) and a significant increase in steroid usage. In particular, PAs in Medicare Advantage (MA) plans are harmful to Medicare beneficiaries.

The Improving Seniors’ Timely Access to Care Act (H.R.8702 / S.4532) aims to reform PAs used in MA plans, making the process more efficient and transparent to improve access to care for seniors. Unfortunately, it does not cover Part D drugs and may only cover Part B drugs depending on the MA plan’s benefit package. Here are the key provisions of the act:

• Electronic PA: Implementing real-time decisions for routinely approved items and services.
• Transparency: Requiring annual publication of PA information, such as the percentage of requests approved and the average response time.
• Quality and Timeliness Standards: The Centers for Medicare & Medicaid Services (CMS) will set standards for the quality and timeliness of PA determinations.
• Streamlining Approvals: Simplifying the approval process and reducing the time allowed for health plans to consider PA requests.

This bill passed the House in September 2022 but stalled in the Senate because of an unfavorable Congressional Budget Office score. CMS has since finalized portions of this bill via regulation, zeroing out the CBO score and increasing the chances of its passage.
 

Delinking Drug Prices from PBM Income and Pass-Through of Price Concessions

Affordability is a crucial aspect of accessibility, especially when it comes to medications. Over the years, we’ve learned that PBMs often favor placing the highest list price drugs on formularies because the rebates and various fees they receive from manufacturers are based on a percentage of the list price. In other words, the higher the medication’s price, the more money the PBM makes.

This practice is evident in both commercial and government formularies, where brand-name drugs are often preferred, while lower-priced generics are either excluded or placed on higher tiers. As a result, while major PBMs benefit from these rebates and fees, patients continue to pay their cost share based on the list price of the medication.

To improve the affordability of medications, a key aspect of PBM reform should be to disincentivize PBMs from selecting higher-priced medications and/or require the pass-through of manufacturer price concessions to patients.

Several major PBM reform bills are currently being considered that address either the delinking of price concessions from the list price of the drug or some form of pass-through of these concessions. These reforms are essential to ensure that patients can access affordable medications without being burdened by inflated costs.

The legislation includes the Pharmacy Benefit Manager Reform Act (S.1339); the Modernizing & Ensuring PBM Accountability Act (S.2973); the Better Mental Health Care, Lower Cost Drugs, and Extenders Act (S.3430); the Protecting Patients Against PBM Abuses Act (H.R. 2880); the DRUG Act (S.2474 / H.R.6283); and the Share the Savings with Seniors Act (S.2474 / H.R.5376).

As with all legislation, there are limitations and compromises in each of these. However, these bills are a good first step in addressing PBM remuneration (rebates and fees) based on the list price of the drug and/or passing through to the patient the benefit of manufacturer price concessions. By focusing on key areas like utilization management, delinking drug prices from PBM income, and allowing patients to directly benefit from manufacturer price concessions, we can work toward a more equitable and efficient healthcare system. Reigning in PBM bad behavior is a challenge, but the potential benefits for patient care and access make it a crucial fight worth pursuing.

Please help in efforts to improve patients’ access to available and affordable medications by contacting your representatives in Congress to impart to them the importance of passing legislation. The CSRO’s legislative map tool can help to inform you of the latest information on these and other bills and assist you in engaging with your representatives on them.

Dr. Feldman is a rheumatologist in private practice with The Rheumatology Group in New Orleans. She is the CSRO’s vice president of Advocacy and Government Affairs and its immediate past president, as well as past chair of the Alliance for Safe Biologic Medicines and a past member of the American College of Rheumatology insurance subcommittee. She has no relevant conflicts of interest to disclose. You can reach her at [email protected].

TOPLINE:

A greater proportion of patients with active systemic lupus erythematosus (SLE) treated with belimumab plus standard therapy achieved the newest definitions for remission and low disease activity compared with those treated with placebo plus standard therapy, with benefits observed as early as week 28 for remission and week 8 for disease activity, according to pooled results from five clinical trials.

METHODOLOGY:

• Researchers conducted an integrated post hoc analysis of five randomized phase 3 clinical trials to evaluate the attainment of remission and low disease activity in adult patients with active, autoantibody-positive SLE.
• A total of 3086 patients (median age, 36 years; 94% women) were randomly assigned to receive standard therapy with intravenous belimumab 10 mg/kg monthly or subcutaneous belimumab 200 mg weekly (n = 1869) or placebo (n = 1217).
• The proportion of patients who achieved definitions of remission in SLE (DORIS) remission and lupus low disease activity state (LLDAS) by visit up to week 52 was assessed.
• The analysis also evaluated the time taken to achieve sustained (at least two consecutive visits) and maintained (up to week 52) DORIS remission and LLDAS.

TAKEAWAY:

• At week 52, a higher proportion of patients receiving belimumab vs placebo achieved DORIS remission (8% vs 6%; risk ratio [RR], 1.51; P = .0055) and LLDAS (17% vs 10%; RR, 1.74; P < .0001).
• The earliest observed significant benefit of belimumab over placebo in patients with a higher baseline disease activity was at week 20 for DORIS remission (RR, 2.09; P = .043) and at week 16 for LLDAS (RR, 1.46; P = .034), with both maintained through week 52.
• The proportion of patients who attained DORIS remission and LLDAS as early as week 28 and week 8, respectively, was higher in the belimumab group than in the placebo group, with both maintained through week 52.
• Patients on belimumab were more likely to have a sustained and maintained DORIS remission (hazard ratio [HR], 1.53; P = .013) and LLDAS (HR, 1.79; P < .0001) at any timepoint.

IN PRACTICE:

“The data clearly support that belimumab is a valuable addition toward accomplishing and maintaining remission or LLDAS,” George Bertsias, MD, PhD, University of Crete Medical School, Heraklion, Greece, and Jinoos Yazdany, MD, University of California San Francisco, wrote in a related comment.

SOURCE:

This study, led by Ioannis Parodis, MD, Karolinska Institutet and Karolinska University Hospital, Stockholm, Sweden, was published online on August 26, 2024, in The Lancet Rheumatology.

LIMITATIONS: 

Due to the post hoc nature of the analysis, the trials were not specifically designed to have adequate statistical power to demonstrate the difference between patients who did or did not achieve DORIS remission or LLDAS. The analysis was limited to patients who met the eligibility criteria, and the outcomes are not generalizable to populations outside a clinical trial setting. The study population had high disease activity, which made it challenging to attain the treatment targets.

DISCLOSURES:

The five trials included in this analysis were funded by GSK. The study was supported by the Swedish Rheumatism Association, King Gustaf V’s 80-year Foundation, the Swedish Society of Medicine, Nyckelfonden, Professor Nanna Svartz Foundation, Ulla and Roland Gustafsson Foundation, Region Stockholm, and Karolinska Institutet. Some authors reported receiving grants, speaker honoraria, or consulting fees from various pharmaceutical companies. Some authors reported being employees and owning stocks and shares of GSK.
 

This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article appeared on Medscape.com.

TOPLINE:

A greater proportion of patients with active systemic lupus erythematosus (SLE) treated with belimumab plus standard therapy achieved the newest definitions for remission and low disease activity compared with those treated with placebo plus standard therapy, with benefits observed as early as week 28 for remission and week 8 for disease activity, according to pooled results from five clinical trials.

METHODOLOGY:

• Researchers conducted an integrated post hoc analysis of five randomized phase 3 clinical trials to evaluate the attainment of remission and low disease activity in adult patients with active, autoantibody-positive SLE.
• A total of 3086 patients (median age, 36 years; 94% women) were randomly assigned to receive standard therapy with intravenous belimumab 10 mg/kg monthly or subcutaneous belimumab 200 mg weekly (n = 1869) or placebo (n = 1217).
• The proportion of patients who achieved definitions of remission in SLE (DORIS) remission and lupus low disease activity state (LLDAS) by visit up to week 52 was assessed.
• The analysis also evaluated the time taken to achieve sustained (at least two consecutive visits) and maintained (up to week 52) DORIS remission and LLDAS.

TAKEAWAY:

• At week 52, a higher proportion of patients receiving belimumab vs placebo achieved DORIS remission (8% vs 6%; risk ratio [RR], 1.51; P = .0055) and LLDAS (17% vs 10%; RR, 1.74; P < .0001).
• The earliest observed significant benefit of belimumab over placebo in patients with a higher baseline disease activity was at week 20 for DORIS remission (RR, 2.09; P = .043) and at week 16 for LLDAS (RR, 1.46; P = .034), with both maintained through week 52.
• The proportion of patients who attained DORIS remission and LLDAS as early as week 28 and week 8, respectively, was higher in the belimumab group than in the placebo group, with both maintained through week 52.
• Patients on belimumab were more likely to have a sustained and maintained DORIS remission (hazard ratio [HR], 1.53; P = .013) and LLDAS (HR, 1.79; P < .0001) at any timepoint.

IN PRACTICE:

“The data clearly support that belimumab is a valuable addition toward accomplishing and maintaining remission or LLDAS,” George Bertsias, MD, PhD, University of Crete Medical School, Heraklion, Greece, and Jinoos Yazdany, MD, University of California San Francisco, wrote in a related comment.

SOURCE:

This study, led by Ioannis Parodis, MD, Karolinska Institutet and Karolinska University Hospital, Stockholm, Sweden, was published online on August 26, 2024, in The Lancet Rheumatology.

LIMITATIONS: 

Due to the post hoc nature of the analysis, the trials were not specifically designed to have adequate statistical power to demonstrate the difference between patients who did or did not achieve DORIS remission or LLDAS. The analysis was limited to patients who met the eligibility criteria, and the outcomes are not generalizable to populations outside a clinical trial setting. The study population had high disease activity, which made it challenging to attain the treatment targets.

DISCLOSURES:

The five trials included in this analysis were funded by GSK. The study was supported by the Swedish Rheumatism Association, King Gustaf V’s 80-year Foundation, the Swedish Society of Medicine, Nyckelfonden, Professor Nanna Svartz Foundation, Ulla and Roland Gustafsson Foundation, Region Stockholm, and Karolinska Institutet. Some authors reported receiving grants, speaker honoraria, or consulting fees from various pharmaceutical companies. Some authors reported being employees and owning stocks and shares of GSK.
 

This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article appeared on Medscape.com.

TOPLINE:

A greater proportion of patients with active systemic lupus erythematosus (SLE) treated with belimumab plus standard therapy achieved the newest definitions for remission and low disease activity compared with those treated with placebo plus standard therapy, with benefits observed as early as week 28 for remission and week 8 for disease activity, according to pooled results from five clinical trials.

METHODOLOGY:

• Researchers conducted an integrated post hoc analysis of five randomized phase 3 clinical trials to evaluate the attainment of remission and low disease activity in adult patients with active, autoantibody-positive SLE.
• A total of 3086 patients (median age, 36 years; 94% women) were randomly assigned to receive standard therapy with intravenous belimumab 10 mg/kg monthly or subcutaneous belimumab 200 mg weekly (n = 1869) or placebo (n = 1217).
• The proportion of patients who achieved definitions of remission in SLE (DORIS) remission and lupus low disease activity state (LLDAS) by visit up to week 52 was assessed.
• The analysis also evaluated the time taken to achieve sustained (at least two consecutive visits) and maintained (up to week 52) DORIS remission and LLDAS.

TAKEAWAY:

• At week 52, a higher proportion of patients receiving belimumab vs placebo achieved DORIS remission (8% vs 6%; risk ratio [RR], 1.51; P = .0055) and LLDAS (17% vs 10%; RR, 1.74; P < .0001).
• The earliest observed significant benefit of belimumab over placebo in patients with a higher baseline disease activity was at week 20 for DORIS remission (RR, 2.09; P = .043) and at week 16 for LLDAS (RR, 1.46; P = .034), with both maintained through week 52.
• The proportion of patients who attained DORIS remission and LLDAS as early as week 28 and week 8, respectively, was higher in the belimumab group than in the placebo group, with both maintained through week 52.
• Patients on belimumab were more likely to have a sustained and maintained DORIS remission (hazard ratio [HR], 1.53; P = .013) and LLDAS (HR, 1.79; P < .0001) at any timepoint.

IN PRACTICE:

“The data clearly support that belimumab is a valuable addition toward accomplishing and maintaining remission or LLDAS,” George Bertsias, MD, PhD, University of Crete Medical School, Heraklion, Greece, and Jinoos Yazdany, MD, University of California San Francisco, wrote in a related comment.

SOURCE:

This study, led by Ioannis Parodis, MD, Karolinska Institutet and Karolinska University Hospital, Stockholm, Sweden, was published online on August 26, 2024, in The Lancet Rheumatology.

LIMITATIONS: 

Due to the post hoc nature of the analysis, the trials were not specifically designed to have adequate statistical power to demonstrate the difference between patients who did or did not achieve DORIS remission or LLDAS. The analysis was limited to patients who met the eligibility criteria, and the outcomes are not generalizable to populations outside a clinical trial setting. The study population had high disease activity, which made it challenging to attain the treatment targets.

DISCLOSURES:

The five trials included in this analysis were funded by GSK. The study was supported by the Swedish Rheumatism Association, King Gustaf V’s 80-year Foundation, the Swedish Society of Medicine, Nyckelfonden, Professor Nanna Svartz Foundation, Ulla and Roland Gustafsson Foundation, Region Stockholm, and Karolinska Institutet. Some authors reported receiving grants, speaker honoraria, or consulting fees from various pharmaceutical companies. Some authors reported being employees and owning stocks and shares of GSK.
 

This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article appeared on Medscape.com.

This transcript has been edited for clarity. 

Matthew F. Watto, MD: Welcome back to The Curbsiders. I’m Dr Matthew Frank Watto, here with my great friend and America’s primary care physician, Dr. Paul Nelson Williams. 

Paul, we’re going to talk about our primary hyperparathyroidism podcast with Dr. Lindsay Kuo. It’s a topic that I feel much more clear on now.

Now, Paul, in primary care, you see a lot of calcium that is just slightly high. Can we just blame that on thiazide diuretics?

Paul N. Williams, MD: It’s a place to start. As you’re starting to think about the possible etiologies, primary hyperparathyroidism and malignancy are the two that roll right off the tongue, but it is worth going back to the patient’s medication list and making sure you’re not missing something.

Thiazides famously cause hypercalcemia, but in some of the reading I did for this episode, they may just uncover it a little bit early. Patients who are on thiazides who become hypercalcemic seem to go on to develop primary hyperthyroidism anyway. So I don’t think you can solely blame the thiazide.

Another medication that can be causative is lithium. So a good place to look first after you’ve repeated the labs and confirmed hypercalcemia is the patient’s medication list. 

Dr. Watto: We’ve talked before about the basic workup for hypercalcemia, and determining whether it’s PTH dependent or PTH independent. On the podcast, we talk more about the full workup, but I wanted to talk about the classic symptoms. Our expert made the point that we don’t see them as much anymore, although we do see kidney stones. People used to present very late in the disease because they weren’t having labs done routinely.

The classic symptoms include osteoporosis and bone tumors. People can get nephrocalcinosis and kidney stones. I hadn’t really thought of it this way because we’re used to diagnosing it early now. Do you feel the same? 

Dr. Williams: As labs have started routinely reporting calcium levels, this is more and more often how it’s picked up. The other aspect is that as we are screening for and finding osteoporosis, part of the workup almost always involves getting a parathyroid hormone and a calcium level. We’re seeing these lab abnormalities before we’re seeing symptoms, which is good.

But it also makes things more diagnostically thorny.

Dr. Watto: Dr. Lindsay Kuo made the point that when she sees patients before and after surgery, she’s aware of these nonclassic symptoms — the stones, bones, groans, and the psychiatric overtones that can be anything from fatigue or irritability to dysphoria.

Some people have a generalized weakness that’s very nonspecific. Dr. Kuo said that sometimes these symptoms will disappear after surgery. The patients may just have gotten used to them, or they thought these symptoms were caused by something else, but after surgery they went away.

There are these nonclassic symptoms that are harder to pin down. I was surprised by that.

Dr. Williams: She mentioned polydipsia and polyuria, which have been reported in other studies. It seems like it can be anything. You have to take a good history, but none of those things in and of themselves is an indication for operating unless the patient has the classic renal or bone manifestations. 

Dr. Watto: The other thing we talked about is a normal calcium level in a patient with primary hyperparathyroidism, or the finding of a PTH level in the normal range but with a high calcium level that is inappropriate. Can you talk a little bit about those two situations? 

Dr. Williams: They’re hard to say but kind of easy to manage because you treat them the same way as someone who has elevated calcium and PTH levels. 

The normocalcemic patient is something we might stumble across with osteoporosis screening. Initially the calcium level is elevated, so you repeat it and it’s normal but with an elevated PTH level. You’re like, shoot. Now what?

It turns out that most endocrine surgeons say that the indications for surgery for the classic form of primary hyperparathyroidism apply to these patients as well, and it probably helps with the bone outcomes, which is one of the things they follow most closely. If you have hypercalcemia, you should have a suppressed PTH level, the so-called normohormonal hyperparathyroidism, which is not normal at all. So even if the PTH is in the normal range, it’s still relatively elevated compared with what it should be. That situation is treated in the same way as the classic elevated PTH and elevated calcium levels.

Dr. Watto: If the calcium is abnormal and the PTH is not quite what you’d expect it to be, you can always ask your friendly neighborhood endocrinologist to help you figure out whether the patient really has one of these conditions. You have to make sure that they don’t have a simple secondary cause like a low vitamin D level. In that case, you fix the vitamin D and then recheck the numbers to see if they’ve normalized. But I have found a bunch of these edge cases in which it has been helpful to confer with an endocrinologist, especially before you send someone to a surgeon to take out their parathyroid gland. 

This was a really fantastic conversation. If you want to hear the full podcast episode, click here.
 

Dr. Watto, Clinical Assistant Professor, Department of Medicine, Perelman School of Medicine at University of Pennsylvania; Internist, Department of Medicine, Hospital Medicine Section, Pennsylvania Hospital, Philadelphia, Pennsylvania, has disclosed no relevant financial relationships. Dr. Williams, Associate Professor of Clinical Medicine, Department of General Internal Medicine, Lewis Katz School of Medicine; Staff Physician, Department of General Internal Medicine, Temple Internal Medicine Associates, Philadelphia, Pennsylvania, served as a director, officer, partner, employee, adviser, consultant, or trustee for The Curbsiders, and has received income in an amount equal to or greater than $250 from The Curbsiders.

A version of this article first appeared on Medscape.com.

This transcript has been edited for clarity. 

Matthew F. Watto, MD: Welcome back to The Curbsiders. I’m Dr Matthew Frank Watto, here with my great friend and America’s primary care physician, Dr. Paul Nelson Williams. 

Paul, we’re going to talk about our primary hyperparathyroidism podcast with Dr. Lindsay Kuo. It’s a topic that I feel much more clear on now.

Now, Paul, in primary care, you see a lot of calcium that is just slightly high. Can we just blame that on thiazide diuretics?

Paul N. Williams, MD: It’s a place to start. As you’re starting to think about the possible etiologies, primary hyperparathyroidism and malignancy are the two that roll right off the tongue, but it is worth going back to the patient’s medication list and making sure you’re not missing something.

Thiazides famously cause hypercalcemia, but in some of the reading I did for this episode, they may just uncover it a little bit early. Patients who are on thiazides who become hypercalcemic seem to go on to develop primary hyperthyroidism anyway. So I don’t think you can solely blame the thiazide.

Another medication that can be causative is lithium. So a good place to look first after you’ve repeated the labs and confirmed hypercalcemia is the patient’s medication list. 

Dr. Watto: We’ve talked before about the basic workup for hypercalcemia, and determining whether it’s PTH dependent or PTH independent. On the podcast, we talk more about the full workup, but I wanted to talk about the classic symptoms. Our expert made the point that we don’t see them as much anymore, although we do see kidney stones. People used to present very late in the disease because they weren’t having labs done routinely.

The classic symptoms include osteoporosis and bone tumors. People can get nephrocalcinosis and kidney stones. I hadn’t really thought of it this way because we’re used to diagnosing it early now. Do you feel the same? 

Dr. Williams: As labs have started routinely reporting calcium levels, this is more and more often how it’s picked up. The other aspect is that as we are screening for and finding osteoporosis, part of the workup almost always involves getting a parathyroid hormone and a calcium level. We’re seeing these lab abnormalities before we’re seeing symptoms, which is good.

But it also makes things more diagnostically thorny.

Dr. Watto: Dr. Lindsay Kuo made the point that when she sees patients before and after surgery, she’s aware of these nonclassic symptoms — the stones, bones, groans, and the psychiatric overtones that can be anything from fatigue or irritability to dysphoria.

Some people have a generalized weakness that’s very nonspecific. Dr. Kuo said that sometimes these symptoms will disappear after surgery. The patients may just have gotten used to them, or they thought these symptoms were caused by something else, but after surgery they went away.

There are these nonclassic symptoms that are harder to pin down. I was surprised by that.

Dr. Williams: She mentioned polydipsia and polyuria, which have been reported in other studies. It seems like it can be anything. You have to take a good history, but none of those things in and of themselves is an indication for operating unless the patient has the classic renal or bone manifestations. 

Dr. Watto: The other thing we talked about is a normal calcium level in a patient with primary hyperparathyroidism, or the finding of a PTH level in the normal range but with a high calcium level that is inappropriate. Can you talk a little bit about those two situations? 

Dr. Williams: They’re hard to say but kind of easy to manage because you treat them the same way as someone who has elevated calcium and PTH levels. 

The normocalcemic patient is something we might stumble across with osteoporosis screening. Initially the calcium level is elevated, so you repeat it and it’s normal but with an elevated PTH level. You’re like, shoot. Now what?

It turns out that most endocrine surgeons say that the indications for surgery for the classic form of primary hyperparathyroidism apply to these patients as well, and it probably helps with the bone outcomes, which is one of the things they follow most closely. If you have hypercalcemia, you should have a suppressed PTH level, the so-called normohormonal hyperparathyroidism, which is not normal at all. So even if the PTH is in the normal range, it’s still relatively elevated compared with what it should be. That situation is treated in the same way as the classic elevated PTH and elevated calcium levels.

Dr. Watto: If the calcium is abnormal and the PTH is not quite what you’d expect it to be, you can always ask your friendly neighborhood endocrinologist to help you figure out whether the patient really has one of these conditions. You have to make sure that they don’t have a simple secondary cause like a low vitamin D level. In that case, you fix the vitamin D and then recheck the numbers to see if they’ve normalized. But I have found a bunch of these edge cases in which it has been helpful to confer with an endocrinologist, especially before you send someone to a surgeon to take out their parathyroid gland. 

This was a really fantastic conversation. If you want to hear the full podcast episode, click here.
 

Dr. Watto, Clinical Assistant Professor, Department of Medicine, Perelman School of Medicine at University of Pennsylvania; Internist, Department of Medicine, Hospital Medicine Section, Pennsylvania Hospital, Philadelphia, Pennsylvania, has disclosed no relevant financial relationships. Dr. Williams, Associate Professor of Clinical Medicine, Department of General Internal Medicine, Lewis Katz School of Medicine; Staff Physician, Department of General Internal Medicine, Temple Internal Medicine Associates, Philadelphia, Pennsylvania, served as a director, officer, partner, employee, adviser, consultant, or trustee for The Curbsiders, and has received income in an amount equal to or greater than $250 from The Curbsiders.

A version of this article first appeared on Medscape.com.

This transcript has been edited for clarity. 

Matthew F. Watto, MD: Welcome back to The Curbsiders. I’m Dr Matthew Frank Watto, here with my great friend and America’s primary care physician, Dr. Paul Nelson Williams. 

Paul, we’re going to talk about our primary hyperparathyroidism podcast with Dr. Lindsay Kuo. It’s a topic that I feel much more clear on now.

Now, Paul, in primary care, you see a lot of calcium that is just slightly high. Can we just blame that on thiazide diuretics?

Paul N. Williams, MD: It’s a place to start. As you’re starting to think about the possible etiologies, primary hyperparathyroidism and malignancy are the two that roll right off the tongue, but it is worth going back to the patient’s medication list and making sure you’re not missing something.

Thiazides famously cause hypercalcemia, but in some of the reading I did for this episode, they may just uncover it a little bit early. Patients who are on thiazides who become hypercalcemic seem to go on to develop primary hyperthyroidism anyway. So I don’t think you can solely blame the thiazide.

Another medication that can be causative is lithium. So a good place to look first after you’ve repeated the labs and confirmed hypercalcemia is the patient’s medication list. 

Dr. Watto: We’ve talked before about the basic workup for hypercalcemia, and determining whether it’s PTH dependent or PTH independent. On the podcast, we talk more about the full workup, but I wanted to talk about the classic symptoms. Our expert made the point that we don’t see them as much anymore, although we do see kidney stones. People used to present very late in the disease because they weren’t having labs done routinely.

The classic symptoms include osteoporosis and bone tumors. People can get nephrocalcinosis and kidney stones. I hadn’t really thought of it this way because we’re used to diagnosing it early now. Do you feel the same? 

Dr. Williams: As labs have started routinely reporting calcium levels, this is more and more often how it’s picked up. The other aspect is that as we are screening for and finding osteoporosis, part of the workup almost always involves getting a parathyroid hormone and a calcium level. We’re seeing these lab abnormalities before we’re seeing symptoms, which is good.

But it also makes things more diagnostically thorny.

Dr. Watto: Dr. Lindsay Kuo made the point that when she sees patients before and after surgery, she’s aware of these nonclassic symptoms — the stones, bones, groans, and the psychiatric overtones that can be anything from fatigue or irritability to dysphoria.

Some people have a generalized weakness that’s very nonspecific. Dr. Kuo said that sometimes these symptoms will disappear after surgery. The patients may just have gotten used to them, or they thought these symptoms were caused by something else, but after surgery they went away.

There are these nonclassic symptoms that are harder to pin down. I was surprised by that.

Dr. Williams: She mentioned polydipsia and polyuria, which have been reported in other studies. It seems like it can be anything. You have to take a good history, but none of those things in and of themselves is an indication for operating unless the patient has the classic renal or bone manifestations. 

Dr. Watto: The other thing we talked about is a normal calcium level in a patient with primary hyperparathyroidism, or the finding of a PTH level in the normal range but with a high calcium level that is inappropriate. Can you talk a little bit about those two situations? 

Dr. Williams: They’re hard to say but kind of easy to manage because you treat them the same way as someone who has elevated calcium and PTH levels. 

The normocalcemic patient is something we might stumble across with osteoporosis screening. Initially the calcium level is elevated, so you repeat it and it’s normal but with an elevated PTH level. You’re like, shoot. Now what?

It turns out that most endocrine surgeons say that the indications for surgery for the classic form of primary hyperparathyroidism apply to these patients as well, and it probably helps with the bone outcomes, which is one of the things they follow most closely. If you have hypercalcemia, you should have a suppressed PTH level, the so-called normohormonal hyperparathyroidism, which is not normal at all. So even if the PTH is in the normal range, it’s still relatively elevated compared with what it should be. That situation is treated in the same way as the classic elevated PTH and elevated calcium levels.

Dr. Watto: If the calcium is abnormal and the PTH is not quite what you’d expect it to be, you can always ask your friendly neighborhood endocrinologist to help you figure out whether the patient really has one of these conditions. You have to make sure that they don’t have a simple secondary cause like a low vitamin D level. In that case, you fix the vitamin D and then recheck the numbers to see if they’ve normalized. But I have found a bunch of these edge cases in which it has been helpful to confer with an endocrinologist, especially before you send someone to a surgeon to take out their parathyroid gland. 

This was a really fantastic conversation. If you want to hear the full podcast episode, click here.
 

Dr. Watto, Clinical Assistant Professor, Department of Medicine, Perelman School of Medicine at University of Pennsylvania; Internist, Department of Medicine, Hospital Medicine Section, Pennsylvania Hospital, Philadelphia, Pennsylvania, has disclosed no relevant financial relationships. Dr. Williams, Associate Professor of Clinical Medicine, Department of General Internal Medicine, Lewis Katz School of Medicine; Staff Physician, Department of General Internal Medicine, Temple Internal Medicine Associates, Philadelphia, Pennsylvania, served as a director, officer, partner, employee, adviser, consultant, or trustee for The Curbsiders, and has received income in an amount equal to or greater than $250 from The Curbsiders.

A version of this article first appeared on Medscape.com.

The US Food and Drug Administration (FDA) has approved a subcutaneous formulation of the anti-CD20 antibody ocrelizumab (Ocrevus Zunovo, Genentech) for the treatment of relapsing multiple sclerosis (RMS) and primary progressive multiple sclerosis (PPMS). 

The subcutaneous (SC) injection can be administered by a healthcare professional in approximately 10 minutes and is the first and only twice-a-year SC injection approved for both RMS and PPMS, according to a company news release.

The FDA approval is based on pivotal data from the phase 3 OCARINA II trial, which showed no clinically significant difference in blood levels of ocrelizumab when administered subcutaneously and an efficacy profile consistent with the intravenous (IV) formulation. 

“The trial met its primary and secondary endpoints, demonstrating SC injection was noninferior to IV infusion based on [ocrelizumab] levels in the blood, and consistent control of clinical (relapses) and radiological (MRI lesions) disease activity,” the company said in the release. 

The safety profile of SC ocrelizumab was consistent with the safety profile of IV ocrelizumab, with the exception of injection site reactions, the most common adverse event.

Injection reactions were more often reported with the first injection, with 49% of trial participants experiencing an injection reaction after the first injection. All injection reactions were mild or moderate, and none led to treatment withdrawal.

Ocrevus Zunovo “may offer greater flexibility for healthcare providers and people living with multiple sclerosis, based on their individual treatment needs,” Levi Garraway, MD, PhD, chief medical officer for Genentech, said in the press release. “We are pleased that with a new method of delivery, there is now an additional option for those who need flexibility in the route of administration or treatment time,” Natalie Blake, executive director of the MS Foundation, said in the release. 

The SC formulation of ocrelizumab was approved by the European Commission in June.

Complete prescribing information is available online.

A version of this article appeared on Medscape.com.

The US Food and Drug Administration (FDA) has approved a subcutaneous formulation of the anti-CD20 antibody ocrelizumab (Ocrevus Zunovo, Genentech) for the treatment of relapsing multiple sclerosis (RMS) and primary progressive multiple sclerosis (PPMS). 

The subcutaneous (SC) injection can be administered by a healthcare professional in approximately 10 minutes and is the first and only twice-a-year SC injection approved for both RMS and PPMS, according to a company news release.

The FDA approval is based on pivotal data from the phase 3 OCARINA II trial, which showed no clinically significant difference in blood levels of ocrelizumab when administered subcutaneously and an efficacy profile consistent with the intravenous (IV) formulation. 

“The trial met its primary and secondary endpoints, demonstrating SC injection was noninferior to IV infusion based on [ocrelizumab] levels in the blood, and consistent control of clinical (relapses) and radiological (MRI lesions) disease activity,” the company said in the release. 

The safety profile of SC ocrelizumab was consistent with the safety profile of IV ocrelizumab, with the exception of injection site reactions, the most common adverse event.

Injection reactions were more often reported with the first injection, with 49% of trial participants experiencing an injection reaction after the first injection. All injection reactions were mild or moderate, and none led to treatment withdrawal.

Ocrevus Zunovo “may offer greater flexibility for healthcare providers and people living with multiple sclerosis, based on their individual treatment needs,” Levi Garraway, MD, PhD, chief medical officer for Genentech, said in the press release. “We are pleased that with a new method of delivery, there is now an additional option for those who need flexibility in the route of administration or treatment time,” Natalie Blake, executive director of the MS Foundation, said in the release. 

The SC formulation of ocrelizumab was approved by the European Commission in June.

Complete prescribing information is available online.

A version of this article appeared on Medscape.com.

The US Food and Drug Administration (FDA) has approved a subcutaneous formulation of the anti-CD20 antibody ocrelizumab (Ocrevus Zunovo, Genentech) for the treatment of relapsing multiple sclerosis (RMS) and primary progressive multiple sclerosis (PPMS). 

The subcutaneous (SC) injection can be administered by a healthcare professional in approximately 10 minutes and is the first and only twice-a-year SC injection approved for both RMS and PPMS, according to a company news release.

The FDA approval is based on pivotal data from the phase 3 OCARINA II trial, which showed no clinically significant difference in blood levels of ocrelizumab when administered subcutaneously and an efficacy profile consistent with the intravenous (IV) formulation. 

“The trial met its primary and secondary endpoints, demonstrating SC injection was noninferior to IV infusion based on [ocrelizumab] levels in the blood, and consistent control of clinical (relapses) and radiological (MRI lesions) disease activity,” the company said in the release. 

The safety profile of SC ocrelizumab was consistent with the safety profile of IV ocrelizumab, with the exception of injection site reactions, the most common adverse event.

Injection reactions were more often reported with the first injection, with 49% of trial participants experiencing an injection reaction after the first injection. All injection reactions were mild or moderate, and none led to treatment withdrawal.

Ocrevus Zunovo “may offer greater flexibility for healthcare providers and people living with multiple sclerosis, based on their individual treatment needs,” Levi Garraway, MD, PhD, chief medical officer for Genentech, said in the press release. “We are pleased that with a new method of delivery, there is now an additional option for those who need flexibility in the route of administration or treatment time,” Natalie Blake, executive director of the MS Foundation, said in the release. 

The SC formulation of ocrelizumab was approved by the European Commission in June.

Complete prescribing information is available online.

A version of this article appeared on Medscape.com.

TOPLINE:

An artificial intelligence (AI)-powered clinical documentation tool helped reduce time spent on electronic health records (EHR) at home for almost 48% physicians, and nearly 45% reported less weekly time spent on EHR tasks outside of normal work hours.

METHODOLOGY:

• Researchers recruited 112 clinicians from family medicine, internal medicine, and general pediatrics in North Carolina and Georgia.
• Patients were divided into an intervention group (n = 85) and control group (n = 55), with the intervention group receiving a 1-hour training program on a commercially available AI tool.
• A seven-question survey was administered to participants before and 5 weeks after the intervention to evaluate their experience.

TAKEAWAY:

• The researchers found 47.1% of clinicians in the intervention group reported spending less time on the EHR at home compared with 14.5% in the control group (P < .001); 44.7% reported decreased weekly time on the EHR outside normal work hours compared with 20% in the control group (P = .003).
• The study revealed 43.5% of physicians who used the AI instrument reported spending less time on documentation after visits compared with 18.2% in the control group (P = .002).
• Further, 44.7% reported less frustration when using the EHR compared with 14.5% in the control group (P < .001).

IN PRACTICE:

“Approximately half of clinicians using the AI-powered clinical documentation tool based on interest reported a positive outcome, potentially reducing burnout. However, a significant subset did not find time-saving benefits or improved EHR experience,” the authors of the study wrote.

SOURCE:

The study was led by Tsai-Ling Liu, PhD, Center for Health System Sciences, Atrium Health in Charlotte, North Carolina. It was published online in JAMA Network Open.

LIMITATIONS:

The researchers reported potential selection and recall bias in both groups. Additional research is needed to find areas of improvement and assess the effects on clinician groups and health systems, they said.

DISCLOSURES:

Andrew McWilliams, MD, MPH, reported receiving grants from the Agency for Healthcare Research Quality, the National Institutes of Health, and the Duke Endowment unrelated to this work. Ajay Dharod, MD, reported his role as an electronic health record consultant for the Association of American Medical College CORE program. Jeffrey Cleveland, MD, disclosed his participation on the Executive Client Council, a noncompensated advisory group, for Nuance/Microsoft.

This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article first appeared on Medscape.com.

TOPLINE:

An artificial intelligence (AI)-powered clinical documentation tool helped reduce time spent on electronic health records (EHR) at home for almost 48% physicians, and nearly 45% reported less weekly time spent on EHR tasks outside of normal work hours.

METHODOLOGY:

• Researchers recruited 112 clinicians from family medicine, internal medicine, and general pediatrics in North Carolina and Georgia.
• Patients were divided into an intervention group (n = 85) and control group (n = 55), with the intervention group receiving a 1-hour training program on a commercially available AI tool.
• A seven-question survey was administered to participants before and 5 weeks after the intervention to evaluate their experience.

TAKEAWAY:

• The researchers found 47.1% of clinicians in the intervention group reported spending less time on the EHR at home compared with 14.5% in the control group (P < .001); 44.7% reported decreased weekly time on the EHR outside normal work hours compared with 20% in the control group (P = .003).
• The study revealed 43.5% of physicians who used the AI instrument reported spending less time on documentation after visits compared with 18.2% in the control group (P = .002).
• Further, 44.7% reported less frustration when using the EHR compared with 14.5% in the control group (P < .001).

IN PRACTICE:

“Approximately half of clinicians using the AI-powered clinical documentation tool based on interest reported a positive outcome, potentially reducing burnout. However, a significant subset did not find time-saving benefits or improved EHR experience,” the authors of the study wrote.

SOURCE:

The study was led by Tsai-Ling Liu, PhD, Center for Health System Sciences, Atrium Health in Charlotte, North Carolina. It was published online in JAMA Network Open.

LIMITATIONS:

The researchers reported potential selection and recall bias in both groups. Additional research is needed to find areas of improvement and assess the effects on clinician groups and health systems, they said.

DISCLOSURES:

Andrew McWilliams, MD, MPH, reported receiving grants from the Agency for Healthcare Research Quality, the National Institutes of Health, and the Duke Endowment unrelated to this work. Ajay Dharod, MD, reported his role as an electronic health record consultant for the Association of American Medical College CORE program. Jeffrey Cleveland, MD, disclosed his participation on the Executive Client Council, a noncompensated advisory group, for Nuance/Microsoft.

This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article first appeared on Medscape.com.

TOPLINE:

An artificial intelligence (AI)-powered clinical documentation tool helped reduce time spent on electronic health records (EHR) at home for almost 48% physicians, and nearly 45% reported less weekly time spent on EHR tasks outside of normal work hours.

METHODOLOGY:

• Researchers recruited 112 clinicians from family medicine, internal medicine, and general pediatrics in North Carolina and Georgia.
• Patients were divided into an intervention group (n = 85) and control group (n = 55), with the intervention group receiving a 1-hour training program on a commercially available AI tool.
• A seven-question survey was administered to participants before and 5 weeks after the intervention to evaluate their experience.

TAKEAWAY:

• The researchers found 47.1% of clinicians in the intervention group reported spending less time on the EHR at home compared with 14.5% in the control group (P < .001); 44.7% reported decreased weekly time on the EHR outside normal work hours compared with 20% in the control group (P = .003).
• The study revealed 43.5% of physicians who used the AI instrument reported spending less time on documentation after visits compared with 18.2% in the control group (P = .002).
• Further, 44.7% reported less frustration when using the EHR compared with 14.5% in the control group (P < .001).

IN PRACTICE:

“Approximately half of clinicians using the AI-powered clinical documentation tool based on interest reported a positive outcome, potentially reducing burnout. However, a significant subset did not find time-saving benefits or improved EHR experience,” the authors of the study wrote.

SOURCE:

The study was led by Tsai-Ling Liu, PhD, Center for Health System Sciences, Atrium Health in Charlotte, North Carolina. It was published online in JAMA Network Open.

LIMITATIONS:

The researchers reported potential selection and recall bias in both groups. Additional research is needed to find areas of improvement and assess the effects on clinician groups and health systems, they said.

DISCLOSURES:

Andrew McWilliams, MD, MPH, reported receiving grants from the Agency for Healthcare Research Quality, the National Institutes of Health, and the Duke Endowment unrelated to this work. Ajay Dharod, MD, reported his role as an electronic health record consultant for the Association of American Medical College CORE program. Jeffrey Cleveland, MD, disclosed his participation on the Executive Client Council, a noncompensated advisory group, for Nuance/Microsoft.

This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article first appeared on Medscape.com.

To the Editor:

Kratom (Mitragyna speciosa) is an evergreen tree native to Southeast Asia.¹ Its leaves contain psychoactive compounds including mitragynine and 7-­hydroxymitragynine, which exert dose-dependent effects on the central nervous system through opioid and monoaminergic receptors.^2,3 At low doses (1–5 g), kratom elicits mild stimulant effects such as increased sociability, alertness, and talkativeness. At high doses (5–15 g), kratom has depressant effects that can provide relief from pain and opioid-withdrawal symptoms.³

Traditionally, kratom has been used in Southeast Asia for recreational and ceremonial purposes, to ease opioid-withdrawal symptoms, and to reduce fatigue from manual labor.⁴ In the 21st century, availability of kratom expanded to Europe, Australia, and the United States, largely facilitated by widespread dissemination of deceitful ­marketing and unregulated sales on the internet.¹ Although large-scale epidemiologic studies evaluating kratom’s prevalence are scarce, available evidence indicates rising worldwide usage, with a notable increase in kratom-related poison center calls between 2011 and 2017 in the United States.⁵ In July 2023, kratom made headlines due to the death of a woman in Florida following use of the substance.⁶

A cross-sectional study revealed that in the United States, kratom typically is used by White individuals for self-treatment of anxiety, depression, pain, and opioid withdrawal.⁷ However, the potential for severe adverse effects and dependence on kratom can outweigh the benefits.^6,8 Reported adverse effects of kratom include tachycardia, hypercholesteremia, liver injury, hallucinations, respiratory depression, seizure, coma, and death.^9,10 We present a case of kratom-induced photodistributed hyperpigmentation.

A 63-year-old man presented to the dermatology clinic with diffuse tender, pruritic, hyperpigmented skin lesions that developed over the course of 1 year. The lesions were distributed on sun-exposed areas, including the face, neck, and forearms (Figure 1). The patient reported no other major symptoms, and his health was otherwise unremarkable. He had a medical history of psoriasiform and spongiotic dermatitis consistent with eczema, psoriasis, hypercholesteremia, and hyperlipidemia. The patient was not taking any medications at the time of presentation. He had a family history of plaque psoriasis in his father. Five years prior to the current presentation, the patient was treated with adalimumab for steroid-resistant psoriasis; however, despite initial improvement, he experienced recurrence of scaly erythematous plaques and had discontinued adalimumab the year prior to presentation.

To the Editor:

Kratom (Mitragyna speciosa) is an evergreen tree native to Southeast Asia.¹ Its leaves contain psychoactive compounds including mitragynine and 7-­hydroxymitragynine, which exert dose-dependent effects on the central nervous system through opioid and monoaminergic receptors.^2,3 At low doses (1–5 g), kratom elicits mild stimulant effects such as increased sociability, alertness, and talkativeness. At high doses (5–15 g), kratom has depressant effects that can provide relief from pain and opioid-withdrawal symptoms.³

Traditionally, kratom has been used in Southeast Asia for recreational and ceremonial purposes, to ease opioid-withdrawal symptoms, and to reduce fatigue from manual labor.⁴ In the 21st century, availability of kratom expanded to Europe, Australia, and the United States, largely facilitated by widespread dissemination of deceitful ­marketing and unregulated sales on the internet.¹ Although large-scale epidemiologic studies evaluating kratom’s prevalence are scarce, available evidence indicates rising worldwide usage, with a notable increase in kratom-related poison center calls between 2011 and 2017 in the United States.⁵ In July 2023, kratom made headlines due to the death of a woman in Florida following use of the substance.⁶

A cross-sectional study revealed that in the United States, kratom typically is used by White individuals for self-treatment of anxiety, depression, pain, and opioid withdrawal.⁷ However, the potential for severe adverse effects and dependence on kratom can outweigh the benefits.^6,8 Reported adverse effects of kratom include tachycardia, hypercholesteremia, liver injury, hallucinations, respiratory depression, seizure, coma, and death.^9,10 We present a case of kratom-induced photodistributed hyperpigmentation.

A 63-year-old man presented to the dermatology clinic with diffuse tender, pruritic, hyperpigmented skin lesions that developed over the course of 1 year. The lesions were distributed on sun-exposed areas, including the face, neck, and forearms (Figure 1). The patient reported no other major symptoms, and his health was otherwise unremarkable. He had a medical history of psoriasiform and spongiotic dermatitis consistent with eczema, psoriasis, hypercholesteremia, and hyperlipidemia. The patient was not taking any medications at the time of presentation. He had a family history of plaque psoriasis in his father. Five years prior to the current presentation, the patient was treated with adalimumab for steroid-resistant psoriasis; however, despite initial improvement, he experienced recurrence of scaly erythematous plaques and had discontinued adalimumab the year prior to presentation.

To the Editor:

Kratom (Mitragyna speciosa) is an evergreen tree native to Southeast Asia.¹ Its leaves contain psychoactive compounds including mitragynine and 7-­hydroxymitragynine, which exert dose-dependent effects on the central nervous system through opioid and monoaminergic receptors.^2,3 At low doses (1–5 g), kratom elicits mild stimulant effects such as increased sociability, alertness, and talkativeness. At high doses (5–15 g), kratom has depressant effects that can provide relief from pain and opioid-withdrawal symptoms.³

Traditionally, kratom has been used in Southeast Asia for recreational and ceremonial purposes, to ease opioid-withdrawal symptoms, and to reduce fatigue from manual labor.⁴ In the 21st century, availability of kratom expanded to Europe, Australia, and the United States, largely facilitated by widespread dissemination of deceitful ­marketing and unregulated sales on the internet.¹ Although large-scale epidemiologic studies evaluating kratom’s prevalence are scarce, available evidence indicates rising worldwide usage, with a notable increase in kratom-related poison center calls between 2011 and 2017 in the United States.⁵ In July 2023, kratom made headlines due to the death of a woman in Florida following use of the substance.⁶

A cross-sectional study revealed that in the United States, kratom typically is used by White individuals for self-treatment of anxiety, depression, pain, and opioid withdrawal.⁷ However, the potential for severe adverse effects and dependence on kratom can outweigh the benefits.^6,8 Reported adverse effects of kratom include tachycardia, hypercholesteremia, liver injury, hallucinations, respiratory depression, seizure, coma, and death.^9,10 We present a case of kratom-induced photodistributed hyperpigmentation.

A 63-year-old man presented to the dermatology clinic with diffuse tender, pruritic, hyperpigmented skin lesions that developed over the course of 1 year. The lesions were distributed on sun-exposed areas, including the face, neck, and forearms (Figure 1). The patient reported no other major symptoms, and his health was otherwise unremarkable. He had a medical history of psoriasiform and spongiotic dermatitis consistent with eczema, psoriasis, hypercholesteremia, and hyperlipidemia. The patient was not taking any medications at the time of presentation. He had a family history of plaque psoriasis in his father. Five years prior to the current presentation, the patient was treated with adalimumab for steroid-resistant psoriasis; however, despite initial improvement, he experienced recurrence of scaly erythematous plaques and had discontinued adalimumab the year prior to presentation.

TOPLINE:

Reports of blood and lymphatic disorders were higher in pediatric patients treated with Janus kinase (JAK) inhibitors than in adults in a review of US and Canadian adverse event (AE) data, which also found that acne was the most common skin-related AE in children, and serious AEs were less common.

METHODOLOGY:

• Researchers analyzed 399,649 AEs in 133,216 adult patients and 2883 AEs in 955 pediatric patients (age, < 18 years) from November 2011 to February 2023 using the US Food and Drug Administration Adverse Event Reporting System and the Canada Vigilance Adverse Reaction Online Database.
• AEs were categorized on the basis of the Medical Dictionary for Regulatory Activities system organ class.
• Five JAK inhibitors approved for use in children were included in the study: Baricitinib, upadacitinib, abrocitinib, ruxolitinib, and tofacitinib.

TAKEAWAY:

• The most frequently reported AEs in children were blood and lymphatic system disorders, including neutropenia, thrombocytopenia, and anemia (24%); viral, fungal, and bacterial infections, such as pneumonia and sepsis (17.2%); constitutional symptoms and administrative concerns, including pyrexia and fatigue (15.7%); gastrointestinal disorders, such as vomiting and abdominal pain (13.6%); and respiratory disorders, such as cough and respiratory distress (5.3%).
• In adults, the most common AEs were viral, fungal, and bacterial infections (16.8%); constitutional symptoms and administrative concerns (13.5%); musculoskeletal and connective tissue disorders (7.04%); and gastrointestinal (5.8%) and nervous system (5%) disorders.
• Acne (30.6%), atopic dermatitis (22.2%), and psoriasis (16.7%) were the most common skin and subcutaneous tissue AEs reported in children. Skin and subcutaneous AEs were more common with upadacitinib (21.1%), abrocitinib (9.1%), and tofacitinib (6.3%) in children.
• Serious AEs included in the boxed warning for JAK inhibitors — serious infection, mortality, malignancy, cardiovascular events, and thrombosis — were similar for baricitinib in children (4 of 49 patients, 8.2%) and adults (325 of 3707, 8.8%). For other JAK inhibitors, absolute numbers of these AEs in children were small and rates were lower in children than in adults.

IN PRACTICE:

“This information can support customized treatment and minimize the potential for undesired or intolerable AEs,” the authors wrote.

SOURCE:

This study was led by Sahithi Talasila, BS, Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, and was published online in Pediatric Dermatology.

LIMITATIONS:

Pharmacovigilance registries did not fully capture the complete range of AEs because of potential reporting bias or recall bias. Additionally, events lacking sufficient objective evidence were underreported, while common AEs associated with JAK inhibitor therapy were overreported.

DISCLOSURES:

No specific funding sources for the study were reported. One author reported being a consultant, one reported serving as a principal investigator in clinical trials, and another reported serving on data and safety monitoring boards of various pharmaceutical companies.

This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article first appeared on Medscape.com.

TOPLINE:

Reports of blood and lymphatic disorders were higher in pediatric patients treated with Janus kinase (JAK) inhibitors than in adults in a review of US and Canadian adverse event (AE) data, which also found that acne was the most common skin-related AE in children, and serious AEs were less common.

METHODOLOGY:

• Researchers analyzed 399,649 AEs in 133,216 adult patients and 2883 AEs in 955 pediatric patients (age, < 18 years) from November 2011 to February 2023 using the US Food and Drug Administration Adverse Event Reporting System and the Canada Vigilance Adverse Reaction Online Database.
• AEs were categorized on the basis of the Medical Dictionary for Regulatory Activities system organ class.
• Five JAK inhibitors approved for use in children were included in the study: Baricitinib, upadacitinib, abrocitinib, ruxolitinib, and tofacitinib.

TAKEAWAY:

• The most frequently reported AEs in children were blood and lymphatic system disorders, including neutropenia, thrombocytopenia, and anemia (24%); viral, fungal, and bacterial infections, such as pneumonia and sepsis (17.2%); constitutional symptoms and administrative concerns, including pyrexia and fatigue (15.7%); gastrointestinal disorders, such as vomiting and abdominal pain (13.6%); and respiratory disorders, such as cough and respiratory distress (5.3%).
• In adults, the most common AEs were viral, fungal, and bacterial infections (16.8%); constitutional symptoms and administrative concerns (13.5%); musculoskeletal and connective tissue disorders (7.04%); and gastrointestinal (5.8%) and nervous system (5%) disorders.
• Acne (30.6%), atopic dermatitis (22.2%), and psoriasis (16.7%) were the most common skin and subcutaneous tissue AEs reported in children. Skin and subcutaneous AEs were more common with upadacitinib (21.1%), abrocitinib (9.1%), and tofacitinib (6.3%) in children.
• Serious AEs included in the boxed warning for JAK inhibitors — serious infection, mortality, malignancy, cardiovascular events, and thrombosis — were similar for baricitinib in children (4 of 49 patients, 8.2%) and adults (325 of 3707, 8.8%). For other JAK inhibitors, absolute numbers of these AEs in children were small and rates were lower in children than in adults.

IN PRACTICE:

“This information can support customized treatment and minimize the potential for undesired or intolerable AEs,” the authors wrote.

SOURCE:

This study was led by Sahithi Talasila, BS, Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, and was published online in Pediatric Dermatology.

LIMITATIONS:

Pharmacovigilance registries did not fully capture the complete range of AEs because of potential reporting bias or recall bias. Additionally, events lacking sufficient objective evidence were underreported, while common AEs associated with JAK inhibitor therapy were overreported.

DISCLOSURES:

No specific funding sources for the study were reported. One author reported being a consultant, one reported serving as a principal investigator in clinical trials, and another reported serving on data and safety monitoring boards of various pharmaceutical companies.

This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article first appeared on Medscape.com.

TOPLINE:

Reports of blood and lymphatic disorders were higher in pediatric patients treated with Janus kinase (JAK) inhibitors than in adults in a review of US and Canadian adverse event (AE) data, which also found that acne was the most common skin-related AE in children, and serious AEs were less common.

METHODOLOGY:

• Researchers analyzed 399,649 AEs in 133,216 adult patients and 2883 AEs in 955 pediatric patients (age, < 18 years) from November 2011 to February 2023 using the US Food and Drug Administration Adverse Event Reporting System and the Canada Vigilance Adverse Reaction Online Database.
• AEs were categorized on the basis of the Medical Dictionary for Regulatory Activities system organ class.
• Five JAK inhibitors approved for use in children were included in the study: Baricitinib, upadacitinib, abrocitinib, ruxolitinib, and tofacitinib.

TAKEAWAY:

• The most frequently reported AEs in children were blood and lymphatic system disorders, including neutropenia, thrombocytopenia, and anemia (24%); viral, fungal, and bacterial infections, such as pneumonia and sepsis (17.2%); constitutional symptoms and administrative concerns, including pyrexia and fatigue (15.7%); gastrointestinal disorders, such as vomiting and abdominal pain (13.6%); and respiratory disorders, such as cough and respiratory distress (5.3%).
• In adults, the most common AEs were viral, fungal, and bacterial infections (16.8%); constitutional symptoms and administrative concerns (13.5%); musculoskeletal and connective tissue disorders (7.04%); and gastrointestinal (5.8%) and nervous system (5%) disorders.
• Acne (30.6%), atopic dermatitis (22.2%), and psoriasis (16.7%) were the most common skin and subcutaneous tissue AEs reported in children. Skin and subcutaneous AEs were more common with upadacitinib (21.1%), abrocitinib (9.1%), and tofacitinib (6.3%) in children.
• Serious AEs included in the boxed warning for JAK inhibitors — serious infection, mortality, malignancy, cardiovascular events, and thrombosis — were similar for baricitinib in children (4 of 49 patients, 8.2%) and adults (325 of 3707, 8.8%). For other JAK inhibitors, absolute numbers of these AEs in children were small and rates were lower in children than in adults.

IN PRACTICE:

“This information can support customized treatment and minimize the potential for undesired or intolerable AEs,” the authors wrote.

SOURCE:

This study was led by Sahithi Talasila, BS, Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, and was published online in Pediatric Dermatology.

LIMITATIONS:

Pharmacovigilance registries did not fully capture the complete range of AEs because of potential reporting bias or recall bias. Additionally, events lacking sufficient objective evidence were underreported, while common AEs associated with JAK inhibitor therapy were overreported.

DISCLOSURES:

No specific funding sources for the study were reported. One author reported being a consultant, one reported serving as a principal investigator in clinical trials, and another reported serving on data and safety monitoring boards of various pharmaceutical companies.

This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article first appeared on Medscape.com.

The Food and Drug Administration (FDA) has approved atezolizumab and hyaluronidase-tqjs (Tecentriq Hybreza, Genentech) as a subcutaneous injection in adults, covering all approved indications of the intravenous (IV) formulation.

Approved indications include non–small cell lung cancer (NSCLC), SCLC, hepatocellular carcinoma, melanoma, and alveolar soft part sarcoma. Specific indications are available with the full prescribing information at Drugs@FDA.

This is the first programmed death–ligand 1 inhibitor to gain approval for subcutaneous administration.

“This approval represents a significant option to improve the patient experience,” Ann Fish-Steagall, RN, Senior Vice President of Patient Services at the LUNGevity Foundation stated in a Genentech press release.

Subcutaneous atezolizumab and hyaluronidase-tqjs was evaluated in the open-label, randomized IMscin001 trial of 371 adult patients with locally advanced or metastatic NSCLC who were not previously exposed to cancer immunotherapy and who had disease progression following treatment with platinum-based chemotherapy. Patients were randomized 2:1 to receive subcutaneous or IV administration until disease progression or unacceptable toxicity.

Atezolizumab exposure, the primary outcome measure of the study, met the lower limit of geometric mean ratio above the prespecified threshold of 0.8 (cycle 1C trough, 1.05; area under the curve for days 0-21, 0.87).

No notable differences were observed in overall response rate, progression-free survival, or overall survival between the two formulations, according to the FDA approval notice.

The confirmed overall response rate was 9% in the subcutaneous arm and 8% intravenous arm.

Adverse events of any grade occurring in at least 10% of patients were fatigue, musculoskeletal pain, cough, dyspnea, and decreased appetite.

The recommended dose for subcutaneous injection is one 15 mL injection, which contains 1875 mg of atezolizumab and 30,000 units of hyaluronidase.

Injections should be administered in the thigh over approximately 7 minutes every 3 weeks. By contrast, IV administration generally takes 30-60 minutes.

A version of this article first appeared on Medscape.com.

The Food and Drug Administration (FDA) has approved atezolizumab and hyaluronidase-tqjs (Tecentriq Hybreza, Genentech) as a subcutaneous injection in adults, covering all approved indications of the intravenous (IV) formulation.

Approved indications include non–small cell lung cancer (NSCLC), SCLC, hepatocellular carcinoma, melanoma, and alveolar soft part sarcoma. Specific indications are available with the full prescribing information at Drugs@FDA.

This is the first programmed death–ligand 1 inhibitor to gain approval for subcutaneous administration.

“This approval represents a significant option to improve the patient experience,” Ann Fish-Steagall, RN, Senior Vice President of Patient Services at the LUNGevity Foundation stated in a Genentech press release.

Subcutaneous atezolizumab and hyaluronidase-tqjs was evaluated in the open-label, randomized IMscin001 trial of 371 adult patients with locally advanced or metastatic NSCLC who were not previously exposed to cancer immunotherapy and who had disease progression following treatment with platinum-based chemotherapy. Patients were randomized 2:1 to receive subcutaneous or IV administration until disease progression or unacceptable toxicity.

Atezolizumab exposure, the primary outcome measure of the study, met the lower limit of geometric mean ratio above the prespecified threshold of 0.8 (cycle 1C trough, 1.05; area under the curve for days 0-21, 0.87).

No notable differences were observed in overall response rate, progression-free survival, or overall survival between the two formulations, according to the FDA approval notice.

The confirmed overall response rate was 9% in the subcutaneous arm and 8% intravenous arm.

Adverse events of any grade occurring in at least 10% of patients were fatigue, musculoskeletal pain, cough, dyspnea, and decreased appetite.

The recommended dose for subcutaneous injection is one 15 mL injection, which contains 1875 mg of atezolizumab and 30,000 units of hyaluronidase.

Injections should be administered in the thigh over approximately 7 minutes every 3 weeks. By contrast, IV administration generally takes 30-60 minutes.

A version of this article first appeared on Medscape.com.

The Food and Drug Administration (FDA) has approved atezolizumab and hyaluronidase-tqjs (Tecentriq Hybreza, Genentech) as a subcutaneous injection in adults, covering all approved indications of the intravenous (IV) formulation.

Approved indications include non–small cell lung cancer (NSCLC), SCLC, hepatocellular carcinoma, melanoma, and alveolar soft part sarcoma. Specific indications are available with the full prescribing information at Drugs@FDA.

This is the first programmed death–ligand 1 inhibitor to gain approval for subcutaneous administration.

“This approval represents a significant option to improve the patient experience,” Ann Fish-Steagall, RN, Senior Vice President of Patient Services at the LUNGevity Foundation stated in a Genentech press release.

Subcutaneous atezolizumab and hyaluronidase-tqjs was evaluated in the open-label, randomized IMscin001 trial of 371 adult patients with locally advanced or metastatic NSCLC who were not previously exposed to cancer immunotherapy and who had disease progression following treatment with platinum-based chemotherapy. Patients were randomized 2:1 to receive subcutaneous or IV administration until disease progression or unacceptable toxicity.

Atezolizumab exposure, the primary outcome measure of the study, met the lower limit of geometric mean ratio above the prespecified threshold of 0.8 (cycle 1C trough, 1.05; area under the curve for days 0-21, 0.87).

No notable differences were observed in overall response rate, progression-free survival, or overall survival between the two formulations, according to the FDA approval notice.

The confirmed overall response rate was 9% in the subcutaneous arm and 8% intravenous arm.

Adverse events of any grade occurring in at least 10% of patients were fatigue, musculoskeletal pain, cough, dyspnea, and decreased appetite.

The recommended dose for subcutaneous injection is one 15 mL injection, which contains 1875 mg of atezolizumab and 30,000 units of hyaluronidase.

Injections should be administered in the thigh over approximately 7 minutes every 3 weeks. By contrast, IV administration generally takes 30-60 minutes.

A version of this article first appeared on Medscape.com.

SAN DIEGO — Combination therapy with osimertinib and savolitinib could become a novel first-line treatment option for patients with de novo MET-aberrant, EGFR-mutated advanced non–small cell lung cancer (NSCLC), according to results of the phase 2 FLOWERS study.

Compared with EGFR inhibitor osimertinib alone, the combination demonstrated a clinically meaningful improvement in the objective response rate — the study’s primary endpoint — with a positive trend in progression-free survival and a manageable safety profile.

About 30% patients with EGFR-mutated NSCLC fail to respond well to EGFR–tyrosine kinase inhibitors (TKIs), explained Jin-Ji Yang, MD, with Guangdong Lung Cancer Institute, Guangzhou, China, who reported the study results at the annual meeting of the World Conference on Lung Cancer.

Data suggested that de novo MET amplification occurs in up to 5% patients with treatment-naive, EGFR-mutated advanced NSCLC, and MET overexpression occurs in up to 15% these patients.

Coexistence of EGFR mutation and MET amplification/overexpression reduces sensitivity to EGFR-TKI therapy “and is likely the mechanism for mediating primary resistance to first-line EGFR-TKI monotherapy,” Dr. Yang explained in her presentation.

Osimertinib is a third-generation EGFR-TKI recommended as the first-line treatment for EGFR-mutant advanced NSCLC. Savolitinib is a highly selective MET-TKI which has demonstrated antitumor activity in various cancers with MET alterations.

The FLOWERS study is the first to test whether combining the two agents could improve efficacy and overcome MET-driven primary resistance in these patients.

The phase 2 study enrolled 44 treatment-naive patients with de novo MET-aberrant, EGFR-mutant, stage IIIB-IV NSCLC; 23 were randomly allocated to receive oral osimertinib (80 mg once daily) alone and 21 to receive oral osimertinib (80 mg once daily) plus savolitinib (300 mg twice daily).

At a median follow-up of 8.2 months, the objective response rate was 60.9% with osimertinib monotherapy vs 90.5% with combination therapy. The disease control rate was also better with the combination therapy than with monotherapy (95.2% vs 87%).

Median duration of response (not yet mature) was 8.4 months with monotherapy vs 18.6 months with combination therapy.

Preliminary progression-free survival data also showed a trend in favor of combination therapy over monotherapy (a median of 19.3 vs 9.3 months; hazard ratio, 0.59).

Most treatment-related adverse events were grade 1 or 2, and there were no fatal adverse events.

Treatment-related adverse events of grade 3 or higher were more common with combination therapy (57.1% vs 8.7%). The most common events with monotherapy were diarrhea (56.5%), rash (52.2%), and pruritus (43.5%) and with dual therapy were rash (52.4%), thrombocytopenia (52.4%), and peripheral edema (42.9%).

The results showed that the combination therapy has the potential to become a first-line treatment option for patients who do not respond well to EGFR-TKIs alone, Dr. Yang said in a press release.

Discussant for the study Paul Paik, MD, thoracic oncologist at Memorial Sloan Kettering Cancer Center in New York City, said this study “adds to data suggesting high MET expression might be a poor prognostic or predictive marker, the outcomes of which are improved with MET inhibition.”

He cautioned, however, that there appears to be “quality of life, side-effect trade-offs with dual MET plus EGFR TKI upfront.”

Dr. Paik said he looks forward to results from FLOWERS on serial circulating tumor DNA and formal androgen receptor testing, which “might aid in further assessing clonality and characterizing MET as a co-driver in this setting.”

The study was funded by AstraZeneca China. Dr. Yang had no disclosures. Dr. Paik disclosed relationships with EMD Serono, Bicara, Novartis, and Summit.

A version of this article first appeared on Medscape.com.

SAN DIEGO — Combination therapy with osimertinib and savolitinib could become a novel first-line treatment option for patients with de novo MET-aberrant, EGFR-mutated advanced non–small cell lung cancer (NSCLC), according to results of the phase 2 FLOWERS study.

Compared with EGFR inhibitor osimertinib alone, the combination demonstrated a clinically meaningful improvement in the objective response rate — the study’s primary endpoint — with a positive trend in progression-free survival and a manageable safety profile.

About 30% patients with EGFR-mutated NSCLC fail to respond well to EGFR–tyrosine kinase inhibitors (TKIs), explained Jin-Ji Yang, MD, with Guangdong Lung Cancer Institute, Guangzhou, China, who reported the study results at the annual meeting of the World Conference on Lung Cancer.

Data suggested that de novo MET amplification occurs in up to 5% patients with treatment-naive, EGFR-mutated advanced NSCLC, and MET overexpression occurs in up to 15% these patients.

Coexistence of EGFR mutation and MET amplification/overexpression reduces sensitivity to EGFR-TKI therapy “and is likely the mechanism for mediating primary resistance to first-line EGFR-TKI monotherapy,” Dr. Yang explained in her presentation.

Osimertinib is a third-generation EGFR-TKI recommended as the first-line treatment for EGFR-mutant advanced NSCLC. Savolitinib is a highly selective MET-TKI which has demonstrated antitumor activity in various cancers with MET alterations.

The FLOWERS study is the first to test whether combining the two agents could improve efficacy and overcome MET-driven primary resistance in these patients.

The phase 2 study enrolled 44 treatment-naive patients with de novo MET-aberrant, EGFR-mutant, stage IIIB-IV NSCLC; 23 were randomly allocated to receive oral osimertinib (80 mg once daily) alone and 21 to receive oral osimertinib (80 mg once daily) plus savolitinib (300 mg twice daily).

At a median follow-up of 8.2 months, the objective response rate was 60.9% with osimertinib monotherapy vs 90.5% with combination therapy. The disease control rate was also better with the combination therapy than with monotherapy (95.2% vs 87%).

Median duration of response (not yet mature) was 8.4 months with monotherapy vs 18.6 months with combination therapy.

Preliminary progression-free survival data also showed a trend in favor of combination therapy over monotherapy (a median of 19.3 vs 9.3 months; hazard ratio, 0.59).

Most treatment-related adverse events were grade 1 or 2, and there were no fatal adverse events.

Treatment-related adverse events of grade 3 or higher were more common with combination therapy (57.1% vs 8.7%). The most common events with monotherapy were diarrhea (56.5%), rash (52.2%), and pruritus (43.5%) and with dual therapy were rash (52.4%), thrombocytopenia (52.4%), and peripheral edema (42.9%).

The results showed that the combination therapy has the potential to become a first-line treatment option for patients who do not respond well to EGFR-TKIs alone, Dr. Yang said in a press release.

Discussant for the study Paul Paik, MD, thoracic oncologist at Memorial Sloan Kettering Cancer Center in New York City, said this study “adds to data suggesting high MET expression might be a poor prognostic or predictive marker, the outcomes of which are improved with MET inhibition.”

He cautioned, however, that there appears to be “quality of life, side-effect trade-offs with dual MET plus EGFR TKI upfront.”

Dr. Paik said he looks forward to results from FLOWERS on serial circulating tumor DNA and formal androgen receptor testing, which “might aid in further assessing clonality and characterizing MET as a co-driver in this setting.”

The study was funded by AstraZeneca China. Dr. Yang had no disclosures. Dr. Paik disclosed relationships with EMD Serono, Bicara, Novartis, and Summit.

A version of this article first appeared on Medscape.com.

SAN DIEGO — Combination therapy with osimertinib and savolitinib could become a novel first-line treatment option for patients with de novo MET-aberrant, EGFR-mutated advanced non–small cell lung cancer (NSCLC), according to results of the phase 2 FLOWERS study.

Compared with EGFR inhibitor osimertinib alone, the combination demonstrated a clinically meaningful improvement in the objective response rate — the study’s primary endpoint — with a positive trend in progression-free survival and a manageable safety profile.

About 30% patients with EGFR-mutated NSCLC fail to respond well to EGFR–tyrosine kinase inhibitors (TKIs), explained Jin-Ji Yang, MD, with Guangdong Lung Cancer Institute, Guangzhou, China, who reported the study results at the annual meeting of the World Conference on Lung Cancer.

Data suggested that de novo MET amplification occurs in up to 5% patients with treatment-naive, EGFR-mutated advanced NSCLC, and MET overexpression occurs in up to 15% these patients.

Coexistence of EGFR mutation and MET amplification/overexpression reduces sensitivity to EGFR-TKI therapy “and is likely the mechanism for mediating primary resistance to first-line EGFR-TKI monotherapy,” Dr. Yang explained in her presentation.

Osimertinib is a third-generation EGFR-TKI recommended as the first-line treatment for EGFR-mutant advanced NSCLC. Savolitinib is a highly selective MET-TKI which has demonstrated antitumor activity in various cancers with MET alterations.

The FLOWERS study is the first to test whether combining the two agents could improve efficacy and overcome MET-driven primary resistance in these patients.

The phase 2 study enrolled 44 treatment-naive patients with de novo MET-aberrant, EGFR-mutant, stage IIIB-IV NSCLC; 23 were randomly allocated to receive oral osimertinib (80 mg once daily) alone and 21 to receive oral osimertinib (80 mg once daily) plus savolitinib (300 mg twice daily).

At a median follow-up of 8.2 months, the objective response rate was 60.9% with osimertinib monotherapy vs 90.5% with combination therapy. The disease control rate was also better with the combination therapy than with monotherapy (95.2% vs 87%).

Median duration of response (not yet mature) was 8.4 months with monotherapy vs 18.6 months with combination therapy.

Preliminary progression-free survival data also showed a trend in favor of combination therapy over monotherapy (a median of 19.3 vs 9.3 months; hazard ratio, 0.59).

Most treatment-related adverse events were grade 1 or 2, and there were no fatal adverse events.

Treatment-related adverse events of grade 3 or higher were more common with combination therapy (57.1% vs 8.7%). The most common events with monotherapy were diarrhea (56.5%), rash (52.2%), and pruritus (43.5%) and with dual therapy were rash (52.4%), thrombocytopenia (52.4%), and peripheral edema (42.9%).

The results showed that the combination therapy has the potential to become a first-line treatment option for patients who do not respond well to EGFR-TKIs alone, Dr. Yang said in a press release.

Discussant for the study Paul Paik, MD, thoracic oncologist at Memorial Sloan Kettering Cancer Center in New York City, said this study “adds to data suggesting high MET expression might be a poor prognostic or predictive marker, the outcomes of which are improved with MET inhibition.”

He cautioned, however, that there appears to be “quality of life, side-effect trade-offs with dual MET plus EGFR TKI upfront.”

Dr. Paik said he looks forward to results from FLOWERS on serial circulating tumor DNA and formal androgen receptor testing, which “might aid in further assessing clonality and characterizing MET as a co-driver in this setting.”

The study was funded by AstraZeneca China. Dr. Yang had no disclosures. Dr. Paik disclosed relationships with EMD Serono, Bicara, Novartis, and Summit.

A version of this article first appeared on Medscape.com.