Photo by Esther Dyson

The American Society of Clinical Oncology (ASCO) has issued a policy statement addressing financial barriers to patient participation in cancer clinical trials.

ASCO’s policy statement outlines a series of recommendations designed to address multiple financial barriers that impede access to clinical trials, including patient costs that aren’t covered consistently by health insurance; a lack of information provided to patients about clinical trial costs; and limited available research data on financial hardships related to participation in clinical trials.

“Clinical trials are essential for evaluating the safety and efficacy of new cancer treatments, but cancer researchers have seen consistently low patient participation levels—especially among underserved patient populations—in part, due to the financial burdens facing many patients with cancer,” said ASCO President Monica M. Bertagnolli, MD.

“Addressing financial barriers will help improve the enrollment rate and the efficiency, quality, and applicability of cancer research. By including more—and more diverse—participants in our research studies, we expand our ability to care for all patients.”

The recommendations in ASCO’s policy statement include:

1. Improve payer clinical trial coverage policies. Payment policies should be revised to be made consistent, streamlined, and transparent to all stakeholders.

   1. Payers should have clear definitions of “routine costs.”
   2. Payers should streamline prior authorization processes and facilitate trial enrollment through provider reimbursement of clinical trial-related services.
   3. State Medicaid programs should universally guarantee coverage of routine care costs of clinical trials for their beneficiaries.
   4. The U.S. Centers for Medicare & Medicaid Services (CMS) should revise current policy that requires Medicare Advantage beneficiaries to revert to fee-for-service coverage during clinical trials.
   5. CMS’s Innovation Center should explore the effectiveness of alternative payment models in support of clinical trial accrual.

2. During the clinical trials development and enrollment process, provide patients with clear, transparent information about potential trial-related out-of-pocket costs and include mechanisms to support patient financial/health literacy.

   1. Clinical trial sponsors should perform—and make available to enrolling institutions—comprehensive, prospective coverage analyses.
   2. Research sites should consider offering in-house financial navigation/counseling to patients or consider partnering with organizations that provide such services.
   3. Design clinical trials to minimize incremental costs, consistent with scientific objectives and participant safety.

3. Remove impediments to ethically appropriate financial compensation for trial-related out-of-pocket costs. Provision of such financial support should not be considered undue inducement.

   1. Office for Human Research Protections should develop guidance on targeted financial support.

4. Incentivize research that will better characterize patient costs incurred for participating in cancer clinical trials and support the longer-term development of tools to identify and mitigate the risk of trial-associated financial hardship.

“Continued progress against cancer depends on improving patient access to participation in clinical research,” Dr. Bertagnolli said.

“The recommendations in ASCO’s statement aim to ensure that no patient is denied access to a clinical trial for financial reasons and that patients are not harmed financially because of their contributions to advancing science. Ultimately, this is about strengthening the nation’s cancer research enterprise as a whole.”

Photo by Esther Dyson

The American Society of Clinical Oncology (ASCO) has issued a policy statement addressing financial barriers to patient participation in cancer clinical trials.

ASCO’s policy statement outlines a series of recommendations designed to address multiple financial barriers that impede access to clinical trials, including patient costs that aren’t covered consistently by health insurance; a lack of information provided to patients about clinical trial costs; and limited available research data on financial hardships related to participation in clinical trials.

“Clinical trials are essential for evaluating the safety and efficacy of new cancer treatments, but cancer researchers have seen consistently low patient participation levels—especially among underserved patient populations—in part, due to the financial burdens facing many patients with cancer,” said ASCO President Monica M. Bertagnolli, MD.

“Addressing financial barriers will help improve the enrollment rate and the efficiency, quality, and applicability of cancer research. By including more—and more diverse—participants in our research studies, we expand our ability to care for all patients.”

The recommendations in ASCO’s policy statement include:

1. Improve payer clinical trial coverage policies. Payment policies should be revised to be made consistent, streamlined, and transparent to all stakeholders.

   1. Payers should have clear definitions of “routine costs.”
   2. Payers should streamline prior authorization processes and facilitate trial enrollment through provider reimbursement of clinical trial-related services.
   3. State Medicaid programs should universally guarantee coverage of routine care costs of clinical trials for their beneficiaries.
   4. The U.S. Centers for Medicare & Medicaid Services (CMS) should revise current policy that requires Medicare Advantage beneficiaries to revert to fee-for-service coverage during clinical trials.
   5. CMS’s Innovation Center should explore the effectiveness of alternative payment models in support of clinical trial accrual.

2. During the clinical trials development and enrollment process, provide patients with clear, transparent information about potential trial-related out-of-pocket costs and include mechanisms to support patient financial/health literacy.

   1. Clinical trial sponsors should perform—and make available to enrolling institutions—comprehensive, prospective coverage analyses.
   2. Research sites should consider offering in-house financial navigation/counseling to patients or consider partnering with organizations that provide such services.
   3. Design clinical trials to minimize incremental costs, consistent with scientific objectives and participant safety.

3. Remove impediments to ethically appropriate financial compensation for trial-related out-of-pocket costs. Provision of such financial support should not be considered undue inducement.

   1. Office for Human Research Protections should develop guidance on targeted financial support.

4. Incentivize research that will better characterize patient costs incurred for participating in cancer clinical trials and support the longer-term development of tools to identify and mitigate the risk of trial-associated financial hardship.

“Continued progress against cancer depends on improving patient access to participation in clinical research,” Dr. Bertagnolli said.

“The recommendations in ASCO’s statement aim to ensure that no patient is denied access to a clinical trial for financial reasons and that patients are not harmed financially because of their contributions to advancing science. Ultimately, this is about strengthening the nation’s cancer research enterprise as a whole.”

Photo by Esther Dyson

The American Society of Clinical Oncology (ASCO) has issued a policy statement addressing financial barriers to patient participation in cancer clinical trials.

ASCO’s policy statement outlines a series of recommendations designed to address multiple financial barriers that impede access to clinical trials, including patient costs that aren’t covered consistently by health insurance; a lack of information provided to patients about clinical trial costs; and limited available research data on financial hardships related to participation in clinical trials.

“Clinical trials are essential for evaluating the safety and efficacy of new cancer treatments, but cancer researchers have seen consistently low patient participation levels—especially among underserved patient populations—in part, due to the financial burdens facing many patients with cancer,” said ASCO President Monica M. Bertagnolli, MD.

“Addressing financial barriers will help improve the enrollment rate and the efficiency, quality, and applicability of cancer research. By including more—and more diverse—participants in our research studies, we expand our ability to care for all patients.”

The recommendations in ASCO’s policy statement include:

1. Improve payer clinical trial coverage policies. Payment policies should be revised to be made consistent, streamlined, and transparent to all stakeholders.

   1. Payers should have clear definitions of “routine costs.”
   2. Payers should streamline prior authorization processes and facilitate trial enrollment through provider reimbursement of clinical trial-related services.
   3. State Medicaid programs should universally guarantee coverage of routine care costs of clinical trials for their beneficiaries.
   4. The U.S. Centers for Medicare & Medicaid Services (CMS) should revise current policy that requires Medicare Advantage beneficiaries to revert to fee-for-service coverage during clinical trials.
   5. CMS’s Innovation Center should explore the effectiveness of alternative payment models in support of clinical trial accrual.

2. During the clinical trials development and enrollment process, provide patients with clear, transparent information about potential trial-related out-of-pocket costs and include mechanisms to support patient financial/health literacy.

   1. Clinical trial sponsors should perform—and make available to enrolling institutions—comprehensive, prospective coverage analyses.
   2. Research sites should consider offering in-house financial navigation/counseling to patients or consider partnering with organizations that provide such services.
   3. Design clinical trials to minimize incremental costs, consistent with scientific objectives and participant safety.

3. Remove impediments to ethically appropriate financial compensation for trial-related out-of-pocket costs. Provision of such financial support should not be considered undue inducement.

   1. Office for Human Research Protections should develop guidance on targeted financial support.

4. Incentivize research that will better characterize patient costs incurred for participating in cancer clinical trials and support the longer-term development of tools to identify and mitigate the risk of trial-associated financial hardship.

“Continued progress against cancer depends on improving patient access to participation in clinical research,” Dr. Bertagnolli said.

“The recommendations in ASCO’s statement aim to ensure that no patient is denied access to a clinical trial for financial reasons and that patients are not harmed financially because of their contributions to advancing science. Ultimately, this is about strengthening the nation’s cancer research enterprise as a whole.”

Photo by George Hodan

Physician burnout may jeopardize patient care, according to research published in JAMA Internal Medicine.

A review and meta-analysis suggested that physician burnout was associated with a higher risk of patient safety incidents, reduced patient satisfaction, and low professionalism.

Burnout was defined as “a response to prolonged exposure to occupational stress encompassing feelings of emotional exhaustion, depersonalization, and reduced professional efficacy.”

This research was conducted by Maria Panagioti, PhD, of the University of Manchester in the U.K., and her colleagues.

The researchers analyzed 47 studies on the topics of physician burnout and patient care, which included data from a pooled cohort of 42,473 physicians.

Nearly 45% of studies included physicians in their residency or early career (up to 5 years post-residency), and 55.3% included more experienced physicians. The studies included physicians in a hospital setting (63.8%), primary care setting (27.7%), or a mix of health care settings (8.5%).

The data indicated that physician burnout was significantly associated with:

• An increased risk of patient safety incidents—odds ratio [OR], 1.96 (P<0.001)
• Low professionalism—OR, 2.31 (P<0.001)
• Reduced patient satisfaction—OR, 2.28 (P<0.001).

The researchers noted that the reporting method had an impact on the results. According to physician report, burnout was associated with significantly increased risks of safety incidents (OR, 2.07) and low professionalism (OR, 2.67).

However, according to system reports, there was no significant association between physician burnout and safety incidents (OR, 1.00) or low professionalism (OR, 1.15).

Another factor that impacted results was physician experience. The association between burnout and low professionalism was significantly larger in studies of residents and early career physicians (OR, 3.39) than in studies of middle- and late-career physicians (OR, 1.73).

The researchers noted that this review had its limitations, including variation in outcomes across studies, heterogeneity among studies, potential selection bias by excluding gray literature, and the inability to establish causal links from findings because of the cross-sectional nature of the studies analyzed.

This research was funded by the United Kingdom National Institute for Health Research (NIHR) School for Primary Care Research and the NIHR Greater Manchester Patient Safety Translational Research Centre. Study authors reported no relevant conflicts of interest.

Photo by George Hodan

Physician burnout may jeopardize patient care, according to research published in JAMA Internal Medicine.

A review and meta-analysis suggested that physician burnout was associated with a higher risk of patient safety incidents, reduced patient satisfaction, and low professionalism.

Burnout was defined as “a response to prolonged exposure to occupational stress encompassing feelings of emotional exhaustion, depersonalization, and reduced professional efficacy.”

This research was conducted by Maria Panagioti, PhD, of the University of Manchester in the U.K., and her colleagues.

The researchers analyzed 47 studies on the topics of physician burnout and patient care, which included data from a pooled cohort of 42,473 physicians.

Nearly 45% of studies included physicians in their residency or early career (up to 5 years post-residency), and 55.3% included more experienced physicians. The studies included physicians in a hospital setting (63.8%), primary care setting (27.7%), or a mix of health care settings (8.5%).

The data indicated that physician burnout was significantly associated with:

• An increased risk of patient safety incidents—odds ratio [OR], 1.96 (P<0.001)
• Low professionalism—OR, 2.31 (P<0.001)
• Reduced patient satisfaction—OR, 2.28 (P<0.001).

The researchers noted that the reporting method had an impact on the results. According to physician report, burnout was associated with significantly increased risks of safety incidents (OR, 2.07) and low professionalism (OR, 2.67).

However, according to system reports, there was no significant association between physician burnout and safety incidents (OR, 1.00) or low professionalism (OR, 1.15).

Another factor that impacted results was physician experience. The association between burnout and low professionalism was significantly larger in studies of residents and early career physicians (OR, 3.39) than in studies of middle- and late-career physicians (OR, 1.73).

The researchers noted that this review had its limitations, including variation in outcomes across studies, heterogeneity among studies, potential selection bias by excluding gray literature, and the inability to establish causal links from findings because of the cross-sectional nature of the studies analyzed.

This research was funded by the United Kingdom National Institute for Health Research (NIHR) School for Primary Care Research and the NIHR Greater Manchester Patient Safety Translational Research Centre. Study authors reported no relevant conflicts of interest.

Photo by George Hodan

Physician burnout may jeopardize patient care, according to research published in JAMA Internal Medicine.

A review and meta-analysis suggested that physician burnout was associated with a higher risk of patient safety incidents, reduced patient satisfaction, and low professionalism.

Burnout was defined as “a response to prolonged exposure to occupational stress encompassing feelings of emotional exhaustion, depersonalization, and reduced professional efficacy.”

This research was conducted by Maria Panagioti, PhD, of the University of Manchester in the U.K., and her colleagues.

The researchers analyzed 47 studies on the topics of physician burnout and patient care, which included data from a pooled cohort of 42,473 physicians.

Nearly 45% of studies included physicians in their residency or early career (up to 5 years post-residency), and 55.3% included more experienced physicians. The studies included physicians in a hospital setting (63.8%), primary care setting (27.7%), or a mix of health care settings (8.5%).

The data indicated that physician burnout was significantly associated with:

• An increased risk of patient safety incidents—odds ratio [OR], 1.96 (P<0.001)
• Low professionalism—OR, 2.31 (P<0.001)
• Reduced patient satisfaction—OR, 2.28 (P<0.001).

The researchers noted that the reporting method had an impact on the results. According to physician report, burnout was associated with significantly increased risks of safety incidents (OR, 2.07) and low professionalism (OR, 2.67).

However, according to system reports, there was no significant association between physician burnout and safety incidents (OR, 1.00) or low professionalism (OR, 1.15).

Another factor that impacted results was physician experience. The association between burnout and low professionalism was significantly larger in studies of residents and early career physicians (OR, 3.39) than in studies of middle- and late-career physicians (OR, 1.73).

The researchers noted that this review had its limitations, including variation in outcomes across studies, heterogeneity among studies, potential selection bias by excluding gray literature, and the inability to establish causal links from findings because of the cross-sectional nature of the studies analyzed.

This research was funded by the United Kingdom National Institute for Health Research (NIHR) School for Primary Care Research and the NIHR Greater Manchester Patient Safety Translational Research Centre. Study authors reported no relevant conflicts of interest.

Multiple sclerosis (MS) is a chronic, autoimmune-mediated ­disorder of the central nervous system that affects more than 40,000 people in the United States. About 85% of cases are categorized as relapsing remitting multiple sclerosis (RRMS), based on the clinical and radiographic pattern of focal demyelination in different regions of the brain and spinal cord over time. Though not fully understood, the pathophysiology of RRMS involves axonal degeneration and inflammatory demyelination; the latter is considered a relapse in patients with an established MS diagnosis.

OVERVIEW

MS relapse can have a significant impact on patients’ short- and long-term function, quality of life, and finances. Relapse may be identified via

• New neurologic symptoms reported by the patient
• New neurologic findings on physical examination
• New radiographic findings on contrast-enhanced MRI of the central nervous system, or
• Abnormal results of cerebrospinal fluid analysis.

Patient-reported symptoms and abnormal signs identified on physical exam should correspond with the area of the central nervous system affected. In some cases, patients may have radiographic evidence of relapse without symptoms or signs.

It is essential for health care providers to identify relapse, as it is an important marker of disease activity that may warrant treatment—particularly if symptoms are impacting function or if there is optic neuritis. MS relapse is also an indicator of suboptimal response to disease-modifying therapies.

Treatment of relapse is one component of RRMS management, which also includes symptom management and use of disease-modifying therapy to reduce risk for disease activity and decline in function.

DIAGNOSING RELAPSE

Because risk for MS relapse cannot be predicted, both patients and providers need to have a high index of suspicion in the setting of new neurologic symptoms or decline in function. Relapse should be considered when these symptoms last longer than 24 hours in the absence of fever or infection. The clinical features of relapse should have corresponding radiographic evidence of active demyelination on contrast-enhanced MRI.

A pseudo-relapse is characterized by new or worsening neurologic symptoms lasting longer than 24 hours with concurrent fever, infection, or other metabolic derangement. Pseudo-relapse does not show radiographic evidence of active demyelination on contrast-enhanced MRI.

Continue to: Aggravation of longstanding neurologic symptoms...

Aggravation of longstanding neurologic symptoms is not considered a relapse, as no new radiographic evidence of disease progression will be seen on MRI. Factors that may contribute to aggravation of established symptoms include an increase in core body temperature, sleep deprivation, and psychosocial stress.

When a patient with suspected or diagnosed RRMS presents with new neurologic symptoms of more than 24 hours’ duration, the first step is to conduct a physical exam to assess for objective evidence of neurologic deficits and signs of infection, including fever. The provider should also order select laboratory testing—including a complete blood cell count and urinalysis with culture—to exclude infection. In certain cases, contrast-enhanced MRI of the brain and/or spine may be ordered; however, this may delay treatment initiation if the study cannot be promptly scheduled.

Evaluation and management should involve communication, if not face-to-face consultation, with the patient’s neurology provider who is responsible for MS management.

IMMEDIATE MANAGEMENT

Acute relapses are managed with anti-inflammatory agents. For some patients, treatment may provide symptomatic relief, shorten the recovery phase, and improve motor function. Long-term benefits have not been demonstrated, except in patients with optic neuritis.

Firstline therapy for MS relapse is high-dose corticosteroids, which can be administered at home, at an ambulatory infusion center, or (in some cases) in a hospital setting. The preferred regimen is methylprednisolone (1 g IV for 3-5 d), with or without prednisone taper. Another option is dexamethasone (80 mg bid for 3-5 d), with or without prednisone taper.^1-3

Continue to: Common adverse effects of corticosteroids include...

Common adverse effects of corticosteroids include headache, emotional lability, insomnia, glucose intolerance, hypertension, dyspepsia, and exacerbation of psychiatric conditions; drug interactions should also be considered. Patients with diabetes may need to be admitted to the hospital for glycemic monitoring and control.

High-dose corticosteroids are associated with a rare, non–dose-dependent risk for aseptic femoral necrosis. For patients who are refractory to or not candidates for corticosteroids, adrenocorticotropic hormone (ACTH) gel (80 U/d IM or subQ daily for 10 d) is an option. This medication may be better tolerated, although it is much more expensive than corticosteroids. Plasmapheresis and IV immunoglobulin are also options for patients with refractory symptoms or contraindications to recommended therapies.^1-3

ONGOING MANAGEMENT

Once a treatment plan is initiated, providers should carefully follow the patient’s response in terms of adverse effects, symptom improvement, and functional recovery. Those with refractory symptoms may need additional doses of the initial therapy or an alternative therapy.

The relapse recovery period may last several months and be complete or incomplete, so providers may also need to manage neurologic symptoms and functional deficits (with pharmacologic and/or nonpharmacologic options). Patients who have had a relapse should also meet with their neurology provider to discuss their disease-modifying therapy plan, since relapse indicates a suboptimal response to current therapy.

Multiple sclerosis (MS) is a chronic, autoimmune-mediated ­disorder of the central nervous system that affects more than 40,000 people in the United States. About 85% of cases are categorized as relapsing remitting multiple sclerosis (RRMS), based on the clinical and radiographic pattern of focal demyelination in different regions of the brain and spinal cord over time. Though not fully understood, the pathophysiology of RRMS involves axonal degeneration and inflammatory demyelination; the latter is considered a relapse in patients with an established MS diagnosis.

OVERVIEW

MS relapse can have a significant impact on patients’ short- and long-term function, quality of life, and finances. Relapse may be identified via

• New neurologic symptoms reported by the patient
• New neurologic findings on physical examination
• New radiographic findings on contrast-enhanced MRI of the central nervous system, or
• Abnormal results of cerebrospinal fluid analysis.

Patient-reported symptoms and abnormal signs identified on physical exam should correspond with the area of the central nervous system affected. In some cases, patients may have radiographic evidence of relapse without symptoms or signs.

It is essential for health care providers to identify relapse, as it is an important marker of disease activity that may warrant treatment—particularly if symptoms are impacting function or if there is optic neuritis. MS relapse is also an indicator of suboptimal response to disease-modifying therapies.

Treatment of relapse is one component of RRMS management, which also includes symptom management and use of disease-modifying therapy to reduce risk for disease activity and decline in function.

DIAGNOSING RELAPSE

Because risk for MS relapse cannot be predicted, both patients and providers need to have a high index of suspicion in the setting of new neurologic symptoms or decline in function. Relapse should be considered when these symptoms last longer than 24 hours in the absence of fever or infection. The clinical features of relapse should have corresponding radiographic evidence of active demyelination on contrast-enhanced MRI.

A pseudo-relapse is characterized by new or worsening neurologic symptoms lasting longer than 24 hours with concurrent fever, infection, or other metabolic derangement. Pseudo-relapse does not show radiographic evidence of active demyelination on contrast-enhanced MRI.

Continue to: Aggravation of longstanding neurologic symptoms...

Aggravation of longstanding neurologic symptoms is not considered a relapse, as no new radiographic evidence of disease progression will be seen on MRI. Factors that may contribute to aggravation of established symptoms include an increase in core body temperature, sleep deprivation, and psychosocial stress.

When a patient with suspected or diagnosed RRMS presents with new neurologic symptoms of more than 24 hours’ duration, the first step is to conduct a physical exam to assess for objective evidence of neurologic deficits and signs of infection, including fever. The provider should also order select laboratory testing—including a complete blood cell count and urinalysis with culture—to exclude infection. In certain cases, contrast-enhanced MRI of the brain and/or spine may be ordered; however, this may delay treatment initiation if the study cannot be promptly scheduled.

Evaluation and management should involve communication, if not face-to-face consultation, with the patient’s neurology provider who is responsible for MS management.

IMMEDIATE MANAGEMENT

Acute relapses are managed with anti-inflammatory agents. For some patients, treatment may provide symptomatic relief, shorten the recovery phase, and improve motor function. Long-term benefits have not been demonstrated, except in patients with optic neuritis.

Firstline therapy for MS relapse is high-dose corticosteroids, which can be administered at home, at an ambulatory infusion center, or (in some cases) in a hospital setting. The preferred regimen is methylprednisolone (1 g IV for 3-5 d), with or without prednisone taper. Another option is dexamethasone (80 mg bid for 3-5 d), with or without prednisone taper.^1-3

Continue to: Common adverse effects of corticosteroids include...

Common adverse effects of corticosteroids include headache, emotional lability, insomnia, glucose intolerance, hypertension, dyspepsia, and exacerbation of psychiatric conditions; drug interactions should also be considered. Patients with diabetes may need to be admitted to the hospital for glycemic monitoring and control.

High-dose corticosteroids are associated with a rare, non–dose-dependent risk for aseptic femoral necrosis. For patients who are refractory to or not candidates for corticosteroids, adrenocorticotropic hormone (ACTH) gel (80 U/d IM or subQ daily for 10 d) is an option. This medication may be better tolerated, although it is much more expensive than corticosteroids. Plasmapheresis and IV immunoglobulin are also options for patients with refractory symptoms or contraindications to recommended therapies.^1-3

ONGOING MANAGEMENT

Once a treatment plan is initiated, providers should carefully follow the patient’s response in terms of adverse effects, symptom improvement, and functional recovery. Those with refractory symptoms may need additional doses of the initial therapy or an alternative therapy.

The relapse recovery period may last several months and be complete or incomplete, so providers may also need to manage neurologic symptoms and functional deficits (with pharmacologic and/or nonpharmacologic options). Patients who have had a relapse should also meet with their neurology provider to discuss their disease-modifying therapy plan, since relapse indicates a suboptimal response to current therapy.

Multiple sclerosis (MS) is a chronic, autoimmune-mediated ­disorder of the central nervous system that affects more than 40,000 people in the United States. About 85% of cases are categorized as relapsing remitting multiple sclerosis (RRMS), based on the clinical and radiographic pattern of focal demyelination in different regions of the brain and spinal cord over time. Though not fully understood, the pathophysiology of RRMS involves axonal degeneration and inflammatory demyelination; the latter is considered a relapse in patients with an established MS diagnosis.

OVERVIEW

MS relapse can have a significant impact on patients’ short- and long-term function, quality of life, and finances. Relapse may be identified via

• New neurologic symptoms reported by the patient
• New neurologic findings on physical examination
• New radiographic findings on contrast-enhanced MRI of the central nervous system, or
• Abnormal results of cerebrospinal fluid analysis.

Patient-reported symptoms and abnormal signs identified on physical exam should correspond with the area of the central nervous system affected. In some cases, patients may have radiographic evidence of relapse without symptoms or signs.

It is essential for health care providers to identify relapse, as it is an important marker of disease activity that may warrant treatment—particularly if symptoms are impacting function or if there is optic neuritis. MS relapse is also an indicator of suboptimal response to disease-modifying therapies.

Treatment of relapse is one component of RRMS management, which also includes symptom management and use of disease-modifying therapy to reduce risk for disease activity and decline in function.

DIAGNOSING RELAPSE

Because risk for MS relapse cannot be predicted, both patients and providers need to have a high index of suspicion in the setting of new neurologic symptoms or decline in function. Relapse should be considered when these symptoms last longer than 24 hours in the absence of fever or infection. The clinical features of relapse should have corresponding radiographic evidence of active demyelination on contrast-enhanced MRI.

A pseudo-relapse is characterized by new or worsening neurologic symptoms lasting longer than 24 hours with concurrent fever, infection, or other metabolic derangement. Pseudo-relapse does not show radiographic evidence of active demyelination on contrast-enhanced MRI.

Continue to: Aggravation of longstanding neurologic symptoms...

Aggravation of longstanding neurologic symptoms is not considered a relapse, as no new radiographic evidence of disease progression will be seen on MRI. Factors that may contribute to aggravation of established symptoms include an increase in core body temperature, sleep deprivation, and psychosocial stress.

When a patient with suspected or diagnosed RRMS presents with new neurologic symptoms of more than 24 hours’ duration, the first step is to conduct a physical exam to assess for objective evidence of neurologic deficits and signs of infection, including fever. The provider should also order select laboratory testing—including a complete blood cell count and urinalysis with culture—to exclude infection. In certain cases, contrast-enhanced MRI of the brain and/or spine may be ordered; however, this may delay treatment initiation if the study cannot be promptly scheduled.

Evaluation and management should involve communication, if not face-to-face consultation, with the patient’s neurology provider who is responsible for MS management.

IMMEDIATE MANAGEMENT

Acute relapses are managed with anti-inflammatory agents. For some patients, treatment may provide symptomatic relief, shorten the recovery phase, and improve motor function. Long-term benefits have not been demonstrated, except in patients with optic neuritis.

Firstline therapy for MS relapse is high-dose corticosteroids, which can be administered at home, at an ambulatory infusion center, or (in some cases) in a hospital setting. The preferred regimen is methylprednisolone (1 g IV for 3-5 d), with or without prednisone taper. Another option is dexamethasone (80 mg bid for 3-5 d), with or without prednisone taper.^1-3

Continue to: Common adverse effects of corticosteroids include...

Common adverse effects of corticosteroids include headache, emotional lability, insomnia, glucose intolerance, hypertension, dyspepsia, and exacerbation of psychiatric conditions; drug interactions should also be considered. Patients with diabetes may need to be admitted to the hospital for glycemic monitoring and control.

High-dose corticosteroids are associated with a rare, non–dose-dependent risk for aseptic femoral necrosis. For patients who are refractory to or not candidates for corticosteroids, adrenocorticotropic hormone (ACTH) gel (80 U/d IM or subQ daily for 10 d) is an option. This medication may be better tolerated, although it is much more expensive than corticosteroids. Plasmapheresis and IV immunoglobulin are also options for patients with refractory symptoms or contraindications to recommended therapies.^1-3

ONGOING MANAGEMENT

Once a treatment plan is initiated, providers should carefully follow the patient’s response in terms of adverse effects, symptom improvement, and functional recovery. Those with refractory symptoms may need additional doses of the initial therapy or an alternative therapy.

The relapse recovery period may last several months and be complete or incomplete, so providers may also need to manage neurologic symptoms and functional deficits (with pharmacologic and/or nonpharmacologic options). Patients who have had a relapse should also meet with their neurology provider to discuss their disease-modifying therapy plan, since relapse indicates a suboptimal response to current therapy.

Canakinumab, an interleukin-1–beta blocker, reduced the risk of a gout attack by 52% when administered every 3 months, according to a secondary exploratory analysis of data from the multicenter, randomized, double-blind, placebo-controlled CANTOS trial (NCT01327846). The results of this analysis were published Sept. 17 in the Annals of Internal Medicine (doi: 10.7326/M18-1167).

We covered this story before it was published in the journal. Find our conference coverage at the links below.

Canakinumab, an interleukin-1–beta blocker, reduced the risk of a gout attack by 52% when administered every 3 months, according to a secondary exploratory analysis of data from the multicenter, randomized, double-blind, placebo-controlled CANTOS trial (NCT01327846). The results of this analysis were published Sept. 17 in the Annals of Internal Medicine (doi: 10.7326/M18-1167).

We covered this story before it was published in the journal. Find our conference coverage at the links below.

Canakinumab, an interleukin-1–beta blocker, reduced the risk of a gout attack by 52% when administered every 3 months, according to a secondary exploratory analysis of data from the multicenter, randomized, double-blind, placebo-controlled CANTOS trial (NCT01327846). The results of this analysis were published Sept. 17 in the Annals of Internal Medicine (doi: 10.7326/M18-1167).

We covered this story before it was published in the journal. Find our conference coverage at the links below.

Patients with incident psoriatic arthritis are at a significantly increased risk of developing type 2 diabetes when compared against patients with psoriasis alone and with the general population, according to recent research published in Rheumatology.

Tashatuvango/Thinkstock

Rachel Charlton, PhD, of the department of pharmacy and pharmacology at the University of Bath (England), and her colleagues performed an analysis of 6,783 incident cases of psoriatic arthritis (PsA) from the U.K. Clinical Practice Research Datalink who were diagnosed during 1998-2014. Patients were between 18 years and 89 years old with a median age of 49 years at PsA diagnosis.

In the study, the researchers randomly matched PsA cases at a 1:4 ratio to either a cohort of general population patients with no PsA, psoriasis, or inflammatory arthritis or a cohort of patients with psoriasis but no PsA or inflammatory arthritis. Patients were followed from match to the point where they either no longer met inclusion criteria for the cohort or received a diagnosis of type 2 diabetes, cerebrovascular disease (CVD), ischemic heart disease (IHD), or peripheral vascular disease (PVD) with a mean follow-up duration of approximately 5.5 years across all patient groups.

Patients in the PsA group had a significantly higher incidence of type 2 diabetes, compared with the general population (adjusted relative risk, 1.40; 95% confidence interval, 1.15-1.70; P = .0007) and psoriasis groups (adjusted RR, 1.53; 95% CI, 1.19-1.97; P = .0009). In the PsA group, risk of CVD (adjusted RR, 1.24; 95% CI, 0.99-1.56; P = .06), IHD (adjusted RR, 1.27; 95% CI, 1.05-1.54; P = .02), and PVD (adjusted RR, 1.40; 95% CI, 1.02-1.92; P = .04) were significantly higher than in the general population but not when compared with the psoriasis group. The overall risk of cardiovascular disease (including CVD, IHD, and PVD) for the PsA group was significantly higher (adjusted RR, 1.29; 95% CI, 1.12-1.48; P = .0005), compared with the general population.

“These results support the proposal in existing clinical guidelines that, in order to reduce cardiovascular risk in patients with PsA, it is important to treat inflammatory disease as well as to screen and treat traditional risk factors early in the disease course,” Ms. Charlton and her colleagues wrote in their study.

This study was funded by a grant from the National Institute for Health Research in the United Kingdom. The authors reported no relevant conflicts of interest.

SOURCE: Charlton RA et al. Rheumatology. 2018 Sep 6. doi: 10.1093/rheumatology/key286.

Patients with incident psoriatic arthritis are at a significantly increased risk of developing type 2 diabetes when compared against patients with psoriasis alone and with the general population, according to recent research published in Rheumatology.

Tashatuvango/Thinkstock

Rachel Charlton, PhD, of the department of pharmacy and pharmacology at the University of Bath (England), and her colleagues performed an analysis of 6,783 incident cases of psoriatic arthritis (PsA) from the U.K. Clinical Practice Research Datalink who were diagnosed during 1998-2014. Patients were between 18 years and 89 years old with a median age of 49 years at PsA diagnosis.

In the study, the researchers randomly matched PsA cases at a 1:4 ratio to either a cohort of general population patients with no PsA, psoriasis, or inflammatory arthritis or a cohort of patients with psoriasis but no PsA or inflammatory arthritis. Patients were followed from match to the point where they either no longer met inclusion criteria for the cohort or received a diagnosis of type 2 diabetes, cerebrovascular disease (CVD), ischemic heart disease (IHD), or peripheral vascular disease (PVD) with a mean follow-up duration of approximately 5.5 years across all patient groups.

Patients in the PsA group had a significantly higher incidence of type 2 diabetes, compared with the general population (adjusted relative risk, 1.40; 95% confidence interval, 1.15-1.70; P = .0007) and psoriasis groups (adjusted RR, 1.53; 95% CI, 1.19-1.97; P = .0009). In the PsA group, risk of CVD (adjusted RR, 1.24; 95% CI, 0.99-1.56; P = .06), IHD (adjusted RR, 1.27; 95% CI, 1.05-1.54; P = .02), and PVD (adjusted RR, 1.40; 95% CI, 1.02-1.92; P = .04) were significantly higher than in the general population but not when compared with the psoriasis group. The overall risk of cardiovascular disease (including CVD, IHD, and PVD) for the PsA group was significantly higher (adjusted RR, 1.29; 95% CI, 1.12-1.48; P = .0005), compared with the general population.

“These results support the proposal in existing clinical guidelines that, in order to reduce cardiovascular risk in patients with PsA, it is important to treat inflammatory disease as well as to screen and treat traditional risk factors early in the disease course,” Ms. Charlton and her colleagues wrote in their study.

This study was funded by a grant from the National Institute for Health Research in the United Kingdom. The authors reported no relevant conflicts of interest.

SOURCE: Charlton RA et al. Rheumatology. 2018 Sep 6. doi: 10.1093/rheumatology/key286.

Patients with incident psoriatic arthritis are at a significantly increased risk of developing type 2 diabetes when compared against patients with psoriasis alone and with the general population, according to recent research published in Rheumatology.

Tashatuvango/Thinkstock

Rachel Charlton, PhD, of the department of pharmacy and pharmacology at the University of Bath (England), and her colleagues performed an analysis of 6,783 incident cases of psoriatic arthritis (PsA) from the U.K. Clinical Practice Research Datalink who were diagnosed during 1998-2014. Patients were between 18 years and 89 years old with a median age of 49 years at PsA diagnosis.

In the study, the researchers randomly matched PsA cases at a 1:4 ratio to either a cohort of general population patients with no PsA, psoriasis, or inflammatory arthritis or a cohort of patients with psoriasis but no PsA or inflammatory arthritis. Patients were followed from match to the point where they either no longer met inclusion criteria for the cohort or received a diagnosis of type 2 diabetes, cerebrovascular disease (CVD), ischemic heart disease (IHD), or peripheral vascular disease (PVD) with a mean follow-up duration of approximately 5.5 years across all patient groups.

Patients in the PsA group had a significantly higher incidence of type 2 diabetes, compared with the general population (adjusted relative risk, 1.40; 95% confidence interval, 1.15-1.70; P = .0007) and psoriasis groups (adjusted RR, 1.53; 95% CI, 1.19-1.97; P = .0009). In the PsA group, risk of CVD (adjusted RR, 1.24; 95% CI, 0.99-1.56; P = .06), IHD (adjusted RR, 1.27; 95% CI, 1.05-1.54; P = .02), and PVD (adjusted RR, 1.40; 95% CI, 1.02-1.92; P = .04) were significantly higher than in the general population but not when compared with the psoriasis group. The overall risk of cardiovascular disease (including CVD, IHD, and PVD) for the PsA group was significantly higher (adjusted RR, 1.29; 95% CI, 1.12-1.48; P = .0005), compared with the general population.

“These results support the proposal in existing clinical guidelines that, in order to reduce cardiovascular risk in patients with PsA, it is important to treat inflammatory disease as well as to screen and treat traditional risk factors early in the disease course,” Ms. Charlton and her colleagues wrote in their study.

This study was funded by a grant from the National Institute for Health Research in the United Kingdom. The authors reported no relevant conflicts of interest.

SOURCE: Charlton RA et al. Rheumatology. 2018 Sep 6. doi: 10.1093/rheumatology/key286.

QUESTION: A groundskeeper alleges he developed terminal lymphoma from the use of the weed killer Roundup. A homeowner injures his leg while using a lawnmower. One thousand litigants allege Lipitor caused them to develop diabetes. A patient sues his doctor for a serious allergic reaction to an antibiotic.

Which of the following statements is incorrect?

A. These are all examples of product liability.

B. If successful, the groundskeeper may be awarded hundreds of millions of dollars in damages.

C. The homeowner has a cause of action against the manufacturer, even if it’s a borrowed lawnmower from a neighbor.

D. It is now harder to include multiple plaintiffs in a class-action lawsuit.

E. The “learned intermediary doctrine” immunizes the drug manufacturer from liability for a patient’s allergic reaction.



ANSWER: A. Johnson v. Monsanto was a recent case in San Francisco that resulted in a verdict for the plaintiff to the tune of $289 million.¹ DeWayne Johnson, a 46-year-old groundskeeper, had developed non-Hodgkin lymphoma after using the weed killer, Roundup, to treat the school grounds, sometimes spraying the herbicide for several hours a day. Mr. Johnson alleged that Roundup’s active ingredient, glyphosate, is a known carcinogen, and that Monsanto, its manufacturer, failed to provide appropriate warning regarding this dangerous product.

The judge in the case allowed into evidence internal emails and experts’ warnings, as well as a critical 2015 position paper of the World Health Organization’s international agency for research on cancer, which classified glyphosate as “probably carcinogenic to humans.”² Yet the herbicide, used widely in households and in commerce, is registered in 130 countries and approved for use on more than 100 crops. It was the first such case involving Roundup.

At trial, the jury unanimously found that Roundup was a substantial contributing factor in causing Mr. Johnson’s malignancy, that Monsanto failed to warn him of its health hazards (marketing “defect”), and that it knew or should have known that its product was unreasonably dangerous. The main portion, $250 million (of the $289 million award), was awarded as punitive damages.

Tort damages are of two types: compensatory and punitive. The former is to compensate the victim for past and future losses such as wages and medical expenses, pain and suffering, and/or emotional distress. On the other hand, punitive damages, also called exemplary damages, are awarded where there is a reckless, willful, or wanton disregard of the obvious risk of harm.

The case is currently under appeal. Meanwhile, another Roundup trial will soon take place in St. Louis, and the company is facing a class-action suit in U.S. district court in San Francisco, as well as several thousand claims in state courts throughout the country.

Johnson v. Monsanto is a typical product liability action. According to Section 102(2) of the Uniform Product Liability Act, product liability includes “all claims or action brought for personal injury, death, or property damage caused by the manufacture, design, formula, preparation, assembly, installation, testing, warnings, instructions, marketing, packaging, or labeling of any product.”

There are basically three legal theories in a product liability claim: negligence, breach of warranty, and strict product liability. The latter is the most favored by plaintiffs, as there is no need to prove fault or warranty.

In a seminal case in 1963, William Greenman was injured when he used a power tool that was given to him as a gift.³ He sued the manufacturer, although there was no direct contract of warranty between him and the manufacturer, as he did not make the purchase himself.

Dr. Tan is emeritus professor of medicine and former adjunct professor of law at the University of Hawaii, Honolulu. This article is meant to be educational and does not constitute medical, ethical, or legal advice. For additional information, readers may contact the author at [email protected].

References

1. DeWayne Johnson v. Monsanto Co., Superior Court of California, County of San Francisco, Case No. CGC-16-550128, June 18, 2018.

2. The Monsanto Papers: Roundup (Glyphosate) Cancer Case Key Documents & Analysis. Available at usrtk.org.

3. Greenman v. Yuba Power Products Inc., 377 P.2d 897 (Cal. 1963).

4. “Defective and unreasonably dangerous,” Internal Medicine News, Nov. 4, 2014.

5. “Class-action lawsuits,” Internal Medicine News, April 1, 2015.

6. Bristol-Myers Squibb Co. v. Superior Court of California, 582 U.S. ____ (2017).

QUESTION: A groundskeeper alleges he developed terminal lymphoma from the use of the weed killer Roundup. A homeowner injures his leg while using a lawnmower. One thousand litigants allege Lipitor caused them to develop diabetes. A patient sues his doctor for a serious allergic reaction to an antibiotic.

Which of the following statements is incorrect?

A. These are all examples of product liability.

B. If successful, the groundskeeper may be awarded hundreds of millions of dollars in damages.

C. The homeowner has a cause of action against the manufacturer, even if it’s a borrowed lawnmower from a neighbor.

D. It is now harder to include multiple plaintiffs in a class-action lawsuit.

E. The “learned intermediary doctrine” immunizes the drug manufacturer from liability for a patient’s allergic reaction.



ANSWER: A. Johnson v. Monsanto was a recent case in San Francisco that resulted in a verdict for the plaintiff to the tune of $289 million.¹ DeWayne Johnson, a 46-year-old groundskeeper, had developed non-Hodgkin lymphoma after using the weed killer, Roundup, to treat the school grounds, sometimes spraying the herbicide for several hours a day. Mr. Johnson alleged that Roundup’s active ingredient, glyphosate, is a known carcinogen, and that Monsanto, its manufacturer, failed to provide appropriate warning regarding this dangerous product.

The judge in the case allowed into evidence internal emails and experts’ warnings, as well as a critical 2015 position paper of the World Health Organization’s international agency for research on cancer, which classified glyphosate as “probably carcinogenic to humans.”² Yet the herbicide, used widely in households and in commerce, is registered in 130 countries and approved for use on more than 100 crops. It was the first such case involving Roundup.

At trial, the jury unanimously found that Roundup was a substantial contributing factor in causing Mr. Johnson’s malignancy, that Monsanto failed to warn him of its health hazards (marketing “defect”), and that it knew or should have known that its product was unreasonably dangerous. The main portion, $250 million (of the $289 million award), was awarded as punitive damages.

Tort damages are of two types: compensatory and punitive. The former is to compensate the victim for past and future losses such as wages and medical expenses, pain and suffering, and/or emotional distress. On the other hand, punitive damages, also called exemplary damages, are awarded where there is a reckless, willful, or wanton disregard of the obvious risk of harm.

The case is currently under appeal. Meanwhile, another Roundup trial will soon take place in St. Louis, and the company is facing a class-action suit in U.S. district court in San Francisco, as well as several thousand claims in state courts throughout the country.

Johnson v. Monsanto is a typical product liability action. According to Section 102(2) of the Uniform Product Liability Act, product liability includes “all claims or action brought for personal injury, death, or property damage caused by the manufacture, design, formula, preparation, assembly, installation, testing, warnings, instructions, marketing, packaging, or labeling of any product.”

There are basically three legal theories in a product liability claim: negligence, breach of warranty, and strict product liability. The latter is the most favored by plaintiffs, as there is no need to prove fault or warranty.

In a seminal case in 1963, William Greenman was injured when he used a power tool that was given to him as a gift.³ He sued the manufacturer, although there was no direct contract of warranty between him and the manufacturer, as he did not make the purchase himself.

Dr. Tan is emeritus professor of medicine and former adjunct professor of law at the University of Hawaii, Honolulu. This article is meant to be educational and does not constitute medical, ethical, or legal advice. For additional information, readers may contact the author at [email protected].

References

1. DeWayne Johnson v. Monsanto Co., Superior Court of California, County of San Francisco, Case No. CGC-16-550128, June 18, 2018.

2. The Monsanto Papers: Roundup (Glyphosate) Cancer Case Key Documents & Analysis. Available at usrtk.org.

3. Greenman v. Yuba Power Products Inc., 377 P.2d 897 (Cal. 1963).

4. “Defective and unreasonably dangerous,” Internal Medicine News, Nov. 4, 2014.

5. “Class-action lawsuits,” Internal Medicine News, April 1, 2015.

6. Bristol-Myers Squibb Co. v. Superior Court of California, 582 U.S. ____ (2017).

QUESTION: A groundskeeper alleges he developed terminal lymphoma from the use of the weed killer Roundup. A homeowner injures his leg while using a lawnmower. One thousand litigants allege Lipitor caused them to develop diabetes. A patient sues his doctor for a serious allergic reaction to an antibiotic.

Which of the following statements is incorrect?

A. These are all examples of product liability.

B. If successful, the groundskeeper may be awarded hundreds of millions of dollars in damages.

C. The homeowner has a cause of action against the manufacturer, even if it’s a borrowed lawnmower from a neighbor.

D. It is now harder to include multiple plaintiffs in a class-action lawsuit.

E. The “learned intermediary doctrine” immunizes the drug manufacturer from liability for a patient’s allergic reaction.



ANSWER: A. Johnson v. Monsanto was a recent case in San Francisco that resulted in a verdict for the plaintiff to the tune of $289 million.¹ DeWayne Johnson, a 46-year-old groundskeeper, had developed non-Hodgkin lymphoma after using the weed killer, Roundup, to treat the school grounds, sometimes spraying the herbicide for several hours a day. Mr. Johnson alleged that Roundup’s active ingredient, glyphosate, is a known carcinogen, and that Monsanto, its manufacturer, failed to provide appropriate warning regarding this dangerous product.

The judge in the case allowed into evidence internal emails and experts’ warnings, as well as a critical 2015 position paper of the World Health Organization’s international agency for research on cancer, which classified glyphosate as “probably carcinogenic to humans.”² Yet the herbicide, used widely in households and in commerce, is registered in 130 countries and approved for use on more than 100 crops. It was the first such case involving Roundup.

At trial, the jury unanimously found that Roundup was a substantial contributing factor in causing Mr. Johnson’s malignancy, that Monsanto failed to warn him of its health hazards (marketing “defect”), and that it knew or should have known that its product was unreasonably dangerous. The main portion, $250 million (of the $289 million award), was awarded as punitive damages.

Tort damages are of two types: compensatory and punitive. The former is to compensate the victim for past and future losses such as wages and medical expenses, pain and suffering, and/or emotional distress. On the other hand, punitive damages, also called exemplary damages, are awarded where there is a reckless, willful, or wanton disregard of the obvious risk of harm.

The case is currently under appeal. Meanwhile, another Roundup trial will soon take place in St. Louis, and the company is facing a class-action suit in U.S. district court in San Francisco, as well as several thousand claims in state courts throughout the country.

Johnson v. Monsanto is a typical product liability action. According to Section 102(2) of the Uniform Product Liability Act, product liability includes “all claims or action brought for personal injury, death, or property damage caused by the manufacture, design, formula, preparation, assembly, installation, testing, warnings, instructions, marketing, packaging, or labeling of any product.”

There are basically three legal theories in a product liability claim: negligence, breach of warranty, and strict product liability. The latter is the most favored by plaintiffs, as there is no need to prove fault or warranty.

In a seminal case in 1963, William Greenman was injured when he used a power tool that was given to him as a gift.³ He sued the manufacturer, although there was no direct contract of warranty between him and the manufacturer, as he did not make the purchase himself.

Dr. Tan is emeritus professor of medicine and former adjunct professor of law at the University of Hawaii, Honolulu. This article is meant to be educational and does not constitute medical, ethical, or legal advice. For additional information, readers may contact the author at [email protected].

References

1. DeWayne Johnson v. Monsanto Co., Superior Court of California, County of San Francisco, Case No. CGC-16-550128, June 18, 2018.

2. The Monsanto Papers: Roundup (Glyphosate) Cancer Case Key Documents & Analysis. Available at usrtk.org.

3. Greenman v. Yuba Power Products Inc., 377 P.2d 897 (Cal. 1963).

4. “Defective and unreasonably dangerous,” Internal Medicine News, Nov. 4, 2014.

5. “Class-action lawsuits,” Internal Medicine News, April 1, 2015.

6. Bristol-Myers Squibb Co. v. Superior Court of California, 582 U.S. ____ (2017).

Click here to read the digital edition of the supplement

This supplement is supported by an educational education grant from Celgene and Janssen Biotech, Inc.

Topics Include:

• Advances in diagnosis and prognosis
• Management of the newly diagnosed patient
• Treatment advances and current management strategies for relapsed/refractory patients
• Future treatment directions

About the Author

Thomas R. Chauncey, MD, PhD
Associate Professor of Medicine and Oncology
University of Washington
Associate Member
Fred Hutchinson Cancer Research Center
Director, Marrow Transplant Unit
VA Puget Sound Health Care System
Seattle, WA

Click here to read the digital edition of the supplement

Click here to read the digital edition of the supplement

This supplement is supported by an educational education grant from Celgene and Janssen Biotech, Inc.

Topics Include:

• Advances in diagnosis and prognosis
• Management of the newly diagnosed patient
• Treatment advances and current management strategies for relapsed/refractory patients
• Future treatment directions

About the Author

Thomas R. Chauncey, MD, PhD
Associate Professor of Medicine and Oncology
University of Washington
Associate Member
Fred Hutchinson Cancer Research Center
Director, Marrow Transplant Unit
VA Puget Sound Health Care System
Seattle, WA

Click here to read the digital edition of the supplement

Click here to read the digital edition of the supplement

This supplement is supported by an educational education grant from Celgene and Janssen Biotech, Inc.

Topics Include:

• Advances in diagnosis and prognosis
• Management of the newly diagnosed patient
• Treatment advances and current management strategies for relapsed/refractory patients
• Future treatment directions

About the Author

Thomas R. Chauncey, MD, PhD
Associate Professor of Medicine and Oncology
University of Washington
Associate Member
Fred Hutchinson Cancer Research Center
Director, Marrow Transplant Unit
VA Puget Sound Health Care System
Seattle, WA

Click here to read the digital edition of the supplement

The cost-effectiveness of tisagenlecleucel (Kymriah) depends on long-term clinical outcomes, which are presently unknown, according to investigators.

Courtesy Stanford University

If the long-term outcomes are more modest than clinical trials suggest, then payers may be unwilling to cover the costly therapy, reported John K. Lin, MD, of the Center for Primary Care and Outcomes Research at Stanford (Calif.) University, and his colleagues. Lowering the price or setting up an outcomes-based pricing structure may be necessary to get insurers to cover the therapy.

Tisagenlecleucel is an anti-CD19 chimeric antigen receptor (CAR) T-cell therapy that was approved by the Food and Drug Administration in August 2017 for relapsed or refractory pediatric B-cell acute lymphoblastic leukemia (ALL). In 2018, the FDA expanded the indication for tisagenlecleucel to include adults with relapsed or refractory large B-cell lymphoma, though outcomes from lymphoma trials are not analyzed in the current study.

At a wholesale acquisition cost of $475,000 per infusion, it is the most expensive existing oncology therapy to date, and can be accompanied by expensive, potentially fatal adverse effects. However, clinical trials suggest that tisagenlecleucel can offer years of relapse-free remission, thereby allowing patients to forgo other expensive therapies such as hematopoietic stem cell transplantation (HSCT).

“Although tisagenlecleucel-induced remission rates are promising, compared with those of established therapies (greater than 80% vs. less than 50%), only short-term follow-up data currently exist,” the investigators wrote in the Journal of Clinical Oncology. “Given the high cost and broad applicability in other malignancies of tisagenlecleucel, a pressing question for policy makers, payers, patients, and clinicians is whether the cost of therapy represents reasonable value.”

The study used a Markov model to assess various long-term clinical outcome rates and cost thresholds of tisagenlecleucel. The lifetime cost of therapy was assessed and compared with costs of existing therapies.

The results showed that a 5-year relapse free survival rate of 40% would make the present cost ($475,000) of tisagenlecleucel economically reasonable. In this scenario, the increased life expectancy would be 12.1 years and would result in an additional 5.07 quality-adjusted life years (QALY) gained at a cost of $61,000 per QALY, compared with blinatumomab.

But if long-term outcomes are less favorable, tisagenlecleucel becomes much less cost effective. A 5-year relapse-free survival rate of 20% would drop increased life expectancy to 3.8 years, resulting in 1.80 QALYs gained and raising the cost to $151,000 per QALY.

“Our results suggest that at tisagenlecleucel’s current price and payment structure, its economic value is uncertain,” the investigators wrote.

They suggested a price drop to $200,000 or $350,000, which would allow the drug to remain cost effective even in a worse-case scenario, in which patients relapse and tisagenlecleucel is a bridge to transplant. Another option is to move to outcomes-based pricing. Making payment conditional on 7 months of remission would make the treatment cost effective, according to the analysis.

“Price reductions of tisagenlecleucel or payment only for longer-term remissions would favorably influence cost-effectiveness, even if long-term clinical outcomes are modest,” the investigators wrote.

The study was funded by a Veterans Affairs Office of Academic Affiliations advanced fellowship in health service and research development, and a National Center for Advancing Translational Science Clinical and Translational Science Award. One of the study coauthors reported consulting and research funding from Novartis.

SOURCE: Lin et al. J Clin Oncol. 2018 Sep 13. doi: 10.1200/JCO.2018.79.0642.

The cost-effectiveness of tisagenlecleucel (Kymriah) depends on long-term clinical outcomes, which are presently unknown, according to investigators.

Courtesy Stanford University

If the long-term outcomes are more modest than clinical trials suggest, then payers may be unwilling to cover the costly therapy, reported John K. Lin, MD, of the Center for Primary Care and Outcomes Research at Stanford (Calif.) University, and his colleagues. Lowering the price or setting up an outcomes-based pricing structure may be necessary to get insurers to cover the therapy.

Tisagenlecleucel is an anti-CD19 chimeric antigen receptor (CAR) T-cell therapy that was approved by the Food and Drug Administration in August 2017 for relapsed or refractory pediatric B-cell acute lymphoblastic leukemia (ALL). In 2018, the FDA expanded the indication for tisagenlecleucel to include adults with relapsed or refractory large B-cell lymphoma, though outcomes from lymphoma trials are not analyzed in the current study.

At a wholesale acquisition cost of $475,000 per infusion, it is the most expensive existing oncology therapy to date, and can be accompanied by expensive, potentially fatal adverse effects. However, clinical trials suggest that tisagenlecleucel can offer years of relapse-free remission, thereby allowing patients to forgo other expensive therapies such as hematopoietic stem cell transplantation (HSCT).

“Although tisagenlecleucel-induced remission rates are promising, compared with those of established therapies (greater than 80% vs. less than 50%), only short-term follow-up data currently exist,” the investigators wrote in the Journal of Clinical Oncology. “Given the high cost and broad applicability in other malignancies of tisagenlecleucel, a pressing question for policy makers, payers, patients, and clinicians is whether the cost of therapy represents reasonable value.”

The study used a Markov model to assess various long-term clinical outcome rates and cost thresholds of tisagenlecleucel. The lifetime cost of therapy was assessed and compared with costs of existing therapies.

The results showed that a 5-year relapse free survival rate of 40% would make the present cost ($475,000) of tisagenlecleucel economically reasonable. In this scenario, the increased life expectancy would be 12.1 years and would result in an additional 5.07 quality-adjusted life years (QALY) gained at a cost of $61,000 per QALY, compared with blinatumomab.

But if long-term outcomes are less favorable, tisagenlecleucel becomes much less cost effective. A 5-year relapse-free survival rate of 20% would drop increased life expectancy to 3.8 years, resulting in 1.80 QALYs gained and raising the cost to $151,000 per QALY.

“Our results suggest that at tisagenlecleucel’s current price and payment structure, its economic value is uncertain,” the investigators wrote.

They suggested a price drop to $200,000 or $350,000, which would allow the drug to remain cost effective even in a worse-case scenario, in which patients relapse and tisagenlecleucel is a bridge to transplant. Another option is to move to outcomes-based pricing. Making payment conditional on 7 months of remission would make the treatment cost effective, according to the analysis.

“Price reductions of tisagenlecleucel or payment only for longer-term remissions would favorably influence cost-effectiveness, even if long-term clinical outcomes are modest,” the investigators wrote.

The study was funded by a Veterans Affairs Office of Academic Affiliations advanced fellowship in health service and research development, and a National Center for Advancing Translational Science Clinical and Translational Science Award. One of the study coauthors reported consulting and research funding from Novartis.

SOURCE: Lin et al. J Clin Oncol. 2018 Sep 13. doi: 10.1200/JCO.2018.79.0642.

The cost-effectiveness of tisagenlecleucel (Kymriah) depends on long-term clinical outcomes, which are presently unknown, according to investigators.

Courtesy Stanford University

If the long-term outcomes are more modest than clinical trials suggest, then payers may be unwilling to cover the costly therapy, reported John K. Lin, MD, of the Center for Primary Care and Outcomes Research at Stanford (Calif.) University, and his colleagues. Lowering the price or setting up an outcomes-based pricing structure may be necessary to get insurers to cover the therapy.

Tisagenlecleucel is an anti-CD19 chimeric antigen receptor (CAR) T-cell therapy that was approved by the Food and Drug Administration in August 2017 for relapsed or refractory pediatric B-cell acute lymphoblastic leukemia (ALL). In 2018, the FDA expanded the indication for tisagenlecleucel to include adults with relapsed or refractory large B-cell lymphoma, though outcomes from lymphoma trials are not analyzed in the current study.

At a wholesale acquisition cost of $475,000 per infusion, it is the most expensive existing oncology therapy to date, and can be accompanied by expensive, potentially fatal adverse effects. However, clinical trials suggest that tisagenlecleucel can offer years of relapse-free remission, thereby allowing patients to forgo other expensive therapies such as hematopoietic stem cell transplantation (HSCT).

“Although tisagenlecleucel-induced remission rates are promising, compared with those of established therapies (greater than 80% vs. less than 50%), only short-term follow-up data currently exist,” the investigators wrote in the Journal of Clinical Oncology. “Given the high cost and broad applicability in other malignancies of tisagenlecleucel, a pressing question for policy makers, payers, patients, and clinicians is whether the cost of therapy represents reasonable value.”

The study used a Markov model to assess various long-term clinical outcome rates and cost thresholds of tisagenlecleucel. The lifetime cost of therapy was assessed and compared with costs of existing therapies.

The results showed that a 5-year relapse free survival rate of 40% would make the present cost ($475,000) of tisagenlecleucel economically reasonable. In this scenario, the increased life expectancy would be 12.1 years and would result in an additional 5.07 quality-adjusted life years (QALY) gained at a cost of $61,000 per QALY, compared with blinatumomab.

But if long-term outcomes are less favorable, tisagenlecleucel becomes much less cost effective. A 5-year relapse-free survival rate of 20% would drop increased life expectancy to 3.8 years, resulting in 1.80 QALYs gained and raising the cost to $151,000 per QALY.

“Our results suggest that at tisagenlecleucel’s current price and payment structure, its economic value is uncertain,” the investigators wrote.

They suggested a price drop to $200,000 or $350,000, which would allow the drug to remain cost effective even in a worse-case scenario, in which patients relapse and tisagenlecleucel is a bridge to transplant. Another option is to move to outcomes-based pricing. Making payment conditional on 7 months of remission would make the treatment cost effective, according to the analysis.

“Price reductions of tisagenlecleucel or payment only for longer-term remissions would favorably influence cost-effectiveness, even if long-term clinical outcomes are modest,” the investigators wrote.

The study was funded by a Veterans Affairs Office of Academic Affiliations advanced fellowship in health service and research development, and a National Center for Advancing Translational Science Clinical and Translational Science Award. One of the study coauthors reported consulting and research funding from Novartis.

SOURCE: Lin et al. J Clin Oncol. 2018 Sep 13. doi: 10.1200/JCO.2018.79.0642.

Disease flares are common but are hard to predict in people with rheumatoid arthritis who achieve low disease activity (LDA), and these flares are “undeniably” associated with worse disease activity, quality of life, and radiographic progression, researchers report in an analysis of a prospectively observed cohort.

First author Katie Bechman, MBChB, of the academic rheumatology department at King’s College London, and her colleagues reported online in the Journal of Rheumatology that nearly one-third of patients with RA in stable LDA states, including remission, had flares during a year of follow-up in the observational prospective REMIRA study, similar to previous reports in cohort studies.

Suze777/Thinkstock

The cohort of 152 patients had 28-joint Disease Activity Scores (DAS28) less than 3.2 for at least 1 month apart, and 66% (n = 97) of the cohort fulfilled DAS28 remission criteria (DAS28 less than 2.6). The authors defined disease flare as a DAS28 increase of more than 1.2, compared with baseline, or a DAS28 increase of more than 0.6, compared with baseline, and concurrent DAS28 of 3.2 or greater. A total of 69 (35%) were taking disease-modifying antirheumatic drug monotherapy.

Nearly one-third of RA patients (30%, n = 46) with LDA states experienced a flare during 12 months of follow-up. When limiting the cohort to patients who were in remission at baseline, 25% (n = 24) had at least one flare.

Patients who had a flare experienced significantly worse clinical outcomes at 12 months than did patients in sustained remission, reflected by higher disease activity, worse functional outcomes, and higher radiographic progression scores.

For example, patients who flared had more than a threefold greater risk for erosive progression, defined as new or larger erosions over 1 year on radiographs (hazard ratio, 3.6; 95% confidence interval, 2.77-4.67; P less than .01).

Patients’ baseline values on the Health Assessment Questionnaire-Disability Index – a measure of functional activity that is reflected by difficulties in activities of daily living – proved to be a significant independent predictor of flare (HR, 1.76; 95% CI, 1.05-2.93; P = .03) in multivariate analyses.

The researchers also found that serum biomarkers were modestly correlated with DAS28 at the time of flare. DAS28 and its components significantly correlated with multibiomarker disease activity score and calprotectin at time of flare, but correlation coefficients were low at 0.52 and 0.49, respectively. Two-thirds of flares were not associated with a rise in biomarkers.

“This might be because a flare is defined by worsening of the DAS28 composite score, and an increase in [tender joint count] and [patient’s global assessment] alone may increase the DAS28 score to a sufficient level to define a flare,” the investigators suggested.

“It is possible that a flare event is not solely the result of direct synovial inflammation but may be driven by other pathways, for example chronification of pain due to central sensitization and abnormal regulatory mechanisms. This heterogeneity may partly explain why identifying predictors of flare is challenging,” they said.

“In our study, we have shown that the occurrence of a flare is hard to predict, but undeniably associated with worse clinical outcomes at 12 months,” the researchers concluded.

They suggested that it was possible that two “distinct subtypes” of flare might exist: an “inflammatory” flare that was predominantly driven by an increase in swollen joint count and erythrocyte sedimentation rate, and a “noninflammatory” flare with a disproportionately elevated tender joint count and a high patient global assessment score.

“Differentiating these two flare types may identify potential predictors. Further research is needed to determine whether distinct flares exist and to categorize the potential predictors of each,” they added.

The research was partly funded by the U.K. National Institute for Health Research Biomedical Research Centre at Guy’s and St. Thomas’ NHS Foundation Trust and King’s College London.

SOURCE: Bechman K et al. J Rheumatol. 2018 Sep 1. doi: 10.3899/jrheum.171375.

Disease flares are common but are hard to predict in people with rheumatoid arthritis who achieve low disease activity (LDA), and these flares are “undeniably” associated with worse disease activity, quality of life, and radiographic progression, researchers report in an analysis of a prospectively observed cohort.

First author Katie Bechman, MBChB, of the academic rheumatology department at King’s College London, and her colleagues reported online in the Journal of Rheumatology that nearly one-third of patients with RA in stable LDA states, including remission, had flares during a year of follow-up in the observational prospective REMIRA study, similar to previous reports in cohort studies.

Suze777/Thinkstock

The cohort of 152 patients had 28-joint Disease Activity Scores (DAS28) less than 3.2 for at least 1 month apart, and 66% (n = 97) of the cohort fulfilled DAS28 remission criteria (DAS28 less than 2.6). The authors defined disease flare as a DAS28 increase of more than 1.2, compared with baseline, or a DAS28 increase of more than 0.6, compared with baseline, and concurrent DAS28 of 3.2 or greater. A total of 69 (35%) were taking disease-modifying antirheumatic drug monotherapy.

Nearly one-third of RA patients (30%, n = 46) with LDA states experienced a flare during 12 months of follow-up. When limiting the cohort to patients who were in remission at baseline, 25% (n = 24) had at least one flare.

Patients who had a flare experienced significantly worse clinical outcomes at 12 months than did patients in sustained remission, reflected by higher disease activity, worse functional outcomes, and higher radiographic progression scores.

For example, patients who flared had more than a threefold greater risk for erosive progression, defined as new or larger erosions over 1 year on radiographs (hazard ratio, 3.6; 95% confidence interval, 2.77-4.67; P less than .01).

Patients’ baseline values on the Health Assessment Questionnaire-Disability Index – a measure of functional activity that is reflected by difficulties in activities of daily living – proved to be a significant independent predictor of flare (HR, 1.76; 95% CI, 1.05-2.93; P = .03) in multivariate analyses.

The researchers also found that serum biomarkers were modestly correlated with DAS28 at the time of flare. DAS28 and its components significantly correlated with multibiomarker disease activity score and calprotectin at time of flare, but correlation coefficients were low at 0.52 and 0.49, respectively. Two-thirds of flares were not associated with a rise in biomarkers.

“This might be because a flare is defined by worsening of the DAS28 composite score, and an increase in [tender joint count] and [patient’s global assessment] alone may increase the DAS28 score to a sufficient level to define a flare,” the investigators suggested.

“It is possible that a flare event is not solely the result of direct synovial inflammation but may be driven by other pathways, for example chronification of pain due to central sensitization and abnormal regulatory mechanisms. This heterogeneity may partly explain why identifying predictors of flare is challenging,” they said.

“In our study, we have shown that the occurrence of a flare is hard to predict, but undeniably associated with worse clinical outcomes at 12 months,” the researchers concluded.

They suggested that it was possible that two “distinct subtypes” of flare might exist: an “inflammatory” flare that was predominantly driven by an increase in swollen joint count and erythrocyte sedimentation rate, and a “noninflammatory” flare with a disproportionately elevated tender joint count and a high patient global assessment score.

“Differentiating these two flare types may identify potential predictors. Further research is needed to determine whether distinct flares exist and to categorize the potential predictors of each,” they added.

The research was partly funded by the U.K. National Institute for Health Research Biomedical Research Centre at Guy’s and St. Thomas’ NHS Foundation Trust and King’s College London.

SOURCE: Bechman K et al. J Rheumatol. 2018 Sep 1. doi: 10.3899/jrheum.171375.

Disease flares are common but are hard to predict in people with rheumatoid arthritis who achieve low disease activity (LDA), and these flares are “undeniably” associated with worse disease activity, quality of life, and radiographic progression, researchers report in an analysis of a prospectively observed cohort.

First author Katie Bechman, MBChB, of the academic rheumatology department at King’s College London, and her colleagues reported online in the Journal of Rheumatology that nearly one-third of patients with RA in stable LDA states, including remission, had flares during a year of follow-up in the observational prospective REMIRA study, similar to previous reports in cohort studies.

Suze777/Thinkstock

The cohort of 152 patients had 28-joint Disease Activity Scores (DAS28) less than 3.2 for at least 1 month apart, and 66% (n = 97) of the cohort fulfilled DAS28 remission criteria (DAS28 less than 2.6). The authors defined disease flare as a DAS28 increase of more than 1.2, compared with baseline, or a DAS28 increase of more than 0.6, compared with baseline, and concurrent DAS28 of 3.2 or greater. A total of 69 (35%) were taking disease-modifying antirheumatic drug monotherapy.

Nearly one-third of RA patients (30%, n = 46) with LDA states experienced a flare during 12 months of follow-up. When limiting the cohort to patients who were in remission at baseline, 25% (n = 24) had at least one flare.

Patients who had a flare experienced significantly worse clinical outcomes at 12 months than did patients in sustained remission, reflected by higher disease activity, worse functional outcomes, and higher radiographic progression scores.

For example, patients who flared had more than a threefold greater risk for erosive progression, defined as new or larger erosions over 1 year on radiographs (hazard ratio, 3.6; 95% confidence interval, 2.77-4.67; P less than .01).

Patients’ baseline values on the Health Assessment Questionnaire-Disability Index – a measure of functional activity that is reflected by difficulties in activities of daily living – proved to be a significant independent predictor of flare (HR, 1.76; 95% CI, 1.05-2.93; P = .03) in multivariate analyses.

The researchers also found that serum biomarkers were modestly correlated with DAS28 at the time of flare. DAS28 and its components significantly correlated with multibiomarker disease activity score and calprotectin at time of flare, but correlation coefficients were low at 0.52 and 0.49, respectively. Two-thirds of flares were not associated with a rise in biomarkers.

“This might be because a flare is defined by worsening of the DAS28 composite score, and an increase in [tender joint count] and [patient’s global assessment] alone may increase the DAS28 score to a sufficient level to define a flare,” the investigators suggested.

“It is possible that a flare event is not solely the result of direct synovial inflammation but may be driven by other pathways, for example chronification of pain due to central sensitization and abnormal regulatory mechanisms. This heterogeneity may partly explain why identifying predictors of flare is challenging,” they said.

“In our study, we have shown that the occurrence of a flare is hard to predict, but undeniably associated with worse clinical outcomes at 12 months,” the researchers concluded.

They suggested that it was possible that two “distinct subtypes” of flare might exist: an “inflammatory” flare that was predominantly driven by an increase in swollen joint count and erythrocyte sedimentation rate, and a “noninflammatory” flare with a disproportionately elevated tender joint count and a high patient global assessment score.

“Differentiating these two flare types may identify potential predictors. Further research is needed to determine whether distinct flares exist and to categorize the potential predictors of each,” they added.

The research was partly funded by the U.K. National Institute for Health Research Biomedical Research Centre at Guy’s and St. Thomas’ NHS Foundation Trust and King’s College London.

SOURCE: Bechman K et al. J Rheumatol. 2018 Sep 1. doi: 10.3899/jrheum.171375.

CHICAGO – There’s another reason to worry about hypertension in children: cognitive decline later in life.

In a pilot study, Marc Lande, MD, a professor of pediatric nephrology at the University of Rochester (N.Y.), and his colleagues found evidence of impaired white matter integrity on MRI in a handful of hypertensive children, similar to what’s found in adults with cognitive impairment from hypertension.

The work is ongoing, but it helps explain the subtle deficits on cognitive testing that have been previously demonstrated in children with hypertension.

“The fact that we are finding anything at this very early stage of disease is striking and somewhat bothersome. The hope is that, by improving blood pressure in children, you can improve subsequent cognition and maybe even delay the onset of dementia further down the road,” Dr. Lande said.

For now, the findings underscore the need to diagnose and manage hypertension in children, but there might be additional treatment implications in the future, especially if blood pressure targets are found that ameliorate the problem.

Dr. Lande explained the issues and the emerging evidence in a video interview at the joint scientific sessions of the American Heart Association Council on Hypertension, AHA Council on Kidney in Cardiovascular Disease, and American Society of Hypertension.

[email protected]

CHICAGO – There’s another reason to worry about hypertension in children: cognitive decline later in life.

In a pilot study, Marc Lande, MD, a professor of pediatric nephrology at the University of Rochester (N.Y.), and his colleagues found evidence of impaired white matter integrity on MRI in a handful of hypertensive children, similar to what’s found in adults with cognitive impairment from hypertension.

The work is ongoing, but it helps explain the subtle deficits on cognitive testing that have been previously demonstrated in children with hypertension.

“The fact that we are finding anything at this very early stage of disease is striking and somewhat bothersome. The hope is that, by improving blood pressure in children, you can improve subsequent cognition and maybe even delay the onset of dementia further down the road,” Dr. Lande said.

For now, the findings underscore the need to diagnose and manage hypertension in children, but there might be additional treatment implications in the future, especially if blood pressure targets are found that ameliorate the problem.

Dr. Lande explained the issues and the emerging evidence in a video interview at the joint scientific sessions of the American Heart Association Council on Hypertension, AHA Council on Kidney in Cardiovascular Disease, and American Society of Hypertension.

[email protected]

CHICAGO – There’s another reason to worry about hypertension in children: cognitive decline later in life.

In a pilot study, Marc Lande, MD, a professor of pediatric nephrology at the University of Rochester (N.Y.), and his colleagues found evidence of impaired white matter integrity on MRI in a handful of hypertensive children, similar to what’s found in adults with cognitive impairment from hypertension.

The work is ongoing, but it helps explain the subtle deficits on cognitive testing that have been previously demonstrated in children with hypertension.

“The fact that we are finding anything at this very early stage of disease is striking and somewhat bothersome. The hope is that, by improving blood pressure in children, you can improve subsequent cognition and maybe even delay the onset of dementia further down the road,” Dr. Lande said.

For now, the findings underscore the need to diagnose and manage hypertension in children, but there might be additional treatment implications in the future, especially if blood pressure targets are found that ameliorate the problem.

Dr. Lande explained the issues and the emerging evidence in a video interview at the joint scientific sessions of the American Heart Association Council on Hypertension, AHA Council on Kidney in Cardiovascular Disease, and American Society of Hypertension.

[email protected]