References

1. Grohskopf LA, Sokolow LZ, Broder KR, et al. Prevention and control of seasonal influenza with vaccines: recommendations of the Advisory Committee on Immunization Practices—United States, 2018-19 influenza season. MMWR Recomm Rep. 2018;67:1-20.  
2. Liang JL, Tiwari T, Moro P, et al. Prevention of pertussis, tetanus, and diphtheria with vaccines in the United States: recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Recomm Rep. 2018;67:1-44.
3. Dooling KL, Guo A, Patel M, et al. Recommendations of the Advisory Committee on Immunization Practices for use of herpes zoster vaccines. MMWR Morb Mortal Wkly Rep. 2018;67:103-108.
4. Kobayashi M, Bennett NM, Gierke R, et al. Intervals between PCV13 and PPSV23 vaccines: recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Morb Mortal Wkly Rep. 2015;64;944-947.
5. Meites E, Kempe A, Markowitz LE. Use of a 2-dose schedule for human papillomavirus vaccination—updated recommendations of the Advisory Committee on Immunization Practices. MMWR Morb Mortal Wkly Rep. 2016;65:1405-1408.
6. Adult immunization schedule. Centers for Disease Control and Prevention website. https://www.cdc.gov/vaccines/schedules/hcp/imz/adult.html. Reviewed February 5, 2019. Accessed April 23, 2019.

References

1. Grohskopf LA, Sokolow LZ, Broder KR, et al. Prevention and control of seasonal influenza with vaccines: recommendations of the Advisory Committee on Immunization Practices—United States, 2018-19 influenza season. MMWR Recomm Rep. 2018;67:1-20.  
2. Liang JL, Tiwari T, Moro P, et al. Prevention of pertussis, tetanus, and diphtheria with vaccines in the United States: recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Recomm Rep. 2018;67:1-44.
3. Dooling KL, Guo A, Patel M, et al. Recommendations of the Advisory Committee on Immunization Practices for use of herpes zoster vaccines. MMWR Morb Mortal Wkly Rep. 2018;67:103-108.
4. Kobayashi M, Bennett NM, Gierke R, et al. Intervals between PCV13 and PPSV23 vaccines: recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Morb Mortal Wkly Rep. 2015;64;944-947.
5. Meites E, Kempe A, Markowitz LE. Use of a 2-dose schedule for human papillomavirus vaccination—updated recommendations of the Advisory Committee on Immunization Practices. MMWR Morb Mortal Wkly Rep. 2016;65:1405-1408.
6. Adult immunization schedule. Centers for Disease Control and Prevention website. https://www.cdc.gov/vaccines/schedules/hcp/imz/adult.html. Reviewed February 5, 2019. Accessed April 23, 2019.

References

1. Grohskopf LA, Sokolow LZ, Broder KR, et al. Prevention and control of seasonal influenza with vaccines: recommendations of the Advisory Committee on Immunization Practices—United States, 2018-19 influenza season. MMWR Recomm Rep. 2018;67:1-20.  
2. Liang JL, Tiwari T, Moro P, et al. Prevention of pertussis, tetanus, and diphtheria with vaccines in the United States: recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Recomm Rep. 2018;67:1-44.
3. Dooling KL, Guo A, Patel M, et al. Recommendations of the Advisory Committee on Immunization Practices for use of herpes zoster vaccines. MMWR Morb Mortal Wkly Rep. 2018;67:103-108.
4. Kobayashi M, Bennett NM, Gierke R, et al. Intervals between PCV13 and PPSV23 vaccines: recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Morb Mortal Wkly Rep. 2015;64;944-947.
5. Meites E, Kempe A, Markowitz LE. Use of a 2-dose schedule for human papillomavirus vaccination—updated recommendations of the Advisory Committee on Immunization Practices. MMWR Morb Mortal Wkly Rep. 2016;65:1405-1408.
6. Adult immunization schedule. Centers for Disease Control and Prevention website. https://www.cdc.gov/vaccines/schedules/hcp/imz/adult.html. Reviewed February 5, 2019. Accessed April 23, 2019.

For infants with newly diagnosed X-linked severe combined immunodeficiency (SCID-X1), lentiviral gene therapy and targeted busulfan conditioning successfully induced multilineage engraftment of transduced cells, researchers reported.

Pogonic/Getty Images

By 3-4 months after infusion, seven of eight patients had normal numbers of CD3+, CD4+, and naive CD4+ T cells; normal counts of natural killer (NK) cells; and vector marking of T cells, B cells, NK cells, myeloid cells, and bone marrow progenitors, Ewelina Mamcarz, MD, of St. Jude Children’s Research Hospital in Memphis, and her associates reported in the New England Journal of Medicine.

The eighth infant at first lacked a sufficient T-cell response but responded to a boost of gene-corrected cells without busulfan conditioning.

By 6-12 months after infusion, IgM levels also had normalized in seven of the eight infants and showed polyclonal patterns without clonal dominance, according to the investigators. Among four infants who were able to stop intravenous immunoglobulin therapy, three responded to vaccinations with tetanus, diphtheria, pertussis, polio, and pneumococcal polysaccharide. Such restoration of humoral immunity “has not been achieved in previously reported trials of gene therapy for infants with newly diagnosed SCID-X1,” wrote the investigators of this dual-center, phase 1/2 study.

X-linked severe combined immunodeficiency – “bubble boy disease” – is characterized by a lack of T cells, NK cells, and B cells, and is caused by mutations in IL2RG. Some 80% of affected infants have no matched sibling donor for hematopoietic stem cell transplantation, and transplantation from other donors can produce an inadequate response and graft-versus-host disease. Prior attempts at gene therapy with gamma-retroviral vectors had led to vector-induced leukemia or had failed to induce humoral immunity or normal NK cell production.

“Our new lentiviral vector gene therapy combined with nonmyeloablative busulfan conditioning has been successful in restoring immunity in five patients 7-23 years of age in whom a previous allogeneic hematopoietic stem cell transplantation for SCID-X1 had failed,” the investigators wrote. “We hypothesized that the combination of this lentiviral vector and low-exposure busulfan administered by means of pharmacokinetic dose targeting would be safe and effective as the primary treatment in infants with newly diagnosed SCID-X1.”

Their protocol included one to two daily intravenous doses of busulfan, targeting a cumulative area under the curve of 22 mg per hr/L. They calculated the first dose by weight and age using a population-based pharmacokinetic model and adjusted the second dose based on first-dose pharmacokinetics.

After a median of 16.4 months, all infants continued to grow normally and cleared previous infections, and there were no unanticipated side effects from bone marrow harvest, busulfan conditioning, or cell infusion.

“It is hoped that durable, complete adaptive immunity will be achieved in the majority of the patients over time,” the researchers wrote.

They continue to follow the patients to assess therapeutic safety, immune durability, and persistence of the transferred gene in hematopoietic and immune cells.

Study funders included the American Lebanese Syrian Associated Charities, the National Institutes of Health, the California Institute of Regenerative Medicine, and the Assisi Foundation of Memphis. St. Jude Children’s Research Hospital has licensed the gene therapy and partnered with Mustang Bio to develop and commercialize it. Dr. Mamcarz reported receiving grant support from the study funders.

SOURCE: Mamcarz E et al. N Engl J Med. 2019; 380:1525-34.

For infants with newly diagnosed X-linked severe combined immunodeficiency (SCID-X1), lentiviral gene therapy and targeted busulfan conditioning successfully induced multilineage engraftment of transduced cells, researchers reported.

Pogonic/Getty Images

By 3-4 months after infusion, seven of eight patients had normal numbers of CD3+, CD4+, and naive CD4+ T cells; normal counts of natural killer (NK) cells; and vector marking of T cells, B cells, NK cells, myeloid cells, and bone marrow progenitors, Ewelina Mamcarz, MD, of St. Jude Children’s Research Hospital in Memphis, and her associates reported in the New England Journal of Medicine.

The eighth infant at first lacked a sufficient T-cell response but responded to a boost of gene-corrected cells without busulfan conditioning.

By 6-12 months after infusion, IgM levels also had normalized in seven of the eight infants and showed polyclonal patterns without clonal dominance, according to the investigators. Among four infants who were able to stop intravenous immunoglobulin therapy, three responded to vaccinations with tetanus, diphtheria, pertussis, polio, and pneumococcal polysaccharide. Such restoration of humoral immunity “has not been achieved in previously reported trials of gene therapy for infants with newly diagnosed SCID-X1,” wrote the investigators of this dual-center, phase 1/2 study.

X-linked severe combined immunodeficiency – “bubble boy disease” – is characterized by a lack of T cells, NK cells, and B cells, and is caused by mutations in IL2RG. Some 80% of affected infants have no matched sibling donor for hematopoietic stem cell transplantation, and transplantation from other donors can produce an inadequate response and graft-versus-host disease. Prior attempts at gene therapy with gamma-retroviral vectors had led to vector-induced leukemia or had failed to induce humoral immunity or normal NK cell production.

“Our new lentiviral vector gene therapy combined with nonmyeloablative busulfan conditioning has been successful in restoring immunity in five patients 7-23 years of age in whom a previous allogeneic hematopoietic stem cell transplantation for SCID-X1 had failed,” the investigators wrote. “We hypothesized that the combination of this lentiviral vector and low-exposure busulfan administered by means of pharmacokinetic dose targeting would be safe and effective as the primary treatment in infants with newly diagnosed SCID-X1.”

Their protocol included one to two daily intravenous doses of busulfan, targeting a cumulative area under the curve of 22 mg per hr/L. They calculated the first dose by weight and age using a population-based pharmacokinetic model and adjusted the second dose based on first-dose pharmacokinetics.

After a median of 16.4 months, all infants continued to grow normally and cleared previous infections, and there were no unanticipated side effects from bone marrow harvest, busulfan conditioning, or cell infusion.

“It is hoped that durable, complete adaptive immunity will be achieved in the majority of the patients over time,” the researchers wrote.

They continue to follow the patients to assess therapeutic safety, immune durability, and persistence of the transferred gene in hematopoietic and immune cells.

Study funders included the American Lebanese Syrian Associated Charities, the National Institutes of Health, the California Institute of Regenerative Medicine, and the Assisi Foundation of Memphis. St. Jude Children’s Research Hospital has licensed the gene therapy and partnered with Mustang Bio to develop and commercialize it. Dr. Mamcarz reported receiving grant support from the study funders.

SOURCE: Mamcarz E et al. N Engl J Med. 2019; 380:1525-34.

For infants with newly diagnosed X-linked severe combined immunodeficiency (SCID-X1), lentiviral gene therapy and targeted busulfan conditioning successfully induced multilineage engraftment of transduced cells, researchers reported.

Pogonic/Getty Images

By 3-4 months after infusion, seven of eight patients had normal numbers of CD3+, CD4+, and naive CD4+ T cells; normal counts of natural killer (NK) cells; and vector marking of T cells, B cells, NK cells, myeloid cells, and bone marrow progenitors, Ewelina Mamcarz, MD, of St. Jude Children’s Research Hospital in Memphis, and her associates reported in the New England Journal of Medicine.

The eighth infant at first lacked a sufficient T-cell response but responded to a boost of gene-corrected cells without busulfan conditioning.

By 6-12 months after infusion, IgM levels also had normalized in seven of the eight infants and showed polyclonal patterns without clonal dominance, according to the investigators. Among four infants who were able to stop intravenous immunoglobulin therapy, three responded to vaccinations with tetanus, diphtheria, pertussis, polio, and pneumococcal polysaccharide. Such restoration of humoral immunity “has not been achieved in previously reported trials of gene therapy for infants with newly diagnosed SCID-X1,” wrote the investigators of this dual-center, phase 1/2 study.

X-linked severe combined immunodeficiency – “bubble boy disease” – is characterized by a lack of T cells, NK cells, and B cells, and is caused by mutations in IL2RG. Some 80% of affected infants have no matched sibling donor for hematopoietic stem cell transplantation, and transplantation from other donors can produce an inadequate response and graft-versus-host disease. Prior attempts at gene therapy with gamma-retroviral vectors had led to vector-induced leukemia or had failed to induce humoral immunity or normal NK cell production.

“Our new lentiviral vector gene therapy combined with nonmyeloablative busulfan conditioning has been successful in restoring immunity in five patients 7-23 years of age in whom a previous allogeneic hematopoietic stem cell transplantation for SCID-X1 had failed,” the investigators wrote. “We hypothesized that the combination of this lentiviral vector and low-exposure busulfan administered by means of pharmacokinetic dose targeting would be safe and effective as the primary treatment in infants with newly diagnosed SCID-X1.”

Their protocol included one to two daily intravenous doses of busulfan, targeting a cumulative area under the curve of 22 mg per hr/L. They calculated the first dose by weight and age using a population-based pharmacokinetic model and adjusted the second dose based on first-dose pharmacokinetics.

After a median of 16.4 months, all infants continued to grow normally and cleared previous infections, and there were no unanticipated side effects from bone marrow harvest, busulfan conditioning, or cell infusion.

“It is hoped that durable, complete adaptive immunity will be achieved in the majority of the patients over time,” the researchers wrote.

They continue to follow the patients to assess therapeutic safety, immune durability, and persistence of the transferred gene in hematopoietic and immune cells.

Study funders included the American Lebanese Syrian Associated Charities, the National Institutes of Health, the California Institute of Regenerative Medicine, and the Assisi Foundation of Memphis. St. Jude Children’s Research Hospital has licensed the gene therapy and partnered with Mustang Bio to develop and commercialize it. Dr. Mamcarz reported receiving grant support from the study funders.

SOURCE: Mamcarz E et al. N Engl J Med. 2019; 380:1525-34.

Transcranial magnetic stimulation (TMS) appears to improve recollection memory in cognitively normal older adults, according to a small pilot study published online ahead of print April 17 in Neurology. Stimulation also increased functional MRI signals associated with recollection throughout the hippocampal-cortical network.

“Disruption and abnormal functioning of the hippocampal-cortical network, the region of the brain involved in memory formation, has been linked to age-related memory decline, so it’s exciting to see that, by targeting this region, magnetic stimulation may help improve memory in older adults,” said Joel L. Voss, PhD, of Northwestern University in Chicago. “These results may help us better understand how this network supports memory.”

Recollection is the type of memory most impaired during normal aging. Other types of memory, such as recognition, are relatively spared. Research indicates that multiple sessions of TMS improve recollection and hippocampal-cortical network function in young adults.

Dr. Voss and colleagues performed a pilot study to evaluate whether TMS could improve recollection in older adults. They enrolled 15 cognitively normal older adults (mean age, 72.46 years) into a sham-controlled, single-blind, counterbalanced experiment. Eleven subjects were women. Participants underwent fMRI while learning objects paired with scenes and locations. Investigators administered TMS to lateral parietal locations that were based on each participant’s fMRI connectivity with the hippocampus. Using a within-subjects crossover design, Dr. Voss’s group assessed participants’ recollection and recognition memory at baseline and 24 hours and also 1 week after five consecutive daily sessions of full-intensity stimulation, compared with low-intensity sham stimulation.

At baseline, participants had impaired recollection, but not impaired recognition, compared with a historical sample of younger adults. At 24 hours, TMS provided robust recollection improvement and weak recognition improvement, compared with sham. TMS improved recollection by 31.1% from baseline, and sham yielded a nonsignificant change of −3.1%. Recollection improvements after TMS were consistent across participants. Recognition changed by a nonsignificant 2.8% following TMS and by a nonsignificant −2.9% following sham.

The investigators also found a significant and consistent increase in fMRI recollection activity for the targeted hippocampal-cortical network, but not for the control frontal-parietal network. They observed no increased fMRI activity for recognition.

“These findings demonstrate a causal link between recollection and the hippocampal-cortical network in older adults,” said Dr. Voss. “While our small study examined age-related memory loss, it did not examine this stimulation in people with memory loss from more serious conditions such as mild cognitive impairment or Alzheimer’s disease.” Furthermore, the study was designed to test for neural and behavioral target engagement, but not clinical efficacy, he added.

The study’s limitations included its small sample size, its single-site design, and its lack of active control stimulation. Nevertheless, it identified specific and consistent effects of stimulation across participants that were consistent with previous findings in younger adults. “These findings motivate future studies to optimize the effectiveness of noninvasive stimulation for treatment of age-related memory impairment and to improve mechanistic understanding of the hippocampal-cortical networks that support episodic memory across the lifespan,” said Dr. Voss.

The National Institute on Aging, as well as the Northwestern University Cognitive Neurology and Alzheimer’s Disease Center, supported the study.

egreb@mdedge.com

SOURCE: Nilakantan AS et al. Neurology. 2019 Apr 17 doi: 10.1212/WNL.0000000000007502.

Transcranial magnetic stimulation (TMS) appears to improve recollection memory in cognitively normal older adults, according to a small pilot study published online ahead of print April 17 in Neurology. Stimulation also increased functional MRI signals associated with recollection throughout the hippocampal-cortical network.

“Disruption and abnormal functioning of the hippocampal-cortical network, the region of the brain involved in memory formation, has been linked to age-related memory decline, so it’s exciting to see that, by targeting this region, magnetic stimulation may help improve memory in older adults,” said Joel L. Voss, PhD, of Northwestern University in Chicago. “These results may help us better understand how this network supports memory.”

Recollection is the type of memory most impaired during normal aging. Other types of memory, such as recognition, are relatively spared. Research indicates that multiple sessions of TMS improve recollection and hippocampal-cortical network function in young adults.

Dr. Voss and colleagues performed a pilot study to evaluate whether TMS could improve recollection in older adults. They enrolled 15 cognitively normal older adults (mean age, 72.46 years) into a sham-controlled, single-blind, counterbalanced experiment. Eleven subjects were women. Participants underwent fMRI while learning objects paired with scenes and locations. Investigators administered TMS to lateral parietal locations that were based on each participant’s fMRI connectivity with the hippocampus. Using a within-subjects crossover design, Dr. Voss’s group assessed participants’ recollection and recognition memory at baseline and 24 hours and also 1 week after five consecutive daily sessions of full-intensity stimulation, compared with low-intensity sham stimulation.

At baseline, participants had impaired recollection, but not impaired recognition, compared with a historical sample of younger adults. At 24 hours, TMS provided robust recollection improvement and weak recognition improvement, compared with sham. TMS improved recollection by 31.1% from baseline, and sham yielded a nonsignificant change of −3.1%. Recollection improvements after TMS were consistent across participants. Recognition changed by a nonsignificant 2.8% following TMS and by a nonsignificant −2.9% following sham.

The investigators also found a significant and consistent increase in fMRI recollection activity for the targeted hippocampal-cortical network, but not for the control frontal-parietal network. They observed no increased fMRI activity for recognition.

“These findings demonstrate a causal link between recollection and the hippocampal-cortical network in older adults,” said Dr. Voss. “While our small study examined age-related memory loss, it did not examine this stimulation in people with memory loss from more serious conditions such as mild cognitive impairment or Alzheimer’s disease.” Furthermore, the study was designed to test for neural and behavioral target engagement, but not clinical efficacy, he added.

The study’s limitations included its small sample size, its single-site design, and its lack of active control stimulation. Nevertheless, it identified specific and consistent effects of stimulation across participants that were consistent with previous findings in younger adults. “These findings motivate future studies to optimize the effectiveness of noninvasive stimulation for treatment of age-related memory impairment and to improve mechanistic understanding of the hippocampal-cortical networks that support episodic memory across the lifespan,” said Dr. Voss.

The National Institute on Aging, as well as the Northwestern University Cognitive Neurology and Alzheimer’s Disease Center, supported the study.

egreb@mdedge.com

SOURCE: Nilakantan AS et al. Neurology. 2019 Apr 17 doi: 10.1212/WNL.0000000000007502.

Transcranial magnetic stimulation (TMS) appears to improve recollection memory in cognitively normal older adults, according to a small pilot study published online ahead of print April 17 in Neurology. Stimulation also increased functional MRI signals associated with recollection throughout the hippocampal-cortical network.

“Disruption and abnormal functioning of the hippocampal-cortical network, the region of the brain involved in memory formation, has been linked to age-related memory decline, so it’s exciting to see that, by targeting this region, magnetic stimulation may help improve memory in older adults,” said Joel L. Voss, PhD, of Northwestern University in Chicago. “These results may help us better understand how this network supports memory.”

Recollection is the type of memory most impaired during normal aging. Other types of memory, such as recognition, are relatively spared. Research indicates that multiple sessions of TMS improve recollection and hippocampal-cortical network function in young adults.

Dr. Voss and colleagues performed a pilot study to evaluate whether TMS could improve recollection in older adults. They enrolled 15 cognitively normal older adults (mean age, 72.46 years) into a sham-controlled, single-blind, counterbalanced experiment. Eleven subjects were women. Participants underwent fMRI while learning objects paired with scenes and locations. Investigators administered TMS to lateral parietal locations that were based on each participant’s fMRI connectivity with the hippocampus. Using a within-subjects crossover design, Dr. Voss’s group assessed participants’ recollection and recognition memory at baseline and 24 hours and also 1 week after five consecutive daily sessions of full-intensity stimulation, compared with low-intensity sham stimulation.

At baseline, participants had impaired recollection, but not impaired recognition, compared with a historical sample of younger adults. At 24 hours, TMS provided robust recollection improvement and weak recognition improvement, compared with sham. TMS improved recollection by 31.1% from baseline, and sham yielded a nonsignificant change of −3.1%. Recollection improvements after TMS were consistent across participants. Recognition changed by a nonsignificant 2.8% following TMS and by a nonsignificant −2.9% following sham.

The investigators also found a significant and consistent increase in fMRI recollection activity for the targeted hippocampal-cortical network, but not for the control frontal-parietal network. They observed no increased fMRI activity for recognition.

“These findings demonstrate a causal link between recollection and the hippocampal-cortical network in older adults,” said Dr. Voss. “While our small study examined age-related memory loss, it did not examine this stimulation in people with memory loss from more serious conditions such as mild cognitive impairment or Alzheimer’s disease.” Furthermore, the study was designed to test for neural and behavioral target engagement, but not clinical efficacy, he added.

The study’s limitations included its small sample size, its single-site design, and its lack of active control stimulation. Nevertheless, it identified specific and consistent effects of stimulation across participants that were consistent with previous findings in younger adults. “These findings motivate future studies to optimize the effectiveness of noninvasive stimulation for treatment of age-related memory impairment and to improve mechanistic understanding of the hippocampal-cortical networks that support episodic memory across the lifespan,” said Dr. Voss.

The National Institute on Aging, as well as the Northwestern University Cognitive Neurology and Alzheimer’s Disease Center, supported the study.

egreb@mdedge.com

SOURCE: Nilakantan AS et al. Neurology. 2019 Apr 17 doi: 10.1212/WNL.0000000000007502.

Medicare officials aim to shift the program’s focus from sickness to wellness with the introduction of two new primary care value-based payment care models.

Wikimedia Commons/WWsgConnect/CC-SA 4.0

“We’re launching CMS Primary Cares, an initiative of two new payment models that will enroll a quarter or more of traditional Medicare beneficiaries and a quarter of providers in arrangements that pay for keeping patients healthy, rather than ordering procedures,” Alex Azar, secretary of Health and Human Services, said April 22 during a press conference.

“Today’s announcement creates innovation in primary care that has the potential to entirely transform our fee-for-service system – which is about 65% of the Medicare program – into one that drives value,” Seema Verma, administrator of the Centers for Medicare & Medicaid Services, said during the press conference.

The voluntary models are an array of “new payment options that are all designed to reward [physicians] for keeping people healthy, improving quality of life and delivering positive health outcomes,” Ms. Verma said. “These models are intended to allow clinicians to focus on patient care, not billing, and to do what they’ve been trained to do.”

One option, the Primary Care First model, is aimed at small and solo primary care practices.

The model will “provide participating practices with a predictable payment stream, including a partial cap and some fee-for-service spend,” Ms. Verma said, adding that payments will be adjusted for performance in reducing hospitalizations.

TheaDesign/Thinkstock

The American Medical Association also voiced its support.

“Providing adequate financial support for high-quality primary care must be an essential element of any strategy to improve the quality and affordability of our country’s health care system, Gerald E. Harmon, MD, immediate past chair of the AMA Board of Trustees, said in a statement. “Many primary care physicians have been struggling to deliver the care their patients need and to financially sustain their practices under current Medicare payments. The new primary care payment models announced today will provide practices with more resources and more flexibility to deliver the highest-quality care to their patients.”

The American College of Physicians also noted their support of the new models.

“ACP is optimistic that the new models will emphasize the important role primary care plays in value-based care delivery, that models are voluntary and have a range of risk options, and that practices should use population health management data to reap potential benefits, Robert McLean, MD, ACP president, said in a statement. “ACP is supportive of the fact that the new models aim to reduce administrative burdens – potentially allowing physicians to spend more time with their patients.

“The success and viability of these models will depend on the extent that they are supported by payers in addition to Medicare and Medicaid, are adequately adjusted for differences in the risk and health status of patients seen by each practice, are provided predictable and adequate payments to support and sustain practices (especially smaller independent ones), are appropriately scaled for the financial risk expected of a practice, are provided meaningful and timely data to support improvement, and are truly able to reduce administrative tasks and costs, among other things,” he noted.

gtwachtman@mdedge.com

Medicare officials aim to shift the program’s focus from sickness to wellness with the introduction of two new primary care value-based payment care models.

Wikimedia Commons/WWsgConnect/CC-SA 4.0

“We’re launching CMS Primary Cares, an initiative of two new payment models that will enroll a quarter or more of traditional Medicare beneficiaries and a quarter of providers in arrangements that pay for keeping patients healthy, rather than ordering procedures,” Alex Azar, secretary of Health and Human Services, said April 22 during a press conference.

“Today’s announcement creates innovation in primary care that has the potential to entirely transform our fee-for-service system – which is about 65% of the Medicare program – into one that drives value,” Seema Verma, administrator of the Centers for Medicare & Medicaid Services, said during the press conference.

The voluntary models are an array of “new payment options that are all designed to reward [physicians] for keeping people healthy, improving quality of life and delivering positive health outcomes,” Ms. Verma said. “These models are intended to allow clinicians to focus on patient care, not billing, and to do what they’ve been trained to do.”

One option, the Primary Care First model, is aimed at small and solo primary care practices.

The model will “provide participating practices with a predictable payment stream, including a partial cap and some fee-for-service spend,” Ms. Verma said, adding that payments will be adjusted for performance in reducing hospitalizations.

TheaDesign/Thinkstock

The American Medical Association also voiced its support.

“Providing adequate financial support for high-quality primary care must be an essential element of any strategy to improve the quality and affordability of our country’s health care system, Gerald E. Harmon, MD, immediate past chair of the AMA Board of Trustees, said in a statement. “Many primary care physicians have been struggling to deliver the care their patients need and to financially sustain their practices under current Medicare payments. The new primary care payment models announced today will provide practices with more resources and more flexibility to deliver the highest-quality care to their patients.”

The American College of Physicians also noted their support of the new models.

“ACP is optimistic that the new models will emphasize the important role primary care plays in value-based care delivery, that models are voluntary and have a range of risk options, and that practices should use population health management data to reap potential benefits, Robert McLean, MD, ACP president, said in a statement. “ACP is supportive of the fact that the new models aim to reduce administrative burdens – potentially allowing physicians to spend more time with their patients.

“The success and viability of these models will depend on the extent that they are supported by payers in addition to Medicare and Medicaid, are adequately adjusted for differences in the risk and health status of patients seen by each practice, are provided predictable and adequate payments to support and sustain practices (especially smaller independent ones), are appropriately scaled for the financial risk expected of a practice, are provided meaningful and timely data to support improvement, and are truly able to reduce administrative tasks and costs, among other things,” he noted.

gtwachtman@mdedge.com

Medicare officials aim to shift the program’s focus from sickness to wellness with the introduction of two new primary care value-based payment care models.

Wikimedia Commons/WWsgConnect/CC-SA 4.0

“We’re launching CMS Primary Cares, an initiative of two new payment models that will enroll a quarter or more of traditional Medicare beneficiaries and a quarter of providers in arrangements that pay for keeping patients healthy, rather than ordering procedures,” Alex Azar, secretary of Health and Human Services, said April 22 during a press conference.

“Today’s announcement creates innovation in primary care that has the potential to entirely transform our fee-for-service system – which is about 65% of the Medicare program – into one that drives value,” Seema Verma, administrator of the Centers for Medicare & Medicaid Services, said during the press conference.

The voluntary models are an array of “new payment options that are all designed to reward [physicians] for keeping people healthy, improving quality of life and delivering positive health outcomes,” Ms. Verma said. “These models are intended to allow clinicians to focus on patient care, not billing, and to do what they’ve been trained to do.”

One option, the Primary Care First model, is aimed at small and solo primary care practices.

The model will “provide participating practices with a predictable payment stream, including a partial cap and some fee-for-service spend,” Ms. Verma said, adding that payments will be adjusted for performance in reducing hospitalizations.

TheaDesign/Thinkstock

The American Medical Association also voiced its support.

“Providing adequate financial support for high-quality primary care must be an essential element of any strategy to improve the quality and affordability of our country’s health care system, Gerald E. Harmon, MD, immediate past chair of the AMA Board of Trustees, said in a statement. “Many primary care physicians have been struggling to deliver the care their patients need and to financially sustain their practices under current Medicare payments. The new primary care payment models announced today will provide practices with more resources and more flexibility to deliver the highest-quality care to their patients.”

The American College of Physicians also noted their support of the new models.

“ACP is optimistic that the new models will emphasize the important role primary care plays in value-based care delivery, that models are voluntary and have a range of risk options, and that practices should use population health management data to reap potential benefits, Robert McLean, MD, ACP president, said in a statement. “ACP is supportive of the fact that the new models aim to reduce administrative burdens – potentially allowing physicians to spend more time with their patients.

“The success and viability of these models will depend on the extent that they are supported by payers in addition to Medicare and Medicaid, are adequately adjusted for differences in the risk and health status of patients seen by each practice, are provided predictable and adequate payments to support and sustain practices (especially smaller independent ones), are appropriately scaled for the financial risk expected of a practice, are provided meaningful and timely data to support improvement, and are truly able to reduce administrative tasks and costs, among other things,” he noted.

gtwachtman@mdedge.com

Alvogen has issued a voluntary recall of two lots of its Fentanyl Transdermal System 12-mcg/h transdermal patches because of a product mislabeling, according to the Food and Drug Administration.

The recall was issued because a small number of cartons labeled as containing 12-mcg/h patches contained 50-mcg/h patches. The 50-mcg/h patches were labeled as such within the package. The cartons were distributed to pharmacies nationwide.

Application of a 50-mcg/h patch instead of a 12-mcg/h patch could result in serious, life-threatening, or fatal respiratory depression. Groups at potential risk for such adverse events include first-time users of the patch, children, and the elderly. No reports of serious adverse events have yet been reported.

“Pharmacies are requested not to dispense any product subject to this recall,” the FDA said in a press release. Patients who “have product subject to this recall should immediately remove any patch currently in use and contact their health care provider. Patients with unused product should return it to point of purchase for replacement.”

Find more information on the recall at the FDA website.

lfranki@mdedge.com

Alvogen has issued a voluntary recall of two lots of its Fentanyl Transdermal System 12-mcg/h transdermal patches because of a product mislabeling, according to the Food and Drug Administration.

The recall was issued because a small number of cartons labeled as containing 12-mcg/h patches contained 50-mcg/h patches. The 50-mcg/h patches were labeled as such within the package. The cartons were distributed to pharmacies nationwide.

Application of a 50-mcg/h patch instead of a 12-mcg/h patch could result in serious, life-threatening, or fatal respiratory depression. Groups at potential risk for such adverse events include first-time users of the patch, children, and the elderly. No reports of serious adverse events have yet been reported.

“Pharmacies are requested not to dispense any product subject to this recall,” the FDA said in a press release. Patients who “have product subject to this recall should immediately remove any patch currently in use and contact their health care provider. Patients with unused product should return it to point of purchase for replacement.”

Find more information on the recall at the FDA website.

lfranki@mdedge.com

Alvogen has issued a voluntary recall of two lots of its Fentanyl Transdermal System 12-mcg/h transdermal patches because of a product mislabeling, according to the Food and Drug Administration.

The recall was issued because a small number of cartons labeled as containing 12-mcg/h patches contained 50-mcg/h patches. The 50-mcg/h patches were labeled as such within the package. The cartons were distributed to pharmacies nationwide.

Application of a 50-mcg/h patch instead of a 12-mcg/h patch could result in serious, life-threatening, or fatal respiratory depression. Groups at potential risk for such adverse events include first-time users of the patch, children, and the elderly. No reports of serious adverse events have yet been reported.

“Pharmacies are requested not to dispense any product subject to this recall,” the FDA said in a press release. Patients who “have product subject to this recall should immediately remove any patch currently in use and contact their health care provider. Patients with unused product should return it to point of purchase for replacement.”

Find more information on the recall at the FDA website.

lfranki@mdedge.com

Sharon, a 19-year-old woman, has a history of right optic neuritis and paraparesis that occurred 2 years ago. At that time, the diagnosis of multiple sclerosis (MS) was confirmed by a brain MRI and lumbar puncture. She has been taking disease-modifying therapy for 2 years and rarely misses a dose. Lately, however, she has experienced worsening symptoms and feels that her MS is progressing. Her neurologist doesn’t agree; he informs her that a recent MRI shows no changes, and her neurologic examination is within normal limits. At his suggestion, she presents to her primary care provider for an annual check-up.

HISTORY & PHYSICAL EXAM

Sharon’s height is 5 ft 2 in and her weight, 170 lb. Her blood pressure is 140/88 mm Hg and pulse, 80 beats/min and regular. Review of systems is remarkable for fatigue, visual changes when she is overheated, and weight gain of about 50 lb during the past year. Her lungs are clear to percussion and auscultation.

Her current medications include oral disease-modifying therapy, which she takes daily; an oral contraceptive (for regulation of her menstrual cycle; she says she is not sexually active); and an occasional pain reliever for headache.

CLINICAL IMPRESSION

Following history-taking and examination, the clinician notes the following impressions about Sharon’s health status:

Obesity: Examination reveals an overweight female with a BMI of 31.1.

Physical inactivity: As a legal secretary, Sharon sits at her desk most of the day. Her exercise is limited to walking to and from the bus to get to work. She has limited time for social activities due to fatigue. She spends most of her time watching television or visiting her parents.

Heat intolerance: While describing her lifestyle, Sharon notes that she does not participate in outdoor activity due to heat intolerance.

Continue to: Ambulation difficulty

Ambulation difficulty: Sharon’s walking and balance are worse than they were 6 months ago—a problem she relates to her MS, not her increased weight. She walks with a wide-based ataxic gait and transfers with difficulty, using the arms of her chair to stand up.

Poor nutritional habits: Sharon reports an irregular diet with an occasional breakfast, a sandwich for lunch, and a microwavable meal for dinner. Between meals, she snacks on nutrition bars, chocolate, and hot and cold coffee.

Smoking: Sharon smokes 1 pack of cigarettes daily.

Headache: As noted, Sharon reports occasional analgesic use for relief of headache pain.

The clinician’s impression is as follows: relapsing MS treated with disease-modifying therapy; obesity; ambulation difficulty; heat intolerance; sedentary lifestyle; and headache. In addition, the patient has the following risk factors: smoking; suboptimal activity and exercise; and poor nutritional habits.

Continue to: DISCUSSION

Sharon has relapsing MS treated with ­disease-modifying therapy. But she also demonstrates or reports several independent risk factors, including borderline hypertension; obesity; inadequate diet; lack of activity and exercise; and possible lack of insight into her disease.¹

The plan of care for Sharon should include a review of her MS disease course. As this is explained, it is important to emphasize how adherence to the care plan will yield positive outcomes from the treatment. For example, the patient should understand that the underlying cause of damage in MS is related to the immune system. Providing this education might involve 1 or 2 sessions with written material, simple graphics, and explanation on how disease-modifying therapies work. Even a simple statement such as “Your therapy works as long as you take it on a regular basis” empowers the patient to sustain adherence and take control of her disease.

The next step is to review Sharon’s risk factors for worsening MS, along with the impact these have on her general health. This might entail a long discussion focusing on the patient’s diet, minimal activity and exercise, and smoking. Sharon’s provider explained how all 3 factors can contribute to poor general health and have been shown to negatively affect MS. There is a general impression that wellness and neurologic diseases such as MS are disconnected. The clinician must “reconnect” the 2 through encouragement, education, and coaching.

By working closely with the patient and providing the education to help her make informed decisions about her health, the clinician can develop a plan to implement that has the patient’s full support. For a patient like Sharon, this includes

• Dietary modifications to improve nutrition and promote healthy weight loss
• A program of daily walking to improve stamina and support the patient’s weight loss program²
• Smoking cessation, including participation in a local support group of former smokers.³

Continue to: In Sharon's case...

In Sharon’s case, both she and her clinician agreed that it was important to meet regularly to assess progress toward their mutually agreed-upon goals. It is not enough to devise a plan—providers need to support patients in their efforts to improve their health. Meeting regularly can motivate patients to stay on track, and it gives providers an opportunity to address problems or concerns that might interfere with the patient’s progress.

Sharon, a 19-year-old woman, has a history of right optic neuritis and paraparesis that occurred 2 years ago. At that time, the diagnosis of multiple sclerosis (MS) was confirmed by a brain MRI and lumbar puncture. She has been taking disease-modifying therapy for 2 years and rarely misses a dose. Lately, however, she has experienced worsening symptoms and feels that her MS is progressing. Her neurologist doesn’t agree; he informs her that a recent MRI shows no changes, and her neurologic examination is within normal limits. At his suggestion, she presents to her primary care provider for an annual check-up.

HISTORY & PHYSICAL EXAM

Sharon’s height is 5 ft 2 in and her weight, 170 lb. Her blood pressure is 140/88 mm Hg and pulse, 80 beats/min and regular. Review of systems is remarkable for fatigue, visual changes when she is overheated, and weight gain of about 50 lb during the past year. Her lungs are clear to percussion and auscultation.

Her current medications include oral disease-modifying therapy, which she takes daily; an oral contraceptive (for regulation of her menstrual cycle; she says she is not sexually active); and an occasional pain reliever for headache.

CLINICAL IMPRESSION

Following history-taking and examination, the clinician notes the following impressions about Sharon’s health status:

Obesity: Examination reveals an overweight female with a BMI of 31.1.

Physical inactivity: As a legal secretary, Sharon sits at her desk most of the day. Her exercise is limited to walking to and from the bus to get to work. She has limited time for social activities due to fatigue. She spends most of her time watching television or visiting her parents.

Heat intolerance: While describing her lifestyle, Sharon notes that she does not participate in outdoor activity due to heat intolerance.

Continue to: Ambulation difficulty

Ambulation difficulty: Sharon’s walking and balance are worse than they were 6 months ago—a problem she relates to her MS, not her increased weight. She walks with a wide-based ataxic gait and transfers with difficulty, using the arms of her chair to stand up.

Poor nutritional habits: Sharon reports an irregular diet with an occasional breakfast, a sandwich for lunch, and a microwavable meal for dinner. Between meals, she snacks on nutrition bars, chocolate, and hot and cold coffee.

Smoking: Sharon smokes 1 pack of cigarettes daily.

Headache: As noted, Sharon reports occasional analgesic use for relief of headache pain.

The clinician’s impression is as follows: relapsing MS treated with disease-modifying therapy; obesity; ambulation difficulty; heat intolerance; sedentary lifestyle; and headache. In addition, the patient has the following risk factors: smoking; suboptimal activity and exercise; and poor nutritional habits.

Continue to: DISCUSSION

Sharon has relapsing MS treated with ­disease-modifying therapy. But she also demonstrates or reports several independent risk factors, including borderline hypertension; obesity; inadequate diet; lack of activity and exercise; and possible lack of insight into her disease.¹

The plan of care for Sharon should include a review of her MS disease course. As this is explained, it is important to emphasize how adherence to the care plan will yield positive outcomes from the treatment. For example, the patient should understand that the underlying cause of damage in MS is related to the immune system. Providing this education might involve 1 or 2 sessions with written material, simple graphics, and explanation on how disease-modifying therapies work. Even a simple statement such as “Your therapy works as long as you take it on a regular basis” empowers the patient to sustain adherence and take control of her disease.

The next step is to review Sharon’s risk factors for worsening MS, along with the impact these have on her general health. This might entail a long discussion focusing on the patient’s diet, minimal activity and exercise, and smoking. Sharon’s provider explained how all 3 factors can contribute to poor general health and have been shown to negatively affect MS. There is a general impression that wellness and neurologic diseases such as MS are disconnected. The clinician must “reconnect” the 2 through encouragement, education, and coaching.

By working closely with the patient and providing the education to help her make informed decisions about her health, the clinician can develop a plan to implement that has the patient’s full support. For a patient like Sharon, this includes

• Dietary modifications to improve nutrition and promote healthy weight loss
• A program of daily walking to improve stamina and support the patient’s weight loss program²
• Smoking cessation, including participation in a local support group of former smokers.³

Continue to: In Sharon's case...

In Sharon’s case, both she and her clinician agreed that it was important to meet regularly to assess progress toward their mutually agreed-upon goals. It is not enough to devise a plan—providers need to support patients in their efforts to improve their health. Meeting regularly can motivate patients to stay on track, and it gives providers an opportunity to address problems or concerns that might interfere with the patient’s progress.

Sharon, a 19-year-old woman, has a history of right optic neuritis and paraparesis that occurred 2 years ago. At that time, the diagnosis of multiple sclerosis (MS) was confirmed by a brain MRI and lumbar puncture. She has been taking disease-modifying therapy for 2 years and rarely misses a dose. Lately, however, she has experienced worsening symptoms and feels that her MS is progressing. Her neurologist doesn’t agree; he informs her that a recent MRI shows no changes, and her neurologic examination is within normal limits. At his suggestion, she presents to her primary care provider for an annual check-up.

HISTORY & PHYSICAL EXAM

Sharon’s height is 5 ft 2 in and her weight, 170 lb. Her blood pressure is 140/88 mm Hg and pulse, 80 beats/min and regular. Review of systems is remarkable for fatigue, visual changes when she is overheated, and weight gain of about 50 lb during the past year. Her lungs are clear to percussion and auscultation.

Her current medications include oral disease-modifying therapy, which she takes daily; an oral contraceptive (for regulation of her menstrual cycle; she says she is not sexually active); and an occasional pain reliever for headache.

CLINICAL IMPRESSION

Following history-taking and examination, the clinician notes the following impressions about Sharon’s health status:

Obesity: Examination reveals an overweight female with a BMI of 31.1.

Physical inactivity: As a legal secretary, Sharon sits at her desk most of the day. Her exercise is limited to walking to and from the bus to get to work. She has limited time for social activities due to fatigue. She spends most of her time watching television or visiting her parents.

Heat intolerance: While describing her lifestyle, Sharon notes that she does not participate in outdoor activity due to heat intolerance.

Continue to: Ambulation difficulty

Ambulation difficulty: Sharon’s walking and balance are worse than they were 6 months ago—a problem she relates to her MS, not her increased weight. She walks with a wide-based ataxic gait and transfers with difficulty, using the arms of her chair to stand up.

Poor nutritional habits: Sharon reports an irregular diet with an occasional breakfast, a sandwich for lunch, and a microwavable meal for dinner. Between meals, she snacks on nutrition bars, chocolate, and hot and cold coffee.

Smoking: Sharon smokes 1 pack of cigarettes daily.

Headache: As noted, Sharon reports occasional analgesic use for relief of headache pain.

The clinician’s impression is as follows: relapsing MS treated with disease-modifying therapy; obesity; ambulation difficulty; heat intolerance; sedentary lifestyle; and headache. In addition, the patient has the following risk factors: smoking; suboptimal activity and exercise; and poor nutritional habits.

Continue to: DISCUSSION

Sharon has relapsing MS treated with ­disease-modifying therapy. But she also demonstrates or reports several independent risk factors, including borderline hypertension; obesity; inadequate diet; lack of activity and exercise; and possible lack of insight into her disease.¹

The plan of care for Sharon should include a review of her MS disease course. As this is explained, it is important to emphasize how adherence to the care plan will yield positive outcomes from the treatment. For example, the patient should understand that the underlying cause of damage in MS is related to the immune system. Providing this education might involve 1 or 2 sessions with written material, simple graphics, and explanation on how disease-modifying therapies work. Even a simple statement such as “Your therapy works as long as you take it on a regular basis” empowers the patient to sustain adherence and take control of her disease.

The next step is to review Sharon’s risk factors for worsening MS, along with the impact these have on her general health. This might entail a long discussion focusing on the patient’s diet, minimal activity and exercise, and smoking. Sharon’s provider explained how all 3 factors can contribute to poor general health and have been shown to negatively affect MS. There is a general impression that wellness and neurologic diseases such as MS are disconnected. The clinician must “reconnect” the 2 through encouragement, education, and coaching.

By working closely with the patient and providing the education to help her make informed decisions about her health, the clinician can develop a plan to implement that has the patient’s full support. For a patient like Sharon, this includes

• Dietary modifications to improve nutrition and promote healthy weight loss
• A program of daily walking to improve stamina and support the patient’s weight loss program²
• Smoking cessation, including participation in a local support group of former smokers.³

Continue to: In Sharon's case...

In Sharon’s case, both she and her clinician agreed that it was important to meet regularly to assess progress toward their mutually agreed-upon goals. It is not enough to devise a plan—providers need to support patients in their efforts to improve their health. Meeting regularly can motivate patients to stay on track, and it gives providers an opportunity to address problems or concerns that might interfere with the patient’s progress.

NEWPORT BEACH, CALIF. — A model that mimics the recommender system used by Netflix and Amazon can help predict outcomes of lenalidomide treatment in patients with non–deletion 5q (non-del[5q]) myelodysplastic syndromes (MDS), according to new research.

The model was used to identify genomic biomarkers that were associated with resistance or response to lenalidomide. Researchers found these associations in 39% of patients with non-del(5q) MDS, and the model predicted response or resistance with 82% accuracy.

Yazan Madanat, MD, of the Cleveland Clinic, and his colleagues presented these findings at the Acute Leukemia Forum of Hemedicus.

Dr. Madanat explained that his group’s model is similar to the recommender system used by Netflix and Amazon, which makes suggestions for new products based on customers’ past behavior. Dr. Madanat and his colleagues used their model to show that patients with certain molecular or cytogenetic abnormalities are likely to respond or not respond to lenalidomide.

The researchers began by looking at 139 patients who had received at least two cycles of lenalidomide treatment. There were 118 patients with MDS, and 108 who had received lenalidomide monotherapy. However, the team focused on the 100 patients who had non-del(5q) MDS, 58 of whom had normal karyotype (NK) and 19 of whom had complex karyotype (CK).

The model revealed several combinations of genomic/cytogenetic abnormalities that could predict resistance to lenalidomide, including the following:

• DNMT3A and SF3B1
• EZH2 and NK
• ASXL1, TET2, and NK
• STAG2, IDH1/2, and NK
• TP53, del(5q), and CK
• BCOR/BCORL1 and NK
• JAK2, TET2, and NK
• U2AF1, +/– ETV6, and NK

However, only the following two combinations could predict response to lenalidomide:

• DDX41 and NK
• MECOM and KDM6A/B

These combinations could be applied to 39% of the patients with non-del(5q) MDS, and the model predicted response or resistance to lenalidomide with 82% accuracy.

Although the biomarkers were found in only a subset of patients, Dr. Madanat said these findings may help physicians tailor therapy for MDS patients, given the high level of accuracy the researchers observed.

“It’s really important to validate the results in a prospective manner and to ensure that we’re able to apply them clinically and potentially change the way we’re treating our patients,” he added.

Dr. Madanat and his colleagues reported having no relevant conflicts of interest.

The Acute Leukemia Forum is held by Hemedicus, which is owned by the same company as this news organization.

jensmith@mdedge.com

NEWPORT BEACH, CALIF. — A model that mimics the recommender system used by Netflix and Amazon can help predict outcomes of lenalidomide treatment in patients with non–deletion 5q (non-del[5q]) myelodysplastic syndromes (MDS), according to new research.

The model was used to identify genomic biomarkers that were associated with resistance or response to lenalidomide. Researchers found these associations in 39% of patients with non-del(5q) MDS, and the model predicted response or resistance with 82% accuracy.

Yazan Madanat, MD, of the Cleveland Clinic, and his colleagues presented these findings at the Acute Leukemia Forum of Hemedicus.

Dr. Madanat explained that his group’s model is similar to the recommender system used by Netflix and Amazon, which makes suggestions for new products based on customers’ past behavior. Dr. Madanat and his colleagues used their model to show that patients with certain molecular or cytogenetic abnormalities are likely to respond or not respond to lenalidomide.

The researchers began by looking at 139 patients who had received at least two cycles of lenalidomide treatment. There were 118 patients with MDS, and 108 who had received lenalidomide monotherapy. However, the team focused on the 100 patients who had non-del(5q) MDS, 58 of whom had normal karyotype (NK) and 19 of whom had complex karyotype (CK).

The model revealed several combinations of genomic/cytogenetic abnormalities that could predict resistance to lenalidomide, including the following:

• DNMT3A and SF3B1
• EZH2 and NK
• ASXL1, TET2, and NK
• STAG2, IDH1/2, and NK
• TP53, del(5q), and CK
• BCOR/BCORL1 and NK
• JAK2, TET2, and NK
• U2AF1, +/– ETV6, and NK

However, only the following two combinations could predict response to lenalidomide:

• DDX41 and NK
• MECOM and KDM6A/B

These combinations could be applied to 39% of the patients with non-del(5q) MDS, and the model predicted response or resistance to lenalidomide with 82% accuracy.

Although the biomarkers were found in only a subset of patients, Dr. Madanat said these findings may help physicians tailor therapy for MDS patients, given the high level of accuracy the researchers observed.

“It’s really important to validate the results in a prospective manner and to ensure that we’re able to apply them clinically and potentially change the way we’re treating our patients,” he added.

Dr. Madanat and his colleagues reported having no relevant conflicts of interest.

The Acute Leukemia Forum is held by Hemedicus, which is owned by the same company as this news organization.

jensmith@mdedge.com

NEWPORT BEACH, CALIF. — A model that mimics the recommender system used by Netflix and Amazon can help predict outcomes of lenalidomide treatment in patients with non–deletion 5q (non-del[5q]) myelodysplastic syndromes (MDS), according to new research.

The model was used to identify genomic biomarkers that were associated with resistance or response to lenalidomide. Researchers found these associations in 39% of patients with non-del(5q) MDS, and the model predicted response or resistance with 82% accuracy.

Yazan Madanat, MD, of the Cleveland Clinic, and his colleagues presented these findings at the Acute Leukemia Forum of Hemedicus.

Dr. Madanat explained that his group’s model is similar to the recommender system used by Netflix and Amazon, which makes suggestions for new products based on customers’ past behavior. Dr. Madanat and his colleagues used their model to show that patients with certain molecular or cytogenetic abnormalities are likely to respond or not respond to lenalidomide.

The researchers began by looking at 139 patients who had received at least two cycles of lenalidomide treatment. There were 118 patients with MDS, and 108 who had received lenalidomide monotherapy. However, the team focused on the 100 patients who had non-del(5q) MDS, 58 of whom had normal karyotype (NK) and 19 of whom had complex karyotype (CK).

The model revealed several combinations of genomic/cytogenetic abnormalities that could predict resistance to lenalidomide, including the following:

• DNMT3A and SF3B1
• EZH2 and NK
• ASXL1, TET2, and NK
• STAG2, IDH1/2, and NK
• TP53, del(5q), and CK
• BCOR/BCORL1 and NK
• JAK2, TET2, and NK
• U2AF1, +/– ETV6, and NK

However, only the following two combinations could predict response to lenalidomide:

• DDX41 and NK
• MECOM and KDM6A/B

These combinations could be applied to 39% of the patients with non-del(5q) MDS, and the model predicted response or resistance to lenalidomide with 82% accuracy.

Although the biomarkers were found in only a subset of patients, Dr. Madanat said these findings may help physicians tailor therapy for MDS patients, given the high level of accuracy the researchers observed.

“It’s really important to validate the results in a prospective manner and to ensure that we’re able to apply them clinically and potentially change the way we’re treating our patients,” he added.

Dr. Madanat and his colleagues reported having no relevant conflicts of interest.

The Acute Leukemia Forum is held by Hemedicus, which is owned by the same company as this news organization.

jensmith@mdedge.com

A text messaging–based mobile health (mHealth) intervention that relied on lay health supporters improved medication adherence among rural Chinese patients with schizophrenia by 27%, according to results of a study published in PLoS Medicine.

The researchers developed a mHealth protocol intervention that used text messaging and lay health supporters to help patients with schizophrenia to transition from facility-based care to community-based care. The study randomized 278 community-dwelling villagers with schizophrenia to receive care through a community-based free-medicine program either with or without support from the mHealth intervention. Among the 271 patients successfully followed, medication adherence – the primary outcome – was higher in the mHealth group than it was in the control group (adjusted mean difference, 0.12; 95% confidence interval, 0.03-0.22; P = .013). Adherence was primarily assessed by unannounced home-based pill counts.

The investigators wrote that the treatment gaps for schizophrenia in resource-poor areas remain substantial and that text messaging plus lay health support could form a simple and low-cost means of improving the situation in these settings.

cpalmer@mdedge.com

SOURCE: Xu D et al. PLoS Med. 2019 Apr 23. doi: 10.1371/journal.pmed.1002785.

A text messaging–based mobile health (mHealth) intervention that relied on lay health supporters improved medication adherence among rural Chinese patients with schizophrenia by 27%, according to results of a study published in PLoS Medicine.

The researchers developed a mHealth protocol intervention that used text messaging and lay health supporters to help patients with schizophrenia to transition from facility-based care to community-based care. The study randomized 278 community-dwelling villagers with schizophrenia to receive care through a community-based free-medicine program either with or without support from the mHealth intervention. Among the 271 patients successfully followed, medication adherence – the primary outcome – was higher in the mHealth group than it was in the control group (adjusted mean difference, 0.12; 95% confidence interval, 0.03-0.22; P = .013). Adherence was primarily assessed by unannounced home-based pill counts.

The investigators wrote that the treatment gaps for schizophrenia in resource-poor areas remain substantial and that text messaging plus lay health support could form a simple and low-cost means of improving the situation in these settings.

cpalmer@mdedge.com

SOURCE: Xu D et al. PLoS Med. 2019 Apr 23. doi: 10.1371/journal.pmed.1002785.

A text messaging–based mobile health (mHealth) intervention that relied on lay health supporters improved medication adherence among rural Chinese patients with schizophrenia by 27%, according to results of a study published in PLoS Medicine.

The researchers developed a mHealth protocol intervention that used text messaging and lay health supporters to help patients with schizophrenia to transition from facility-based care to community-based care. The study randomized 278 community-dwelling villagers with schizophrenia to receive care through a community-based free-medicine program either with or without support from the mHealth intervention. Among the 271 patients successfully followed, medication adherence – the primary outcome – was higher in the mHealth group than it was in the control group (adjusted mean difference, 0.12; 95% confidence interval, 0.03-0.22; P = .013). Adherence was primarily assessed by unannounced home-based pill counts.

The investigators wrote that the treatment gaps for schizophrenia in resource-poor areas remain substantial and that text messaging plus lay health support could form a simple and low-cost means of improving the situation in these settings.

cpalmer@mdedge.com

SOURCE: Xu D et al. PLoS Med. 2019 Apr 23. doi: 10.1371/journal.pmed.1002785.

Neurofilament light (NfL) levels in plasma appear to track cognitive decline in dementia, as well as cortical thinning and hippocampal atrophy that accompany progression from normal cognition to mild cognitive impairment (MCI) to Alzheimer’s disease.

Plasma levels of the axonal protein also correlated with its presence in cerebrospinal fluid, and mirrored the changes in amyloid beta (Abeta) 42, Niklas Mattsson, MD, and colleagues wrote in JAMA Neurology.

“Taken together, these findings suggest that the neurofilament light level is a dynamic biomarker that changes throughout the course of Alzheimer’s disease and is sensitive to progressive neurodegeneration,” wrote Dr. Mattsson of Lund (Sweden) University and his coauthors. “This has important implications, given the unmet need for noninvasive blood-based methods to objectively track longitudinal neurodegeneration in Alzheimer’s disease.”

A blood-based biomarker of Alzheimer’s disease progression could open a new door for drug trials, the authors noted. Previously, NfL levels have only been available by lumbar puncture – a invasive and expensive test that many patients resist. If NfL plasma levels do reliably track dementia progression, the test could become a standard part of clinical trials, providing regular drug response data as the study progresses.

Neurofilaments are polypeptides that give structure to the neuronal cytoskeleton and regulate microtubule function. Injured cells release the protein very quickly. Neurofilaments are elevated in traumatic brain injury, multiple sclerosis, and some psychiatric illnesses. Neurofilament levels have even been used to predict neurologic recovery after cardiac arrest.

Dr. Mattsson and his team used data obtained over 11 years from 1,583 subjects enrolled in the Alzheimer’s Disease Neuroimaging Initiative study. The sample comprised three groups: cognitively unimpaired controls (401), patients with MCI (855), and patients with Alzheimer’s dementia (327). The investigators analyzed 4,326 samples.

In addition to the NfL measurements, they tracked Abeta and tau in cerebrospinal fluid (CSF), structural brain changes by 18fluorodeoxyglucose (FDG)–PET and MRI, and cognitive and functional performance. The primary outcome was NfL’s association with these changes. The team set the lower limit of NfL as 6.7 ng/L and the upper, 1,620 ng/L.

At baseline, only advancing age correlated with NfL levels. But it was significantly higher in patients with MCI (37.9 ng/L) and Alzheimer’s dementia (45.9 ng/L) than it was in the control subjects (32.1 ng/L). Over the years of follow-up, levels increased in all groups, but NfL increased more rapidly among patients with MCI and Alzheimer’s dementia than controls (2.7 vs. 2.4 ng/L per year). The difference was most pronounced when comparing levels in patients with Alzheimer’s dementia and MCI with controls. However, control subjects who were Abeta positive by CSF had greater NfL changes than Abeta-negative controls.

Baseline measures of CSF Abeta and tau, as well as hippocampal and ventricular volume and cortical thickness, also correlated with NfL levels, as did cognition and functional scores.

During follow-up, the diagnostic groups showed different NfL trajectories, which correlated strongly with the other measures.

In the control group, NfL increases correlated with lower FDG-PET measures, lower CSF Abeta, reduced hippocampal volume, and higher ventricular volume. Among patients with MCI, NfL increases correlated most strongly with hippocampal volume, temporal region, and cognition. Among patients with Alzheimer’s dementia, the NfL increase most strongly tracked cognitive decline,

When the investigators applied these findings to the A/T/N (amyloid, tau, neurodegeneration) classification system, NfL most often correlated with neurodegeneration, but not always. This might suggest that the neuronal damage occurred separately from Abeta changes. In all three groups, rapid NfL increases mirrored the rate of change in most other measures.

“In controls and patients with MCI and Alzheimer’s dementia, greater rates of NfL were associated with accelerated reduction in FDG-PET measures … expansion of ventricular volume,” and a reduction in cognitive and functional performance, Dr. Mattsson and his colleagues wrote.“ In addition, greater increases in NfL levels were associated with accelerated loss of hippocampal volume and entorhinal cortical thickness in controls and patients with MCI and with accelerated increases in total tau level, phosphorylated tau level, and white matter lesions in patients with MCI. In general, the concentrations of blood-based NfL appears to reflect the intensity of the neuronal injury.”

Dr Mattsson reported being a consultant for the Alzheimer’s Disease Neuroimaging Initiative.

msullivan@mdedge.com

SOURCE: Mattsson N et al. JAMA Neurol. 2019 Apr 22. doi: 10.1001/jamaneurol.2019.0765.

Neurofilament light (NfL) levels in plasma appear to track cognitive decline in dementia, as well as cortical thinning and hippocampal atrophy that accompany progression from normal cognition to mild cognitive impairment (MCI) to Alzheimer’s disease.

Plasma levels of the axonal protein also correlated with its presence in cerebrospinal fluid, and mirrored the changes in amyloid beta (Abeta) 42, Niklas Mattsson, MD, and colleagues wrote in JAMA Neurology.

“Taken together, these findings suggest that the neurofilament light level is a dynamic biomarker that changes throughout the course of Alzheimer’s disease and is sensitive to progressive neurodegeneration,” wrote Dr. Mattsson of Lund (Sweden) University and his coauthors. “This has important implications, given the unmet need for noninvasive blood-based methods to objectively track longitudinal neurodegeneration in Alzheimer’s disease.”

A blood-based biomarker of Alzheimer’s disease progression could open a new door for drug trials, the authors noted. Previously, NfL levels have only been available by lumbar puncture – a invasive and expensive test that many patients resist. If NfL plasma levels do reliably track dementia progression, the test could become a standard part of clinical trials, providing regular drug response data as the study progresses.

Neurofilaments are polypeptides that give structure to the neuronal cytoskeleton and regulate microtubule function. Injured cells release the protein very quickly. Neurofilaments are elevated in traumatic brain injury, multiple sclerosis, and some psychiatric illnesses. Neurofilament levels have even been used to predict neurologic recovery after cardiac arrest.

Dr. Mattsson and his team used data obtained over 11 years from 1,583 subjects enrolled in the Alzheimer’s Disease Neuroimaging Initiative study. The sample comprised three groups: cognitively unimpaired controls (401), patients with MCI (855), and patients with Alzheimer’s dementia (327). The investigators analyzed 4,326 samples.

In addition to the NfL measurements, they tracked Abeta and tau in cerebrospinal fluid (CSF), structural brain changes by 18fluorodeoxyglucose (FDG)–PET and MRI, and cognitive and functional performance. The primary outcome was NfL’s association with these changes. The team set the lower limit of NfL as 6.7 ng/L and the upper, 1,620 ng/L.

At baseline, only advancing age correlated with NfL levels. But it was significantly higher in patients with MCI (37.9 ng/L) and Alzheimer’s dementia (45.9 ng/L) than it was in the control subjects (32.1 ng/L). Over the years of follow-up, levels increased in all groups, but NfL increased more rapidly among patients with MCI and Alzheimer’s dementia than controls (2.7 vs. 2.4 ng/L per year). The difference was most pronounced when comparing levels in patients with Alzheimer’s dementia and MCI with controls. However, control subjects who were Abeta positive by CSF had greater NfL changes than Abeta-negative controls.

Baseline measures of CSF Abeta and tau, as well as hippocampal and ventricular volume and cortical thickness, also correlated with NfL levels, as did cognition and functional scores.

During follow-up, the diagnostic groups showed different NfL trajectories, which correlated strongly with the other measures.

In the control group, NfL increases correlated with lower FDG-PET measures, lower CSF Abeta, reduced hippocampal volume, and higher ventricular volume. Among patients with MCI, NfL increases correlated most strongly with hippocampal volume, temporal region, and cognition. Among patients with Alzheimer’s dementia, the NfL increase most strongly tracked cognitive decline,

When the investigators applied these findings to the A/T/N (amyloid, tau, neurodegeneration) classification system, NfL most often correlated with neurodegeneration, but not always. This might suggest that the neuronal damage occurred separately from Abeta changes. In all three groups, rapid NfL increases mirrored the rate of change in most other measures.

“In controls and patients with MCI and Alzheimer’s dementia, greater rates of NfL were associated with accelerated reduction in FDG-PET measures … expansion of ventricular volume,” and a reduction in cognitive and functional performance, Dr. Mattsson and his colleagues wrote.“ In addition, greater increases in NfL levels were associated with accelerated loss of hippocampal volume and entorhinal cortical thickness in controls and patients with MCI and with accelerated increases in total tau level, phosphorylated tau level, and white matter lesions in patients with MCI. In general, the concentrations of blood-based NfL appears to reflect the intensity of the neuronal injury.”

Dr Mattsson reported being a consultant for the Alzheimer’s Disease Neuroimaging Initiative.

msullivan@mdedge.com

SOURCE: Mattsson N et al. JAMA Neurol. 2019 Apr 22. doi: 10.1001/jamaneurol.2019.0765.

Neurofilament light (NfL) levels in plasma appear to track cognitive decline in dementia, as well as cortical thinning and hippocampal atrophy that accompany progression from normal cognition to mild cognitive impairment (MCI) to Alzheimer’s disease.

Plasma levels of the axonal protein also correlated with its presence in cerebrospinal fluid, and mirrored the changes in amyloid beta (Abeta) 42, Niklas Mattsson, MD, and colleagues wrote in JAMA Neurology.

“Taken together, these findings suggest that the neurofilament light level is a dynamic biomarker that changes throughout the course of Alzheimer’s disease and is sensitive to progressive neurodegeneration,” wrote Dr. Mattsson of Lund (Sweden) University and his coauthors. “This has important implications, given the unmet need for noninvasive blood-based methods to objectively track longitudinal neurodegeneration in Alzheimer’s disease.”

A blood-based biomarker of Alzheimer’s disease progression could open a new door for drug trials, the authors noted. Previously, NfL levels have only been available by lumbar puncture – a invasive and expensive test that many patients resist. If NfL plasma levels do reliably track dementia progression, the test could become a standard part of clinical trials, providing regular drug response data as the study progresses.

Neurofilaments are polypeptides that give structure to the neuronal cytoskeleton and regulate microtubule function. Injured cells release the protein very quickly. Neurofilaments are elevated in traumatic brain injury, multiple sclerosis, and some psychiatric illnesses. Neurofilament levels have even been used to predict neurologic recovery after cardiac arrest.

Dr. Mattsson and his team used data obtained over 11 years from 1,583 subjects enrolled in the Alzheimer’s Disease Neuroimaging Initiative study. The sample comprised three groups: cognitively unimpaired controls (401), patients with MCI (855), and patients with Alzheimer’s dementia (327). The investigators analyzed 4,326 samples.

In addition to the NfL measurements, they tracked Abeta and tau in cerebrospinal fluid (CSF), structural brain changes by 18fluorodeoxyglucose (FDG)–PET and MRI, and cognitive and functional performance. The primary outcome was NfL’s association with these changes. The team set the lower limit of NfL as 6.7 ng/L and the upper, 1,620 ng/L.

At baseline, only advancing age correlated with NfL levels. But it was significantly higher in patients with MCI (37.9 ng/L) and Alzheimer’s dementia (45.9 ng/L) than it was in the control subjects (32.1 ng/L). Over the years of follow-up, levels increased in all groups, but NfL increased more rapidly among patients with MCI and Alzheimer’s dementia than controls (2.7 vs. 2.4 ng/L per year). The difference was most pronounced when comparing levels in patients with Alzheimer’s dementia and MCI with controls. However, control subjects who were Abeta positive by CSF had greater NfL changes than Abeta-negative controls.

Baseline measures of CSF Abeta and tau, as well as hippocampal and ventricular volume and cortical thickness, also correlated with NfL levels, as did cognition and functional scores.

During follow-up, the diagnostic groups showed different NfL trajectories, which correlated strongly with the other measures.

In the control group, NfL increases correlated with lower FDG-PET measures, lower CSF Abeta, reduced hippocampal volume, and higher ventricular volume. Among patients with MCI, NfL increases correlated most strongly with hippocampal volume, temporal region, and cognition. Among patients with Alzheimer’s dementia, the NfL increase most strongly tracked cognitive decline,

When the investigators applied these findings to the A/T/N (amyloid, tau, neurodegeneration) classification system, NfL most often correlated with neurodegeneration, but not always. This might suggest that the neuronal damage occurred separately from Abeta changes. In all three groups, rapid NfL increases mirrored the rate of change in most other measures.

“In controls and patients with MCI and Alzheimer’s dementia, greater rates of NfL were associated with accelerated reduction in FDG-PET measures … expansion of ventricular volume,” and a reduction in cognitive and functional performance, Dr. Mattsson and his colleagues wrote.“ In addition, greater increases in NfL levels were associated with accelerated loss of hippocampal volume and entorhinal cortical thickness in controls and patients with MCI and with accelerated increases in total tau level, phosphorylated tau level, and white matter lesions in patients with MCI. In general, the concentrations of blood-based NfL appears to reflect the intensity of the neuronal injury.”

Dr Mattsson reported being a consultant for the Alzheimer’s Disease Neuroimaging Initiative.

msullivan@mdedge.com

SOURCE: Mattsson N et al. JAMA Neurol. 2019 Apr 22. doi: 10.1001/jamaneurol.2019.0765.

SAN FRANCISCO – A host of novel clinical and serologic findings that physicians can put to good use right now in helping to distinguish early SLE from its many mimickers have been identified in a large study conducted on four continents, Marta Mosca, MD, PhD, observed at an international congress on systemic lupus erythematosus.

Bruce Jancin/MDedge News

These useful findings aren’t incorporated into the current American College of Rheumatology (ACR) or Systemic Lupus International Collaborating Clinics (SLICC) lupus classification criteria, which have come under criticism for limited sensitivity in identifying early SLE. Some of the novel findings provide support for increased suspicion of early SLE, while others suggest a need to veer in another direction and assess a patient for a disease other than lupus. The study has served to provide input for the proposed new ACR/EULAR weighted SLE classification criteria, although that scheme is meant to be used only for research and not in clinical practice, explained Dr. Mosca of the University of Pisa (Italy).

She was lead author of the four-continent study, which included 616 patients referred to experienced academic lupus centers for possible SLE with a symptom duration of less than 1 year. During up to 3 years of follow-up, 389 patients were diagnosed as having SLE by experienced rheumatologists based upon their clinical judgment, without any requirement to meet the full ACR or SLICC classification criteria. The other 227 patients were determined to be SLE mimickers with conditions including lymphoma, Sjögren’s syndrome, systemic sclerosis, interstitial lung disease, fibromyalgia, antinuclear antibody–positive thyroiditis, and undifferentiated connective tissue disease.

Dr. Mosca also highlighted key recent work by other investigators aimed at speeding the diagnosis of SLE and shortening the duration of what she called “the gray zone” of diagnostic uncertainty, when autoantibodies and insidious symptoms are present but not yet sufficient to make the diagnosis of SLE by conventional criteria. It’s well established that 60%-70% of patients with mild undifferentiated connective tissue disease will remain stable without evolving into SLE during long years of follow-up.

The ultimate objective of all this work is to try to change the natural history of the disease through targeted early aggressive therapy aimed at minimizing the extent of active disease and preventing severe organ involvement.


Among the key takeaways from the four-continent study led by Dr. Mosca: Fever not related to infection was far more prevalent in early SLE than in mimicking conditions, by a margin of 34.5% versus 13.7%. On the other hand, Raynaud’s phenomenon was more than twice as prevalent among patients with mimicking conditions: 22.1% in early SLE, compared with 48.5% in SLE mimickers. Sicca symptoms were present in just 4.4% of early SLE patients versus 34.4% of SLE mimickers. Only 0.3% of early SLE patients complained of dysphagia; the rate was 20-fold higher in the SLE mimickers. Rashes atypical for lupus were twice as frequent in the SLE mimicking conditions (Arthritis Rheumatol. 2019 Jan;71[1]:91-8).

Turning to key differentiating serologic findings, Dr. Mosca noted that anti-double stranded DNA (anti-dsDNA) and anti-Sm antibodies were present in 71.7% and 30.2% of early SLE patients, respectively, compared with 6.9% and 2.6% of SLE mimickers. Anticardiolipin IgM, a positive Coombs test, anti-beta2 glycoprotein-I antibodies, leukopenia, autoimmune hemolytic anemia, and hypocomplementemia were all significantly more common in the early SLE cohort.

In contrast, antibodies to Ro (SS-A) and La (SS-B) were of no value in separating early SLE from its mimickers, according to Dr. Mosca.

Other tipoffs to early SLE

Two separate teams of British researchers have advanced the field in a highly practical way. One group showed in a study of 1,739 newly diagnosed SLE patients and 6,956 controls that in the 5 years prior to diagnosis, the SLE group averaged 9.2 primary care visits per year, compared with 3.8 for controls. The visits clustered around nonspecific complaints of arthritis and arthralgias, alopecia, and rash (Arthritis Care Res. 2017 Jun;69[6]:833-41).

“An accumulating number of primary care office visits and referrals over time should raise suspicion,” Dr. Mosca said.

Other investigators, working with 1,426 cases of newly diagnosed SLE in the U.K. Clinical Practice Research Database, observed that the proportion of patients with disease manifestations in three or more British Isles Lupus Activity Group (BILAG) symptom domains rose from 18.7% at 3 years prior to diagnosis to 39.7% in the year before diagnosis (Lupus Sci Med. 2017 Feb 10;4[1]:e000172. doi: 10.1136/lupus-2016-000172).

“These patients accrue clinical manifestations. It’s not just one symptom, it’s more of a state of being unwell. This is a suspicious factor for the development of lupus,” she continued.

And just as patients who will eventually be diagnosed with SLE accrue a growing number of signs and symptoms during the run up to diagnosis, they also accrue multiple autoantibodies. Moreover, as demonstrated by a multicenter group of U.S. investigators, patients also develop elevated levels of multiple soluble inflammatory markers more than 3.5 years prior to diagnosis of SLE. These include interleukins-5 and -6 and interferon-gamma. And less than 10 months prior to being classified as having SLE, patients develop significantly higher levels of B lymphocyte stimulator (BLyS) and a proliferation-inducing ligand known as APRIL. The investigators developed a predictive model incorporating IL-5, -6, and interferon-gamma levels with antinuclear antibody status that identified future SLE patients with 84% accuracy more than 3.5 years before diagnosis. This could prove useful in selecting high-risk patients for clinical prevention trials (J Autoimmun. 2016 Nov;74:182-93).

Researchers at the University of Leeds (England) have also zeroed in on interferon activity as playing a key role in progression from asymptomatic antinuclear antigen positivity, which is present in up to 25% of the general population, to symptomatic autoimmune connective tissue disease, which affects less than 1%. A multivariate logistic regression analysis identified two independent predictors of development of autoimmune connective tissue disease within the next 12 months: a family history of autoimmune rheumatic disease, which was associated with an 8.2-fold increased risk; and positivity for a pattern of interferon-stimulated gene activity they call IFN-Score-B (Ann Rheum Dis. 2018 Oct;77[10]:1432-9).

All of this work has led up to what Dr. Mosca called “a glance into the future”: the National Institutes of Health–supported Study of Anti-Malarials in Incomplete Lupus Erythematosus (SMILE), which is now recruiting patients. This randomized, double-blind, placebo-controlled multicenter U.S. trial involves patients who are antinuclear antibody positive at a titer of 1:80 or more plus one or two additional criteria from the SLICC classification scheme. Participants are being randomized to 96 weeks of hydroxychloroquine or placebo. The goal is to learn whether hydroxychloroquine can slow disease progression, with the primary endpoint being the number of SLICC criteria met at the study’s end. The trial will also scrutinize potential biomarkers that could be used to guide treatment decisions (Trials. 2018 Dec 20;19[1]:694. doi: 10.1186/s13063-018-3076-7).

Dr. Mosca reported serving as an adviser to UCB and Lilly.

bjancin@mdedge.com

SAN FRANCISCO – A host of novel clinical and serologic findings that physicians can put to good use right now in helping to distinguish early SLE from its many mimickers have been identified in a large study conducted on four continents, Marta Mosca, MD, PhD, observed at an international congress on systemic lupus erythematosus.

Bruce Jancin/MDedge News

These useful findings aren’t incorporated into the current American College of Rheumatology (ACR) or Systemic Lupus International Collaborating Clinics (SLICC) lupus classification criteria, which have come under criticism for limited sensitivity in identifying early SLE. Some of the novel findings provide support for increased suspicion of early SLE, while others suggest a need to veer in another direction and assess a patient for a disease other than lupus. The study has served to provide input for the proposed new ACR/EULAR weighted SLE classification criteria, although that scheme is meant to be used only for research and not in clinical practice, explained Dr. Mosca of the University of Pisa (Italy).

She was lead author of the four-continent study, which included 616 patients referred to experienced academic lupus centers for possible SLE with a symptom duration of less than 1 year. During up to 3 years of follow-up, 389 patients were diagnosed as having SLE by experienced rheumatologists based upon their clinical judgment, without any requirement to meet the full ACR or SLICC classification criteria. The other 227 patients were determined to be SLE mimickers with conditions including lymphoma, Sjögren’s syndrome, systemic sclerosis, interstitial lung disease, fibromyalgia, antinuclear antibody–positive thyroiditis, and undifferentiated connective tissue disease.

Dr. Mosca also highlighted key recent work by other investigators aimed at speeding the diagnosis of SLE and shortening the duration of what she called “the gray zone” of diagnostic uncertainty, when autoantibodies and insidious symptoms are present but not yet sufficient to make the diagnosis of SLE by conventional criteria. It’s well established that 60%-70% of patients with mild undifferentiated connective tissue disease will remain stable without evolving into SLE during long years of follow-up.

The ultimate objective of all this work is to try to change the natural history of the disease through targeted early aggressive therapy aimed at minimizing the extent of active disease and preventing severe organ involvement.


Among the key takeaways from the four-continent study led by Dr. Mosca: Fever not related to infection was far more prevalent in early SLE than in mimicking conditions, by a margin of 34.5% versus 13.7%. On the other hand, Raynaud’s phenomenon was more than twice as prevalent among patients with mimicking conditions: 22.1% in early SLE, compared with 48.5% in SLE mimickers. Sicca symptoms were present in just 4.4% of early SLE patients versus 34.4% of SLE mimickers. Only 0.3% of early SLE patients complained of dysphagia; the rate was 20-fold higher in the SLE mimickers. Rashes atypical for lupus were twice as frequent in the SLE mimicking conditions (Arthritis Rheumatol. 2019 Jan;71[1]:91-8).

Turning to key differentiating serologic findings, Dr. Mosca noted that anti-double stranded DNA (anti-dsDNA) and anti-Sm antibodies were present in 71.7% and 30.2% of early SLE patients, respectively, compared with 6.9% and 2.6% of SLE mimickers. Anticardiolipin IgM, a positive Coombs test, anti-beta2 glycoprotein-I antibodies, leukopenia, autoimmune hemolytic anemia, and hypocomplementemia were all significantly more common in the early SLE cohort.

In contrast, antibodies to Ro (SS-A) and La (SS-B) were of no value in separating early SLE from its mimickers, according to Dr. Mosca.

Other tipoffs to early SLE

Two separate teams of British researchers have advanced the field in a highly practical way. One group showed in a study of 1,739 newly diagnosed SLE patients and 6,956 controls that in the 5 years prior to diagnosis, the SLE group averaged 9.2 primary care visits per year, compared with 3.8 for controls. The visits clustered around nonspecific complaints of arthritis and arthralgias, alopecia, and rash (Arthritis Care Res. 2017 Jun;69[6]:833-41).

“An accumulating number of primary care office visits and referrals over time should raise suspicion,” Dr. Mosca said.

Other investigators, working with 1,426 cases of newly diagnosed SLE in the U.K. Clinical Practice Research Database, observed that the proportion of patients with disease manifestations in three or more British Isles Lupus Activity Group (BILAG) symptom domains rose from 18.7% at 3 years prior to diagnosis to 39.7% in the year before diagnosis (Lupus Sci Med. 2017 Feb 10;4[1]:e000172. doi: 10.1136/lupus-2016-000172).

“These patients accrue clinical manifestations. It’s not just one symptom, it’s more of a state of being unwell. This is a suspicious factor for the development of lupus,” she continued.

And just as patients who will eventually be diagnosed with SLE accrue a growing number of signs and symptoms during the run up to diagnosis, they also accrue multiple autoantibodies. Moreover, as demonstrated by a multicenter group of U.S. investigators, patients also develop elevated levels of multiple soluble inflammatory markers more than 3.5 years prior to diagnosis of SLE. These include interleukins-5 and -6 and interferon-gamma. And less than 10 months prior to being classified as having SLE, patients develop significantly higher levels of B lymphocyte stimulator (BLyS) and a proliferation-inducing ligand known as APRIL. The investigators developed a predictive model incorporating IL-5, -6, and interferon-gamma levels with antinuclear antibody status that identified future SLE patients with 84% accuracy more than 3.5 years before diagnosis. This could prove useful in selecting high-risk patients for clinical prevention trials (J Autoimmun. 2016 Nov;74:182-93).

Researchers at the University of Leeds (England) have also zeroed in on interferon activity as playing a key role in progression from asymptomatic antinuclear antigen positivity, which is present in up to 25% of the general population, to symptomatic autoimmune connective tissue disease, which affects less than 1%. A multivariate logistic regression analysis identified two independent predictors of development of autoimmune connective tissue disease within the next 12 months: a family history of autoimmune rheumatic disease, which was associated with an 8.2-fold increased risk; and positivity for a pattern of interferon-stimulated gene activity they call IFN-Score-B (Ann Rheum Dis. 2018 Oct;77[10]:1432-9).

All of this work has led up to what Dr. Mosca called “a glance into the future”: the National Institutes of Health–supported Study of Anti-Malarials in Incomplete Lupus Erythematosus (SMILE), which is now recruiting patients. This randomized, double-blind, placebo-controlled multicenter U.S. trial involves patients who are antinuclear antibody positive at a titer of 1:80 or more plus one or two additional criteria from the SLICC classification scheme. Participants are being randomized to 96 weeks of hydroxychloroquine or placebo. The goal is to learn whether hydroxychloroquine can slow disease progression, with the primary endpoint being the number of SLICC criteria met at the study’s end. The trial will also scrutinize potential biomarkers that could be used to guide treatment decisions (Trials. 2018 Dec 20;19[1]:694. doi: 10.1186/s13063-018-3076-7).

Dr. Mosca reported serving as an adviser to UCB and Lilly.

bjancin@mdedge.com

SAN FRANCISCO – A host of novel clinical and serologic findings that physicians can put to good use right now in helping to distinguish early SLE from its many mimickers have been identified in a large study conducted on four continents, Marta Mosca, MD, PhD, observed at an international congress on systemic lupus erythematosus.

Bruce Jancin/MDedge News

These useful findings aren’t incorporated into the current American College of Rheumatology (ACR) or Systemic Lupus International Collaborating Clinics (SLICC) lupus classification criteria, which have come under criticism for limited sensitivity in identifying early SLE. Some of the novel findings provide support for increased suspicion of early SLE, while others suggest a need to veer in another direction and assess a patient for a disease other than lupus. The study has served to provide input for the proposed new ACR/EULAR weighted SLE classification criteria, although that scheme is meant to be used only for research and not in clinical practice, explained Dr. Mosca of the University of Pisa (Italy).

She was lead author of the four-continent study, which included 616 patients referred to experienced academic lupus centers for possible SLE with a symptom duration of less than 1 year. During up to 3 years of follow-up, 389 patients were diagnosed as having SLE by experienced rheumatologists based upon their clinical judgment, without any requirement to meet the full ACR or SLICC classification criteria. The other 227 patients were determined to be SLE mimickers with conditions including lymphoma, Sjögren’s syndrome, systemic sclerosis, interstitial lung disease, fibromyalgia, antinuclear antibody–positive thyroiditis, and undifferentiated connective tissue disease.

Dr. Mosca also highlighted key recent work by other investigators aimed at speeding the diagnosis of SLE and shortening the duration of what she called “the gray zone” of diagnostic uncertainty, when autoantibodies and insidious symptoms are present but not yet sufficient to make the diagnosis of SLE by conventional criteria. It’s well established that 60%-70% of patients with mild undifferentiated connective tissue disease will remain stable without evolving into SLE during long years of follow-up.

The ultimate objective of all this work is to try to change the natural history of the disease through targeted early aggressive therapy aimed at minimizing the extent of active disease and preventing severe organ involvement.


Among the key takeaways from the four-continent study led by Dr. Mosca: Fever not related to infection was far more prevalent in early SLE than in mimicking conditions, by a margin of 34.5% versus 13.7%. On the other hand, Raynaud’s phenomenon was more than twice as prevalent among patients with mimicking conditions: 22.1% in early SLE, compared with 48.5% in SLE mimickers. Sicca symptoms were present in just 4.4% of early SLE patients versus 34.4% of SLE mimickers. Only 0.3% of early SLE patients complained of dysphagia; the rate was 20-fold higher in the SLE mimickers. Rashes atypical for lupus were twice as frequent in the SLE mimicking conditions (Arthritis Rheumatol. 2019 Jan;71[1]:91-8).

Turning to key differentiating serologic findings, Dr. Mosca noted that anti-double stranded DNA (anti-dsDNA) and anti-Sm antibodies were present in 71.7% and 30.2% of early SLE patients, respectively, compared with 6.9% and 2.6% of SLE mimickers. Anticardiolipin IgM, a positive Coombs test, anti-beta2 glycoprotein-I antibodies, leukopenia, autoimmune hemolytic anemia, and hypocomplementemia were all significantly more common in the early SLE cohort.

In contrast, antibodies to Ro (SS-A) and La (SS-B) were of no value in separating early SLE from its mimickers, according to Dr. Mosca.

Other tipoffs to early SLE

Two separate teams of British researchers have advanced the field in a highly practical way. One group showed in a study of 1,739 newly diagnosed SLE patients and 6,956 controls that in the 5 years prior to diagnosis, the SLE group averaged 9.2 primary care visits per year, compared with 3.8 for controls. The visits clustered around nonspecific complaints of arthritis and arthralgias, alopecia, and rash (Arthritis Care Res. 2017 Jun;69[6]:833-41).

“An accumulating number of primary care office visits and referrals over time should raise suspicion,” Dr. Mosca said.

Other investigators, working with 1,426 cases of newly diagnosed SLE in the U.K. Clinical Practice Research Database, observed that the proportion of patients with disease manifestations in three or more British Isles Lupus Activity Group (BILAG) symptom domains rose from 18.7% at 3 years prior to diagnosis to 39.7% in the year before diagnosis (Lupus Sci Med. 2017 Feb 10;4[1]:e000172. doi: 10.1136/lupus-2016-000172).

“These patients accrue clinical manifestations. It’s not just one symptom, it’s more of a state of being unwell. This is a suspicious factor for the development of lupus,” she continued.

And just as patients who will eventually be diagnosed with SLE accrue a growing number of signs and symptoms during the run up to diagnosis, they also accrue multiple autoantibodies. Moreover, as demonstrated by a multicenter group of U.S. investigators, patients also develop elevated levels of multiple soluble inflammatory markers more than 3.5 years prior to diagnosis of SLE. These include interleukins-5 and -6 and interferon-gamma. And less than 10 months prior to being classified as having SLE, patients develop significantly higher levels of B lymphocyte stimulator (BLyS) and a proliferation-inducing ligand known as APRIL. The investigators developed a predictive model incorporating IL-5, -6, and interferon-gamma levels with antinuclear antibody status that identified future SLE patients with 84% accuracy more than 3.5 years before diagnosis. This could prove useful in selecting high-risk patients for clinical prevention trials (J Autoimmun. 2016 Nov;74:182-93).

Researchers at the University of Leeds (England) have also zeroed in on interferon activity as playing a key role in progression from asymptomatic antinuclear antigen positivity, which is present in up to 25% of the general population, to symptomatic autoimmune connective tissue disease, which affects less than 1%. A multivariate logistic regression analysis identified two independent predictors of development of autoimmune connective tissue disease within the next 12 months: a family history of autoimmune rheumatic disease, which was associated with an 8.2-fold increased risk; and positivity for a pattern of interferon-stimulated gene activity they call IFN-Score-B (Ann Rheum Dis. 2018 Oct;77[10]:1432-9).

All of this work has led up to what Dr. Mosca called “a glance into the future”: the National Institutes of Health–supported Study of Anti-Malarials in Incomplete Lupus Erythematosus (SMILE), which is now recruiting patients. This randomized, double-blind, placebo-controlled multicenter U.S. trial involves patients who are antinuclear antibody positive at a titer of 1:80 or more plus one or two additional criteria from the SLICC classification scheme. Participants are being randomized to 96 weeks of hydroxychloroquine or placebo. The goal is to learn whether hydroxychloroquine can slow disease progression, with the primary endpoint being the number of SLICC criteria met at the study’s end. The trial will also scrutinize potential biomarkers that could be used to guide treatment decisions (Trials. 2018 Dec 20;19[1]:694. doi: 10.1186/s13063-018-3076-7).

Dr. Mosca reported serving as an adviser to UCB and Lilly.

bjancin@mdedge.com