New data from two phase 3 studies found that in patients with relapsing forms of multiple sclerosis (MS), the new anti-CD20 monoclonal antibody drug, ublituximab, is associated with significant improvement in the multiple sclerosis functional composite (MSFC) score, a measure of disability, compared with teriflunomide (Aubagio).

The results were presented by Lawrence Steinman, MD, of Stanford (Calif.) University, at the annual meeting of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS).   

Main results from the ULTIMATE I and II phase 3 trials, reported previously, showed a significant reduction in annualized relapse rate (ARR) over a 96-week period (22 months) with ublituximab versus teriflunomide, as well as significant reductions in MRI lesions and improvements in the number of patients with no evidence of disease activity (NEDA).

Data from these two trials are being used to support a recent approval application to the U.S. Food and Drug Administration for ublituximab to treat patients with relapsing remitting MS.

Although ublituximab was associated with an increased proportion of patients with 12-week and 24-week confirmed disability improvement compared with teriflunomide, there was no significant difference between the two groups in confirmed disability progression.

Another ULTIMATE investigator, University of California, San Francisco neurologist Bruce Cree, MD, PhD, explained that the measures of confirmed disability improvement and confirmed disability progression used in MS clinical trials are based on changes in the Expanded Disability Status Scale (EDSS). But he pointed out that this scale is a challenging score to use, as it typically changes very slightly over the course of a trial. He adds that the scale can also be variable.  

“Because confirmed disability worsening was not met as one of the secondary endpoints, one of the critiques of these trials could be that there wasn’t an effect of ublituximab. But worsening disability was rare in both treatment arms, so it would be very difficult, if not impossible to demonstrate a difference without much greater numbers of patients being included,” he said.

Dr. Cree noted that the multiple sclerosis functional composite (MSFC) score was an alternative, more sensitive, measure of disability that includes three different tests: the 9-hole peg test, which assesses upper arm mobility; the timed 25-foot walk test, which gauges walking ability; and the paced auditory serial addition test (PASAT), a measure of attention and processing.

He reported results showing that ublituximab significantly improved the MFSC score in ULTIMATE I by 76% and by 89% in ULTIMATE II, compared with teriflunomide. In ULTIMATE 1, the MSFC score improved by 0.266 points during the 96-week trial in the teriflunomide group and by 0.469 points in the ublituximab group (P = .048). In ULTIMATE II, the MSFC score improved by 0.275 points in the teriflunomide group and by 0.521 points in the ublituximab group (P = .017).

These changes were driven by improvements in the 9-hole peg test and the timed 25-foot walk test, with no difference seen in the PASAT test.

Asked how ublituximab compares with other anti-CD20 antibodies already in use such as ocrelizumab (Ocrevus), Dr. Cree noted that ublituximab is associated with fewer infusion reactions, so it can be infused more quickly. It is given over just 1 hour, compared with several hours needed for the ocrelizumab infusion.

“In the ULTIMATE studies the only reaction with ublituximab during infusion was a mild increase in temperature, and this can be minimized by pretreatment with acetaminophen. The allergic-type reactions of itchiness and scratchiness seen with ocrelizumab infusions were far less common with ublituximab.”

Dr. Cree attributes this to the glycol-engineering of the ublituximab antibody, which he says “allows the cytokines released from the B cells to be metabolized within phagocytes rather than to be released into the bloodstream.”

The ULTIMATE trials were funded by TG Therapeutics.

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

New data from two phase 3 studies found that in patients with relapsing forms of multiple sclerosis (MS), the new anti-CD20 monoclonal antibody drug, ublituximab, is associated with significant improvement in the multiple sclerosis functional composite (MSFC) score, a measure of disability, compared with teriflunomide (Aubagio).

The results were presented by Lawrence Steinman, MD, of Stanford (Calif.) University, at the annual meeting of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS).   

Main results from the ULTIMATE I and II phase 3 trials, reported previously, showed a significant reduction in annualized relapse rate (ARR) over a 96-week period (22 months) with ublituximab versus teriflunomide, as well as significant reductions in MRI lesions and improvements in the number of patients with no evidence of disease activity (NEDA).

Data from these two trials are being used to support a recent approval application to the U.S. Food and Drug Administration for ublituximab to treat patients with relapsing remitting MS.

Although ublituximab was associated with an increased proportion of patients with 12-week and 24-week confirmed disability improvement compared with teriflunomide, there was no significant difference between the two groups in confirmed disability progression.

Another ULTIMATE investigator, University of California, San Francisco neurologist Bruce Cree, MD, PhD, explained that the measures of confirmed disability improvement and confirmed disability progression used in MS clinical trials are based on changes in the Expanded Disability Status Scale (EDSS). But he pointed out that this scale is a challenging score to use, as it typically changes very slightly over the course of a trial. He adds that the scale can also be variable.  

“Because confirmed disability worsening was not met as one of the secondary endpoints, one of the critiques of these trials could be that there wasn’t an effect of ublituximab. But worsening disability was rare in both treatment arms, so it would be very difficult, if not impossible to demonstrate a difference without much greater numbers of patients being included,” he said.

Dr. Cree noted that the multiple sclerosis functional composite (MSFC) score was an alternative, more sensitive, measure of disability that includes three different tests: the 9-hole peg test, which assesses upper arm mobility; the timed 25-foot walk test, which gauges walking ability; and the paced auditory serial addition test (PASAT), a measure of attention and processing.

He reported results showing that ublituximab significantly improved the MFSC score in ULTIMATE I by 76% and by 89% in ULTIMATE II, compared with teriflunomide. In ULTIMATE 1, the MSFC score improved by 0.266 points during the 96-week trial in the teriflunomide group and by 0.469 points in the ublituximab group (P = .048). In ULTIMATE II, the MSFC score improved by 0.275 points in the teriflunomide group and by 0.521 points in the ublituximab group (P = .017).

These changes were driven by improvements in the 9-hole peg test and the timed 25-foot walk test, with no difference seen in the PASAT test.

Asked how ublituximab compares with other anti-CD20 antibodies already in use such as ocrelizumab (Ocrevus), Dr. Cree noted that ublituximab is associated with fewer infusion reactions, so it can be infused more quickly. It is given over just 1 hour, compared with several hours needed for the ocrelizumab infusion.

“In the ULTIMATE studies the only reaction with ublituximab during infusion was a mild increase in temperature, and this can be minimized by pretreatment with acetaminophen. The allergic-type reactions of itchiness and scratchiness seen with ocrelizumab infusions were far less common with ublituximab.”

Dr. Cree attributes this to the glycol-engineering of the ublituximab antibody, which he says “allows the cytokines released from the B cells to be metabolized within phagocytes rather than to be released into the bloodstream.”

The ULTIMATE trials were funded by TG Therapeutics.

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

New data from two phase 3 studies found that in patients with relapsing forms of multiple sclerosis (MS), the new anti-CD20 monoclonal antibody drug, ublituximab, is associated with significant improvement in the multiple sclerosis functional composite (MSFC) score, a measure of disability, compared with teriflunomide (Aubagio).

The results were presented by Lawrence Steinman, MD, of Stanford (Calif.) University, at the annual meeting of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS).   

Main results from the ULTIMATE I and II phase 3 trials, reported previously, showed a significant reduction in annualized relapse rate (ARR) over a 96-week period (22 months) with ublituximab versus teriflunomide, as well as significant reductions in MRI lesions and improvements in the number of patients with no evidence of disease activity (NEDA).

Data from these two trials are being used to support a recent approval application to the U.S. Food and Drug Administration for ublituximab to treat patients with relapsing remitting MS.

Although ublituximab was associated with an increased proportion of patients with 12-week and 24-week confirmed disability improvement compared with teriflunomide, there was no significant difference between the two groups in confirmed disability progression.

Another ULTIMATE investigator, University of California, San Francisco neurologist Bruce Cree, MD, PhD, explained that the measures of confirmed disability improvement and confirmed disability progression used in MS clinical trials are based on changes in the Expanded Disability Status Scale (EDSS). But he pointed out that this scale is a challenging score to use, as it typically changes very slightly over the course of a trial. He adds that the scale can also be variable.  

“Because confirmed disability worsening was not met as one of the secondary endpoints, one of the critiques of these trials could be that there wasn’t an effect of ublituximab. But worsening disability was rare in both treatment arms, so it would be very difficult, if not impossible to demonstrate a difference without much greater numbers of patients being included,” he said.

Dr. Cree noted that the multiple sclerosis functional composite (MSFC) score was an alternative, more sensitive, measure of disability that includes three different tests: the 9-hole peg test, which assesses upper arm mobility; the timed 25-foot walk test, which gauges walking ability; and the paced auditory serial addition test (PASAT), a measure of attention and processing.

He reported results showing that ublituximab significantly improved the MFSC score in ULTIMATE I by 76% and by 89% in ULTIMATE II, compared with teriflunomide. In ULTIMATE 1, the MSFC score improved by 0.266 points during the 96-week trial in the teriflunomide group and by 0.469 points in the ublituximab group (P = .048). In ULTIMATE II, the MSFC score improved by 0.275 points in the teriflunomide group and by 0.521 points in the ublituximab group (P = .017).

These changes were driven by improvements in the 9-hole peg test and the timed 25-foot walk test, with no difference seen in the PASAT test.

Asked how ublituximab compares with other anti-CD20 antibodies already in use such as ocrelizumab (Ocrevus), Dr. Cree noted that ublituximab is associated with fewer infusion reactions, so it can be infused more quickly. It is given over just 1 hour, compared with several hours needed for the ocrelizumab infusion.

“In the ULTIMATE studies the only reaction with ublituximab during infusion was a mild increase in temperature, and this can be minimized by pretreatment with acetaminophen. The allergic-type reactions of itchiness and scratchiness seen with ocrelizumab infusions were far less common with ublituximab.”

Dr. Cree attributes this to the glycol-engineering of the ublituximab antibody, which he says “allows the cytokines released from the B cells to be metabolized within phagocytes rather than to be released into the bloodstream.”

The ULTIMATE trials were funded by TG Therapeutics.

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

The Committee for Medicinal Products for Human Use of the European Medicines Agency has recommended that the oral Janus kinase 1 inhibitor abrocitinib be granted marketing authorization in the European Union for treating atopic dermatitis (AD).

The full indication is for the treatment of moderate to severe AD in adults who are candidates for systemic therapy, according to a summary of the opinion, made on Oct. 14. It will be available as 50-mg, 100-mg, and 200-mg tablets, will be marketed under the name Cibinqo, and “should be prescribed by physicians experienced in the treatment of atopic dermatitis,” the statement said.

“The benefits of Cibinqo are its ability to improve the skin condition as measured by improvements in the Investigator’s Global Assessment 0/1 and Eczema Area and Severity Index 75 response and to reduce itching in patients with atopic dermatitis,” according to the opinion. The most common side effects of abrocitinib are nausea, headache, acne, herpes simplex, increased blood creatine phosphokinase, vomiting, dizziness, and upper abdominal pain, the statement said, and infections are the most serious.

Abrocitinib was first approved for AD in the United Kingdom and in Japan in September, and is under review at the Food and Drug Administration for this indication. The first JAK inhibitor approved for AD in the United States is topical ruxolitinib (Opzelura), approved in September, for the short-term, noncontinuous chronic treatment of mild to moderate AD in nonimmunocompromised patients aged 12 years and older whose disease is not adequately controlled with topical prescription treatments, “or when those therapies are not advisable.”
 

[email protected]

The Committee for Medicinal Products for Human Use of the European Medicines Agency has recommended that the oral Janus kinase 1 inhibitor abrocitinib be granted marketing authorization in the European Union for treating atopic dermatitis (AD).

The full indication is for the treatment of moderate to severe AD in adults who are candidates for systemic therapy, according to a summary of the opinion, made on Oct. 14. It will be available as 50-mg, 100-mg, and 200-mg tablets, will be marketed under the name Cibinqo, and “should be prescribed by physicians experienced in the treatment of atopic dermatitis,” the statement said.

“The benefits of Cibinqo are its ability to improve the skin condition as measured by improvements in the Investigator’s Global Assessment 0/1 and Eczema Area and Severity Index 75 response and to reduce itching in patients with atopic dermatitis,” according to the opinion. The most common side effects of abrocitinib are nausea, headache, acne, herpes simplex, increased blood creatine phosphokinase, vomiting, dizziness, and upper abdominal pain, the statement said, and infections are the most serious.

Abrocitinib was first approved for AD in the United Kingdom and in Japan in September, and is under review at the Food and Drug Administration for this indication. The first JAK inhibitor approved for AD in the United States is topical ruxolitinib (Opzelura), approved in September, for the short-term, noncontinuous chronic treatment of mild to moderate AD in nonimmunocompromised patients aged 12 years and older whose disease is not adequately controlled with topical prescription treatments, “or when those therapies are not advisable.”
 

[email protected]

The Committee for Medicinal Products for Human Use of the European Medicines Agency has recommended that the oral Janus kinase 1 inhibitor abrocitinib be granted marketing authorization in the European Union for treating atopic dermatitis (AD).

The full indication is for the treatment of moderate to severe AD in adults who are candidates for systemic therapy, according to a summary of the opinion, made on Oct. 14. It will be available as 50-mg, 100-mg, and 200-mg tablets, will be marketed under the name Cibinqo, and “should be prescribed by physicians experienced in the treatment of atopic dermatitis,” the statement said.

“The benefits of Cibinqo are its ability to improve the skin condition as measured by improvements in the Investigator’s Global Assessment 0/1 and Eczema Area and Severity Index 75 response and to reduce itching in patients with atopic dermatitis,” according to the opinion. The most common side effects of abrocitinib are nausea, headache, acne, herpes simplex, increased blood creatine phosphokinase, vomiting, dizziness, and upper abdominal pain, the statement said, and infections are the most serious.

Abrocitinib was first approved for AD in the United Kingdom and in Japan in September, and is under review at the Food and Drug Administration for this indication. The first JAK inhibitor approved for AD in the United States is topical ruxolitinib (Opzelura), approved in September, for the short-term, noncontinuous chronic treatment of mild to moderate AD in nonimmunocompromised patients aged 12 years and older whose disease is not adequately controlled with topical prescription treatments, “or when those therapies are not advisable.”
 

[email protected]

An 8-month high-intensity resistance and impact training program (HiRIT, Onero) led to greater gains in lumbar spine bone mineral density (BMD) and leg/back strength than a low-intensity Pilates-based program (Buff Bones).
 

BeyondImages/Getty Images

These findings are from the Medication and Exercise for Osteoporosis (MEDEX-OP) trial, which included 115 postmenopausal women with low bone mass. Patients were randomly assigned to attend either the HiRIT or Pilates-based exercise program. The participants attended supervised 45-min sessions twice weekly.

HiRIT was better than the low-intensity Pilates-based exercise program for enhancing bone mass, muscle strength, functional performance, and stature, the researchers reported. The low-intensity program did improve function, but to a lesser extent

Of the 115 participants, most (86) were not taking osteoporosis medicine. For the 29 women who were receiving it, the medication appeared to enhance the effect of exercise.

Melanie Fischbacher, PhD candidate, Griffith University, Gold Coast, Australia, presented these findings in an oral session at the annual meeting of the American Society for Bone and Mineral Research; the study was also published in the Journal of Bone and Mineral Research.

The study’s senior author, Belinda R. Beck, PhD, director of the Bone Clinic in Brisbane, Australia, developed the Onero HiRIT program and has licensed it to others in Australia.

“It is a very effective program and we have shown it can be undertaken safely, but it must be supervised because of the heavy weights and high-risk clientele,” Beck stressed to this news organization.

“This is not a program you should just hand to a patient and tell them to do in a gym,” she said.

“Both forms of exercise in our study were beneficial for functional outcomes but Onero improved back extensor strength, mobility and stature considerably more than Buff Bones,” Ms. Fischbacher said in an interview.

Nevertheless, “the contribution of functional capacity to risk of falling and fracture cannot be overstated, and bone medications do not address function,” she noted.

“More trials combining bone medication and bone-targeted exercise are needed,” the researchers concluded.

Compliance stands out, study supports high-intensity exercise

Kristen M. Beavers, PhD, MPH, RD, who was not involved with this research, told this news organization that participant compliance in the study really stands out.

“Compliance to an 8-month, 2 day/week high-intensity resistance training program among older women with low bone mass was quite good in this study [>80%], with very few adverse events reported,” said Dr. Beavers, of the department of health and exercise science, Wake Forest University, Winston Salem, N.C.

“A lot of individuals wouldn’t even consider recommending this type/intensity of exercise to this population, because they are worried it is too risky and/or the uptake will be low,” she said.

Although the benefit in BMD and strength wasn’t seen universally across all bone/muscle outcomes assessed, the findings do reinforce the idea that high-intensity exercise is more efficacious for bone health than low-intensity exercise, she noted.

“The possible additive effect of high-intensity exercise when combined with medication is worth confirming in larger, adequately designed/powered studies,” according to Dr. Beavers.

“The general consensus in the field is that higher-intensity exercise is more osteogenic than low-intensity exercise, but improving muscle mass, quality, and function (including balance) are also important to reduce the risk of falls, which is a major contributor to incident fracture,” she noted.

Exercise, even low-intensity exercise, reduces the risk for falls, as shown in a recent meta-analysis, she added. This is something antiresorptive medications don’t do.
 

Building on the LIFTMOR and LIFTMOR-M Trials

Previously, the Australian group showed that HiRIT is efficacious and safe for bone formation in individuals with low to very low bone mass – in postmenopausal women in the LIFTMOR study (J Bone Miner Res. 2017 Oct 4 .doi: 10.1002/jbmr.3284), and in men in the LIFTMOR-M study.

The current study compared two exercise programs. The researchers randomly assigned 86 women who were not taking antiresorptive medication to the high-intensity (42) or low-intensity (44) exercise program. They also assigned 29 women who were receiving antiresorptive medication to the high-intensity (15) or low-intensity (14) exercise program.

In the high-intensity exercise plus medication subgroup, the women were taking denosumab (12), risedronate (2) or alendronate (1). In the low-intensity exercise plus medication subgroup, the women were taking denosumab (9), risedronate (1), alendronate (3), or zoledronic acid (1).

The mean age of the women was 64-68 years. The mean lumbar spine T score was –1.5 to –2.3, and the mean femoral neck T score was –1.7 to –2.0 (determined by dual-energy x-ray absorptiometry) .

The HiRIT training program consisted of three free-weight resistance training exercises (deadlift, back squat, overhead press), one high-impact exercise (jump drop), and two balance exercises. The exercises varied each session.

The low-intensity training consisted of bone-specific Pilates-based exercises performed on the mat; standing weight-bearing exercise with 1-kg dumbbells; and impact exercises, such as heel drops and stomping.

At 8 months, compared with women in the low-intensity exercise program, those in the HiRIT program demonstrated greater improvement in lumbar spine BMD (1.9% vs. 0.1%) and stature (0.2 cm vs. 0.0 cm), muscle strength, and functional performance.

Functional performance improved with both exercise programs, but the HiRIT program led to greater leg and back muscle strength and better results in the five times sit-to-stand test (P < .05).

HiRIT plus bone medication improved BMD at the femoral neck and total hip, whereas HiRIT alone did not. Low-intensity exercise plus bone medication improved BMD at the lumbar spine and total hip, whereas low-intensity exercise alone did not.

The retention rate was 90%. The rate of exercise compliance was 83% in the high-intensity group and 82% in the low-intensity group.

Thirty falls were reported by 24 participants (21%). One fracture occurred in each exercise group. Three adverse events occurred in the low-intensity group, and four occurred in the high-intensity group.

Dr. Beck owns the Bone Clinic and sells licenses to the Onero program. The other researchers disclosed no relevant financial relationships.

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

An 8-month high-intensity resistance and impact training program (HiRIT, Onero) led to greater gains in lumbar spine bone mineral density (BMD) and leg/back strength than a low-intensity Pilates-based program (Buff Bones).
 

BeyondImages/Getty Images

These findings are from the Medication and Exercise for Osteoporosis (MEDEX-OP) trial, which included 115 postmenopausal women with low bone mass. Patients were randomly assigned to attend either the HiRIT or Pilates-based exercise program. The participants attended supervised 45-min sessions twice weekly.

HiRIT was better than the low-intensity Pilates-based exercise program for enhancing bone mass, muscle strength, functional performance, and stature, the researchers reported. The low-intensity program did improve function, but to a lesser extent

Of the 115 participants, most (86) were not taking osteoporosis medicine. For the 29 women who were receiving it, the medication appeared to enhance the effect of exercise.

Melanie Fischbacher, PhD candidate, Griffith University, Gold Coast, Australia, presented these findings in an oral session at the annual meeting of the American Society for Bone and Mineral Research; the study was also published in the Journal of Bone and Mineral Research.

The study’s senior author, Belinda R. Beck, PhD, director of the Bone Clinic in Brisbane, Australia, developed the Onero HiRIT program and has licensed it to others in Australia.

“It is a very effective program and we have shown it can be undertaken safely, but it must be supervised because of the heavy weights and high-risk clientele,” Beck stressed to this news organization.

“This is not a program you should just hand to a patient and tell them to do in a gym,” she said.

“Both forms of exercise in our study were beneficial for functional outcomes but Onero improved back extensor strength, mobility and stature considerably more than Buff Bones,” Ms. Fischbacher said in an interview.

Nevertheless, “the contribution of functional capacity to risk of falling and fracture cannot be overstated, and bone medications do not address function,” she noted.

“More trials combining bone medication and bone-targeted exercise are needed,” the researchers concluded.

Compliance stands out, study supports high-intensity exercise

Kristen M. Beavers, PhD, MPH, RD, who was not involved with this research, told this news organization that participant compliance in the study really stands out.

“Compliance to an 8-month, 2 day/week high-intensity resistance training program among older women with low bone mass was quite good in this study [>80%], with very few adverse events reported,” said Dr. Beavers, of the department of health and exercise science, Wake Forest University, Winston Salem, N.C.

“A lot of individuals wouldn’t even consider recommending this type/intensity of exercise to this population, because they are worried it is too risky and/or the uptake will be low,” she said.

Although the benefit in BMD and strength wasn’t seen universally across all bone/muscle outcomes assessed, the findings do reinforce the idea that high-intensity exercise is more efficacious for bone health than low-intensity exercise, she noted.

“The possible additive effect of high-intensity exercise when combined with medication is worth confirming in larger, adequately designed/powered studies,” according to Dr. Beavers.

“The general consensus in the field is that higher-intensity exercise is more osteogenic than low-intensity exercise, but improving muscle mass, quality, and function (including balance) are also important to reduce the risk of falls, which is a major contributor to incident fracture,” she noted.

Exercise, even low-intensity exercise, reduces the risk for falls, as shown in a recent meta-analysis, she added. This is something antiresorptive medications don’t do.
 

Building on the LIFTMOR and LIFTMOR-M Trials

Previously, the Australian group showed that HiRIT is efficacious and safe for bone formation in individuals with low to very low bone mass – in postmenopausal women in the LIFTMOR study (J Bone Miner Res. 2017 Oct 4 .doi: 10.1002/jbmr.3284), and in men in the LIFTMOR-M study.

The current study compared two exercise programs. The researchers randomly assigned 86 women who were not taking antiresorptive medication to the high-intensity (42) or low-intensity (44) exercise program. They also assigned 29 women who were receiving antiresorptive medication to the high-intensity (15) or low-intensity (14) exercise program.

In the high-intensity exercise plus medication subgroup, the women were taking denosumab (12), risedronate (2) or alendronate (1). In the low-intensity exercise plus medication subgroup, the women were taking denosumab (9), risedronate (1), alendronate (3), or zoledronic acid (1).

The mean age of the women was 64-68 years. The mean lumbar spine T score was –1.5 to –2.3, and the mean femoral neck T score was –1.7 to –2.0 (determined by dual-energy x-ray absorptiometry) .

The HiRIT training program consisted of three free-weight resistance training exercises (deadlift, back squat, overhead press), one high-impact exercise (jump drop), and two balance exercises. The exercises varied each session.

The low-intensity training consisted of bone-specific Pilates-based exercises performed on the mat; standing weight-bearing exercise with 1-kg dumbbells; and impact exercises, such as heel drops and stomping.

At 8 months, compared with women in the low-intensity exercise program, those in the HiRIT program demonstrated greater improvement in lumbar spine BMD (1.9% vs. 0.1%) and stature (0.2 cm vs. 0.0 cm), muscle strength, and functional performance.

Functional performance improved with both exercise programs, but the HiRIT program led to greater leg and back muscle strength and better results in the five times sit-to-stand test (P < .05).

HiRIT plus bone medication improved BMD at the femoral neck and total hip, whereas HiRIT alone did not. Low-intensity exercise plus bone medication improved BMD at the lumbar spine and total hip, whereas low-intensity exercise alone did not.

The retention rate was 90%. The rate of exercise compliance was 83% in the high-intensity group and 82% in the low-intensity group.

Thirty falls were reported by 24 participants (21%). One fracture occurred in each exercise group. Three adverse events occurred in the low-intensity group, and four occurred in the high-intensity group.

Dr. Beck owns the Bone Clinic and sells licenses to the Onero program. The other researchers disclosed no relevant financial relationships.

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

An 8-month high-intensity resistance and impact training program (HiRIT, Onero) led to greater gains in lumbar spine bone mineral density (BMD) and leg/back strength than a low-intensity Pilates-based program (Buff Bones).
 

BeyondImages/Getty Images

These findings are from the Medication and Exercise for Osteoporosis (MEDEX-OP) trial, which included 115 postmenopausal women with low bone mass. Patients were randomly assigned to attend either the HiRIT or Pilates-based exercise program. The participants attended supervised 45-min sessions twice weekly.

HiRIT was better than the low-intensity Pilates-based exercise program for enhancing bone mass, muscle strength, functional performance, and stature, the researchers reported. The low-intensity program did improve function, but to a lesser extent

Of the 115 participants, most (86) were not taking osteoporosis medicine. For the 29 women who were receiving it, the medication appeared to enhance the effect of exercise.

Melanie Fischbacher, PhD candidate, Griffith University, Gold Coast, Australia, presented these findings in an oral session at the annual meeting of the American Society for Bone and Mineral Research; the study was also published in the Journal of Bone and Mineral Research.

The study’s senior author, Belinda R. Beck, PhD, director of the Bone Clinic in Brisbane, Australia, developed the Onero HiRIT program and has licensed it to others in Australia.

“It is a very effective program and we have shown it can be undertaken safely, but it must be supervised because of the heavy weights and high-risk clientele,” Beck stressed to this news organization.

“This is not a program you should just hand to a patient and tell them to do in a gym,” she said.

“Both forms of exercise in our study were beneficial for functional outcomes but Onero improved back extensor strength, mobility and stature considerably more than Buff Bones,” Ms. Fischbacher said in an interview.

Nevertheless, “the contribution of functional capacity to risk of falling and fracture cannot be overstated, and bone medications do not address function,” she noted.

“More trials combining bone medication and bone-targeted exercise are needed,” the researchers concluded.

Compliance stands out, study supports high-intensity exercise

Kristen M. Beavers, PhD, MPH, RD, who was not involved with this research, told this news organization that participant compliance in the study really stands out.

“Compliance to an 8-month, 2 day/week high-intensity resistance training program among older women with low bone mass was quite good in this study [>80%], with very few adverse events reported,” said Dr. Beavers, of the department of health and exercise science, Wake Forest University, Winston Salem, N.C.

“A lot of individuals wouldn’t even consider recommending this type/intensity of exercise to this population, because they are worried it is too risky and/or the uptake will be low,” she said.

Although the benefit in BMD and strength wasn’t seen universally across all bone/muscle outcomes assessed, the findings do reinforce the idea that high-intensity exercise is more efficacious for bone health than low-intensity exercise, she noted.

“The possible additive effect of high-intensity exercise when combined with medication is worth confirming in larger, adequately designed/powered studies,” according to Dr. Beavers.

“The general consensus in the field is that higher-intensity exercise is more osteogenic than low-intensity exercise, but improving muscle mass, quality, and function (including balance) are also important to reduce the risk of falls, which is a major contributor to incident fracture,” she noted.

Exercise, even low-intensity exercise, reduces the risk for falls, as shown in a recent meta-analysis, she added. This is something antiresorptive medications don’t do.
 

Building on the LIFTMOR and LIFTMOR-M Trials

Previously, the Australian group showed that HiRIT is efficacious and safe for bone formation in individuals with low to very low bone mass – in postmenopausal women in the LIFTMOR study (J Bone Miner Res. 2017 Oct 4 .doi: 10.1002/jbmr.3284), and in men in the LIFTMOR-M study.

The current study compared two exercise programs. The researchers randomly assigned 86 women who were not taking antiresorptive medication to the high-intensity (42) or low-intensity (44) exercise program. They also assigned 29 women who were receiving antiresorptive medication to the high-intensity (15) or low-intensity (14) exercise program.

In the high-intensity exercise plus medication subgroup, the women were taking denosumab (12), risedronate (2) or alendronate (1). In the low-intensity exercise plus medication subgroup, the women were taking denosumab (9), risedronate (1), alendronate (3), or zoledronic acid (1).

The mean age of the women was 64-68 years. The mean lumbar spine T score was –1.5 to –2.3, and the mean femoral neck T score was –1.7 to –2.0 (determined by dual-energy x-ray absorptiometry) .

The HiRIT training program consisted of three free-weight resistance training exercises (deadlift, back squat, overhead press), one high-impact exercise (jump drop), and two balance exercises. The exercises varied each session.

The low-intensity training consisted of bone-specific Pilates-based exercises performed on the mat; standing weight-bearing exercise with 1-kg dumbbells; and impact exercises, such as heel drops and stomping.

At 8 months, compared with women in the low-intensity exercise program, those in the HiRIT program demonstrated greater improvement in lumbar spine BMD (1.9% vs. 0.1%) and stature (0.2 cm vs. 0.0 cm), muscle strength, and functional performance.

Functional performance improved with both exercise programs, but the HiRIT program led to greater leg and back muscle strength and better results in the five times sit-to-stand test (P < .05).

HiRIT plus bone medication improved BMD at the femoral neck and total hip, whereas HiRIT alone did not. Low-intensity exercise plus bone medication improved BMD at the lumbar spine and total hip, whereas low-intensity exercise alone did not.

The retention rate was 90%. The rate of exercise compliance was 83% in the high-intensity group and 82% in the low-intensity group.

Thirty falls were reported by 24 participants (21%). One fracture occurred in each exercise group. Three adverse events occurred in the low-intensity group, and four occurred in the high-intensity group.

Dr. Beck owns the Bone Clinic and sells licenses to the Onero program. The other researchers disclosed no relevant financial relationships.

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

Patients with functional neurological disorders demonstrate higher levels of depression and alexithymia – in addition to signs of an avoidant attachment style – compared with those with other neurological disorders and healthy controls, investigators report.

The pathological mechanism of functional neurological disorders (FND) remains poorly understood, but current models include both psychological and environmental factors, Sofia Cuoco, PhD, and colleagues wrote in a study published in the Journal of Psychosomatic Research.

Previous studies have suggested a relationship between attachment styles (AS) and psychiatric symptoms in FND patients but most have been limited to the FND population, noted Dr. Cuoco, of the University of Salerno, Italy, and colleagues. In FND, “it is unclear to what extent psychiatric features are explained by AS per se or are part of the FND spectrum,” they said.

To conduct the study, the investigators recruited 46 patients with FND, 34 patients with neurological disorders (ND) and 30 healthy controls. Demographic characteristics, including age, education, and gender, were similar among the groups. Overall, depression and alexithymia were significantly more prevalent in the FND group, compared with the other groups. Anxiety was more common in the FND group, compared with healthy controls, but similar compared with the ND group. Patients in the FND group reported significantly lower quality of life, compared with those in the other groups.

In a multivariate analysis aimed at examining AS and psychiatric features, the researchers found that the Experiences in Close Relationships–Revised questionnaire avoidance, Beck Depression Inventory, Somatic Affective, and the 20-item Toronto Alexithymia Scale Difficulty Identifying Feelings scale (TAS-20 Difficulty Identifying Feelings) were significant predictors of FND and accounted for about half of the variance.

The researchers also compared FND to functional seizures, and found that the TAS-20 Difficulty Identifying Feelings scale, the Hamilton Anxiety Scale–Anxiety, and female gender were significant predictors of functional seizures.

The results were mainly in line with those from previous studies, the researchers said. However, “one of the novelties of this study is the inclusion of patients with other ND, whereby we demonstrated that FND patients were more depressed, anxious, and alexithymic than ND, which might suggest that these psychiatric features would not be merely reactive to physical symptoms,” they noted.

The study findings were limited by several factors, including the absence of systematic interviews for personality disorders or traits, monitoring psychotropic medications, and conducting formal psychiatric assessments, the researchers noted. Other limitations include the heterogenous study population and absence of data on symptom severity, history of trauma, or other factors that might contributed to FND, they said.

However, the results suggest that avoidant AS might play an important role in the occurrence of psychiatric features in FND patients and should be considered in managing these conditions. More research is needed to explore the impact of attachment on pathophysiology with more complex instruments, such as the Adult Attachment Interview, Dr. Cuoco and colleagues said.

The study received no outside funding, and the researchers disclosed no financial conflicts.

Patients with functional neurological disorders demonstrate higher levels of depression and alexithymia – in addition to signs of an avoidant attachment style – compared with those with other neurological disorders and healthy controls, investigators report.

The pathological mechanism of functional neurological disorders (FND) remains poorly understood, but current models include both psychological and environmental factors, Sofia Cuoco, PhD, and colleagues wrote in a study published in the Journal of Psychosomatic Research.

Previous studies have suggested a relationship between attachment styles (AS) and psychiatric symptoms in FND patients but most have been limited to the FND population, noted Dr. Cuoco, of the University of Salerno, Italy, and colleagues. In FND, “it is unclear to what extent psychiatric features are explained by AS per se or are part of the FND spectrum,” they said.

To conduct the study, the investigators recruited 46 patients with FND, 34 patients with neurological disorders (ND) and 30 healthy controls. Demographic characteristics, including age, education, and gender, were similar among the groups. Overall, depression and alexithymia were significantly more prevalent in the FND group, compared with the other groups. Anxiety was more common in the FND group, compared with healthy controls, but similar compared with the ND group. Patients in the FND group reported significantly lower quality of life, compared with those in the other groups.

In a multivariate analysis aimed at examining AS and psychiatric features, the researchers found that the Experiences in Close Relationships–Revised questionnaire avoidance, Beck Depression Inventory, Somatic Affective, and the 20-item Toronto Alexithymia Scale Difficulty Identifying Feelings scale (TAS-20 Difficulty Identifying Feelings) were significant predictors of FND and accounted for about half of the variance.

The researchers also compared FND to functional seizures, and found that the TAS-20 Difficulty Identifying Feelings scale, the Hamilton Anxiety Scale–Anxiety, and female gender were significant predictors of functional seizures.

The results were mainly in line with those from previous studies, the researchers said. However, “one of the novelties of this study is the inclusion of patients with other ND, whereby we demonstrated that FND patients were more depressed, anxious, and alexithymic than ND, which might suggest that these psychiatric features would not be merely reactive to physical symptoms,” they noted.

The study findings were limited by several factors, including the absence of systematic interviews for personality disorders or traits, monitoring psychotropic medications, and conducting formal psychiatric assessments, the researchers noted. Other limitations include the heterogenous study population and absence of data on symptom severity, history of trauma, or other factors that might contributed to FND, they said.

However, the results suggest that avoidant AS might play an important role in the occurrence of psychiatric features in FND patients and should be considered in managing these conditions. More research is needed to explore the impact of attachment on pathophysiology with more complex instruments, such as the Adult Attachment Interview, Dr. Cuoco and colleagues said.

The study received no outside funding, and the researchers disclosed no financial conflicts.

Patients with functional neurological disorders demonstrate higher levels of depression and alexithymia – in addition to signs of an avoidant attachment style – compared with those with other neurological disorders and healthy controls, investigators report.

The pathological mechanism of functional neurological disorders (FND) remains poorly understood, but current models include both psychological and environmental factors, Sofia Cuoco, PhD, and colleagues wrote in a study published in the Journal of Psychosomatic Research.

Previous studies have suggested a relationship between attachment styles (AS) and psychiatric symptoms in FND patients but most have been limited to the FND population, noted Dr. Cuoco, of the University of Salerno, Italy, and colleagues. In FND, “it is unclear to what extent psychiatric features are explained by AS per se or are part of the FND spectrum,” they said.

To conduct the study, the investigators recruited 46 patients with FND, 34 patients with neurological disorders (ND) and 30 healthy controls. Demographic characteristics, including age, education, and gender, were similar among the groups. Overall, depression and alexithymia were significantly more prevalent in the FND group, compared with the other groups. Anxiety was more common in the FND group, compared with healthy controls, but similar compared with the ND group. Patients in the FND group reported significantly lower quality of life, compared with those in the other groups.

In a multivariate analysis aimed at examining AS and psychiatric features, the researchers found that the Experiences in Close Relationships–Revised questionnaire avoidance, Beck Depression Inventory, Somatic Affective, and the 20-item Toronto Alexithymia Scale Difficulty Identifying Feelings scale (TAS-20 Difficulty Identifying Feelings) were significant predictors of FND and accounted for about half of the variance.

The researchers also compared FND to functional seizures, and found that the TAS-20 Difficulty Identifying Feelings scale, the Hamilton Anxiety Scale–Anxiety, and female gender were significant predictors of functional seizures.

The results were mainly in line with those from previous studies, the researchers said. However, “one of the novelties of this study is the inclusion of patients with other ND, whereby we demonstrated that FND patients were more depressed, anxious, and alexithymic than ND, which might suggest that these psychiatric features would not be merely reactive to physical symptoms,” they noted.

The study findings were limited by several factors, including the absence of systematic interviews for personality disorders or traits, monitoring psychotropic medications, and conducting formal psychiatric assessments, the researchers noted. Other limitations include the heterogenous study population and absence of data on symptom severity, history of trauma, or other factors that might contributed to FND, they said.

However, the results suggest that avoidant AS might play an important role in the occurrence of psychiatric features in FND patients and should be considered in managing these conditions. More research is needed to explore the impact of attachment on pathophysiology with more complex instruments, such as the Adult Attachment Interview, Dr. Cuoco and colleagues said.

The study received no outside funding, and the researchers disclosed no financial conflicts.

COVID-19 has killed Native Americans at twice the rate of White Americans, underscoring the health inequities and deep-rooted distrust tribal nations have of federal government entities.

And yet, Native Americans have the highest vaccination rates of any major racial or ethnic group in the United States. Like many other tribal nations, the Navajo had to embrace Western science to reclaim its social customs and ceremonies. “We’re a very social culture, so having to isolate really impacted our mental health,” said Mary Hasbah Roessel, MD, DLFAPA, a Navajo psychiatrist who is affiliated with Santa Fe Indian Hospital in New Mexico.

The Navajo nation occupies the largest Native American reservation in the United States, spanning New Mexico, Arizona, and Utah. As of mid-October, the nation had reported more than 34,000 COVID-19 cases and 1,400 deaths in its jurisdiction.

In an interview with this news organization, Dr. Roessel described the partnerships that mobilized a nation of more than 250,000 individuals to get vaccinated.

Question: Why has the death rate been so high in the Navajo nation?

Answer: A lot of health disparities before the pandemic were blatantly revealed during COVID. Only 40% of people on the reservation had running water. Having to stay home and isolate led to food insecurity. Further insecurity issues affected our ability to stay healthy, such as having good sanitation. There’s a lot of poverty, a high unemployment rate. Some people had to go to work off reservation and were potentially bringing the virus home. A lot of generations live in the same household. Elders were vulnerable to getting the infection, and there was little ability to isolate if someone wasn’t having symptoms. Hospitals nearby didn’t have ICUs.

Therefore, the rate of cases skyrocketed early on. We were disproportionately affected. The Navajo nation per capita had the highest rate of cases in any state.
 

Q: What changes took place within the Navajo nation to get people vaccinated? What role did the federal Indian Health Service have in promoting this?

A: There had to be a shift in acceptance of the vaccinations. I think what particularly helped the Navajo nation was seeing the IHS rise up and provide access for treatments and vaccinations early on.

With the IHS, we went into a disaster response mode with all-hands-on deck meetings. We had to figure out how we could access mass vaccination clinics. Partnering with the Navajo Department of Health, we did that right away with hospitals and small clinics across the Navajo nation. Casinos owned by tribal entities that closed during COVID reopened and were used as vaccination clinics.

Vaccinations were sent to us fairly quickly. I ended up getting vaccinated in December 2020, when it was first rolled out.

Native and Navajo individuals have been reluctant to rely on government services. Because IHS came through with the vaccines, COVID reduced that stigma to access its services. Even the Navajo Department of Health partnered with the Indian Health Service to provide culturally relevant campaigns that explain why the vaccine is valuable.

I think because people were so impacted, they saw something valuable with the vaccine. Given the education and access, people were ready to get vaccinated. They realized if a whole household got vaccinated, they could see early on that they could be social again.
 

Q: What cultural factors have been contributing to this positive development?

A: In our Navajo culture, we’ve dealt with monsters before. We talk about that in terms of how we teach our young people to be strong and resilient. We talked about this virus as being another monster we had to tackle and control. The teaching was along those lines. We’ve dealt with this before, and we can handle it. We’re resilient. Our culture is very strong in that way. So how do we do it? We have to partner; we have to embrace Western medicine to return back to the ceremonies we want to have again and be social again. We focus on positive things, so if we see something as potentially positive, such as the vaccine, we see that and know that’s something to help us come into our life again.

Q: I would expect that protecting elders in the tribe would be a big incentive in taking the vaccine.

A: Yes, we didn’t want to lose our language and culture, and we wanted to protect our elders. Having a way to do that was very important as well. They were among the first to get vaccinated.

Q: What is the current vaccination rate in the Navajo nation?

A: I think it’s in the upper 80th percentile. It’s very high.

Q: What have been the biggest takeaways so far, and what are your hopes for the future?

A: Even though the Navajo Nation has been impacted and devastated with the loss of elders and knowledge keepers, we still have our culture and ceremonies intact to the point that we know we can be resilient get through this difficult time.

Through collaborations with the federal and state governments and the clinics, we see that things are different now. Going forward, my hope is these partnerships will continue, that we’ll build those relationships and not be so siloed in our care. When the New Mexico Department of Health rolled out its first vaccination clinic, for example, we jumped on and saw how they did it. We were then able to do our own, collaborating with the state.

We also saw how important our culture was, how it helped our Navajo people through these difficult times.

Dr. Roessel, a distinguished fellow of the American Psychiatric Association, has special expertise in cultural psychiatry. Her childhood was spent growing up in the Navajo nation with her grandfather, who was a Navajo medicine man. Her psychiatric practice focuses on integrating Indigenous knowledge and principles.

References

American Public Media Research Lab. “The Color of Coronavirus: COVID-19 Deaths by Race and Ethnicity in the U.S.” 2021 Mar 5.

Centers for Disease Control and Prevention. “Demographic Characteristics of People Receiving COVID-19 Vaccinations in the United States.” Data as of 2021 Oct 14.

Navajo Nation. Indian Health Service. U.S. Department of Health & Human Services.

The Navajo Nation’s Office of the President and Vice President. “11 New Cases, 32,735 Recoveries, and Six Recent Deaths Related to COVID-19.” 2021 Oct 13.

Navajo Nation Government web page.

COVID-19 has killed Native Americans at twice the rate of White Americans, underscoring the health inequities and deep-rooted distrust tribal nations have of federal government entities.

And yet, Native Americans have the highest vaccination rates of any major racial or ethnic group in the United States. Like many other tribal nations, the Navajo had to embrace Western science to reclaim its social customs and ceremonies. “We’re a very social culture, so having to isolate really impacted our mental health,” said Mary Hasbah Roessel, MD, DLFAPA, a Navajo psychiatrist who is affiliated with Santa Fe Indian Hospital in New Mexico.

The Navajo nation occupies the largest Native American reservation in the United States, spanning New Mexico, Arizona, and Utah. As of mid-October, the nation had reported more than 34,000 COVID-19 cases and 1,400 deaths in its jurisdiction.

In an interview with this news organization, Dr. Roessel described the partnerships that mobilized a nation of more than 250,000 individuals to get vaccinated.

Question: Why has the death rate been so high in the Navajo nation?

Answer: A lot of health disparities before the pandemic were blatantly revealed during COVID. Only 40% of people on the reservation had running water. Having to stay home and isolate led to food insecurity. Further insecurity issues affected our ability to stay healthy, such as having good sanitation. There’s a lot of poverty, a high unemployment rate. Some people had to go to work off reservation and were potentially bringing the virus home. A lot of generations live in the same household. Elders were vulnerable to getting the infection, and there was little ability to isolate if someone wasn’t having symptoms. Hospitals nearby didn’t have ICUs.

Therefore, the rate of cases skyrocketed early on. We were disproportionately affected. The Navajo nation per capita had the highest rate of cases in any state.
 

Q: What changes took place within the Navajo nation to get people vaccinated? What role did the federal Indian Health Service have in promoting this?

A: There had to be a shift in acceptance of the vaccinations. I think what particularly helped the Navajo nation was seeing the IHS rise up and provide access for treatments and vaccinations early on.

With the IHS, we went into a disaster response mode with all-hands-on deck meetings. We had to figure out how we could access mass vaccination clinics. Partnering with the Navajo Department of Health, we did that right away with hospitals and small clinics across the Navajo nation. Casinos owned by tribal entities that closed during COVID reopened and were used as vaccination clinics.

Vaccinations were sent to us fairly quickly. I ended up getting vaccinated in December 2020, when it was first rolled out.

Native and Navajo individuals have been reluctant to rely on government services. Because IHS came through with the vaccines, COVID reduced that stigma to access its services. Even the Navajo Department of Health partnered with the Indian Health Service to provide culturally relevant campaigns that explain why the vaccine is valuable.

I think because people were so impacted, they saw something valuable with the vaccine. Given the education and access, people were ready to get vaccinated. They realized if a whole household got vaccinated, they could see early on that they could be social again.
 

Q: What cultural factors have been contributing to this positive development?

A: In our Navajo culture, we’ve dealt with monsters before. We talk about that in terms of how we teach our young people to be strong and resilient. We talked about this virus as being another monster we had to tackle and control. The teaching was along those lines. We’ve dealt with this before, and we can handle it. We’re resilient. Our culture is very strong in that way. So how do we do it? We have to partner; we have to embrace Western medicine to return back to the ceremonies we want to have again and be social again. We focus on positive things, so if we see something as potentially positive, such as the vaccine, we see that and know that’s something to help us come into our life again.

Q: I would expect that protecting elders in the tribe would be a big incentive in taking the vaccine.

A: Yes, we didn’t want to lose our language and culture, and we wanted to protect our elders. Having a way to do that was very important as well. They were among the first to get vaccinated.

Q: What is the current vaccination rate in the Navajo nation?

A: I think it’s in the upper 80th percentile. It’s very high.

Q: What have been the biggest takeaways so far, and what are your hopes for the future?

A: Even though the Navajo Nation has been impacted and devastated with the loss of elders and knowledge keepers, we still have our culture and ceremonies intact to the point that we know we can be resilient get through this difficult time.

Through collaborations with the federal and state governments and the clinics, we see that things are different now. Going forward, my hope is these partnerships will continue, that we’ll build those relationships and not be so siloed in our care. When the New Mexico Department of Health rolled out its first vaccination clinic, for example, we jumped on and saw how they did it. We were then able to do our own, collaborating with the state.

We also saw how important our culture was, how it helped our Navajo people through these difficult times.

Dr. Roessel, a distinguished fellow of the American Psychiatric Association, has special expertise in cultural psychiatry. Her childhood was spent growing up in the Navajo nation with her grandfather, who was a Navajo medicine man. Her psychiatric practice focuses on integrating Indigenous knowledge and principles.

References

American Public Media Research Lab. “The Color of Coronavirus: COVID-19 Deaths by Race and Ethnicity in the U.S.” 2021 Mar 5.

Centers for Disease Control and Prevention. “Demographic Characteristics of People Receiving COVID-19 Vaccinations in the United States.” Data as of 2021 Oct 14.

Navajo Nation. Indian Health Service. U.S. Department of Health & Human Services.

The Navajo Nation’s Office of the President and Vice President. “11 New Cases, 32,735 Recoveries, and Six Recent Deaths Related to COVID-19.” 2021 Oct 13.

Navajo Nation Government web page.

COVID-19 has killed Native Americans at twice the rate of White Americans, underscoring the health inequities and deep-rooted distrust tribal nations have of federal government entities.

And yet, Native Americans have the highest vaccination rates of any major racial or ethnic group in the United States. Like many other tribal nations, the Navajo had to embrace Western science to reclaim its social customs and ceremonies. “We’re a very social culture, so having to isolate really impacted our mental health,” said Mary Hasbah Roessel, MD, DLFAPA, a Navajo psychiatrist who is affiliated with Santa Fe Indian Hospital in New Mexico.

The Navajo nation occupies the largest Native American reservation in the United States, spanning New Mexico, Arizona, and Utah. As of mid-October, the nation had reported more than 34,000 COVID-19 cases and 1,400 deaths in its jurisdiction.

In an interview with this news organization, Dr. Roessel described the partnerships that mobilized a nation of more than 250,000 individuals to get vaccinated.

Question: Why has the death rate been so high in the Navajo nation?

Answer: A lot of health disparities before the pandemic were blatantly revealed during COVID. Only 40% of people on the reservation had running water. Having to stay home and isolate led to food insecurity. Further insecurity issues affected our ability to stay healthy, such as having good sanitation. There’s a lot of poverty, a high unemployment rate. Some people had to go to work off reservation and were potentially bringing the virus home. A lot of generations live in the same household. Elders were vulnerable to getting the infection, and there was little ability to isolate if someone wasn’t having symptoms. Hospitals nearby didn’t have ICUs.

Therefore, the rate of cases skyrocketed early on. We were disproportionately affected. The Navajo nation per capita had the highest rate of cases in any state.
 

Q: What changes took place within the Navajo nation to get people vaccinated? What role did the federal Indian Health Service have in promoting this?

A: There had to be a shift in acceptance of the vaccinations. I think what particularly helped the Navajo nation was seeing the IHS rise up and provide access for treatments and vaccinations early on.

With the IHS, we went into a disaster response mode with all-hands-on deck meetings. We had to figure out how we could access mass vaccination clinics. Partnering with the Navajo Department of Health, we did that right away with hospitals and small clinics across the Navajo nation. Casinos owned by tribal entities that closed during COVID reopened and were used as vaccination clinics.

Vaccinations were sent to us fairly quickly. I ended up getting vaccinated in December 2020, when it was first rolled out.

Native and Navajo individuals have been reluctant to rely on government services. Because IHS came through with the vaccines, COVID reduced that stigma to access its services. Even the Navajo Department of Health partnered with the Indian Health Service to provide culturally relevant campaigns that explain why the vaccine is valuable.

I think because people were so impacted, they saw something valuable with the vaccine. Given the education and access, people were ready to get vaccinated. They realized if a whole household got vaccinated, they could see early on that they could be social again.
 

Q: What cultural factors have been contributing to this positive development?

A: In our Navajo culture, we’ve dealt with monsters before. We talk about that in terms of how we teach our young people to be strong and resilient. We talked about this virus as being another monster we had to tackle and control. The teaching was along those lines. We’ve dealt with this before, and we can handle it. We’re resilient. Our culture is very strong in that way. So how do we do it? We have to partner; we have to embrace Western medicine to return back to the ceremonies we want to have again and be social again. We focus on positive things, so if we see something as potentially positive, such as the vaccine, we see that and know that’s something to help us come into our life again.

Q: I would expect that protecting elders in the tribe would be a big incentive in taking the vaccine.

A: Yes, we didn’t want to lose our language and culture, and we wanted to protect our elders. Having a way to do that was very important as well. They were among the first to get vaccinated.

Q: What is the current vaccination rate in the Navajo nation?

A: I think it’s in the upper 80th percentile. It’s very high.

Q: What have been the biggest takeaways so far, and what are your hopes for the future?

A: Even though the Navajo Nation has been impacted and devastated with the loss of elders and knowledge keepers, we still have our culture and ceremonies intact to the point that we know we can be resilient get through this difficult time.

Through collaborations with the federal and state governments and the clinics, we see that things are different now. Going forward, my hope is these partnerships will continue, that we’ll build those relationships and not be so siloed in our care. When the New Mexico Department of Health rolled out its first vaccination clinic, for example, we jumped on and saw how they did it. We were then able to do our own, collaborating with the state.

We also saw how important our culture was, how it helped our Navajo people through these difficult times.

Dr. Roessel, a distinguished fellow of the American Psychiatric Association, has special expertise in cultural psychiatry. Her childhood was spent growing up in the Navajo nation with her grandfather, who was a Navajo medicine man. Her psychiatric practice focuses on integrating Indigenous knowledge and principles.

References

American Public Media Research Lab. “The Color of Coronavirus: COVID-19 Deaths by Race and Ethnicity in the U.S.” 2021 Mar 5.

Centers for Disease Control and Prevention. “Demographic Characteristics of People Receiving COVID-19 Vaccinations in the United States.” Data as of 2021 Oct 14.

Navajo Nation. Indian Health Service. U.S. Department of Health & Human Services.

The Navajo Nation’s Office of the President and Vice President. “11 New Cases, 32,735 Recoveries, and Six Recent Deaths Related to COVID-19.” 2021 Oct 13.

Navajo Nation Government web page.

Despite reporting record profits during the COVID-19 pandemic, major insurance companies are delaying claims payments and making it more difficult for hospitals and physicians to get paid the full amount of claims, observers and physicians say.

Kaiser Health News recently reported that hospitals, in particular, are affected by the slowdown in claims payments from Anthem Blue Cross, the nation’s second largest health insurer. The investigative piece did not focus on outpatient or independent practices. Research by this news organization shows that the health plans’ new policies are also reducing cash flow and raising costs for ambulatory care groups. In addition, it showed that other payers besides Anthem have engaged in the same practices.

“What we’ve seen is that with complex claims, such as those with -25 modifiers, plans are routinely requiring documentation,” Jim Donohue, senior manager and associate principal at ECG Management Consultants, said in an interview. “It’s not a denial, it’s a request for more information for medical records prior to processing payments. That has the effect of slowing down payments.”

This is exactly what one internal medicine group in the Southeast has noticed. The internist who heads the practice, who asked not to be identified, says that about 4-6 months ago, United, Humana, and other payers started to require documentation for prepayment review on a higher percentage of complex claims such as 99214 (established patient), 99204 (new patient), and claims with -25 modifiers. (The latter are appended to evaluation and management [E/M] claims in which patients had comorbidities that were addressed in the same visit as the main complaint.)

“That’s really frustrating, because you have to print out or take the record for that particular visit and computer fax it to them,” the practice leader notes. “And invariably, they’ll say they didn’t get a certain percentage of them. It’s our fault because they lost the claim.”

In the past, he says, health plans would occasionally ask for the note related to a complex visit where they saw issues, and they’ve always done random postpayment chart audits. But the percentage of prepayment reviews has significantly increased in recent months, he says.

Until a plan does this review, the claim can’t be processed because it’s not regarded as a clean claim. And this has implications for insurers’ compliance with laws that, in most states, require them to pay claims within 30-40 days of submission. (Medicare’s limit is 30 days.) According to Mr. Donohue, the clock doesn’t start ticking on this requirement unless and until a claim is clean. So by requiring documentation on complex claims, the plans can not only justify downcoding a claim, but can also delay payment without triggering state penalties.
 

Insurer admits ‘challenges’ with claims processing

VCU Health, a health system affiliated with Virginia Commonwealth University, recently filed a complaint against Anthem with Virginia’s insurance commissioner, asking that the Virginia Bureau of Insurance investigate the company’s claims-processing delays. The complaint claimed Anthem owes VCU more than $385 million, of which $171 million is over 90 days old. Much of that consists of commercial claims, which are subject to the state’s 40-day claims payment rule.

VCU cited several problems it said Anthem had created that slowed claims payments:

Any claim over a certain dollar limit requires an itemized bill.

Anthem requests detailed medical records prior to considering payment of even clean claims.

Documents must be uploaded to a web portal that has technical problems, and Anthem has lost some documents as a result.

Claims are being incorrectly processed for some professionals, “resulting in multi-million-dollar underpayments of anesthesia, nurse practitioners, pathology, and behavioral health providers.”

In addition, as the Kaiser Health News article points out, hospitals have blamed the increase in payment delays or denials partly on “preauthorization hurdles for routine procedures and requirements that doctors themselves – not support staffers – speak to insurance gatekeepers.”

In response to an inquiry from this news organization, an Anthem spokesman admitted that some payments to providers have been delayed, partly because of changes in the company’s claims-processing system. “We recognize there have been some challenges as we work with care providers to update claims processing, and readjust and adapt to a new set of dynamics as we continue to manage the pandemic,” said the spokesman.

The Kaiser Health News piece reported that Anthem’s CFO had told stock analysts on a conference call that the company had slowed claims payments to build up its financial reserves during the pandemic – a statement that some physicians called “outrageous.” But the Anthem spokesman told this news organization the quote was taken out of context and that the CFO was talking not about reserves but about “days in claims payable.” The spokesman said, “The payment delays that the article focuses on are not the primary driver or even a material driver of the increase in our overall reserves or DCPs [defined contribution plans] relative to historical levels. In fact, the vast majority of our claims are being processed in a timely manner.”

Some claims routinely downcoded

Even if that were the case, it would not explain why some physicians are seeing their higher-cost claims routinely downcoded. Will Sawyer, MD, a family physician in Cincinnati, told this news organization, “Anthem has been downcoding relentlessly since October 2020.” More often than not, when his office submits a claim with a 99214 code (office visit, 30-39 minutes, moderate medical decision-making), it’s changed to 99213 (office visit, 20-29 minutes, low medical decision-making) before processing, he says.

This has resulted in a significant diminution of his income, he notes. Anthem pays him less than Medicare for E/M visits, and the downcoding reduces his payment from $86 to $68 for a complex visit that may have taken half an hour or more.

In some cases where his office manager has noticed the downcoding, Dr. Sawyer says, she has resubmitted the claim with a copy of the encounter form. But Anthem hasn’t budged. And the refiling effort takes a toll on his solo practice, which doesn’t have sufficient staff, as it is.

Dr. Sawyer acknowledges that he has sent in a higher percentage of complex claims in the past year than he did previously. But much of that is the result of two factors beyond his control: First, many patients avoided coming into the office early in the pandemic, and when they returned, their preventive and chronic care needs were greater. Second, he says, “There are many comorbidities and mental health aspects, which exacerbate many issues and become an issue. We’re not dealing with engines here; they’re human beings. And it takes time.”

In response to Dr. Sawyer’s comments, Anthem said that it uses “analytical tools to review evaluation and management (E/M) codes during the claims adjudication and processing process.” Physicians who believe that certain claims should not have been downcoded can dispute these decisions; they must supply a statement explaining why they disagree with the decision along with documentation to support their statement, the company said. Anthem added that it reviews claims to lower costs for its members.
 

‘Revenue-grab strategy’

Dr. Sawyer believes that what Anthem is doing to him and other physicians reflects its desire to increase profits by netting extra revenue and keeping physicians’ money while it delays payments to them – a practice known in the trade as “the float.” Moreover, he says, the company depends on many practices not keeping track of their finances during the pandemic.

“When practices are running at warp speed, trying to keep people healthy and getting burned out, they aren’t paying as close attention to the details of payment. It’s an absolute revenue-grab strategy that’s unconscionable,” says Dr. Sawyer.

The Southeast internist also thinks that insurance companies other than Anthem – including United and Humana – are profiting from the float. Besides delaying his payments with gratuitous demands for documentation, he said, they also downcode many claims, forcing the practice to refile the claims and appeal. That forces the practice to pay overtime or bring on more claims staff, which raises administrative costs.

The plans’ strategy, the internist says, is this: “If they downcode millions of claims, a certain number of physicians will give up without appealing, and they’ll raise their profits.”

A United spokesperson said in an interview, “We pay claims appropriately under members’ plans and within the required time frame.” Humana had not responded to this news organization’s request for comment at press time.
 

Challenge to practice economics

Insurer policies that delay payments or downcode claims, ECG’s Mr. Donohue points out, are especially harmful to primary care and other ambulatory practices that have many small-dollar claims.

“That’s where it’s challenging, because it’s not like a $10,000 case where you add $100 to it [to meet records requests]. You’re talking about something that’s relatively low dollar, where the practice makes a small surplus, and when you add administrative costs, it can change the economics,” he says.

While the economic burden on ambulatory care practices may be greater, Anders Gilberg, senior vice president of government affairs for the Medical Group Management Association (MGMA), said that the payment delays and demands for documentation – along with prior authorization – particularly affect inpatient care. The health plans are questioning big-ticket items more than ever, he said, and most of those services occur in hospitals.

However, the greater level of insurer scrutiny also affects physicians who treat patients in the hospital, including surgeons and emergency department physicians who contract with the facilities, he adds.

Mr. Gilberg views the current situation as an exacerbation of the health plan policies that physicians have long struggled with. “It’s not new to have insurers play the float and not pay claims on time. Unfortunately, this is something that medical practices are used to.”

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

Despite reporting record profits during the COVID-19 pandemic, major insurance companies are delaying claims payments and making it more difficult for hospitals and physicians to get paid the full amount of claims, observers and physicians say.

Kaiser Health News recently reported that hospitals, in particular, are affected by the slowdown in claims payments from Anthem Blue Cross, the nation’s second largest health insurer. The investigative piece did not focus on outpatient or independent practices. Research by this news organization shows that the health plans’ new policies are also reducing cash flow and raising costs for ambulatory care groups. In addition, it showed that other payers besides Anthem have engaged in the same practices.

“What we’ve seen is that with complex claims, such as those with -25 modifiers, plans are routinely requiring documentation,” Jim Donohue, senior manager and associate principal at ECG Management Consultants, said in an interview. “It’s not a denial, it’s a request for more information for medical records prior to processing payments. That has the effect of slowing down payments.”

This is exactly what one internal medicine group in the Southeast has noticed. The internist who heads the practice, who asked not to be identified, says that about 4-6 months ago, United, Humana, and other payers started to require documentation for prepayment review on a higher percentage of complex claims such as 99214 (established patient), 99204 (new patient), and claims with -25 modifiers. (The latter are appended to evaluation and management [E/M] claims in which patients had comorbidities that were addressed in the same visit as the main complaint.)

“That’s really frustrating, because you have to print out or take the record for that particular visit and computer fax it to them,” the practice leader notes. “And invariably, they’ll say they didn’t get a certain percentage of them. It’s our fault because they lost the claim.”

In the past, he says, health plans would occasionally ask for the note related to a complex visit where they saw issues, and they’ve always done random postpayment chart audits. But the percentage of prepayment reviews has significantly increased in recent months, he says.

Until a plan does this review, the claim can’t be processed because it’s not regarded as a clean claim. And this has implications for insurers’ compliance with laws that, in most states, require them to pay claims within 30-40 days of submission. (Medicare’s limit is 30 days.) According to Mr. Donohue, the clock doesn’t start ticking on this requirement unless and until a claim is clean. So by requiring documentation on complex claims, the plans can not only justify downcoding a claim, but can also delay payment without triggering state penalties.
 

Insurer admits ‘challenges’ with claims processing

VCU Health, a health system affiliated with Virginia Commonwealth University, recently filed a complaint against Anthem with Virginia’s insurance commissioner, asking that the Virginia Bureau of Insurance investigate the company’s claims-processing delays. The complaint claimed Anthem owes VCU more than $385 million, of which $171 million is over 90 days old. Much of that consists of commercial claims, which are subject to the state’s 40-day claims payment rule.

VCU cited several problems it said Anthem had created that slowed claims payments:

Any claim over a certain dollar limit requires an itemized bill.

Anthem requests detailed medical records prior to considering payment of even clean claims.

Documents must be uploaded to a web portal that has technical problems, and Anthem has lost some documents as a result.

Claims are being incorrectly processed for some professionals, “resulting in multi-million-dollar underpayments of anesthesia, nurse practitioners, pathology, and behavioral health providers.”

In addition, as the Kaiser Health News article points out, hospitals have blamed the increase in payment delays or denials partly on “preauthorization hurdles for routine procedures and requirements that doctors themselves – not support staffers – speak to insurance gatekeepers.”

In response to an inquiry from this news organization, an Anthem spokesman admitted that some payments to providers have been delayed, partly because of changes in the company’s claims-processing system. “We recognize there have been some challenges as we work with care providers to update claims processing, and readjust and adapt to a new set of dynamics as we continue to manage the pandemic,” said the spokesman.

The Kaiser Health News piece reported that Anthem’s CFO had told stock analysts on a conference call that the company had slowed claims payments to build up its financial reserves during the pandemic – a statement that some physicians called “outrageous.” But the Anthem spokesman told this news organization the quote was taken out of context and that the CFO was talking not about reserves but about “days in claims payable.” The spokesman said, “The payment delays that the article focuses on are not the primary driver or even a material driver of the increase in our overall reserves or DCPs [defined contribution plans] relative to historical levels. In fact, the vast majority of our claims are being processed in a timely manner.”

Some claims routinely downcoded

Even if that were the case, it would not explain why some physicians are seeing their higher-cost claims routinely downcoded. Will Sawyer, MD, a family physician in Cincinnati, told this news organization, “Anthem has been downcoding relentlessly since October 2020.” More often than not, when his office submits a claim with a 99214 code (office visit, 30-39 minutes, moderate medical decision-making), it’s changed to 99213 (office visit, 20-29 minutes, low medical decision-making) before processing, he says.

This has resulted in a significant diminution of his income, he notes. Anthem pays him less than Medicare for E/M visits, and the downcoding reduces his payment from $86 to $68 for a complex visit that may have taken half an hour or more.

In some cases where his office manager has noticed the downcoding, Dr. Sawyer says, she has resubmitted the claim with a copy of the encounter form. But Anthem hasn’t budged. And the refiling effort takes a toll on his solo practice, which doesn’t have sufficient staff, as it is.

Dr. Sawyer acknowledges that he has sent in a higher percentage of complex claims in the past year than he did previously. But much of that is the result of two factors beyond his control: First, many patients avoided coming into the office early in the pandemic, and when they returned, their preventive and chronic care needs were greater. Second, he says, “There are many comorbidities and mental health aspects, which exacerbate many issues and become an issue. We’re not dealing with engines here; they’re human beings. And it takes time.”

In response to Dr. Sawyer’s comments, Anthem said that it uses “analytical tools to review evaluation and management (E/M) codes during the claims adjudication and processing process.” Physicians who believe that certain claims should not have been downcoded can dispute these decisions; they must supply a statement explaining why they disagree with the decision along with documentation to support their statement, the company said. Anthem added that it reviews claims to lower costs for its members.
 

‘Revenue-grab strategy’

Dr. Sawyer believes that what Anthem is doing to him and other physicians reflects its desire to increase profits by netting extra revenue and keeping physicians’ money while it delays payments to them – a practice known in the trade as “the float.” Moreover, he says, the company depends on many practices not keeping track of their finances during the pandemic.

“When practices are running at warp speed, trying to keep people healthy and getting burned out, they aren’t paying as close attention to the details of payment. It’s an absolute revenue-grab strategy that’s unconscionable,” says Dr. Sawyer.

The Southeast internist also thinks that insurance companies other than Anthem – including United and Humana – are profiting from the float. Besides delaying his payments with gratuitous demands for documentation, he said, they also downcode many claims, forcing the practice to refile the claims and appeal. That forces the practice to pay overtime or bring on more claims staff, which raises administrative costs.

The plans’ strategy, the internist says, is this: “If they downcode millions of claims, a certain number of physicians will give up without appealing, and they’ll raise their profits.”

A United spokesperson said in an interview, “We pay claims appropriately under members’ plans and within the required time frame.” Humana had not responded to this news organization’s request for comment at press time.
 

Challenge to practice economics

Insurer policies that delay payments or downcode claims, ECG’s Mr. Donohue points out, are especially harmful to primary care and other ambulatory practices that have many small-dollar claims.

“That’s where it’s challenging, because it’s not like a $10,000 case where you add $100 to it [to meet records requests]. You’re talking about something that’s relatively low dollar, where the practice makes a small surplus, and when you add administrative costs, it can change the economics,” he says.

While the economic burden on ambulatory care practices may be greater, Anders Gilberg, senior vice president of government affairs for the Medical Group Management Association (MGMA), said that the payment delays and demands for documentation – along with prior authorization – particularly affect inpatient care. The health plans are questioning big-ticket items more than ever, he said, and most of those services occur in hospitals.

However, the greater level of insurer scrutiny also affects physicians who treat patients in the hospital, including surgeons and emergency department physicians who contract with the facilities, he adds.

Mr. Gilberg views the current situation as an exacerbation of the health plan policies that physicians have long struggled with. “It’s not new to have insurers play the float and not pay claims on time. Unfortunately, this is something that medical practices are used to.”

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

Despite reporting record profits during the COVID-19 pandemic, major insurance companies are delaying claims payments and making it more difficult for hospitals and physicians to get paid the full amount of claims, observers and physicians say.

Kaiser Health News recently reported that hospitals, in particular, are affected by the slowdown in claims payments from Anthem Blue Cross, the nation’s second largest health insurer. The investigative piece did not focus on outpatient or independent practices. Research by this news organization shows that the health plans’ new policies are also reducing cash flow and raising costs for ambulatory care groups. In addition, it showed that other payers besides Anthem have engaged in the same practices.

“What we’ve seen is that with complex claims, such as those with -25 modifiers, plans are routinely requiring documentation,” Jim Donohue, senior manager and associate principal at ECG Management Consultants, said in an interview. “It’s not a denial, it’s a request for more information for medical records prior to processing payments. That has the effect of slowing down payments.”

This is exactly what one internal medicine group in the Southeast has noticed. The internist who heads the practice, who asked not to be identified, says that about 4-6 months ago, United, Humana, and other payers started to require documentation for prepayment review on a higher percentage of complex claims such as 99214 (established patient), 99204 (new patient), and claims with -25 modifiers. (The latter are appended to evaluation and management [E/M] claims in which patients had comorbidities that were addressed in the same visit as the main complaint.)

“That’s really frustrating, because you have to print out or take the record for that particular visit and computer fax it to them,” the practice leader notes. “And invariably, they’ll say they didn’t get a certain percentage of them. It’s our fault because they lost the claim.”

In the past, he says, health plans would occasionally ask for the note related to a complex visit where they saw issues, and they’ve always done random postpayment chart audits. But the percentage of prepayment reviews has significantly increased in recent months, he says.

Until a plan does this review, the claim can’t be processed because it’s not regarded as a clean claim. And this has implications for insurers’ compliance with laws that, in most states, require them to pay claims within 30-40 days of submission. (Medicare’s limit is 30 days.) According to Mr. Donohue, the clock doesn’t start ticking on this requirement unless and until a claim is clean. So by requiring documentation on complex claims, the plans can not only justify downcoding a claim, but can also delay payment without triggering state penalties.
 

Insurer admits ‘challenges’ with claims processing

VCU Health, a health system affiliated with Virginia Commonwealth University, recently filed a complaint against Anthem with Virginia’s insurance commissioner, asking that the Virginia Bureau of Insurance investigate the company’s claims-processing delays. The complaint claimed Anthem owes VCU more than $385 million, of which $171 million is over 90 days old. Much of that consists of commercial claims, which are subject to the state’s 40-day claims payment rule.

VCU cited several problems it said Anthem had created that slowed claims payments:

Any claim over a certain dollar limit requires an itemized bill.

Anthem requests detailed medical records prior to considering payment of even clean claims.

Documents must be uploaded to a web portal that has technical problems, and Anthem has lost some documents as a result.

Claims are being incorrectly processed for some professionals, “resulting in multi-million-dollar underpayments of anesthesia, nurse practitioners, pathology, and behavioral health providers.”

In addition, as the Kaiser Health News article points out, hospitals have blamed the increase in payment delays or denials partly on “preauthorization hurdles for routine procedures and requirements that doctors themselves – not support staffers – speak to insurance gatekeepers.”

In response to an inquiry from this news organization, an Anthem spokesman admitted that some payments to providers have been delayed, partly because of changes in the company’s claims-processing system. “We recognize there have been some challenges as we work with care providers to update claims processing, and readjust and adapt to a new set of dynamics as we continue to manage the pandemic,” said the spokesman.

The Kaiser Health News piece reported that Anthem’s CFO had told stock analysts on a conference call that the company had slowed claims payments to build up its financial reserves during the pandemic – a statement that some physicians called “outrageous.” But the Anthem spokesman told this news organization the quote was taken out of context and that the CFO was talking not about reserves but about “days in claims payable.” The spokesman said, “The payment delays that the article focuses on are not the primary driver or even a material driver of the increase in our overall reserves or DCPs [defined contribution plans] relative to historical levels. In fact, the vast majority of our claims are being processed in a timely manner.”

Some claims routinely downcoded

Even if that were the case, it would not explain why some physicians are seeing their higher-cost claims routinely downcoded. Will Sawyer, MD, a family physician in Cincinnati, told this news organization, “Anthem has been downcoding relentlessly since October 2020.” More often than not, when his office submits a claim with a 99214 code (office visit, 30-39 minutes, moderate medical decision-making), it’s changed to 99213 (office visit, 20-29 minutes, low medical decision-making) before processing, he says.

This has resulted in a significant diminution of his income, he notes. Anthem pays him less than Medicare for E/M visits, and the downcoding reduces his payment from $86 to $68 for a complex visit that may have taken half an hour or more.

In some cases where his office manager has noticed the downcoding, Dr. Sawyer says, she has resubmitted the claim with a copy of the encounter form. But Anthem hasn’t budged. And the refiling effort takes a toll on his solo practice, which doesn’t have sufficient staff, as it is.

Dr. Sawyer acknowledges that he has sent in a higher percentage of complex claims in the past year than he did previously. But much of that is the result of two factors beyond his control: First, many patients avoided coming into the office early in the pandemic, and when they returned, their preventive and chronic care needs were greater. Second, he says, “There are many comorbidities and mental health aspects, which exacerbate many issues and become an issue. We’re not dealing with engines here; they’re human beings. And it takes time.”

In response to Dr. Sawyer’s comments, Anthem said that it uses “analytical tools to review evaluation and management (E/M) codes during the claims adjudication and processing process.” Physicians who believe that certain claims should not have been downcoded can dispute these decisions; they must supply a statement explaining why they disagree with the decision along with documentation to support their statement, the company said. Anthem added that it reviews claims to lower costs for its members.
 

‘Revenue-grab strategy’

Dr. Sawyer believes that what Anthem is doing to him and other physicians reflects its desire to increase profits by netting extra revenue and keeping physicians’ money while it delays payments to them – a practice known in the trade as “the float.” Moreover, he says, the company depends on many practices not keeping track of their finances during the pandemic.

“When practices are running at warp speed, trying to keep people healthy and getting burned out, they aren’t paying as close attention to the details of payment. It’s an absolute revenue-grab strategy that’s unconscionable,” says Dr. Sawyer.

The Southeast internist also thinks that insurance companies other than Anthem – including United and Humana – are profiting from the float. Besides delaying his payments with gratuitous demands for documentation, he said, they also downcode many claims, forcing the practice to refile the claims and appeal. That forces the practice to pay overtime or bring on more claims staff, which raises administrative costs.

The plans’ strategy, the internist says, is this: “If they downcode millions of claims, a certain number of physicians will give up without appealing, and they’ll raise their profits.”

A United spokesperson said in an interview, “We pay claims appropriately under members’ plans and within the required time frame.” Humana had not responded to this news organization’s request for comment at press time.
 

Challenge to practice economics

Insurer policies that delay payments or downcode claims, ECG’s Mr. Donohue points out, are especially harmful to primary care and other ambulatory practices that have many small-dollar claims.

“That’s where it’s challenging, because it’s not like a $10,000 case where you add $100 to it [to meet records requests]. You’re talking about something that’s relatively low dollar, where the practice makes a small surplus, and when you add administrative costs, it can change the economics,” he says.

While the economic burden on ambulatory care practices may be greater, Anders Gilberg, senior vice president of government affairs for the Medical Group Management Association (MGMA), said that the payment delays and demands for documentation – along with prior authorization – particularly affect inpatient care. The health plans are questioning big-ticket items more than ever, he said, and most of those services occur in hospitals.

However, the greater level of insurer scrutiny also affects physicians who treat patients in the hospital, including surgeons and emergency department physicians who contract with the facilities, he adds.

Mr. Gilberg views the current situation as an exacerbation of the health plan policies that physicians have long struggled with. “It’s not new to have insurers play the float and not pay claims on time. Unfortunately, this is something that medical practices are used to.”

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

While the use of Bruton tyrosine kinase inhibitors has significantly enhanced treatment of patients with B-cell malignancies, BTKi resistance is the “Achilles’ heel” of this otherwise effective therapeutic option, Deborah M. Stephens, DO, and John C. Byrd, MD, stated in a review article published in Blood.

Among patients with B-cell malignancies – including chronic lymphocytic leukemia (CLL), Waldenström’s macroglobulinemia (WM), mantle cell lymphoma (MCL), and marginal zone lymphoma (MZL) – BTKis have substantial efficacy. The review article focuses mainly on extremely rare primary or more common acquired BTKi resistance, particularly among patients with acquired resistance to ibrutinib (11%-38% in large studies).

Primary resistance suggests an alternative diagnosis or transformation to a more aggressive lymphoma. Acquired ibrutinib resistance manifests either as progressive CLL (typically after 2 years of therapy) or as early transformation (within the first 2 years of therapy) to more aggressive entities such as diffuse large B-cell lymphoma, Hodgkin lymphoma, or prolymphocytic leukemia. Less studied than ibrutinib, acquired resistance to acalabrutinib and zanubrutinib has been in the 12%-15% range.

Acquired resistance has meant a reduction in expected overall survival, and while the introduction of new therapies like venetoclax has extended OS, short progression-free survival (PFS) provides a rationale for research into mechanisms of resistance and alternative treatments.

Acquired resistance

Most often acquired, resistance to ibrutinib monotherapy in CLL patients has been associated with high-risk genomic features: complex karyotype, TP53 mutation, del(17)p13.1, and heavy pretreatment. In the phase 3 RESONATE trial, patients with both TP53 mutation and del(17)p13.1 had shorter PFS than those with only one or the other genomic feature. This feature may have explained the fairly good ibrutinib monotherapy outcomes in treatment-naive patients with del(17p)13.1.

Through univariable and multivariable analysis, a machine-learning program consistently identified TP53 mutation, prior CLL therapy, beta-2 microglobulin of at least5 mg/L, and lactate dehydrogenase greater than250 U/L as four risk factors associated with impaired survival. A second survival factor program comparing ibrutinib with chemoimmunotherapy identified beta-2 microglobulin levels of at least5 mg/L, lactate dehydrogenase greater than ULN, hemoglobin less than 110 g/L for women or less than120 g/L for men, and time from initiation of last therapy less than 24 months as risk factors.

While the mechanisms leading to ibrutinib resistance are not clearly known for patients with these risk factors, some research suggests that survival of TP53-mutated CLL cells is less dependent on the BCR pathway, making this CLL type more prone to ibrutinib resistance. TP53-mutated CLL cells, compared with T53–wild-type CLL cells, demonstrate a down-regulation of BCR-related genes and an up-regulation of prosurvival and antiapototic genes.
 

BTK mutations

Mutation of the active kinase domain on the BTK enzyme (C481) is the most common BTKi resistance mechanism described in CLL. A thymidine to adenine mutation (nucleotide 1634) leads to a 25-fold decrease in drug potency. Other known gene or chromosome regions affected in BTKi resistance include PLCy2, Del(8p), CARD11, TRAF2&3, BIRC3, MAP3k14, ARID2, SMARCA2, SMARCA4, MYD88, KLH14, and TNFAIP3.

Multiple mutations of PLCy2, the next most common BTKi resistance mechanism, include mutations of arginine to tryptophan, leucine to phenylalanine, serine to tyrosine, and others. When activated, these gain-of-function mutations prolong BCR signaling.

Ibrutinib resistance has also been associated with deletion of the short arm of chromosome 8 (del[8p]), with CLL cells harboring del(8p) insensitive to TRAIL-induced apoptosis, leading to continuous cell growth. Ibrutinib resistance in patients with WM has also been associated with del(8p).

CARD11 mutations, which allow for BTK-independent activation of NFkB, have been documented in ibrutinib-resistant patients with CLL and other lymphoid malignancies, as detailed in this review.
 

Novel therapies suggest promise

Survival in CLL after BTKi resistance develops is quite short, according to the authors, and they expressed hope that continued research into novel agents would prolong this population’s survival.

Venetoclax, an oral inhibitor of the antiapoptotic protein BCL2, is approved for all patients with CLL, both as monotherapy and in combination with an anti-CD20 monoclonal antibody. Data support its use after BTKi resistance has been detected. Some evidence in CLL cell lines supports use of the oral phosphoinositide 3-kinases inhibitors idelalisib and duvelisib in relapsed CLL and the BTK C481S mutation. Early response data with third-generation BTKis, such as ARQ-531 and LOXO-305, suggest promise in this setting. Also, for young and healthy patients who have progressed on both BTKi and venetoclax therapy, allogeneic hematopoietic stem cell transplantation could be considered.

In patients with heavily pretreated CLL, early clinical data support chimeric antigen receptor T-cell therapy (CAR T), a novel therapy where patients’ own T cells are extracted, engineered, and reinfused. A related immunotherapy, using a similar process of retroviral vector insertion of an anti-CD19 CAR into donor NK cells before infusion into the patient, is termed CAR-NK cell therapy. It shows promise in early data from patients with CLL who all had previously been heavily treated with ibrutinib.

More research, more hope

Despite the significant advance that BTKis represent, BTKi resistance, with shortened survival, remains a clinical problem for patients with B-cell malignancies. BTKi resistance has been associated with several genetic and clinical risk factors, with mutations in BTK and PLCy2 the most common and most thoroughly researched. “Ongoing clinical trials of third-generation noncovalent BTKis and cellular therapies, such as CAR T, provide much hope for these patients. ... Continued additional research is needed to further prolong the survival of patients with BTKi-resistant B-cell malignancies.”

Dr. Stephens has received research funding and has served on advisory boards for a variety of pharmaceutical and biotechnology companies. Dr. Byrd has received research funding and has consulted for a variety of pharmaceutical and biotechnology companies.

While the use of Bruton tyrosine kinase inhibitors has significantly enhanced treatment of patients with B-cell malignancies, BTKi resistance is the “Achilles’ heel” of this otherwise effective therapeutic option, Deborah M. Stephens, DO, and John C. Byrd, MD, stated in a review article published in Blood.

Among patients with B-cell malignancies – including chronic lymphocytic leukemia (CLL), Waldenström’s macroglobulinemia (WM), mantle cell lymphoma (MCL), and marginal zone lymphoma (MZL) – BTKis have substantial efficacy. The review article focuses mainly on extremely rare primary or more common acquired BTKi resistance, particularly among patients with acquired resistance to ibrutinib (11%-38% in large studies).

Primary resistance suggests an alternative diagnosis or transformation to a more aggressive lymphoma. Acquired ibrutinib resistance manifests either as progressive CLL (typically after 2 years of therapy) or as early transformation (within the first 2 years of therapy) to more aggressive entities such as diffuse large B-cell lymphoma, Hodgkin lymphoma, or prolymphocytic leukemia. Less studied than ibrutinib, acquired resistance to acalabrutinib and zanubrutinib has been in the 12%-15% range.

Acquired resistance has meant a reduction in expected overall survival, and while the introduction of new therapies like venetoclax has extended OS, short progression-free survival (PFS) provides a rationale for research into mechanisms of resistance and alternative treatments.

Acquired resistance

Most often acquired, resistance to ibrutinib monotherapy in CLL patients has been associated with high-risk genomic features: complex karyotype, TP53 mutation, del(17)p13.1, and heavy pretreatment. In the phase 3 RESONATE trial, patients with both TP53 mutation and del(17)p13.1 had shorter PFS than those with only one or the other genomic feature. This feature may have explained the fairly good ibrutinib monotherapy outcomes in treatment-naive patients with del(17p)13.1.

Through univariable and multivariable analysis, a machine-learning program consistently identified TP53 mutation, prior CLL therapy, beta-2 microglobulin of at least5 mg/L, and lactate dehydrogenase greater than250 U/L as four risk factors associated with impaired survival. A second survival factor program comparing ibrutinib with chemoimmunotherapy identified beta-2 microglobulin levels of at least5 mg/L, lactate dehydrogenase greater than ULN, hemoglobin less than 110 g/L for women or less than120 g/L for men, and time from initiation of last therapy less than 24 months as risk factors.

While the mechanisms leading to ibrutinib resistance are not clearly known for patients with these risk factors, some research suggests that survival of TP53-mutated CLL cells is less dependent on the BCR pathway, making this CLL type more prone to ibrutinib resistance. TP53-mutated CLL cells, compared with T53–wild-type CLL cells, demonstrate a down-regulation of BCR-related genes and an up-regulation of prosurvival and antiapototic genes.
 

BTK mutations

Mutation of the active kinase domain on the BTK enzyme (C481) is the most common BTKi resistance mechanism described in CLL. A thymidine to adenine mutation (nucleotide 1634) leads to a 25-fold decrease in drug potency. Other known gene or chromosome regions affected in BTKi resistance include PLCy2, Del(8p), CARD11, TRAF2&3, BIRC3, MAP3k14, ARID2, SMARCA2, SMARCA4, MYD88, KLH14, and TNFAIP3.

Multiple mutations of PLCy2, the next most common BTKi resistance mechanism, include mutations of arginine to tryptophan, leucine to phenylalanine, serine to tyrosine, and others. When activated, these gain-of-function mutations prolong BCR signaling.

Ibrutinib resistance has also been associated with deletion of the short arm of chromosome 8 (del[8p]), with CLL cells harboring del(8p) insensitive to TRAIL-induced apoptosis, leading to continuous cell growth. Ibrutinib resistance in patients with WM has also been associated with del(8p).

CARD11 mutations, which allow for BTK-independent activation of NFkB, have been documented in ibrutinib-resistant patients with CLL and other lymphoid malignancies, as detailed in this review.
 

Novel therapies suggest promise

Survival in CLL after BTKi resistance develops is quite short, according to the authors, and they expressed hope that continued research into novel agents would prolong this population’s survival.

Venetoclax, an oral inhibitor of the antiapoptotic protein BCL2, is approved for all patients with CLL, both as monotherapy and in combination with an anti-CD20 monoclonal antibody. Data support its use after BTKi resistance has been detected. Some evidence in CLL cell lines supports use of the oral phosphoinositide 3-kinases inhibitors idelalisib and duvelisib in relapsed CLL and the BTK C481S mutation. Early response data with third-generation BTKis, such as ARQ-531 and LOXO-305, suggest promise in this setting. Also, for young and healthy patients who have progressed on both BTKi and venetoclax therapy, allogeneic hematopoietic stem cell transplantation could be considered.

In patients with heavily pretreated CLL, early clinical data support chimeric antigen receptor T-cell therapy (CAR T), a novel therapy where patients’ own T cells are extracted, engineered, and reinfused. A related immunotherapy, using a similar process of retroviral vector insertion of an anti-CD19 CAR into donor NK cells before infusion into the patient, is termed CAR-NK cell therapy. It shows promise in early data from patients with CLL who all had previously been heavily treated with ibrutinib.

More research, more hope

Despite the significant advance that BTKis represent, BTKi resistance, with shortened survival, remains a clinical problem for patients with B-cell malignancies. BTKi resistance has been associated with several genetic and clinical risk factors, with mutations in BTK and PLCy2 the most common and most thoroughly researched. “Ongoing clinical trials of third-generation noncovalent BTKis and cellular therapies, such as CAR T, provide much hope for these patients. ... Continued additional research is needed to further prolong the survival of patients with BTKi-resistant B-cell malignancies.”

Dr. Stephens has received research funding and has served on advisory boards for a variety of pharmaceutical and biotechnology companies. Dr. Byrd has received research funding and has consulted for a variety of pharmaceutical and biotechnology companies.

While the use of Bruton tyrosine kinase inhibitors has significantly enhanced treatment of patients with B-cell malignancies, BTKi resistance is the “Achilles’ heel” of this otherwise effective therapeutic option, Deborah M. Stephens, DO, and John C. Byrd, MD, stated in a review article published in Blood.

Among patients with B-cell malignancies – including chronic lymphocytic leukemia (CLL), Waldenström’s macroglobulinemia (WM), mantle cell lymphoma (MCL), and marginal zone lymphoma (MZL) – BTKis have substantial efficacy. The review article focuses mainly on extremely rare primary or more common acquired BTKi resistance, particularly among patients with acquired resistance to ibrutinib (11%-38% in large studies).

Primary resistance suggests an alternative diagnosis or transformation to a more aggressive lymphoma. Acquired ibrutinib resistance manifests either as progressive CLL (typically after 2 years of therapy) or as early transformation (within the first 2 years of therapy) to more aggressive entities such as diffuse large B-cell lymphoma, Hodgkin lymphoma, or prolymphocytic leukemia. Less studied than ibrutinib, acquired resistance to acalabrutinib and zanubrutinib has been in the 12%-15% range.

Acquired resistance has meant a reduction in expected overall survival, and while the introduction of new therapies like venetoclax has extended OS, short progression-free survival (PFS) provides a rationale for research into mechanisms of resistance and alternative treatments.

Acquired resistance

Most often acquired, resistance to ibrutinib monotherapy in CLL patients has been associated with high-risk genomic features: complex karyotype, TP53 mutation, del(17)p13.1, and heavy pretreatment. In the phase 3 RESONATE trial, patients with both TP53 mutation and del(17)p13.1 had shorter PFS than those with only one or the other genomic feature. This feature may have explained the fairly good ibrutinib monotherapy outcomes in treatment-naive patients with del(17p)13.1.

Through univariable and multivariable analysis, a machine-learning program consistently identified TP53 mutation, prior CLL therapy, beta-2 microglobulin of at least5 mg/L, and lactate dehydrogenase greater than250 U/L as four risk factors associated with impaired survival. A second survival factor program comparing ibrutinib with chemoimmunotherapy identified beta-2 microglobulin levels of at least5 mg/L, lactate dehydrogenase greater than ULN, hemoglobin less than 110 g/L for women or less than120 g/L for men, and time from initiation of last therapy less than 24 months as risk factors.

While the mechanisms leading to ibrutinib resistance are not clearly known for patients with these risk factors, some research suggests that survival of TP53-mutated CLL cells is less dependent on the BCR pathway, making this CLL type more prone to ibrutinib resistance. TP53-mutated CLL cells, compared with T53–wild-type CLL cells, demonstrate a down-regulation of BCR-related genes and an up-regulation of prosurvival and antiapototic genes.
 

BTK mutations

Mutation of the active kinase domain on the BTK enzyme (C481) is the most common BTKi resistance mechanism described in CLL. A thymidine to adenine mutation (nucleotide 1634) leads to a 25-fold decrease in drug potency. Other known gene or chromosome regions affected in BTKi resistance include PLCy2, Del(8p), CARD11, TRAF2&3, BIRC3, MAP3k14, ARID2, SMARCA2, SMARCA4, MYD88, KLH14, and TNFAIP3.

Multiple mutations of PLCy2, the next most common BTKi resistance mechanism, include mutations of arginine to tryptophan, leucine to phenylalanine, serine to tyrosine, and others. When activated, these gain-of-function mutations prolong BCR signaling.

Ibrutinib resistance has also been associated with deletion of the short arm of chromosome 8 (del[8p]), with CLL cells harboring del(8p) insensitive to TRAIL-induced apoptosis, leading to continuous cell growth. Ibrutinib resistance in patients with WM has also been associated with del(8p).

CARD11 mutations, which allow for BTK-independent activation of NFkB, have been documented in ibrutinib-resistant patients with CLL and other lymphoid malignancies, as detailed in this review.
 

Novel therapies suggest promise

Survival in CLL after BTKi resistance develops is quite short, according to the authors, and they expressed hope that continued research into novel agents would prolong this population’s survival.

Venetoclax, an oral inhibitor of the antiapoptotic protein BCL2, is approved for all patients with CLL, both as monotherapy and in combination with an anti-CD20 monoclonal antibody. Data support its use after BTKi resistance has been detected. Some evidence in CLL cell lines supports use of the oral phosphoinositide 3-kinases inhibitors idelalisib and duvelisib in relapsed CLL and the BTK C481S mutation. Early response data with third-generation BTKis, such as ARQ-531 and LOXO-305, suggest promise in this setting. Also, for young and healthy patients who have progressed on both BTKi and venetoclax therapy, allogeneic hematopoietic stem cell transplantation could be considered.

In patients with heavily pretreated CLL, early clinical data support chimeric antigen receptor T-cell therapy (CAR T), a novel therapy where patients’ own T cells are extracted, engineered, and reinfused. A related immunotherapy, using a similar process of retroviral vector insertion of an anti-CD19 CAR into donor NK cells before infusion into the patient, is termed CAR-NK cell therapy. It shows promise in early data from patients with CLL who all had previously been heavily treated with ibrutinib.

More research, more hope

Despite the significant advance that BTKis represent, BTKi resistance, with shortened survival, remains a clinical problem for patients with B-cell malignancies. BTKi resistance has been associated with several genetic and clinical risk factors, with mutations in BTK and PLCy2 the most common and most thoroughly researched. “Ongoing clinical trials of third-generation noncovalent BTKis and cellular therapies, such as CAR T, provide much hope for these patients. ... Continued additional research is needed to further prolong the survival of patients with BTKi-resistant B-cell malignancies.”

Dr. Stephens has received research funding and has served on advisory boards for a variety of pharmaceutical and biotechnology companies. Dr. Byrd has received research funding and has consulted for a variety of pharmaceutical and biotechnology companies.

In patients with basal cell carcinoma (BCC), watchful waiting may be more suitable than active treatment for patients with asymptomatic nodular or superficial BCC and a limited life expectancy, according to a study published in JAMA Dermatology.

“Patient preferences, treatment goals, and the option for proceeding with a watchful waiting approach should be discussed as part of personalized shared decision-making,” wrote Marieke van Winden, MD, MSc, of Radboud University Medical Center in Nijmegen, the Netherlands, and colleagues. “In patients with a limited life expectancy and asymptomatic low-risk tumors, the time to benefit from treatment might exceed life expectancy, and watchful waiting should be discussed as a potentially appropriate approach.”

As little research has been undertaken on watchful waiting in patients with BCC, the expected tumor growth, progression and the chance of developing symptoms while taking this approach are poorly understood. Patients with limited life expectancy might not live long enough to develop BCC symptoms and may benefit more from watchful waiting than active treatment, authors of the study wrote.

This observational cohort study evaluated the reasons for watchful waiting, along with the natural course of 280 BCCs in 89 patients (53% men, median age 83 years) who chose this approach. Patients had one or more untreated BCCs for at least 3 months and the median follow-up was 9 months. The researchers also looked at the reasons for initiating later treatment.

Patient-related factors, including limited life expectancy, comorbidity prioritizations, and frailty, were the most important reasons to choose watchful waiting in 83% of patients, followed by tumor-related factors in 55% of patients. Of the tumors, 47% increased in size. The estimated tumor diameter increase in 1 year was 4.46 mm for infiltrative/micronodular BCCs and 1.06 mm for nodular, superficial, or clinical BCCs. Tumor growth was not associated with initial tumor size and location.

The most common reasons to initiate active treatment were tumor burden, resolved reasons for watchful waiting, and reevaluation of patient-related factors.

“All patients should be followed up regularly to determine whether a watchful waiting approach is still suited and if patients still prefer watchful waiting to reconsider the consequences of refraining from treatment,” the authors wrote.

In an accompanying editorial, Mackenzie R. Wehner, MD, MPhil, of the University of Texas MD Anderson Cancer Center in Houston, said that, while the observational and retrospective design was a limitation of the study, this allowed the authors to observe patients avoiding or delaying treatment for BCC in real clinical practice.

The study “shows that few patients developed new symptoms, and few patients who decided to treat after a delay had more invasive interventions than originally anticipated, an encouraging result as we continue to study the option and hone the details of active surveillance in BCC,” Dr. Wehner wrote. “It is important to note that the authors did not perform actual active surveillance. This study did not prospectively enroll patients and see them in follow-up at set times, nor did it have prespecified end points for recommending treatment.”

“Before evidence-based active surveillance in BCC can become a viable option, prospective studies of active surveillance, with specified follow-up times and clear outcome measures, are needed,” Dr. Wehner wrote.

Dr. van Winden did not report any conflicts of interest.

In patients with basal cell carcinoma (BCC), watchful waiting may be more suitable than active treatment for patients with asymptomatic nodular or superficial BCC and a limited life expectancy, according to a study published in JAMA Dermatology.

“Patient preferences, treatment goals, and the option for proceeding with a watchful waiting approach should be discussed as part of personalized shared decision-making,” wrote Marieke van Winden, MD, MSc, of Radboud University Medical Center in Nijmegen, the Netherlands, and colleagues. “In patients with a limited life expectancy and asymptomatic low-risk tumors, the time to benefit from treatment might exceed life expectancy, and watchful waiting should be discussed as a potentially appropriate approach.”

As little research has been undertaken on watchful waiting in patients with BCC, the expected tumor growth, progression and the chance of developing symptoms while taking this approach are poorly understood. Patients with limited life expectancy might not live long enough to develop BCC symptoms and may benefit more from watchful waiting than active treatment, authors of the study wrote.

This observational cohort study evaluated the reasons for watchful waiting, along with the natural course of 280 BCCs in 89 patients (53% men, median age 83 years) who chose this approach. Patients had one or more untreated BCCs for at least 3 months and the median follow-up was 9 months. The researchers also looked at the reasons for initiating later treatment.

Patient-related factors, including limited life expectancy, comorbidity prioritizations, and frailty, were the most important reasons to choose watchful waiting in 83% of patients, followed by tumor-related factors in 55% of patients. Of the tumors, 47% increased in size. The estimated tumor diameter increase in 1 year was 4.46 mm for infiltrative/micronodular BCCs and 1.06 mm for nodular, superficial, or clinical BCCs. Tumor growth was not associated with initial tumor size and location.

The most common reasons to initiate active treatment were tumor burden, resolved reasons for watchful waiting, and reevaluation of patient-related factors.

“All patients should be followed up regularly to determine whether a watchful waiting approach is still suited and if patients still prefer watchful waiting to reconsider the consequences of refraining from treatment,” the authors wrote.

In an accompanying editorial, Mackenzie R. Wehner, MD, MPhil, of the University of Texas MD Anderson Cancer Center in Houston, said that, while the observational and retrospective design was a limitation of the study, this allowed the authors to observe patients avoiding or delaying treatment for BCC in real clinical practice.

The study “shows that few patients developed new symptoms, and few patients who decided to treat after a delay had more invasive interventions than originally anticipated, an encouraging result as we continue to study the option and hone the details of active surveillance in BCC,” Dr. Wehner wrote. “It is important to note that the authors did not perform actual active surveillance. This study did not prospectively enroll patients and see them in follow-up at set times, nor did it have prespecified end points for recommending treatment.”

“Before evidence-based active surveillance in BCC can become a viable option, prospective studies of active surveillance, with specified follow-up times and clear outcome measures, are needed,” Dr. Wehner wrote.

Dr. van Winden did not report any conflicts of interest.

In patients with basal cell carcinoma (BCC), watchful waiting may be more suitable than active treatment for patients with asymptomatic nodular or superficial BCC and a limited life expectancy, according to a study published in JAMA Dermatology.

“Patient preferences, treatment goals, and the option for proceeding with a watchful waiting approach should be discussed as part of personalized shared decision-making,” wrote Marieke van Winden, MD, MSc, of Radboud University Medical Center in Nijmegen, the Netherlands, and colleagues. “In patients with a limited life expectancy and asymptomatic low-risk tumors, the time to benefit from treatment might exceed life expectancy, and watchful waiting should be discussed as a potentially appropriate approach.”

As little research has been undertaken on watchful waiting in patients with BCC, the expected tumor growth, progression and the chance of developing symptoms while taking this approach are poorly understood. Patients with limited life expectancy might not live long enough to develop BCC symptoms and may benefit more from watchful waiting than active treatment, authors of the study wrote.

This observational cohort study evaluated the reasons for watchful waiting, along with the natural course of 280 BCCs in 89 patients (53% men, median age 83 years) who chose this approach. Patients had one or more untreated BCCs for at least 3 months and the median follow-up was 9 months. The researchers also looked at the reasons for initiating later treatment.

Patient-related factors, including limited life expectancy, comorbidity prioritizations, and frailty, were the most important reasons to choose watchful waiting in 83% of patients, followed by tumor-related factors in 55% of patients. Of the tumors, 47% increased in size. The estimated tumor diameter increase in 1 year was 4.46 mm for infiltrative/micronodular BCCs and 1.06 mm for nodular, superficial, or clinical BCCs. Tumor growth was not associated with initial tumor size and location.

The most common reasons to initiate active treatment were tumor burden, resolved reasons for watchful waiting, and reevaluation of patient-related factors.

“All patients should be followed up regularly to determine whether a watchful waiting approach is still suited and if patients still prefer watchful waiting to reconsider the consequences of refraining from treatment,” the authors wrote.

In an accompanying editorial, Mackenzie R. Wehner, MD, MPhil, of the University of Texas MD Anderson Cancer Center in Houston, said that, while the observational and retrospective design was a limitation of the study, this allowed the authors to observe patients avoiding or delaying treatment for BCC in real clinical practice.

The study “shows that few patients developed new symptoms, and few patients who decided to treat after a delay had more invasive interventions than originally anticipated, an encouraging result as we continue to study the option and hone the details of active surveillance in BCC,” Dr. Wehner wrote. “It is important to note that the authors did not perform actual active surveillance. This study did not prospectively enroll patients and see them in follow-up at set times, nor did it have prespecified end points for recommending treatment.”

“Before evidence-based active surveillance in BCC can become a viable option, prospective studies of active surveillance, with specified follow-up times and clear outcome measures, are needed,” Dr. Wehner wrote.

Dr. van Winden did not report any conflicts of interest.

Three or more cortical lesions at the time of multiple sclerosis (MS) diagnosis predicts long-term cognitive decline, according to findings from a new analysis. The findings had good accuracy, and could help clinicians monitor and treat cognitive impairment as it develops, according to Stefano Ziccardi, PhD, who is a postdoctoral researcher at the University of Verona in Italy.

“The number of cortical lesions at MS diagnosis accurately discriminates between the presence or the absence of cognitive impairment after diagnosis of MS, and this should be considered a predictive marker of long-term cognitive impairment in these patients. Early cortical lesion evaluation should be conducted in each MS patient to anticipate the manifestation of cognitive problems to improve the monitoring of cognitive abilities, improve the diagnosis of cognitive impairment, enable prompt intervention as necessary,” said Dr. Ziccardi at the annual meeting of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS).

Cortical lesions are highly prevalent in MS, perhaps more so than white matter lesions, said Dr. Ziccardi. They are associated with clinical disability and lead to disease progression. “However, prognostic data about the role of early cortical lesions with reference to long-term cognitive impairment are still missing,” said Dr. Ziccardi.

That’s important because cognitive impairment is very common in MS, affecting between one-third and two-thirds of patients. It may appear early in the disease course and worsen over time, and it predicts worse clinical and neurological progression. And it presents a clinical challenge. “Clinicians struggle to predict the evolution of cognitive abilities over time,” said Dr. Ziccardi.

The findings drew praise from Iris-Katharina Penner, PhD, who comoderated the session. “I think the important point … is that the predictive value of cortical lesions is very high, because it indicates finally that we probably have a patient at risk for developing cognitive impairment in the future,” said Dr. Penner, who is a neuropsychologist and cognitive neuroscientist at Heinrich Heine University in Düsseldorf, Germany.

Clinicians often don’t pay enough attention to cognition and the complexities of MS, said Mark Gudesblatt, MD, who was asked to comment. “It’s just adding layers of complexity. We’re peeling back the onion and you realize it’s a really complicated disease. It’s not just white matter plaques, gray matter plaques, disconnection syndrome, wires cut, atrophy, ongoing inflammation, immune deficiency. All these diseases are fascinating. And we think we’re experts. But the fact is, we have much to learn,” said Dr. Gudesblatt, who is medical director of the Comprehensive MS Care Center at South Shore Neurologic Associates in Patchogue, New York.

The researchers analyzed data from 170 patients with MS who had a disease duration of approximately 20 years. Among the study cohort 62 patients were female, and the mean duration of disease was 19.2 years. Each patient had had a 1.5 Tesla magnetic resonance imaging scan to look for cortical lesions within 3 years of diagnosis. They had also undergone periodic MRIs as well as neuropsychological exams, and underwent a neuropsychological assessment at the end of the study, which included the Brief Repeatable Battery of Neuropsychological Tests (BRB-NT) and the Stroop Test.

A total of 41% of subjects had no cortical lesions according to their first MRI; 19% had 1-2 lesions, and 40% had 3 or more. At follow-up, 50% were cognitively normal (failed no tests), 25% had mild cognitive impairment (failed one or more tests), and 25% had severe cognitive impairment (failed three or more tests).

In the overall cohort, the median number of cortical lesions at baseline was 1 (interquartile range, 5.0). Among the 50% with normal cognitive function, the median was 0 (IQR, 2.5), while for the remaining 50% with cognitive impairment, the median was 3 (IQR, 7.0).

Those with 3 or more lesions had increased odds of cognitive impairment at follow-up (odds ratio, 3.70; P < .001), with an accuracy of 65% (95% confidence interval, 58%-72%), specificity of 75% (95% CI, 65%-84%), and a sensitivity of 55% (95% CI, 44%-66%). Three or more lesions discriminated between cognitive impairment and no impairment with an area under the curve of 0.67.

Individuals with no cognitive impairment had a median 0 lesions (IQR, 2.5), those with mild cognitive impairment had a median of 2.0 (IQR, 6.0), and those with severe cognitive impairment had 4.0 (IQR, 7.25).

In a multinomial regression model, 3 or more baseline cortical lesions were associated with a greater than threefold risk of severe cognitive impairment (OR, 3.33; P = .01).

Of subjects with 0 baseline lesions, 62% were cognitively normal at follow-up. In the 1-2 lesion group, 64% were normal. In the 3 or more group, 31% were cognitively normal (P < .001). In the 0 lesion group, 26% had mild cognitive impairment and 12% had severe cognitive impairment. In the 3 or more group, 28% had mild cognitive impairment, and 41% had severe cognitive impairment.

During the Q&A session following the talk, Dr. Ziccardi was asked if the group compared cortical lesions to other MRI correlates of cognitive impairment, such as gray matter volume or white matter integrity. He responded that the group is looking into those comparisons, and recently found that neither the number nor the volume of white matter lesions improved the accuracy of the predictive models based on the number of cortical lesions. The group is also looking into the applicability of gray matter volume.

Three or more cortical lesions at the time of multiple sclerosis (MS) diagnosis predicts long-term cognitive decline, according to findings from a new analysis. The findings had good accuracy, and could help clinicians monitor and treat cognitive impairment as it develops, according to Stefano Ziccardi, PhD, who is a postdoctoral researcher at the University of Verona in Italy.

“The number of cortical lesions at MS diagnosis accurately discriminates between the presence or the absence of cognitive impairment after diagnosis of MS, and this should be considered a predictive marker of long-term cognitive impairment in these patients. Early cortical lesion evaluation should be conducted in each MS patient to anticipate the manifestation of cognitive problems to improve the monitoring of cognitive abilities, improve the diagnosis of cognitive impairment, enable prompt intervention as necessary,” said Dr. Ziccardi at the annual meeting of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS).

Cortical lesions are highly prevalent in MS, perhaps more so than white matter lesions, said Dr. Ziccardi. They are associated with clinical disability and lead to disease progression. “However, prognostic data about the role of early cortical lesions with reference to long-term cognitive impairment are still missing,” said Dr. Ziccardi.

That’s important because cognitive impairment is very common in MS, affecting between one-third and two-thirds of patients. It may appear early in the disease course and worsen over time, and it predicts worse clinical and neurological progression. And it presents a clinical challenge. “Clinicians struggle to predict the evolution of cognitive abilities over time,” said Dr. Ziccardi.

The findings drew praise from Iris-Katharina Penner, PhD, who comoderated the session. “I think the important point … is that the predictive value of cortical lesions is very high, because it indicates finally that we probably have a patient at risk for developing cognitive impairment in the future,” said Dr. Penner, who is a neuropsychologist and cognitive neuroscientist at Heinrich Heine University in Düsseldorf, Germany.

Clinicians often don’t pay enough attention to cognition and the complexities of MS, said Mark Gudesblatt, MD, who was asked to comment. “It’s just adding layers of complexity. We’re peeling back the onion and you realize it’s a really complicated disease. It’s not just white matter plaques, gray matter plaques, disconnection syndrome, wires cut, atrophy, ongoing inflammation, immune deficiency. All these diseases are fascinating. And we think we’re experts. But the fact is, we have much to learn,” said Dr. Gudesblatt, who is medical director of the Comprehensive MS Care Center at South Shore Neurologic Associates in Patchogue, New York.

The researchers analyzed data from 170 patients with MS who had a disease duration of approximately 20 years. Among the study cohort 62 patients were female, and the mean duration of disease was 19.2 years. Each patient had had a 1.5 Tesla magnetic resonance imaging scan to look for cortical lesions within 3 years of diagnosis. They had also undergone periodic MRIs as well as neuropsychological exams, and underwent a neuropsychological assessment at the end of the study, which included the Brief Repeatable Battery of Neuropsychological Tests (BRB-NT) and the Stroop Test.

A total of 41% of subjects had no cortical lesions according to their first MRI; 19% had 1-2 lesions, and 40% had 3 or more. At follow-up, 50% were cognitively normal (failed no tests), 25% had mild cognitive impairment (failed one or more tests), and 25% had severe cognitive impairment (failed three or more tests).

In the overall cohort, the median number of cortical lesions at baseline was 1 (interquartile range, 5.0). Among the 50% with normal cognitive function, the median was 0 (IQR, 2.5), while for the remaining 50% with cognitive impairment, the median was 3 (IQR, 7.0).

Those with 3 or more lesions had increased odds of cognitive impairment at follow-up (odds ratio, 3.70; P < .001), with an accuracy of 65% (95% confidence interval, 58%-72%), specificity of 75% (95% CI, 65%-84%), and a sensitivity of 55% (95% CI, 44%-66%). Three or more lesions discriminated between cognitive impairment and no impairment with an area under the curve of 0.67.

Individuals with no cognitive impairment had a median 0 lesions (IQR, 2.5), those with mild cognitive impairment had a median of 2.0 (IQR, 6.0), and those with severe cognitive impairment had 4.0 (IQR, 7.25).

In a multinomial regression model, 3 or more baseline cortical lesions were associated with a greater than threefold risk of severe cognitive impairment (OR, 3.33; P = .01).

Of subjects with 0 baseline lesions, 62% were cognitively normal at follow-up. In the 1-2 lesion group, 64% were normal. In the 3 or more group, 31% were cognitively normal (P < .001). In the 0 lesion group, 26% had mild cognitive impairment and 12% had severe cognitive impairment. In the 3 or more group, 28% had mild cognitive impairment, and 41% had severe cognitive impairment.

During the Q&A session following the talk, Dr. Ziccardi was asked if the group compared cortical lesions to other MRI correlates of cognitive impairment, such as gray matter volume or white matter integrity. He responded that the group is looking into those comparisons, and recently found that neither the number nor the volume of white matter lesions improved the accuracy of the predictive models based on the number of cortical lesions. The group is also looking into the applicability of gray matter volume.

Three or more cortical lesions at the time of multiple sclerosis (MS) diagnosis predicts long-term cognitive decline, according to findings from a new analysis. The findings had good accuracy, and could help clinicians monitor and treat cognitive impairment as it develops, according to Stefano Ziccardi, PhD, who is a postdoctoral researcher at the University of Verona in Italy.

“The number of cortical lesions at MS diagnosis accurately discriminates between the presence or the absence of cognitive impairment after diagnosis of MS, and this should be considered a predictive marker of long-term cognitive impairment in these patients. Early cortical lesion evaluation should be conducted in each MS patient to anticipate the manifestation of cognitive problems to improve the monitoring of cognitive abilities, improve the diagnosis of cognitive impairment, enable prompt intervention as necessary,” said Dr. Ziccardi at the annual meeting of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS).

Cortical lesions are highly prevalent in MS, perhaps more so than white matter lesions, said Dr. Ziccardi. They are associated with clinical disability and lead to disease progression. “However, prognostic data about the role of early cortical lesions with reference to long-term cognitive impairment are still missing,” said Dr. Ziccardi.

That’s important because cognitive impairment is very common in MS, affecting between one-third and two-thirds of patients. It may appear early in the disease course and worsen over time, and it predicts worse clinical and neurological progression. And it presents a clinical challenge. “Clinicians struggle to predict the evolution of cognitive abilities over time,” said Dr. Ziccardi.

The findings drew praise from Iris-Katharina Penner, PhD, who comoderated the session. “I think the important point … is that the predictive value of cortical lesions is very high, because it indicates finally that we probably have a patient at risk for developing cognitive impairment in the future,” said Dr. Penner, who is a neuropsychologist and cognitive neuroscientist at Heinrich Heine University in Düsseldorf, Germany.

Clinicians often don’t pay enough attention to cognition and the complexities of MS, said Mark Gudesblatt, MD, who was asked to comment. “It’s just adding layers of complexity. We’re peeling back the onion and you realize it’s a really complicated disease. It’s not just white matter plaques, gray matter plaques, disconnection syndrome, wires cut, atrophy, ongoing inflammation, immune deficiency. All these diseases are fascinating. And we think we’re experts. But the fact is, we have much to learn,” said Dr. Gudesblatt, who is medical director of the Comprehensive MS Care Center at South Shore Neurologic Associates in Patchogue, New York.

The researchers analyzed data from 170 patients with MS who had a disease duration of approximately 20 years. Among the study cohort 62 patients were female, and the mean duration of disease was 19.2 years. Each patient had had a 1.5 Tesla magnetic resonance imaging scan to look for cortical lesions within 3 years of diagnosis. They had also undergone periodic MRIs as well as neuropsychological exams, and underwent a neuropsychological assessment at the end of the study, which included the Brief Repeatable Battery of Neuropsychological Tests (BRB-NT) and the Stroop Test.

A total of 41% of subjects had no cortical lesions according to their first MRI; 19% had 1-2 lesions, and 40% had 3 or more. At follow-up, 50% were cognitively normal (failed no tests), 25% had mild cognitive impairment (failed one or more tests), and 25% had severe cognitive impairment (failed three or more tests).

In the overall cohort, the median number of cortical lesions at baseline was 1 (interquartile range, 5.0). Among the 50% with normal cognitive function, the median was 0 (IQR, 2.5), while for the remaining 50% with cognitive impairment, the median was 3 (IQR, 7.0).

Those with 3 or more lesions had increased odds of cognitive impairment at follow-up (odds ratio, 3.70; P < .001), with an accuracy of 65% (95% confidence interval, 58%-72%), specificity of 75% (95% CI, 65%-84%), and a sensitivity of 55% (95% CI, 44%-66%). Three or more lesions discriminated between cognitive impairment and no impairment with an area under the curve of 0.67.

Individuals with no cognitive impairment had a median 0 lesions (IQR, 2.5), those with mild cognitive impairment had a median of 2.0 (IQR, 6.0), and those with severe cognitive impairment had 4.0 (IQR, 7.25).

In a multinomial regression model, 3 or more baseline cortical lesions were associated with a greater than threefold risk of severe cognitive impairment (OR, 3.33; P = .01).

Of subjects with 0 baseline lesions, 62% were cognitively normal at follow-up. In the 1-2 lesion group, 64% were normal. In the 3 or more group, 31% were cognitively normal (P < .001). In the 0 lesion group, 26% had mild cognitive impairment and 12% had severe cognitive impairment. In the 3 or more group, 28% had mild cognitive impairment, and 41% had severe cognitive impairment.

During the Q&A session following the talk, Dr. Ziccardi was asked if the group compared cortical lesions to other MRI correlates of cognitive impairment, such as gray matter volume or white matter integrity. He responded that the group is looking into those comparisons, and recently found that neither the number nor the volume of white matter lesions improved the accuracy of the predictive models based on the number of cortical lesions. The group is also looking into the applicability of gray matter volume.

The number of cortical lesions at baseline may indicate a patient’s risk of developing secondary progressive multiple sclerosis (MS), according to new research. Cortical lesions also may be an early marker of future disability accumulation.

In the study, patients who had developed secondary progressive MS after 20 years of follow-up had approximately 7 cortical lesions at baseline. This number was significantly higher than the baseline number of cortical lesions in patients with clinically isolated syndrome (CIS), relapsing-remitting MS, or primary progressive MS at 20 years.

“Our study represented a clear indication that the assessment, presence, and high number of cortical lesions at diagnosis is one of the tools at the disposal of the neurologist for the early identification of patients with more serious disease course,” said Gian Marco Schiavi, MD, a neurology resident at the University of Verona, Italy, during the presentation of his research.

The study was presented October 14 at the annual meeting of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS).
 

Accumulation of disability

Previous research has indicated that cortical lesions play a role in the accumulation of disability in MS and the conversion to secondary progressive MS. Other observations suggest that the number of cortical lesions after 30 years of follow-up explains more than 40% of the difference in disability between patients with secondary progressive MS.

The current investigators sought to understand whether cortical lesions at diagnosis could predict a patient’s risk for development of secondary progressive MS and risk for disability accumulation. They included 220 patients with MS and approximately 20 years of follow-up in their study.

At the time of diagnosis, all participants underwent 1.5-T MRI with double inversion recovery. Participants also presented for periodic MRI and clinical evaluations.

The researchers used analysis of variance to compare the baseline number of cortical lesions between patients with CIS, relapsing-remitting MS, secondary progressive MS, and primary progressive MS at 20 years. They also performed a multivariable regression analysis to predict patients’ final scores on the Expanded Disability Status Scale (EDSS). Variables included participants’ demographic, clinical, and radiological characteristics.
 

Lesions and disease progression

At baseline (the time of diagnosis), 162 patients had relapsing-remitting MS, 45 had CIS, and 12 had primary progressive MS. In all, 106 patients had no cortical lesions, 47 had 3 or fewer cortical lesions, and 67 had more than 3 cortical lesions.

At 20 years, 12 patients still had CIS, 152 had relapsing-remitting MS, and 44 had developed secondary progressive MS.

The mean number of cortical lesions at diagnosis was 6.6 in patients with secondary progressive MS at 20 years, which was significantly higher than the mean 1.3 cortical lesions in the other patients (P < .001).

In addition, post-hoc analysis showed that the median number of cortical lesions was significantly higher in patients with secondary progressive MS (6), compared with those with CIS (0; P < .001), relapsing-remitting MS (0; P < .001), and primary progressive MS (4.5; P = .013). Patients with primary progressive MS had a higher number of cortical lesions than patients with CIS and those with relapsing-remitting MS (P = .001).

The investigators also examined disability at 20 years. At that timepoint, mean EDSS score was 1.5 in patients with no cortical lesions, 3.0 in patients with 1 to 3 cortical lesions at baseline, and 6.0 in patients with more than 3 cortical lesions.

In a regression analysis, the number of cortical lesions and EDSS at diagnosis were the best predictors of long-term disability (P < .001). These factors explained about 57% of the variance in EDSS score after 20 years.
 

‘Important study’

“This important study supports that the presence of cortical lesions at the time of diagnosis is associated with long-term disability and transition to a secondary progressive disease course,” said Elias S. Sotirchos, MD, assistant professor of neurology at Johns Hopkins University, Baltimore. The study size and long duration of follow-up are important strengths of the findings, he added.

Still, further research is needed to validate cortical lesions as a biomarker in clinical practice. Aside from technical validation issues relating to the identification of cortical lesions, whether cortical lesion burden can be used to guide therapeutic decision-making in MS is not clear, said Dr. Sotirchos.

“Notably, these patients were diagnosed and enrolled in this study 20 years ago, prior to the availability of newer disease-modifying therapies [DMTs] that are more effective at preventing inflammatory disease activity in MS,” he said, referring to the participants in the current study.

While recent observational studies have suggested that early initiation of higher-efficacy disease-modifying therapies (DMTs) may reduce long-term disability and risk for transition to secondary progressive MS, the optimal approach to treatment in patients with a new diagnosis remains unclear, said Dr. Sotirchos.

Furthermore, it is unknown whether use of higher-efficacy DMTs may affect the risk of future disability in patients with high cortical lesion burden at baseline, said Dr. Sotirchos. “Or is it too late, especially considering the modest effects of DMTs in progressive patients and that cortical lesion burden was higher in patients that are progressive?”

One additional question to be addressed is how baseline cortical lesion burden adds to other factors that neurologists use in clinical practice to stratify patients’ risk of future disability, such as spinal cord involvement, motor or sphincter symptoms at onset, poor recovery from attacks, and white matter lesion burden, said Dr. Sotirchos.

The source of funding for this study was not reported. Dr. Schiavi and Dr. Sotirchos have disclosed no relevant financial relationships.

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

The number of cortical lesions at baseline may indicate a patient’s risk of developing secondary progressive multiple sclerosis (MS), according to new research. Cortical lesions also may be an early marker of future disability accumulation.

In the study, patients who had developed secondary progressive MS after 20 years of follow-up had approximately 7 cortical lesions at baseline. This number was significantly higher than the baseline number of cortical lesions in patients with clinically isolated syndrome (CIS), relapsing-remitting MS, or primary progressive MS at 20 years.

“Our study represented a clear indication that the assessment, presence, and high number of cortical lesions at diagnosis is one of the tools at the disposal of the neurologist for the early identification of patients with more serious disease course,” said Gian Marco Schiavi, MD, a neurology resident at the University of Verona, Italy, during the presentation of his research.

The study was presented October 14 at the annual meeting of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS).
 

Accumulation of disability

Previous research has indicated that cortical lesions play a role in the accumulation of disability in MS and the conversion to secondary progressive MS. Other observations suggest that the number of cortical lesions after 30 years of follow-up explains more than 40% of the difference in disability between patients with secondary progressive MS.

The current investigators sought to understand whether cortical lesions at diagnosis could predict a patient’s risk for development of secondary progressive MS and risk for disability accumulation. They included 220 patients with MS and approximately 20 years of follow-up in their study.

At the time of diagnosis, all participants underwent 1.5-T MRI with double inversion recovery. Participants also presented for periodic MRI and clinical evaluations.

The researchers used analysis of variance to compare the baseline number of cortical lesions between patients with CIS, relapsing-remitting MS, secondary progressive MS, and primary progressive MS at 20 years. They also performed a multivariable regression analysis to predict patients’ final scores on the Expanded Disability Status Scale (EDSS). Variables included participants’ demographic, clinical, and radiological characteristics.
 

Lesions and disease progression

At baseline (the time of diagnosis), 162 patients had relapsing-remitting MS, 45 had CIS, and 12 had primary progressive MS. In all, 106 patients had no cortical lesions, 47 had 3 or fewer cortical lesions, and 67 had more than 3 cortical lesions.

At 20 years, 12 patients still had CIS, 152 had relapsing-remitting MS, and 44 had developed secondary progressive MS.

The mean number of cortical lesions at diagnosis was 6.6 in patients with secondary progressive MS at 20 years, which was significantly higher than the mean 1.3 cortical lesions in the other patients (P < .001).

In addition, post-hoc analysis showed that the median number of cortical lesions was significantly higher in patients with secondary progressive MS (6), compared with those with CIS (0; P < .001), relapsing-remitting MS (0; P < .001), and primary progressive MS (4.5; P = .013). Patients with primary progressive MS had a higher number of cortical lesions than patients with CIS and those with relapsing-remitting MS (P = .001).

The investigators also examined disability at 20 years. At that timepoint, mean EDSS score was 1.5 in patients with no cortical lesions, 3.0 in patients with 1 to 3 cortical lesions at baseline, and 6.0 in patients with more than 3 cortical lesions.

In a regression analysis, the number of cortical lesions and EDSS at diagnosis were the best predictors of long-term disability (P < .001). These factors explained about 57% of the variance in EDSS score after 20 years.
 

‘Important study’

“This important study supports that the presence of cortical lesions at the time of diagnosis is associated with long-term disability and transition to a secondary progressive disease course,” said Elias S. Sotirchos, MD, assistant professor of neurology at Johns Hopkins University, Baltimore. The study size and long duration of follow-up are important strengths of the findings, he added.

Still, further research is needed to validate cortical lesions as a biomarker in clinical practice. Aside from technical validation issues relating to the identification of cortical lesions, whether cortical lesion burden can be used to guide therapeutic decision-making in MS is not clear, said Dr. Sotirchos.

“Notably, these patients were diagnosed and enrolled in this study 20 years ago, prior to the availability of newer disease-modifying therapies [DMTs] that are more effective at preventing inflammatory disease activity in MS,” he said, referring to the participants in the current study.

While recent observational studies have suggested that early initiation of higher-efficacy disease-modifying therapies (DMTs) may reduce long-term disability and risk for transition to secondary progressive MS, the optimal approach to treatment in patients with a new diagnosis remains unclear, said Dr. Sotirchos.

Furthermore, it is unknown whether use of higher-efficacy DMTs may affect the risk of future disability in patients with high cortical lesion burden at baseline, said Dr. Sotirchos. “Or is it too late, especially considering the modest effects of DMTs in progressive patients and that cortical lesion burden was higher in patients that are progressive?”

One additional question to be addressed is how baseline cortical lesion burden adds to other factors that neurologists use in clinical practice to stratify patients’ risk of future disability, such as spinal cord involvement, motor or sphincter symptoms at onset, poor recovery from attacks, and white matter lesion burden, said Dr. Sotirchos.

The source of funding for this study was not reported. Dr. Schiavi and Dr. Sotirchos have disclosed no relevant financial relationships.

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

The number of cortical lesions at baseline may indicate a patient’s risk of developing secondary progressive multiple sclerosis (MS), according to new research. Cortical lesions also may be an early marker of future disability accumulation.

In the study, patients who had developed secondary progressive MS after 20 years of follow-up had approximately 7 cortical lesions at baseline. This number was significantly higher than the baseline number of cortical lesions in patients with clinically isolated syndrome (CIS), relapsing-remitting MS, or primary progressive MS at 20 years.

“Our study represented a clear indication that the assessment, presence, and high number of cortical lesions at diagnosis is one of the tools at the disposal of the neurologist for the early identification of patients with more serious disease course,” said Gian Marco Schiavi, MD, a neurology resident at the University of Verona, Italy, during the presentation of his research.

The study was presented October 14 at the annual meeting of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS).
 

Accumulation of disability

Previous research has indicated that cortical lesions play a role in the accumulation of disability in MS and the conversion to secondary progressive MS. Other observations suggest that the number of cortical lesions after 30 years of follow-up explains more than 40% of the difference in disability between patients with secondary progressive MS.

The current investigators sought to understand whether cortical lesions at diagnosis could predict a patient’s risk for development of secondary progressive MS and risk for disability accumulation. They included 220 patients with MS and approximately 20 years of follow-up in their study.

At the time of diagnosis, all participants underwent 1.5-T MRI with double inversion recovery. Participants also presented for periodic MRI and clinical evaluations.

The researchers used analysis of variance to compare the baseline number of cortical lesions between patients with CIS, relapsing-remitting MS, secondary progressive MS, and primary progressive MS at 20 years. They also performed a multivariable regression analysis to predict patients’ final scores on the Expanded Disability Status Scale (EDSS). Variables included participants’ demographic, clinical, and radiological characteristics.
 

Lesions and disease progression

At baseline (the time of diagnosis), 162 patients had relapsing-remitting MS, 45 had CIS, and 12 had primary progressive MS. In all, 106 patients had no cortical lesions, 47 had 3 or fewer cortical lesions, and 67 had more than 3 cortical lesions.

At 20 years, 12 patients still had CIS, 152 had relapsing-remitting MS, and 44 had developed secondary progressive MS.

The mean number of cortical lesions at diagnosis was 6.6 in patients with secondary progressive MS at 20 years, which was significantly higher than the mean 1.3 cortical lesions in the other patients (P < .001).

In addition, post-hoc analysis showed that the median number of cortical lesions was significantly higher in patients with secondary progressive MS (6), compared with those with CIS (0; P < .001), relapsing-remitting MS (0; P < .001), and primary progressive MS (4.5; P = .013). Patients with primary progressive MS had a higher number of cortical lesions than patients with CIS and those with relapsing-remitting MS (P = .001).

The investigators also examined disability at 20 years. At that timepoint, mean EDSS score was 1.5 in patients with no cortical lesions, 3.0 in patients with 1 to 3 cortical lesions at baseline, and 6.0 in patients with more than 3 cortical lesions.

In a regression analysis, the number of cortical lesions and EDSS at diagnosis were the best predictors of long-term disability (P < .001). These factors explained about 57% of the variance in EDSS score after 20 years.
 

‘Important study’

“This important study supports that the presence of cortical lesions at the time of diagnosis is associated with long-term disability and transition to a secondary progressive disease course,” said Elias S. Sotirchos, MD, assistant professor of neurology at Johns Hopkins University, Baltimore. The study size and long duration of follow-up are important strengths of the findings, he added.

Still, further research is needed to validate cortical lesions as a biomarker in clinical practice. Aside from technical validation issues relating to the identification of cortical lesions, whether cortical lesion burden can be used to guide therapeutic decision-making in MS is not clear, said Dr. Sotirchos.

“Notably, these patients were diagnosed and enrolled in this study 20 years ago, prior to the availability of newer disease-modifying therapies [DMTs] that are more effective at preventing inflammatory disease activity in MS,” he said, referring to the participants in the current study.

While recent observational studies have suggested that early initiation of higher-efficacy disease-modifying therapies (DMTs) may reduce long-term disability and risk for transition to secondary progressive MS, the optimal approach to treatment in patients with a new diagnosis remains unclear, said Dr. Sotirchos.

Furthermore, it is unknown whether use of higher-efficacy DMTs may affect the risk of future disability in patients with high cortical lesion burden at baseline, said Dr. Sotirchos. “Or is it too late, especially considering the modest effects of DMTs in progressive patients and that cortical lesion burden was higher in patients that are progressive?”

One additional question to be addressed is how baseline cortical lesion burden adds to other factors that neurologists use in clinical practice to stratify patients’ risk of future disability, such as spinal cord involvement, motor or sphincter symptoms at onset, poor recovery from attacks, and white matter lesion burden, said Dr. Sotirchos.

The source of funding for this study was not reported. Dr. Schiavi and Dr. Sotirchos have disclosed no relevant financial relationships.

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