MILAN – Dazodalibep, an intravenously administered inhibitor of CD40 ligand, shows promise in reducing disease activity and alleviating key subjective symptoms of Sjögren’s syndrome, compared with placebo. These preliminary findings are from the initial phase of the ALISS trial, a phase 2 randomized, double-blind, placebo-controlled, crossover clinical trial presented at the annul European Congress of Rheumatology.

Over the course of the 169-day trial, both the disease activity score and the patient-reported symptom score dropped significantly for patients who were treated with dazodalibep, also known as VIB4920 or HZN4920, compared with those treated with placebo, meeting both primary endpoints. This benefit was particularly evident for patients who had limited systemic organ involvement but substantial symptom burden.

Dazodalibep is a fusion protein that functions as an inhibitor by blocking the interaction between T cells and CD40-expressing B cells. This inhibition effectively suppresses costimulatory signaling between immune cells. Unlike previous CD40-targeting biologics, dazodalibep does not belong to the antibody class. According to Horizon Thereapeutics, this distinction is expected to help mitigate safety concerns, particularly those related to blood clot formation that were encountered with antibody-based biologics such as ruplizumab, according to Horizon, which acquired the trial’s sponsor, Viela Bio.
 

Patients with moderate to high systemic disease activity

The trial investigated dazodalibep in two patient populations. Wan-Fai Ng, MBBCh, PhD, professor of rheumatology at Newcastle University and honorary consultant rheumatologist at Newcastle upon Tyne Hospitals NHS Foundation Trust, England, presented results from the first group, which comprised 74 adult patients with Sjögren’s syndrome with moderate to high systemic disease activity. Disease activity was defined as a score of ≥ 5 on the EULAR Sjögren’s Syndrome Disease Activity Index (ESSDAI).

A post hoc responder analysis demonstrated that dazodalibep outperformed placebo in patients who achieved a 5- or 6-point improvement on the ESSDAI. Response rates for these patients was 61.1% and 60.0%, respectively, compared with 35.1% and 34.3% for patients who received placebo. Patients who received dazodalibep experienced a reduction of –6.3 ± 0.6 points in ESSDAI score, whereas the placebo group experienced a reduction of –4.1 ± 0.6 points, a difference of –2.2 (P = .0167). However, there was no significant change in any symptom-related score in this population.
 

Patients with unacceptable symptom burden but limited systemic involvement

Also at EULAR 2023, Chiara Baldini, MD, of the University of Pisa, Italy, reported the results from the second group of 109 adult patients with Sjögren’s syndrome who had notable symptom burden but limited systemic organ involvement. “These patients represent a significant portion of individuals with reduced quality of life who are largely excluded from other clinical trials,” Dr. Baldini said in an interview. The study population was defined by having a EULAR Sjögren’s Syndrome Patient Reported Index (ESSPRI) ≥ 5 and, in contrast to the previous group, an ESSDAI score < 5.

In this case, treatment with dazodalibep correlated with a substantial reduction in symptom burden, compared with placebo. Among the patients who received dazodalibep, 66.7% achieved ≥ 1 point or ≥ 15% reduction in symptoms, as measured by ESSPRI, compared with 32.7% in the placebo group. The ESSPRI score decreased by –1.80 ± 0.23 points in the dazodalibep group, while it decreased by –0.53 ± 0.23 points in the placebo group, a difference of −1.27 ± 0.33 points favoring dazodalibep (P = .0002). The reduction in symptoms in the dazodalibep group was evident from the first data point on day 29 and was statistically significant for each of the three symptom components included in the ESSPRI score: dryness, pain, and fatigue.

Additionally, a significant improvement was observed in one of the secondary endpoints, namely, a reduction in the Functional Assessment of Chronic Illness Therapy-Fatigue score. The dazodalibep group exhibited a considerably greater reduction (+8.1 ± 1.4, compared with baseline) than did the placebo group (+2.8 ± 1.4; P = .0095).
 

Dazodalibep safety

“Dazodalibep therapy was generally safe and well tolerated,” Dr. Baldini said in her presentation. Adverse events that were reported for both investigations were generally mild and occurred with similar frequency between the treatment groups. The most commonly reported adverse events, each occurring in more than 5% of patients who received dazodalibep, were COVID-19, diarrhea, anemia, dizziness, ligament sprain, upper respiratory tract infection, and nasopharyngitis. The incidence of COVID-19 and nasopharyngitis was comparable between the treatment and placebo arms.

However, in the patient group with moderate to high systemic disease activity, one patient who was treated with dazodalibep experienced two serious adverse events: a grade 3 SARS-CoV-2 infection, and subsequent death from an unknown cause, which occurred 46 days after the last administration of dazodalibep (12 days after COVID-19 diagnosis). Additionally, there was one case of herpes zoster in a patient treated with dazodalibep. In the group with limited systemic organ involvement, three serious adverse events were reported in the dazodalibep group (pneumonia influenza, postacute COVID-19 syndrome [long COVID], and gammopathy); one serious adverse event (neutropenia) was reported in the placebo group. One patient in the dazodalibep group discontinued participation in the study because of an adverse event, compared with two in the placebo group. Investigators determined that, thus far, all serious adverse events in both populations have been unrelated to the medication.

Throughout the trial, eligible participants in both populations were randomly assigned in a 1:1 ratio to receive either intravenous dazodalibep 1,500 mg or placebo every 2 weeks for three doses, followed by every 4 weeks for an additional four doses, up to day 169. The majority of participants in all populations and treatment arms were women (> 90%). Key inclusion criteria were being aged 18 years or older, meeting the 2016 American College of Rheumatology–EULAR classification criteria for Sjögren’s syndrome, and testing positive for anti-SSA and/or rheumatoid factors. Exclusion criteria were having a medical history of thrombosis or anticoagulant use, as well as prior treatment with B cell–depleting therapies. The proportions of patients who received glucocorticoids, antimalarials, or disease-modifying antirheumatic drugs were consistent between both arms of each population.

“Larger clinical trials are necessary to validate the clinical effectiveness and safety of dazodalibep therapy in this specific subgroup of patients,” Dr. Baldini concluded. Currently, dazodalibep is being studied for the treatment of rheumatoid arthritis and renal transplant rejection, and Horizon Therapeutics has plans to explore its use in focal segmental glomerulosclerosis.

Dr. Ng has served as a consultant to Novartis, GlaxoSmithKline, AbbVie, Bristol-Myers Squibb, Sanofi, MedImmune, Resolves Therapeutics, Janssen, and UCB. Dr. Baldini has served as a consultant to GlaxoSmithKline and Sanofi.

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

MILAN – Dazodalibep, an intravenously administered inhibitor of CD40 ligand, shows promise in reducing disease activity and alleviating key subjective symptoms of Sjögren’s syndrome, compared with placebo. These preliminary findings are from the initial phase of the ALISS trial, a phase 2 randomized, double-blind, placebo-controlled, crossover clinical trial presented at the annul European Congress of Rheumatology.

Over the course of the 169-day trial, both the disease activity score and the patient-reported symptom score dropped significantly for patients who were treated with dazodalibep, also known as VIB4920 or HZN4920, compared with those treated with placebo, meeting both primary endpoints. This benefit was particularly evident for patients who had limited systemic organ involvement but substantial symptom burden.

Dazodalibep is a fusion protein that functions as an inhibitor by blocking the interaction between T cells and CD40-expressing B cells. This inhibition effectively suppresses costimulatory signaling between immune cells. Unlike previous CD40-targeting biologics, dazodalibep does not belong to the antibody class. According to Horizon Thereapeutics, this distinction is expected to help mitigate safety concerns, particularly those related to blood clot formation that were encountered with antibody-based biologics such as ruplizumab, according to Horizon, which acquired the trial’s sponsor, Viela Bio.
 

Patients with moderate to high systemic disease activity

The trial investigated dazodalibep in two patient populations. Wan-Fai Ng, MBBCh, PhD, professor of rheumatology at Newcastle University and honorary consultant rheumatologist at Newcastle upon Tyne Hospitals NHS Foundation Trust, England, presented results from the first group, which comprised 74 adult patients with Sjögren’s syndrome with moderate to high systemic disease activity. Disease activity was defined as a score of ≥ 5 on the EULAR Sjögren’s Syndrome Disease Activity Index (ESSDAI).

A post hoc responder analysis demonstrated that dazodalibep outperformed placebo in patients who achieved a 5- or 6-point improvement on the ESSDAI. Response rates for these patients was 61.1% and 60.0%, respectively, compared with 35.1% and 34.3% for patients who received placebo. Patients who received dazodalibep experienced a reduction of –6.3 ± 0.6 points in ESSDAI score, whereas the placebo group experienced a reduction of –4.1 ± 0.6 points, a difference of –2.2 (P = .0167). However, there was no significant change in any symptom-related score in this population.
 

Patients with unacceptable symptom burden but limited systemic involvement

Also at EULAR 2023, Chiara Baldini, MD, of the University of Pisa, Italy, reported the results from the second group of 109 adult patients with Sjögren’s syndrome who had notable symptom burden but limited systemic organ involvement. “These patients represent a significant portion of individuals with reduced quality of life who are largely excluded from other clinical trials,” Dr. Baldini said in an interview. The study population was defined by having a EULAR Sjögren’s Syndrome Patient Reported Index (ESSPRI) ≥ 5 and, in contrast to the previous group, an ESSDAI score < 5.

In this case, treatment with dazodalibep correlated with a substantial reduction in symptom burden, compared with placebo. Among the patients who received dazodalibep, 66.7% achieved ≥ 1 point or ≥ 15% reduction in symptoms, as measured by ESSPRI, compared with 32.7% in the placebo group. The ESSPRI score decreased by –1.80 ± 0.23 points in the dazodalibep group, while it decreased by –0.53 ± 0.23 points in the placebo group, a difference of −1.27 ± 0.33 points favoring dazodalibep (P = .0002). The reduction in symptoms in the dazodalibep group was evident from the first data point on day 29 and was statistically significant for each of the three symptom components included in the ESSPRI score: dryness, pain, and fatigue.

Additionally, a significant improvement was observed in one of the secondary endpoints, namely, a reduction in the Functional Assessment of Chronic Illness Therapy-Fatigue score. The dazodalibep group exhibited a considerably greater reduction (+8.1 ± 1.4, compared with baseline) than did the placebo group (+2.8 ± 1.4; P = .0095).
 

Dazodalibep safety

“Dazodalibep therapy was generally safe and well tolerated,” Dr. Baldini said in her presentation. Adverse events that were reported for both investigations were generally mild and occurred with similar frequency between the treatment groups. The most commonly reported adverse events, each occurring in more than 5% of patients who received dazodalibep, were COVID-19, diarrhea, anemia, dizziness, ligament sprain, upper respiratory tract infection, and nasopharyngitis. The incidence of COVID-19 and nasopharyngitis was comparable between the treatment and placebo arms.

However, in the patient group with moderate to high systemic disease activity, one patient who was treated with dazodalibep experienced two serious adverse events: a grade 3 SARS-CoV-2 infection, and subsequent death from an unknown cause, which occurred 46 days after the last administration of dazodalibep (12 days after COVID-19 diagnosis). Additionally, there was one case of herpes zoster in a patient treated with dazodalibep. In the group with limited systemic organ involvement, three serious adverse events were reported in the dazodalibep group (pneumonia influenza, postacute COVID-19 syndrome [long COVID], and gammopathy); one serious adverse event (neutropenia) was reported in the placebo group. One patient in the dazodalibep group discontinued participation in the study because of an adverse event, compared with two in the placebo group. Investigators determined that, thus far, all serious adverse events in both populations have been unrelated to the medication.

Throughout the trial, eligible participants in both populations were randomly assigned in a 1:1 ratio to receive either intravenous dazodalibep 1,500 mg or placebo every 2 weeks for three doses, followed by every 4 weeks for an additional four doses, up to day 169. The majority of participants in all populations and treatment arms were women (> 90%). Key inclusion criteria were being aged 18 years or older, meeting the 2016 American College of Rheumatology–EULAR classification criteria for Sjögren’s syndrome, and testing positive for anti-SSA and/or rheumatoid factors. Exclusion criteria were having a medical history of thrombosis or anticoagulant use, as well as prior treatment with B cell–depleting therapies. The proportions of patients who received glucocorticoids, antimalarials, or disease-modifying antirheumatic drugs were consistent between both arms of each population.

“Larger clinical trials are necessary to validate the clinical effectiveness and safety of dazodalibep therapy in this specific subgroup of patients,” Dr. Baldini concluded. Currently, dazodalibep is being studied for the treatment of rheumatoid arthritis and renal transplant rejection, and Horizon Therapeutics has plans to explore its use in focal segmental glomerulosclerosis.

Dr. Ng has served as a consultant to Novartis, GlaxoSmithKline, AbbVie, Bristol-Myers Squibb, Sanofi, MedImmune, Resolves Therapeutics, Janssen, and UCB. Dr. Baldini has served as a consultant to GlaxoSmithKline and Sanofi.

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

MILAN – Dazodalibep, an intravenously administered inhibitor of CD40 ligand, shows promise in reducing disease activity and alleviating key subjective symptoms of Sjögren’s syndrome, compared with placebo. These preliminary findings are from the initial phase of the ALISS trial, a phase 2 randomized, double-blind, placebo-controlled, crossover clinical trial presented at the annul European Congress of Rheumatology.

Over the course of the 169-day trial, both the disease activity score and the patient-reported symptom score dropped significantly for patients who were treated with dazodalibep, also known as VIB4920 or HZN4920, compared with those treated with placebo, meeting both primary endpoints. This benefit was particularly evident for patients who had limited systemic organ involvement but substantial symptom burden.

Dazodalibep is a fusion protein that functions as an inhibitor by blocking the interaction between T cells and CD40-expressing B cells. This inhibition effectively suppresses costimulatory signaling between immune cells. Unlike previous CD40-targeting biologics, dazodalibep does not belong to the antibody class. According to Horizon Thereapeutics, this distinction is expected to help mitigate safety concerns, particularly those related to blood clot formation that were encountered with antibody-based biologics such as ruplizumab, according to Horizon, which acquired the trial’s sponsor, Viela Bio.
 

Patients with moderate to high systemic disease activity

The trial investigated dazodalibep in two patient populations. Wan-Fai Ng, MBBCh, PhD, professor of rheumatology at Newcastle University and honorary consultant rheumatologist at Newcastle upon Tyne Hospitals NHS Foundation Trust, England, presented results from the first group, which comprised 74 adult patients with Sjögren’s syndrome with moderate to high systemic disease activity. Disease activity was defined as a score of ≥ 5 on the EULAR Sjögren’s Syndrome Disease Activity Index (ESSDAI).

A post hoc responder analysis demonstrated that dazodalibep outperformed placebo in patients who achieved a 5- or 6-point improvement on the ESSDAI. Response rates for these patients was 61.1% and 60.0%, respectively, compared with 35.1% and 34.3% for patients who received placebo. Patients who received dazodalibep experienced a reduction of –6.3 ± 0.6 points in ESSDAI score, whereas the placebo group experienced a reduction of –4.1 ± 0.6 points, a difference of –2.2 (P = .0167). However, there was no significant change in any symptom-related score in this population.
 

Patients with unacceptable symptom burden but limited systemic involvement

Also at EULAR 2023, Chiara Baldini, MD, of the University of Pisa, Italy, reported the results from the second group of 109 adult patients with Sjögren’s syndrome who had notable symptom burden but limited systemic organ involvement. “These patients represent a significant portion of individuals with reduced quality of life who are largely excluded from other clinical trials,” Dr. Baldini said in an interview. The study population was defined by having a EULAR Sjögren’s Syndrome Patient Reported Index (ESSPRI) ≥ 5 and, in contrast to the previous group, an ESSDAI score < 5.

In this case, treatment with dazodalibep correlated with a substantial reduction in symptom burden, compared with placebo. Among the patients who received dazodalibep, 66.7% achieved ≥ 1 point or ≥ 15% reduction in symptoms, as measured by ESSPRI, compared with 32.7% in the placebo group. The ESSPRI score decreased by –1.80 ± 0.23 points in the dazodalibep group, while it decreased by –0.53 ± 0.23 points in the placebo group, a difference of −1.27 ± 0.33 points favoring dazodalibep (P = .0002). The reduction in symptoms in the dazodalibep group was evident from the first data point on day 29 and was statistically significant for each of the three symptom components included in the ESSPRI score: dryness, pain, and fatigue.

Additionally, a significant improvement was observed in one of the secondary endpoints, namely, a reduction in the Functional Assessment of Chronic Illness Therapy-Fatigue score. The dazodalibep group exhibited a considerably greater reduction (+8.1 ± 1.4, compared with baseline) than did the placebo group (+2.8 ± 1.4; P = .0095).
 

Dazodalibep safety

“Dazodalibep therapy was generally safe and well tolerated,” Dr. Baldini said in her presentation. Adverse events that were reported for both investigations were generally mild and occurred with similar frequency between the treatment groups. The most commonly reported adverse events, each occurring in more than 5% of patients who received dazodalibep, were COVID-19, diarrhea, anemia, dizziness, ligament sprain, upper respiratory tract infection, and nasopharyngitis. The incidence of COVID-19 and nasopharyngitis was comparable between the treatment and placebo arms.

However, in the patient group with moderate to high systemic disease activity, one patient who was treated with dazodalibep experienced two serious adverse events: a grade 3 SARS-CoV-2 infection, and subsequent death from an unknown cause, which occurred 46 days after the last administration of dazodalibep (12 days after COVID-19 diagnosis). Additionally, there was one case of herpes zoster in a patient treated with dazodalibep. In the group with limited systemic organ involvement, three serious adverse events were reported in the dazodalibep group (pneumonia influenza, postacute COVID-19 syndrome [long COVID], and gammopathy); one serious adverse event (neutropenia) was reported in the placebo group. One patient in the dazodalibep group discontinued participation in the study because of an adverse event, compared with two in the placebo group. Investigators determined that, thus far, all serious adverse events in both populations have been unrelated to the medication.

Throughout the trial, eligible participants in both populations were randomly assigned in a 1:1 ratio to receive either intravenous dazodalibep 1,500 mg or placebo every 2 weeks for three doses, followed by every 4 weeks for an additional four doses, up to day 169. The majority of participants in all populations and treatment arms were women (> 90%). Key inclusion criteria were being aged 18 years or older, meeting the 2016 American College of Rheumatology–EULAR classification criteria for Sjögren’s syndrome, and testing positive for anti-SSA and/or rheumatoid factors. Exclusion criteria were having a medical history of thrombosis or anticoagulant use, as well as prior treatment with B cell–depleting therapies. The proportions of patients who received glucocorticoids, antimalarials, or disease-modifying antirheumatic drugs were consistent between both arms of each population.

“Larger clinical trials are necessary to validate the clinical effectiveness and safety of dazodalibep therapy in this specific subgroup of patients,” Dr. Baldini concluded. Currently, dazodalibep is being studied for the treatment of rheumatoid arthritis and renal transplant rejection, and Horizon Therapeutics has plans to explore its use in focal segmental glomerulosclerosis.

Dr. Ng has served as a consultant to Novartis, GlaxoSmithKline, AbbVie, Bristol-Myers Squibb, Sanofi, MedImmune, Resolves Therapeutics, Janssen, and UCB. Dr. Baldini has served as a consultant to GlaxoSmithKline and Sanofi.

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

The introduction of tumor necrosis factor (TNF) inhibitors in the late 1990s revolutionized treatment of rheumatic diseases, such as rheumatoid arthritis (RA) and psoriatic arthritis (PsA), providing patients with another treatment option when conventional therapies were ineffective. However, when these diseases don’t respond to anti-TNF therapy, it is still difficult to determine the next best course of action.

“One of the big challenges we have in treatment of psoriatic arthritis, and I would say rheumatoid arthritis was well, is how to handle patients who have failed their first biologic therapy,” Christopher T. Ritchlin, MD, MPH, professor of allergy, immunology, and rheumatology at the University of Rochester (N.Y.), told this news organization. “In the case of both RA and PsA, that’s quite frequently an anti-TNF agent.”

For an estimated 30% to 40% of patients, TNF inhibitor therapy is discontinued because of nonresponse or intolerance. Clinicians can switch to another biologic or targeted synthetic disease-modifying antirheumatic drug (DMARD) or add another conventional DMARD, such as methotrexate. Now, several case studies as well as promising findings from phase 2 clinical trials suggest that combining two biologics could be an alternative strategy to improve patient response to treatment. However, concerns about safety and higher costs remain.
 

Targeting multiple mechanisms of action

Rheumatic conditions affect multiple areas of the body and involve different signaling pathways, said Dr. Ritchlin, who heads the Clinical Immunology Research Unit at the University of Rochester. PsA, for example, affects the skin, peripheral joints, the axial skeleton, and the entheses.

“The question is, Are these various manifestations – of which multiple [ones] are often seen in one patient – likely to respond to one therapy that targets one single pathway?” he said.

Combination therapies have been effective in treating leukemia and lymphoma as well as infection with HIV, Melek Yalçin Mutlu, MD, and colleagues from Friedrich Alexander University Erlangen-Nuremberg and the University Clinic Erlangen (Germany), wrote in a review about combining biologic DMARDs in the treatment of RA and PsA. The review was published in Joint Bone Spine.

“Cumulative evidence on the success of combination therapies in various diseases supports an akin approach in rheumatology, and simultaneous or sequential blockade of multiple mechanisms that generate or propagate arthritis could theoretically enhance efficacy,” the authors wrote. “On the other hand, intervening on multiple targets in the immune system brings about a risk of adverse events, among which infection is a major concern.”
 

Failed clinical trials

Clinical trials of combination biologic therapies for rheumatic disease have been tried before, but these combinations did not show superior efficacy, and they increased patients’ risk for infection. One study published in 2004 compared monotherapy with the TNF inhibitor etanercept (Enbrel) to the combination of etanercept and anakinra (Kineret), an interleukin-1 (IL-1) antagonist, in 244 patients with active RA despite methotrexate therapy. Researchers found no statistically significant difference in achieving 20% improvement in modified American College of Rheumatology response criteria (ACR20), ACR50, or ACR70 between the groups that received etanercept and anakinra and those that received etanercept alone. There were nine serious infections among patients given etanercept and anakinra, including one death due to pneumonia. There were no serious infections in the etanercept monotherapy group.

In another RA trial, 121 patients were given etanercept 25 mg twice weekly and were randomly assigned to also receive a placebo or low-dose abatacept (Orencia), a T-cell co-stimulation inhibitor. There was no significant difference in disease improvement between the two groups, although the rate of serious adverse events was nearly six times higher in the etanercept-abatacept group (16.5% vs. 2.8%).

These studies had a “chilling effect on the whole field for some years,” Brian G. Feagan, MD, the senior scientific director of the gastrointestinal contract research firm Alimentiv in London, Ontario, told this news organization. People were reluctant to try new biologic combinations, owing to the fear that these safety issues would plague subsequent trials.

University of Western Ontario, London

Promising combinations

But a recent phase 2 trial, led by Dr. Feagan, suggests that certain combinations can be effective. In the Janssen-sponsored VEGA trial, researchers found that a combination of guselkumab (Tremfya), an IL-23 inhibitor, and golimumab (Simponi), an anti-TNF agent, was more effective than either drug used as monotherapy for initial induction treatment for moderate to severe ulcerative colitis. Importantly, there was no difference in adverse events between any of the groups. This same combination therapy is now being tried for patients with active PsA in Janssen’s AFFINITY trial, for which Dr. Ritchlin is one of the lead investigators.

Other trials have also delivered promising results. One study enrolled 51 adults with active RA who were all receiving stable doses of both a TNF inhibitor – either etanercept or adalimumab (Humira) – and methotrexate. Patients were randomly assigned to receive one course of rituximab (Rituxan) or placebo. The researchers found that the safety profile of this TNF inhibitor/methotrexate/rituximab combination was “consistent” with the safety profiles of previous studies of methotrexate/rituximab dual combinations with no TNF inhibitor; there were no new safety signals. At 24 weeks, 30% of the group that received rituximab reached ACR20, compared with 17% of the group that was given placebo. Twelve percent of the rituximab group achieved ACR50, compared with 6% of the group that received placebo.

“B-cell depletion is fundamentally different from cytokine inhibition and even from co-stimulation blockade, making an additive effect more likely,” Dr. Mutlu and colleagues wrote in their review. Reports have also suggested possible benefits of combining a TNF inhibitor and an IL-17 inhibitor in the treatment of RA and PsA, as well as the combination of a TNF inhibitor and an IL-23 antagonist for PsA.

While these combinations require controlled clinical trials, “there’s some smoke signals out there that this might be an effective strategy for some patients,” Dr. Ritchlin said.

In addition to the AFFINITY trial, two clinical trials are underway in France. The first, CRI-RA, is evaluating the combination of baricitinib (Olumiant), a Janus kinase (JAK) inhibitor, and adalimumab. Although baricitinib is not a biologic, as a targeted synthetic DMARD, the therapy is more potent than conventional DMARDs, and the same potential safety concerns apply. However, use of a combination of tofacitinib (Xeljanz) and different biologics for RA patients has been reported; no serious side effects were reported over 11 months of therapy. The randomized, placebo-controlled trial began in July 2021 and will enroll 178 patients. The estimated study completion date is July 2025.

“Of note, baricitinib does not directly block signaling downstream of TNF, even if an indirect effect on TNF production is likely to occur,” the CRI-RA entry on clinicaltrials.gov reads. “Targeting multiple inflammatory cytokines in combination may lead to more effective treatment and enhanced clinical responses in patients with RA compared to the current second-line strategies.”

The second trial, SEQUENS-RA, is evaluating the use of TNF inhibitors followed by abatacept for patients with RA who test positive for anticitrullinated protein autoantibodies (ACPAs). In the past, the combination of a TNF inhibitor and abatacept did not lead to promising results, but in this trial, the drugs will be administered sequentially.

“Although abatacept has shown a very good tolerance profile that might be superior to other bDMARDs [biologic DMARDs], rheumatologists might be reluctant to use it as a first line bDMARD as there is a belief of a slower efficacy compared to other bDMARDs or JAK inhibitors,” according to the clinical trial’s description. “Investigators have hypothesized that first rapidly controlling the inflammation phase, using TNF inhibitors, followed by abatacept to induce an immunological remission, would optimize response and tolerance of ACPA-positive patients with RA.”

The randomized trial of 220 participants began in November 2022. The estimated completion date for the study is November 2025.
 

Finding the right patients

Though these studies have had some promising results, the difference in efficacy between biologic monotherapy and dual therapy has been mostly moderate, Dr. Mutlu and coauthors wrote. Identifying disease subtypes for which there might be a higher likelihood of response to dual biologic treatment, especially multidrug-resistant types, could improve efficacies in future trials, they argued. “The good effects of bDMARD combinations in resistant patients in fact point into this direction, though they were observed in uncontrolled studies,” the authors noted.

Insurance coverage remains a “huge challenge” for these dual therapies because of the higher expense, noted Dr. Ritchlin. Better targeting therapies could help convince these companies to pay for these therapies.

“I would say that if we were able to demonstrate a phenotype of a patient that would respond to biologics and not monotherapies, [then] many companies would be amenable to this kind of approach,” he said.

Dr. Ritchlin reports financial relationships with AbbVie, Bristol-Myers Squibb, Janssen, Pfizer, Eli Lilly, Novartis, and UCB. Dr. Feagan reports financial relationships with AbbVie, Amgen, Janssen, Pfizer, Takeda, and several other pharmaceutical companies.

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

The introduction of tumor necrosis factor (TNF) inhibitors in the late 1990s revolutionized treatment of rheumatic diseases, such as rheumatoid arthritis (RA) and psoriatic arthritis (PsA), providing patients with another treatment option when conventional therapies were ineffective. However, when these diseases don’t respond to anti-TNF therapy, it is still difficult to determine the next best course of action.

“One of the big challenges we have in treatment of psoriatic arthritis, and I would say rheumatoid arthritis was well, is how to handle patients who have failed their first biologic therapy,” Christopher T. Ritchlin, MD, MPH, professor of allergy, immunology, and rheumatology at the University of Rochester (N.Y.), told this news organization. “In the case of both RA and PsA, that’s quite frequently an anti-TNF agent.”

For an estimated 30% to 40% of patients, TNF inhibitor therapy is discontinued because of nonresponse or intolerance. Clinicians can switch to another biologic or targeted synthetic disease-modifying antirheumatic drug (DMARD) or add another conventional DMARD, such as methotrexate. Now, several case studies as well as promising findings from phase 2 clinical trials suggest that combining two biologics could be an alternative strategy to improve patient response to treatment. However, concerns about safety and higher costs remain.
 

Targeting multiple mechanisms of action

Rheumatic conditions affect multiple areas of the body and involve different signaling pathways, said Dr. Ritchlin, who heads the Clinical Immunology Research Unit at the University of Rochester. PsA, for example, affects the skin, peripheral joints, the axial skeleton, and the entheses.

“The question is, Are these various manifestations – of which multiple [ones] are often seen in one patient – likely to respond to one therapy that targets one single pathway?” he said.

Combination therapies have been effective in treating leukemia and lymphoma as well as infection with HIV, Melek Yalçin Mutlu, MD, and colleagues from Friedrich Alexander University Erlangen-Nuremberg and the University Clinic Erlangen (Germany), wrote in a review about combining biologic DMARDs in the treatment of RA and PsA. The review was published in Joint Bone Spine.

“Cumulative evidence on the success of combination therapies in various diseases supports an akin approach in rheumatology, and simultaneous or sequential blockade of multiple mechanisms that generate or propagate arthritis could theoretically enhance efficacy,” the authors wrote. “On the other hand, intervening on multiple targets in the immune system brings about a risk of adverse events, among which infection is a major concern.”
 

Failed clinical trials

Clinical trials of combination biologic therapies for rheumatic disease have been tried before, but these combinations did not show superior efficacy, and they increased patients’ risk for infection. One study published in 2004 compared monotherapy with the TNF inhibitor etanercept (Enbrel) to the combination of etanercept and anakinra (Kineret), an interleukin-1 (IL-1) antagonist, in 244 patients with active RA despite methotrexate therapy. Researchers found no statistically significant difference in achieving 20% improvement in modified American College of Rheumatology response criteria (ACR20), ACR50, or ACR70 between the groups that received etanercept and anakinra and those that received etanercept alone. There were nine serious infections among patients given etanercept and anakinra, including one death due to pneumonia. There were no serious infections in the etanercept monotherapy group.

In another RA trial, 121 patients were given etanercept 25 mg twice weekly and were randomly assigned to also receive a placebo or low-dose abatacept (Orencia), a T-cell co-stimulation inhibitor. There was no significant difference in disease improvement between the two groups, although the rate of serious adverse events was nearly six times higher in the etanercept-abatacept group (16.5% vs. 2.8%).

These studies had a “chilling effect on the whole field for some years,” Brian G. Feagan, MD, the senior scientific director of the gastrointestinal contract research firm Alimentiv in London, Ontario, told this news organization. People were reluctant to try new biologic combinations, owing to the fear that these safety issues would plague subsequent trials.

University of Western Ontario, London

Promising combinations

But a recent phase 2 trial, led by Dr. Feagan, suggests that certain combinations can be effective. In the Janssen-sponsored VEGA trial, researchers found that a combination of guselkumab (Tremfya), an IL-23 inhibitor, and golimumab (Simponi), an anti-TNF agent, was more effective than either drug used as monotherapy for initial induction treatment for moderate to severe ulcerative colitis. Importantly, there was no difference in adverse events between any of the groups. This same combination therapy is now being tried for patients with active PsA in Janssen’s AFFINITY trial, for which Dr. Ritchlin is one of the lead investigators.

Other trials have also delivered promising results. One study enrolled 51 adults with active RA who were all receiving stable doses of both a TNF inhibitor – either etanercept or adalimumab (Humira) – and methotrexate. Patients were randomly assigned to receive one course of rituximab (Rituxan) or placebo. The researchers found that the safety profile of this TNF inhibitor/methotrexate/rituximab combination was “consistent” with the safety profiles of previous studies of methotrexate/rituximab dual combinations with no TNF inhibitor; there were no new safety signals. At 24 weeks, 30% of the group that received rituximab reached ACR20, compared with 17% of the group that was given placebo. Twelve percent of the rituximab group achieved ACR50, compared with 6% of the group that received placebo.

“B-cell depletion is fundamentally different from cytokine inhibition and even from co-stimulation blockade, making an additive effect more likely,” Dr. Mutlu and colleagues wrote in their review. Reports have also suggested possible benefits of combining a TNF inhibitor and an IL-17 inhibitor in the treatment of RA and PsA, as well as the combination of a TNF inhibitor and an IL-23 antagonist for PsA.

While these combinations require controlled clinical trials, “there’s some smoke signals out there that this might be an effective strategy for some patients,” Dr. Ritchlin said.

In addition to the AFFINITY trial, two clinical trials are underway in France. The first, CRI-RA, is evaluating the combination of baricitinib (Olumiant), a Janus kinase (JAK) inhibitor, and adalimumab. Although baricitinib is not a biologic, as a targeted synthetic DMARD, the therapy is more potent than conventional DMARDs, and the same potential safety concerns apply. However, use of a combination of tofacitinib (Xeljanz) and different biologics for RA patients has been reported; no serious side effects were reported over 11 months of therapy. The randomized, placebo-controlled trial began in July 2021 and will enroll 178 patients. The estimated study completion date is July 2025.

“Of note, baricitinib does not directly block signaling downstream of TNF, even if an indirect effect on TNF production is likely to occur,” the CRI-RA entry on clinicaltrials.gov reads. “Targeting multiple inflammatory cytokines in combination may lead to more effective treatment and enhanced clinical responses in patients with RA compared to the current second-line strategies.”

The second trial, SEQUENS-RA, is evaluating the use of TNF inhibitors followed by abatacept for patients with RA who test positive for anticitrullinated protein autoantibodies (ACPAs). In the past, the combination of a TNF inhibitor and abatacept did not lead to promising results, but in this trial, the drugs will be administered sequentially.

“Although abatacept has shown a very good tolerance profile that might be superior to other bDMARDs [biologic DMARDs], rheumatologists might be reluctant to use it as a first line bDMARD as there is a belief of a slower efficacy compared to other bDMARDs or JAK inhibitors,” according to the clinical trial’s description. “Investigators have hypothesized that first rapidly controlling the inflammation phase, using TNF inhibitors, followed by abatacept to induce an immunological remission, would optimize response and tolerance of ACPA-positive patients with RA.”

The randomized trial of 220 participants began in November 2022. The estimated completion date for the study is November 2025.
 

Finding the right patients

Though these studies have had some promising results, the difference in efficacy between biologic monotherapy and dual therapy has been mostly moderate, Dr. Mutlu and coauthors wrote. Identifying disease subtypes for which there might be a higher likelihood of response to dual biologic treatment, especially multidrug-resistant types, could improve efficacies in future trials, they argued. “The good effects of bDMARD combinations in resistant patients in fact point into this direction, though they were observed in uncontrolled studies,” the authors noted.

Insurance coverage remains a “huge challenge” for these dual therapies because of the higher expense, noted Dr. Ritchlin. Better targeting therapies could help convince these companies to pay for these therapies.

“I would say that if we were able to demonstrate a phenotype of a patient that would respond to biologics and not monotherapies, [then] many companies would be amenable to this kind of approach,” he said.

Dr. Ritchlin reports financial relationships with AbbVie, Bristol-Myers Squibb, Janssen, Pfizer, Eli Lilly, Novartis, and UCB. Dr. Feagan reports financial relationships with AbbVie, Amgen, Janssen, Pfizer, Takeda, and several other pharmaceutical companies.

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

The introduction of tumor necrosis factor (TNF) inhibitors in the late 1990s revolutionized treatment of rheumatic diseases, such as rheumatoid arthritis (RA) and psoriatic arthritis (PsA), providing patients with another treatment option when conventional therapies were ineffective. However, when these diseases don’t respond to anti-TNF therapy, it is still difficult to determine the next best course of action.

“One of the big challenges we have in treatment of psoriatic arthritis, and I would say rheumatoid arthritis was well, is how to handle patients who have failed their first biologic therapy,” Christopher T. Ritchlin, MD, MPH, professor of allergy, immunology, and rheumatology at the University of Rochester (N.Y.), told this news organization. “In the case of both RA and PsA, that’s quite frequently an anti-TNF agent.”

For an estimated 30% to 40% of patients, TNF inhibitor therapy is discontinued because of nonresponse or intolerance. Clinicians can switch to another biologic or targeted synthetic disease-modifying antirheumatic drug (DMARD) or add another conventional DMARD, such as methotrexate. Now, several case studies as well as promising findings from phase 2 clinical trials suggest that combining two biologics could be an alternative strategy to improve patient response to treatment. However, concerns about safety and higher costs remain.
 

Targeting multiple mechanisms of action

Rheumatic conditions affect multiple areas of the body and involve different signaling pathways, said Dr. Ritchlin, who heads the Clinical Immunology Research Unit at the University of Rochester. PsA, for example, affects the skin, peripheral joints, the axial skeleton, and the entheses.

“The question is, Are these various manifestations – of which multiple [ones] are often seen in one patient – likely to respond to one therapy that targets one single pathway?” he said.

Combination therapies have been effective in treating leukemia and lymphoma as well as infection with HIV, Melek Yalçin Mutlu, MD, and colleagues from Friedrich Alexander University Erlangen-Nuremberg and the University Clinic Erlangen (Germany), wrote in a review about combining biologic DMARDs in the treatment of RA and PsA. The review was published in Joint Bone Spine.

“Cumulative evidence on the success of combination therapies in various diseases supports an akin approach in rheumatology, and simultaneous or sequential blockade of multiple mechanisms that generate or propagate arthritis could theoretically enhance efficacy,” the authors wrote. “On the other hand, intervening on multiple targets in the immune system brings about a risk of adverse events, among which infection is a major concern.”
 

Failed clinical trials

Clinical trials of combination biologic therapies for rheumatic disease have been tried before, but these combinations did not show superior efficacy, and they increased patients’ risk for infection. One study published in 2004 compared monotherapy with the TNF inhibitor etanercept (Enbrel) to the combination of etanercept and anakinra (Kineret), an interleukin-1 (IL-1) antagonist, in 244 patients with active RA despite methotrexate therapy. Researchers found no statistically significant difference in achieving 20% improvement in modified American College of Rheumatology response criteria (ACR20), ACR50, or ACR70 between the groups that received etanercept and anakinra and those that received etanercept alone. There were nine serious infections among patients given etanercept and anakinra, including one death due to pneumonia. There were no serious infections in the etanercept monotherapy group.

In another RA trial, 121 patients were given etanercept 25 mg twice weekly and were randomly assigned to also receive a placebo or low-dose abatacept (Orencia), a T-cell co-stimulation inhibitor. There was no significant difference in disease improvement between the two groups, although the rate of serious adverse events was nearly six times higher in the etanercept-abatacept group (16.5% vs. 2.8%).

These studies had a “chilling effect on the whole field for some years,” Brian G. Feagan, MD, the senior scientific director of the gastrointestinal contract research firm Alimentiv in London, Ontario, told this news organization. People were reluctant to try new biologic combinations, owing to the fear that these safety issues would plague subsequent trials.

University of Western Ontario, London

Promising combinations

But a recent phase 2 trial, led by Dr. Feagan, suggests that certain combinations can be effective. In the Janssen-sponsored VEGA trial, researchers found that a combination of guselkumab (Tremfya), an IL-23 inhibitor, and golimumab (Simponi), an anti-TNF agent, was more effective than either drug used as monotherapy for initial induction treatment for moderate to severe ulcerative colitis. Importantly, there was no difference in adverse events between any of the groups. This same combination therapy is now being tried for patients with active PsA in Janssen’s AFFINITY trial, for which Dr. Ritchlin is one of the lead investigators.

Other trials have also delivered promising results. One study enrolled 51 adults with active RA who were all receiving stable doses of both a TNF inhibitor – either etanercept or adalimumab (Humira) – and methotrexate. Patients were randomly assigned to receive one course of rituximab (Rituxan) or placebo. The researchers found that the safety profile of this TNF inhibitor/methotrexate/rituximab combination was “consistent” with the safety profiles of previous studies of methotrexate/rituximab dual combinations with no TNF inhibitor; there were no new safety signals. At 24 weeks, 30% of the group that received rituximab reached ACR20, compared with 17% of the group that was given placebo. Twelve percent of the rituximab group achieved ACR50, compared with 6% of the group that received placebo.

“B-cell depletion is fundamentally different from cytokine inhibition and even from co-stimulation blockade, making an additive effect more likely,” Dr. Mutlu and colleagues wrote in their review. Reports have also suggested possible benefits of combining a TNF inhibitor and an IL-17 inhibitor in the treatment of RA and PsA, as well as the combination of a TNF inhibitor and an IL-23 antagonist for PsA.

While these combinations require controlled clinical trials, “there’s some smoke signals out there that this might be an effective strategy for some patients,” Dr. Ritchlin said.

In addition to the AFFINITY trial, two clinical trials are underway in France. The first, CRI-RA, is evaluating the combination of baricitinib (Olumiant), a Janus kinase (JAK) inhibitor, and adalimumab. Although baricitinib is not a biologic, as a targeted synthetic DMARD, the therapy is more potent than conventional DMARDs, and the same potential safety concerns apply. However, use of a combination of tofacitinib (Xeljanz) and different biologics for RA patients has been reported; no serious side effects were reported over 11 months of therapy. The randomized, placebo-controlled trial began in July 2021 and will enroll 178 patients. The estimated study completion date is July 2025.

“Of note, baricitinib does not directly block signaling downstream of TNF, even if an indirect effect on TNF production is likely to occur,” the CRI-RA entry on clinicaltrials.gov reads. “Targeting multiple inflammatory cytokines in combination may lead to more effective treatment and enhanced clinical responses in patients with RA compared to the current second-line strategies.”

The second trial, SEQUENS-RA, is evaluating the use of TNF inhibitors followed by abatacept for patients with RA who test positive for anticitrullinated protein autoantibodies (ACPAs). In the past, the combination of a TNF inhibitor and abatacept did not lead to promising results, but in this trial, the drugs will be administered sequentially.

“Although abatacept has shown a very good tolerance profile that might be superior to other bDMARDs [biologic DMARDs], rheumatologists might be reluctant to use it as a first line bDMARD as there is a belief of a slower efficacy compared to other bDMARDs or JAK inhibitors,” according to the clinical trial’s description. “Investigators have hypothesized that first rapidly controlling the inflammation phase, using TNF inhibitors, followed by abatacept to induce an immunological remission, would optimize response and tolerance of ACPA-positive patients with RA.”

The randomized trial of 220 participants began in November 2022. The estimated completion date for the study is November 2025.
 

Finding the right patients

Though these studies have had some promising results, the difference in efficacy between biologic monotherapy and dual therapy has been mostly moderate, Dr. Mutlu and coauthors wrote. Identifying disease subtypes for which there might be a higher likelihood of response to dual biologic treatment, especially multidrug-resistant types, could improve efficacies in future trials, they argued. “The good effects of bDMARD combinations in resistant patients in fact point into this direction, though they were observed in uncontrolled studies,” the authors noted.

Insurance coverage remains a “huge challenge” for these dual therapies because of the higher expense, noted Dr. Ritchlin. Better targeting therapies could help convince these companies to pay for these therapies.

“I would say that if we were able to demonstrate a phenotype of a patient that would respond to biologics and not monotherapies, [then] many companies would be amenable to this kind of approach,” he said.

Dr. Ritchlin reports financial relationships with AbbVie, Bristol-Myers Squibb, Janssen, Pfizer, Eli Lilly, Novartis, and UCB. Dr. Feagan reports financial relationships with AbbVie, Amgen, Janssen, Pfizer, Takeda, and several other pharmaceutical companies.

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

Pulmonary Vascular & Cardiovascular Network

Pulmonary Vascular Disease Section

The recently published STELLAR trial was a phase 3, multicenter, double-blind, randomized, placebo-controlled study designed to evaluate patients with PAH receiving stable vasodilator therapy after treatment with sotatercept, a first-in-class recombinant fusion protein with parts of the activin receptor type IIA, a member of the BMPR2/TGF-beta superfamily of receptors and ligands (Hoeper. N Engl J Med. 2023;388:1478).

Sotatercept improved 6-minute walk distance, the primary endpoint of the trial at 24-weeks, as well as eight of the trial’s nine secondary endpoints including changes in PVR, NT-ProBNP levels, functional class, French risk score, and time-to-clinical worsening when compared with placebo. However, many questions remain about the mechanisms whereby sotatercept achieved its clinical endpoints, the answers to which may lie within its basic molecular biology.

The focus on BMPR2/TGF-beta cell signaling pathways originated from the identification of loss-of-function mutations in the BMPR2 gene in patients with heritable and idiopathic PAH (Morrell, NW. Eur Respir J. 2019;53[3]: 1900078). An imbalance in BMPR2/TGF-beta signaling (low BMPR2/high TGF-beta function) has been proposed as a central mechanism in the development of PAH. Specifically, researchers have shown increased levels of Activin A, one of 33 ligands that can bind either BMPR2 or TGF-beta receptors, within vascular lesions in the lungs of patients with PAH. It has been thus hypothesized that reducing the amount of circulating Activin A could treat PAH by rebalancing BMPR2/TGF-beta signaling in lung vascular cells. In preclinical experimental models of PAH with elevated Activin A levels, sotatercept has been shown to reduce distal small vessel medial thickness/muscularization and increase the number of patent small vessels (Yung, LM. Sci Transl Med. 2020;12).

The exact mechanism by which sotatercept improves hemodynamics and outcomes remains unclear. Indeed, whether de-remodeling of the lung vasculature or new vessel formation occurs in humans is unknown. The results from STELLAR mark a new era in the development of potential “disease-modifying agents” for PAH; however, the question is: what exactly are we modifying?

Jose Gomez-Arroyo, MD, PhD – Section Fellow-in-Training
Dana Kay, DO – Section Member-at-Large

Pulmonary Vascular & Cardiovascular Network

Pulmonary Vascular Disease Section

The recently published STELLAR trial was a phase 3, multicenter, double-blind, randomized, placebo-controlled study designed to evaluate patients with PAH receiving stable vasodilator therapy after treatment with sotatercept, a first-in-class recombinant fusion protein with parts of the activin receptor type IIA, a member of the BMPR2/TGF-beta superfamily of receptors and ligands (Hoeper. N Engl J Med. 2023;388:1478).

Sotatercept improved 6-minute walk distance, the primary endpoint of the trial at 24-weeks, as well as eight of the trial’s nine secondary endpoints including changes in PVR, NT-ProBNP levels, functional class, French risk score, and time-to-clinical worsening when compared with placebo. However, many questions remain about the mechanisms whereby sotatercept achieved its clinical endpoints, the answers to which may lie within its basic molecular biology.

The focus on BMPR2/TGF-beta cell signaling pathways originated from the identification of loss-of-function mutations in the BMPR2 gene in patients with heritable and idiopathic PAH (Morrell, NW. Eur Respir J. 2019;53[3]: 1900078). An imbalance in BMPR2/TGF-beta signaling (low BMPR2/high TGF-beta function) has been proposed as a central mechanism in the development of PAH. Specifically, researchers have shown increased levels of Activin A, one of 33 ligands that can bind either BMPR2 or TGF-beta receptors, within vascular lesions in the lungs of patients with PAH. It has been thus hypothesized that reducing the amount of circulating Activin A could treat PAH by rebalancing BMPR2/TGF-beta signaling in lung vascular cells. In preclinical experimental models of PAH with elevated Activin A levels, sotatercept has been shown to reduce distal small vessel medial thickness/muscularization and increase the number of patent small vessels (Yung, LM. Sci Transl Med. 2020;12).

The exact mechanism by which sotatercept improves hemodynamics and outcomes remains unclear. Indeed, whether de-remodeling of the lung vasculature or new vessel formation occurs in humans is unknown. The results from STELLAR mark a new era in the development of potential “disease-modifying agents” for PAH; however, the question is: what exactly are we modifying?

Jose Gomez-Arroyo, MD, PhD – Section Fellow-in-Training
Dana Kay, DO – Section Member-at-Large

Pulmonary Vascular & Cardiovascular Network

Pulmonary Vascular Disease Section

The recently published STELLAR trial was a phase 3, multicenter, double-blind, randomized, placebo-controlled study designed to evaluate patients with PAH receiving stable vasodilator therapy after treatment with sotatercept, a first-in-class recombinant fusion protein with parts of the activin receptor type IIA, a member of the BMPR2/TGF-beta superfamily of receptors and ligands (Hoeper. N Engl J Med. 2023;388:1478).

Sotatercept improved 6-minute walk distance, the primary endpoint of the trial at 24-weeks, as well as eight of the trial’s nine secondary endpoints including changes in PVR, NT-ProBNP levels, functional class, French risk score, and time-to-clinical worsening when compared with placebo. However, many questions remain about the mechanisms whereby sotatercept achieved its clinical endpoints, the answers to which may lie within its basic molecular biology.

The focus on BMPR2/TGF-beta cell signaling pathways originated from the identification of loss-of-function mutations in the BMPR2 gene in patients with heritable and idiopathic PAH (Morrell, NW. Eur Respir J. 2019;53[3]: 1900078). An imbalance in BMPR2/TGF-beta signaling (low BMPR2/high TGF-beta function) has been proposed as a central mechanism in the development of PAH. Specifically, researchers have shown increased levels of Activin A, one of 33 ligands that can bind either BMPR2 or TGF-beta receptors, within vascular lesions in the lungs of patients with PAH. It has been thus hypothesized that reducing the amount of circulating Activin A could treat PAH by rebalancing BMPR2/TGF-beta signaling in lung vascular cells. In preclinical experimental models of PAH with elevated Activin A levels, sotatercept has been shown to reduce distal small vessel medial thickness/muscularization and increase the number of patent small vessels (Yung, LM. Sci Transl Med. 2020;12).

The exact mechanism by which sotatercept improves hemodynamics and outcomes remains unclear. Indeed, whether de-remodeling of the lung vasculature or new vessel formation occurs in humans is unknown. The results from STELLAR mark a new era in the development of potential “disease-modifying agents” for PAH; however, the question is: what exactly are we modifying?

Jose Gomez-Arroyo, MD, PhD – Section Fellow-in-Training
Dana Kay, DO – Section Member-at-Large

CHEST INFECTIONS & DISASTER RESPONSE NETWORK

Chest Infections Section

Respiratory syncytial virus (RSV) is an underappreciated cause of hospital admission in adult patients, especially among those who have underlying cardiopulmonary comorbidities (Branche AR, et al. Clin Infect Dis. 2022;74[6]:1004). A meta-analysis estimated an annual incidence rate of 37.6 per 1000 persons per year with a hospital case fatality rate of 11.7% (5.8%-23.4%) in industrialized countries (Shi T, et al. J Infect Dis. 2022;226 [suppl 1]).

Recent work showed RSV to be quite pathogenic in adults (Begley KM, et al. Clin Infect Dis. 2023:ciad031). In 10,311 hospitalized adults with an acute respiratory illness, 6% tested positive for RSV and 18.8% for influenza virus. Compared with influenza virus, patients infected with RSV were more likely to have COPD or CHF and had longer admission and more requirements for mechanical ventilation.

There have been new advances in the prevention of RSV-associated illness. Nirsevimab, an IgG1 monoclonal antibody that locks the RSV F protein in prefusion stage, had an efficacy of 74.5% in preventing RSV-associated lower respiratory tract infection (LRTI) in infants up to 150 days, which is an improvement over palivizumab (Bergeron HC, et al. Expert Opin Investig Drugs. 2022;31 [No. 1]: 23). The FDA advisory committee just approved two RSV vaccines, both of which target prefusion F protein, for elderly adults. The RSVPreF3OA had 82.6% efficacy against LRTI in adults over 60 years of age (Papi A, et al. N Engl J Med. 2023;388:595) and Ad26.RSV.preF-RSV preF protein vaccine had 80% efficacy in adults over 65 years of age (Falsey AR, et al. N Engl J Med. 2023;388:609).

Shekhar Ghamande, MD, MBBS, FCCP – Section Member-at-Large

Paige Marty, MD – Section Fellow-in-Training

CHEST INFECTIONS & DISASTER RESPONSE NETWORK

Chest Infections Section

Respiratory syncytial virus (RSV) is an underappreciated cause of hospital admission in adult patients, especially among those who have underlying cardiopulmonary comorbidities (Branche AR, et al. Clin Infect Dis. 2022;74[6]:1004). A meta-analysis estimated an annual incidence rate of 37.6 per 1000 persons per year with a hospital case fatality rate of 11.7% (5.8%-23.4%) in industrialized countries (Shi T, et al. J Infect Dis. 2022;226 [suppl 1]).

Recent work showed RSV to be quite pathogenic in adults (Begley KM, et al. Clin Infect Dis. 2023:ciad031). In 10,311 hospitalized adults with an acute respiratory illness, 6% tested positive for RSV and 18.8% for influenza virus. Compared with influenza virus, patients infected with RSV were more likely to have COPD or CHF and had longer admission and more requirements for mechanical ventilation.

There have been new advances in the prevention of RSV-associated illness. Nirsevimab, an IgG1 monoclonal antibody that locks the RSV F protein in prefusion stage, had an efficacy of 74.5% in preventing RSV-associated lower respiratory tract infection (LRTI) in infants up to 150 days, which is an improvement over palivizumab (Bergeron HC, et al. Expert Opin Investig Drugs. 2022;31 [No. 1]: 23). The FDA advisory committee just approved two RSV vaccines, both of which target prefusion F protein, for elderly adults. The RSVPreF3OA had 82.6% efficacy against LRTI in adults over 60 years of age (Papi A, et al. N Engl J Med. 2023;388:595) and Ad26.RSV.preF-RSV preF protein vaccine had 80% efficacy in adults over 65 years of age (Falsey AR, et al. N Engl J Med. 2023;388:609).

Shekhar Ghamande, MD, MBBS, FCCP – Section Member-at-Large

Paige Marty, MD – Section Fellow-in-Training

CHEST INFECTIONS & DISASTER RESPONSE NETWORK

Chest Infections Section

Respiratory syncytial virus (RSV) is an underappreciated cause of hospital admission in adult patients, especially among those who have underlying cardiopulmonary comorbidities (Branche AR, et al. Clin Infect Dis. 2022;74[6]:1004). A meta-analysis estimated an annual incidence rate of 37.6 per 1000 persons per year with a hospital case fatality rate of 11.7% (5.8%-23.4%) in industrialized countries (Shi T, et al. J Infect Dis. 2022;226 [suppl 1]).

Recent work showed RSV to be quite pathogenic in adults (Begley KM, et al. Clin Infect Dis. 2023:ciad031). In 10,311 hospitalized adults with an acute respiratory illness, 6% tested positive for RSV and 18.8% for influenza virus. Compared with influenza virus, patients infected with RSV were more likely to have COPD or CHF and had longer admission and more requirements for mechanical ventilation.

There have been new advances in the prevention of RSV-associated illness. Nirsevimab, an IgG1 monoclonal antibody that locks the RSV F protein in prefusion stage, had an efficacy of 74.5% in preventing RSV-associated lower respiratory tract infection (LRTI) in infants up to 150 days, which is an improvement over palivizumab (Bergeron HC, et al. Expert Opin Investig Drugs. 2022;31 [No. 1]: 23). The FDA advisory committee just approved two RSV vaccines, both of which target prefusion F protein, for elderly adults. The RSVPreF3OA had 82.6% efficacy against LRTI in adults over 60 years of age (Papi A, et al. N Engl J Med. 2023;388:595) and Ad26.RSV.preF-RSV preF protein vaccine had 80% efficacy in adults over 65 years of age (Falsey AR, et al. N Engl J Med. 2023;388:609).

Shekhar Ghamande, MD, MBBS, FCCP – Section Member-at-Large

Paige Marty, MD – Section Fellow-in-Training

A new guideline from the World Health Organization on nonsugar sweeteners (NSSs) recommends not using them to control weight or reduce the risk for diabetes, heart disease, or cancer. These sweeteners include aspartame, acesulfame K, advantame, saccharine, sucralose, stevia, and stevia derivatives.

The recommendation is based on the findings of a systematic review that collected data from 283 studies in adults, children, pregnant women, and mixed populations.

The findings suggest that use of NSSs does not confer any long-term benefit in reducing body fat in adults or children. They also suggest that long-term use of NSSs may have potential undesirable effects.

To clarify, short-term NSS use results in a small reduction in body weight and body mass index in adults without significant effects on other measures of adiposity or cardiometabolic health, including fasting glucose, insulin, blood lipids, and blood pressure.

Conversely, on a long-term basis, results from prospective cohort studies suggest that higher NSS intake is associated with increased risk for type 2 diabetes, cardiovascular diseases, and all-cause mortality in adults (very low– to low-certainty evidence). 

Regarding the risk for cancer, results from case-control studies suggest an association between saccharine intake and bladder cancer (very low certainty evidence), but significant associations for other types of cancer were not observed in case-control studies or meta-analysis of prospective cohort studies.

Relatively fewer studies were found for children, and results were largely inconclusive.

Finally, results for pregnant women suggest that higher NSS intake is associated with increased risk for preterm birth (low-certainty evidence) and possibly adiposity in offspring (very low–certainty evidence).
 

Reducing sugar consumption

“Replacing free sugars with NSS does not help with weight control in the long-term. People need to consider other ways to reduce free sugars intake, such as consuming food with naturally occurring sugars, like fruit, or unsweetened food and beverages,” Francesco Branca, MD, PhD, WHO director of the department of nutrition and food safety, said in a press release. 

“NSSs are not essential dietary factors and have no nutritional value. People should reduce the sweetness of the diet altogether, starting early in life, to improve their health,” he added.
 

Applying the guideline

The recommendation applies to all people except individuals with preexisting diabetes and includes all synthetic and naturally occurring or modified nonnutritive sweeteners, said the WHO. 

The recommendation does not apply to personal care and hygiene products containing NSSs, such as toothpaste, skin cream, and medications, or to low-calorie sugars and sugar alcohols (polyols).

Because the link observed in the evidence between NSSs and disease outcomes might be confounded by the baseline characteristics of study participants and complicated patterns of NSS use, the recommendation has been assessed as “conditional” by the WHO. 

“This signals that policy decisions based on this recommendation may require substantive discussion in specific country contexts, linked for example to the extent of consumption in different age groups,” said the WHO press release. 

This article was translated from the Medscape French Edition . A version of the article appeared on Medscape.com.

A new guideline from the World Health Organization on nonsugar sweeteners (NSSs) recommends not using them to control weight or reduce the risk for diabetes, heart disease, or cancer. These sweeteners include aspartame, acesulfame K, advantame, saccharine, sucralose, stevia, and stevia derivatives.

The recommendation is based on the findings of a systematic review that collected data from 283 studies in adults, children, pregnant women, and mixed populations.

The findings suggest that use of NSSs does not confer any long-term benefit in reducing body fat in adults or children. They also suggest that long-term use of NSSs may have potential undesirable effects.

To clarify, short-term NSS use results in a small reduction in body weight and body mass index in adults without significant effects on other measures of adiposity or cardiometabolic health, including fasting glucose, insulin, blood lipids, and blood pressure.

Conversely, on a long-term basis, results from prospective cohort studies suggest that higher NSS intake is associated with increased risk for type 2 diabetes, cardiovascular diseases, and all-cause mortality in adults (very low– to low-certainty evidence). 

Regarding the risk for cancer, results from case-control studies suggest an association between saccharine intake and bladder cancer (very low certainty evidence), but significant associations for other types of cancer were not observed in case-control studies or meta-analysis of prospective cohort studies.

Relatively fewer studies were found for children, and results were largely inconclusive.

Finally, results for pregnant women suggest that higher NSS intake is associated with increased risk for preterm birth (low-certainty evidence) and possibly adiposity in offspring (very low–certainty evidence).
 

Reducing sugar consumption

“Replacing free sugars with NSS does not help with weight control in the long-term. People need to consider other ways to reduce free sugars intake, such as consuming food with naturally occurring sugars, like fruit, or unsweetened food and beverages,” Francesco Branca, MD, PhD, WHO director of the department of nutrition and food safety, said in a press release. 

“NSSs are not essential dietary factors and have no nutritional value. People should reduce the sweetness of the diet altogether, starting early in life, to improve their health,” he added.
 

Applying the guideline

The recommendation applies to all people except individuals with preexisting diabetes and includes all synthetic and naturally occurring or modified nonnutritive sweeteners, said the WHO. 

The recommendation does not apply to personal care and hygiene products containing NSSs, such as toothpaste, skin cream, and medications, or to low-calorie sugars and sugar alcohols (polyols).

Because the link observed in the evidence between NSSs and disease outcomes might be confounded by the baseline characteristics of study participants and complicated patterns of NSS use, the recommendation has been assessed as “conditional” by the WHO. 

“This signals that policy decisions based on this recommendation may require substantive discussion in specific country contexts, linked for example to the extent of consumption in different age groups,” said the WHO press release. 

This article was translated from the Medscape French Edition . A version of the article appeared on Medscape.com.

A new guideline from the World Health Organization on nonsugar sweeteners (NSSs) recommends not using them to control weight or reduce the risk for diabetes, heart disease, or cancer. These sweeteners include aspartame, acesulfame K, advantame, saccharine, sucralose, stevia, and stevia derivatives.

The recommendation is based on the findings of a systematic review that collected data from 283 studies in adults, children, pregnant women, and mixed populations.

The findings suggest that use of NSSs does not confer any long-term benefit in reducing body fat in adults or children. They also suggest that long-term use of NSSs may have potential undesirable effects.

To clarify, short-term NSS use results in a small reduction in body weight and body mass index in adults without significant effects on other measures of adiposity or cardiometabolic health, including fasting glucose, insulin, blood lipids, and blood pressure.

Conversely, on a long-term basis, results from prospective cohort studies suggest that higher NSS intake is associated with increased risk for type 2 diabetes, cardiovascular diseases, and all-cause mortality in adults (very low– to low-certainty evidence). 

Regarding the risk for cancer, results from case-control studies suggest an association between saccharine intake and bladder cancer (very low certainty evidence), but significant associations for other types of cancer were not observed in case-control studies or meta-analysis of prospective cohort studies.

Relatively fewer studies were found for children, and results were largely inconclusive.

Finally, results for pregnant women suggest that higher NSS intake is associated with increased risk for preterm birth (low-certainty evidence) and possibly adiposity in offspring (very low–certainty evidence).
 

Reducing sugar consumption

“Replacing free sugars with NSS does not help with weight control in the long-term. People need to consider other ways to reduce free sugars intake, such as consuming food with naturally occurring sugars, like fruit, or unsweetened food and beverages,” Francesco Branca, MD, PhD, WHO director of the department of nutrition and food safety, said in a press release. 

“NSSs are not essential dietary factors and have no nutritional value. People should reduce the sweetness of the diet altogether, starting early in life, to improve their health,” he added.
 

Applying the guideline

The recommendation applies to all people except individuals with preexisting diabetes and includes all synthetic and naturally occurring or modified nonnutritive sweeteners, said the WHO. 

The recommendation does not apply to personal care and hygiene products containing NSSs, such as toothpaste, skin cream, and medications, or to low-calorie sugars and sugar alcohols (polyols).

Because the link observed in the evidence between NSSs and disease outcomes might be confounded by the baseline characteristics of study participants and complicated patterns of NSS use, the recommendation has been assessed as “conditional” by the WHO. 

“This signals that policy decisions based on this recommendation may require substantive discussion in specific country contexts, linked for example to the extent of consumption in different age groups,” said the WHO press release. 

This article was translated from the Medscape French Edition . A version of the article appeared on Medscape.com.

MAR DEL PLATA, ARGENTINA – In the “active aging” vision promoted by the World Health Organization (WHO), older adults stay physically active, independent, and involved. This concept, though well-intentioned, is not very realistic and could easily be discouraging to individuals suffering from the psychological or physical limitations of old age. It also does not account for diversity among individuals and across cultures. These conclusions were presented by the Geriatric Psychiatry Chapter of the Argentine Psychiatric Association at its XXXVI Argentine Congress of Psychiatry.

“The WHO’s proposal of active aging is a prescriptive, standardized ideology that seems to suggest that being active is the only healthy way to age. However, that’s only part of the picture, and a biased part at that. It doesn’t account for the broad spectrum of aging processes that come in many shades,” said Mariana Pedace, psychologist with the Adult Intensive Care department at the Italian Hospital in Buenos Aires and head of the Older Adults section of the civic association Project: Unite.

“The question is whether the idea of active aging is just one more way to create mandates or rules for older adults, which make up such a heterogeneous and diverse generation,” said Ana Laura Vega, MD, psychiatrist with the Mental Health Department at the Italian Hospital of Buenos Aires.

Might it be better to speak of aging “as expected” or “aging well”? Speakers at the conference did not reach a consensus on which word would be the best to replace the adjective “active.”

“I don’t really see why there has to be an additional term when, at other stages of life, we only talk about ‘infancy,’ ‘adolescence,’ or ‘middle age,’ ” said Dr. Vega.
 

A thorny issue

Since the late 1990s, the WHO has defined active aging as “the process of optimizing opportunities for health, participation, and security to enhance quality of life as people age.” This concept allows older adults to “realize their potential for physical, social, and mental well-being throughout the life course and to participate in society according to their needs, desires, and capacities, while providing them with adequate protection, security, and care when they require assistance.”

The organization clarifies that the word “active” refers to continuing participation in social, economic, cultural, spiritual, and civic affairs, not just the ability to be physically active or to participate in the labor force. “However, in practice, active aging programs invariably promote physical activity and exercise as having health and social benefits,” said sociologist Elizabeth Pike, PhD, head of the Research Unit in Sport, Physical Activity, and Aging at the University of Hertfordshire in the United Kingdom.

“The concept of active aging, as presented, is a thorny issue and can potentially be problematic,” said Dr. Pedace. Along with laying out a single prescriptive way to age healthily, which by default makes passive aging “abnormal,” it also ignores demographic, ethnographic, and cultural differences.

“Each culture has different values. The suggestion of aging well in terms of activity, autonomy, and a happy-go-lucky mindset clearly reflects Western capitalistic values. In Eastern cultures, elderly people occupy a position reflecting their experience and wisdom, while also maintaining a contemplative mindset, which is something that is held in high regard. They are at the heart of the family, and their role is to guide and counsel the younger generations,” said Dr. Pedace.

The specialist added that there are programs inspired by active aging that prioritize outward, dynamic, and observable activities to the detriment of activities that take place behind the scenes such as reflection, analysis, and contemplation. “Following this mindset, an older individual who spends their time in contemplation would be somewhat wasting their sunset years. This raises a problem, because as the years go by and death approaches, spiritual life begins to gain far more significance. And that’s not an activity that is valued or recommended in the terms of this program,” she said.

Dr. Pedace went on to say that another concern with the active-aging program is that it seems to minimize certain characteristics that are unique to old age. Resulting physical, cognitive, and emotional changes can lead to reduced activity but are merely idiosyncrasies of this stage in life and are not pathologic.

Cecilia Guerstein, psychiatrist with the Older Adults Division of Project: United in Buenos Aires, cited Julieta Oddone, PhD, a sociologist on aging who believes that the theory of activity informs the underlying supposition of most programs for older adults: that social activity in itself is beneficial and results in greater fulfillment in life. And that all older people need and desire to stay active and engaged. “The idea is that the more active they are, the happier they will be,” said Dr. Guerstein.

“But ‘doing things’ isn’t necessarily appreciated by every elderly person, nor does it automatically lead to their well-being. The fact that some find a sense of well-being from it doesn’t mean we have to always do the same activities across different contexts. There are ethnographic studies that show that there isn’t necessarily a relationship between activity and well-being, or true social integration,” said Dr. Pedace.
 

Not a burden

Practically speaking, few would question whether physical activity has health benefits and believe that it’s never too late to start moving. Among his more than 45 tips on how to live to a ripe old age and “ripen” slowly and nicely, George D. Lundberg, MD, who is 90 years old, gives six recommendations for exercise: walking at least 2 miles every day, trying to swim every day, learning and practicing the techniques of yoga, deliberately lifting heavy objects (resistance training), and working on balance.

“A key for health care professionals encouraging exercise among older adults is knowing what to listen for and how to identify situations that motivate the person to exercise. For example, it could be walking their granddaughter down to the ice cream parlor,” Carolina Díaz, MD, said in an interview. Dr. Díaz is a geriatrics physician and the medical director of the Hirsch nursing and rehab center for older people in San Miguel, Argentina, which is home to 180 residents with an average age of 82 years.

“Exercise shouldn’t be a burden. If someone has never gone on walks before, I wouldn’t make them walk just because they ought to. Maybe they discover well-being in meeting up with their grandchildren or reading with someone. We believe that well-being is related to mobility, but for someone to move, they need the motivation. And until they have that, there won’t be any change,” said Dr. Díaz.

She added that a physician-patient relationship must be forged and an intervention plan drafted that revolves around the person and focuses on his or her current problems such as loneliness, difficulty walking, or pain. “Based on those problems, we can draw up a plan in which physical activity may play a part; other times, it may not.”

Osvaldo Bodni, psychiatrist and psychoanalyst, former director of the Department for Older Adults within the Argentine Psychoanalytic Association and author of the book, Delegating Power in Human Aging: The Theory of Legacy and Passing the Baton) said in an interview: “Aging isn’t a disease, though it does increase vulnerability. The proposal of physical activity is not the only ‘antidote.’ In my opinion, serenity during aging provides even better protection against life’s storms.”

The physician went on to say, “Active aging programs promote physical activity because it’s easier to go on a walk with someone than it is to have a literature debate with them. However, the goal is to create a feeling of being part of a group. This isn’t bad, but it’s a replacement for family. Being part of a group has come to fill the place that was once filled by one’s children, grandchildren, and students.

“When the flood of change in modern society rushes in so quickly, there is a ‘programmed phase-out’ of knowledge, and the demand for experience drops off. It becomes less valuable, such that older adults often get more comfort from finding someone who is willing to show an interest in their stories. The best therapist is the one who listens; not necessarily the one who invites them on a walk or a bike ride,” concluded Dr. Bodni.

Dr. Vega, Dr. Guerstein, Dr. Díaz, Dr. Bodni, and Dr. Pedace have disclosed no relevant financial relationships.
 

This article was translated from the Medscape Spanish Edition . A version appeared on Medscape.com.

MAR DEL PLATA, ARGENTINA – In the “active aging” vision promoted by the World Health Organization (WHO), older adults stay physically active, independent, and involved. This concept, though well-intentioned, is not very realistic and could easily be discouraging to individuals suffering from the psychological or physical limitations of old age. It also does not account for diversity among individuals and across cultures. These conclusions were presented by the Geriatric Psychiatry Chapter of the Argentine Psychiatric Association at its XXXVI Argentine Congress of Psychiatry.

“The WHO’s proposal of active aging is a prescriptive, standardized ideology that seems to suggest that being active is the only healthy way to age. However, that’s only part of the picture, and a biased part at that. It doesn’t account for the broad spectrum of aging processes that come in many shades,” said Mariana Pedace, psychologist with the Adult Intensive Care department at the Italian Hospital in Buenos Aires and head of the Older Adults section of the civic association Project: Unite.

“The question is whether the idea of active aging is just one more way to create mandates or rules for older adults, which make up such a heterogeneous and diverse generation,” said Ana Laura Vega, MD, psychiatrist with the Mental Health Department at the Italian Hospital of Buenos Aires.

Might it be better to speak of aging “as expected” or “aging well”? Speakers at the conference did not reach a consensus on which word would be the best to replace the adjective “active.”

“I don’t really see why there has to be an additional term when, at other stages of life, we only talk about ‘infancy,’ ‘adolescence,’ or ‘middle age,’ ” said Dr. Vega.
 

A thorny issue

Since the late 1990s, the WHO has defined active aging as “the process of optimizing opportunities for health, participation, and security to enhance quality of life as people age.” This concept allows older adults to “realize their potential for physical, social, and mental well-being throughout the life course and to participate in society according to their needs, desires, and capacities, while providing them with adequate protection, security, and care when they require assistance.”

The organization clarifies that the word “active” refers to continuing participation in social, economic, cultural, spiritual, and civic affairs, not just the ability to be physically active or to participate in the labor force. “However, in practice, active aging programs invariably promote physical activity and exercise as having health and social benefits,” said sociologist Elizabeth Pike, PhD, head of the Research Unit in Sport, Physical Activity, and Aging at the University of Hertfordshire in the United Kingdom.

“The concept of active aging, as presented, is a thorny issue and can potentially be problematic,” said Dr. Pedace. Along with laying out a single prescriptive way to age healthily, which by default makes passive aging “abnormal,” it also ignores demographic, ethnographic, and cultural differences.

“Each culture has different values. The suggestion of aging well in terms of activity, autonomy, and a happy-go-lucky mindset clearly reflects Western capitalistic values. In Eastern cultures, elderly people occupy a position reflecting their experience and wisdom, while also maintaining a contemplative mindset, which is something that is held in high regard. They are at the heart of the family, and their role is to guide and counsel the younger generations,” said Dr. Pedace.

The specialist added that there are programs inspired by active aging that prioritize outward, dynamic, and observable activities to the detriment of activities that take place behind the scenes such as reflection, analysis, and contemplation. “Following this mindset, an older individual who spends their time in contemplation would be somewhat wasting their sunset years. This raises a problem, because as the years go by and death approaches, spiritual life begins to gain far more significance. And that’s not an activity that is valued or recommended in the terms of this program,” she said.

Dr. Pedace went on to say that another concern with the active-aging program is that it seems to minimize certain characteristics that are unique to old age. Resulting physical, cognitive, and emotional changes can lead to reduced activity but are merely idiosyncrasies of this stage in life and are not pathologic.

Cecilia Guerstein, psychiatrist with the Older Adults Division of Project: United in Buenos Aires, cited Julieta Oddone, PhD, a sociologist on aging who believes that the theory of activity informs the underlying supposition of most programs for older adults: that social activity in itself is beneficial and results in greater fulfillment in life. And that all older people need and desire to stay active and engaged. “The idea is that the more active they are, the happier they will be,” said Dr. Guerstein.

“But ‘doing things’ isn’t necessarily appreciated by every elderly person, nor does it automatically lead to their well-being. The fact that some find a sense of well-being from it doesn’t mean we have to always do the same activities across different contexts. There are ethnographic studies that show that there isn’t necessarily a relationship between activity and well-being, or true social integration,” said Dr. Pedace.
 

Not a burden

Practically speaking, few would question whether physical activity has health benefits and believe that it’s never too late to start moving. Among his more than 45 tips on how to live to a ripe old age and “ripen” slowly and nicely, George D. Lundberg, MD, who is 90 years old, gives six recommendations for exercise: walking at least 2 miles every day, trying to swim every day, learning and practicing the techniques of yoga, deliberately lifting heavy objects (resistance training), and working on balance.

“A key for health care professionals encouraging exercise among older adults is knowing what to listen for and how to identify situations that motivate the person to exercise. For example, it could be walking their granddaughter down to the ice cream parlor,” Carolina Díaz, MD, said in an interview. Dr. Díaz is a geriatrics physician and the medical director of the Hirsch nursing and rehab center for older people in San Miguel, Argentina, which is home to 180 residents with an average age of 82 years.

“Exercise shouldn’t be a burden. If someone has never gone on walks before, I wouldn’t make them walk just because they ought to. Maybe they discover well-being in meeting up with their grandchildren or reading with someone. We believe that well-being is related to mobility, but for someone to move, they need the motivation. And until they have that, there won’t be any change,” said Dr. Díaz.

She added that a physician-patient relationship must be forged and an intervention plan drafted that revolves around the person and focuses on his or her current problems such as loneliness, difficulty walking, or pain. “Based on those problems, we can draw up a plan in which physical activity may play a part; other times, it may not.”

Osvaldo Bodni, psychiatrist and psychoanalyst, former director of the Department for Older Adults within the Argentine Psychoanalytic Association and author of the book, Delegating Power in Human Aging: The Theory of Legacy and Passing the Baton) said in an interview: “Aging isn’t a disease, though it does increase vulnerability. The proposal of physical activity is not the only ‘antidote.’ In my opinion, serenity during aging provides even better protection against life’s storms.”

The physician went on to say, “Active aging programs promote physical activity because it’s easier to go on a walk with someone than it is to have a literature debate with them. However, the goal is to create a feeling of being part of a group. This isn’t bad, but it’s a replacement for family. Being part of a group has come to fill the place that was once filled by one’s children, grandchildren, and students.

“When the flood of change in modern society rushes in so quickly, there is a ‘programmed phase-out’ of knowledge, and the demand for experience drops off. It becomes less valuable, such that older adults often get more comfort from finding someone who is willing to show an interest in their stories. The best therapist is the one who listens; not necessarily the one who invites them on a walk or a bike ride,” concluded Dr. Bodni.

Dr. Vega, Dr. Guerstein, Dr. Díaz, Dr. Bodni, and Dr. Pedace have disclosed no relevant financial relationships.
 

This article was translated from the Medscape Spanish Edition . A version appeared on Medscape.com.

MAR DEL PLATA, ARGENTINA – In the “active aging” vision promoted by the World Health Organization (WHO), older adults stay physically active, independent, and involved. This concept, though well-intentioned, is not very realistic and could easily be discouraging to individuals suffering from the psychological or physical limitations of old age. It also does not account for diversity among individuals and across cultures. These conclusions were presented by the Geriatric Psychiatry Chapter of the Argentine Psychiatric Association at its XXXVI Argentine Congress of Psychiatry.

“The WHO’s proposal of active aging is a prescriptive, standardized ideology that seems to suggest that being active is the only healthy way to age. However, that’s only part of the picture, and a biased part at that. It doesn’t account for the broad spectrum of aging processes that come in many shades,” said Mariana Pedace, psychologist with the Adult Intensive Care department at the Italian Hospital in Buenos Aires and head of the Older Adults section of the civic association Project: Unite.

“The question is whether the idea of active aging is just one more way to create mandates or rules for older adults, which make up such a heterogeneous and diverse generation,” said Ana Laura Vega, MD, psychiatrist with the Mental Health Department at the Italian Hospital of Buenos Aires.

Might it be better to speak of aging “as expected” or “aging well”? Speakers at the conference did not reach a consensus on which word would be the best to replace the adjective “active.”

“I don’t really see why there has to be an additional term when, at other stages of life, we only talk about ‘infancy,’ ‘adolescence,’ or ‘middle age,’ ” said Dr. Vega.
 

A thorny issue

Since the late 1990s, the WHO has defined active aging as “the process of optimizing opportunities for health, participation, and security to enhance quality of life as people age.” This concept allows older adults to “realize their potential for physical, social, and mental well-being throughout the life course and to participate in society according to their needs, desires, and capacities, while providing them with adequate protection, security, and care when they require assistance.”

The organization clarifies that the word “active” refers to continuing participation in social, economic, cultural, spiritual, and civic affairs, not just the ability to be physically active or to participate in the labor force. “However, in practice, active aging programs invariably promote physical activity and exercise as having health and social benefits,” said sociologist Elizabeth Pike, PhD, head of the Research Unit in Sport, Physical Activity, and Aging at the University of Hertfordshire in the United Kingdom.

“The concept of active aging, as presented, is a thorny issue and can potentially be problematic,” said Dr. Pedace. Along with laying out a single prescriptive way to age healthily, which by default makes passive aging “abnormal,” it also ignores demographic, ethnographic, and cultural differences.

“Each culture has different values. The suggestion of aging well in terms of activity, autonomy, and a happy-go-lucky mindset clearly reflects Western capitalistic values. In Eastern cultures, elderly people occupy a position reflecting their experience and wisdom, while also maintaining a contemplative mindset, which is something that is held in high regard. They are at the heart of the family, and their role is to guide and counsel the younger generations,” said Dr. Pedace.

The specialist added that there are programs inspired by active aging that prioritize outward, dynamic, and observable activities to the detriment of activities that take place behind the scenes such as reflection, analysis, and contemplation. “Following this mindset, an older individual who spends their time in contemplation would be somewhat wasting their sunset years. This raises a problem, because as the years go by and death approaches, spiritual life begins to gain far more significance. And that’s not an activity that is valued or recommended in the terms of this program,” she said.

Dr. Pedace went on to say that another concern with the active-aging program is that it seems to minimize certain characteristics that are unique to old age. Resulting physical, cognitive, and emotional changes can lead to reduced activity but are merely idiosyncrasies of this stage in life and are not pathologic.

Cecilia Guerstein, psychiatrist with the Older Adults Division of Project: United in Buenos Aires, cited Julieta Oddone, PhD, a sociologist on aging who believes that the theory of activity informs the underlying supposition of most programs for older adults: that social activity in itself is beneficial and results in greater fulfillment in life. And that all older people need and desire to stay active and engaged. “The idea is that the more active they are, the happier they will be,” said Dr. Guerstein.

“But ‘doing things’ isn’t necessarily appreciated by every elderly person, nor does it automatically lead to their well-being. The fact that some find a sense of well-being from it doesn’t mean we have to always do the same activities across different contexts. There are ethnographic studies that show that there isn’t necessarily a relationship between activity and well-being, or true social integration,” said Dr. Pedace.
 

Not a burden

Practically speaking, few would question whether physical activity has health benefits and believe that it’s never too late to start moving. Among his more than 45 tips on how to live to a ripe old age and “ripen” slowly and nicely, George D. Lundberg, MD, who is 90 years old, gives six recommendations for exercise: walking at least 2 miles every day, trying to swim every day, learning and practicing the techniques of yoga, deliberately lifting heavy objects (resistance training), and working on balance.

“A key for health care professionals encouraging exercise among older adults is knowing what to listen for and how to identify situations that motivate the person to exercise. For example, it could be walking their granddaughter down to the ice cream parlor,” Carolina Díaz, MD, said in an interview. Dr. Díaz is a geriatrics physician and the medical director of the Hirsch nursing and rehab center for older people in San Miguel, Argentina, which is home to 180 residents with an average age of 82 years.

“Exercise shouldn’t be a burden. If someone has never gone on walks before, I wouldn’t make them walk just because they ought to. Maybe they discover well-being in meeting up with their grandchildren or reading with someone. We believe that well-being is related to mobility, but for someone to move, they need the motivation. And until they have that, there won’t be any change,” said Dr. Díaz.

She added that a physician-patient relationship must be forged and an intervention plan drafted that revolves around the person and focuses on his or her current problems such as loneliness, difficulty walking, or pain. “Based on those problems, we can draw up a plan in which physical activity may play a part; other times, it may not.”

Osvaldo Bodni, psychiatrist and psychoanalyst, former director of the Department for Older Adults within the Argentine Psychoanalytic Association and author of the book, Delegating Power in Human Aging: The Theory of Legacy and Passing the Baton) said in an interview: “Aging isn’t a disease, though it does increase vulnerability. The proposal of physical activity is not the only ‘antidote.’ In my opinion, serenity during aging provides even better protection against life’s storms.”

The physician went on to say, “Active aging programs promote physical activity because it’s easier to go on a walk with someone than it is to have a literature debate with them. However, the goal is to create a feeling of being part of a group. This isn’t bad, but it’s a replacement for family. Being part of a group has come to fill the place that was once filled by one’s children, grandchildren, and students.

“When the flood of change in modern society rushes in so quickly, there is a ‘programmed phase-out’ of knowledge, and the demand for experience drops off. It becomes less valuable, such that older adults often get more comfort from finding someone who is willing to show an interest in their stories. The best therapist is the one who listens; not necessarily the one who invites them on a walk or a bike ride,” concluded Dr. Bodni.

Dr. Vega, Dr. Guerstein, Dr. Díaz, Dr. Bodni, and Dr. Pedace have disclosed no relevant financial relationships.
 

This article was translated from the Medscape Spanish Edition . A version appeared on Medscape.com.

The identification of an antibody linked to spontaneous reversal of cardiac transthyretin amyloidosis may represent a novel approach to treatment of this normally universally progressive and fatal condition.

Cardiac transthyretin amyloidosis (also called ATTR amyloidosis cardiomyopathy or ATTR-CM) is a progressive disease and a cause of heart failure resulting from accumulation of the protein transthyretin, which misfolds and forms amyloid deposits on the walls of the heart, causing both systolic and diastolic dysfunction.

The condition is progressive and normally fatal within a few years of diagnosis. Treatment options are limited and aimed at slowing progression; nothing has been shown to reverse the course of the disease.

However, an international team of researchers is now reporting the discovery of three patients with ATTR-CM–associated heart failure in whom the condition resolved spontaneously, with reversion to near normal cardiac structure and function. On further investigation, it was found that these three patients had developed circulating polyclonal IgG antibodies to human ATTR amyloid.

They are hopeful that a monoclonal form of these antibodies could be developed and may represent a novel treatment, or even a cure, for the condition.

The researchers report their findings in a letter to the New England Journal of Medicine.

“We are very optimistic about this discovery of these antibodies. They could become the first treatment to clear the amyloid that causes this horribly progressive and fatal condition,” senior author Julian Gillmore, MD, head of the University College London Centre for Amyloidosis, based at the Royal Free Hospital, said in an interview.

“Obviously, there is a lot of work to do before we can say this is the case, but it is very exciting,” he added.

Dr. Gillmore explained how the antibodies were discovered. “This disease has a universally progressive course, but we had one patient who on a repeat appointment said he felt better and on detailed cardiac MRI imaging, we found that the amyloid in his heart had reduced. That is totally unheard of,” he said.

“We then looked back at our cohort of 1,663 patients with ATTR-cardiomyopathy, and we discovered two others who had also improved both on imaging and clinically,” Dr. Gillmore said.

Each of these three patients reported a reduction in symptoms, although they had not received any new or potentially disease-modifying treatments. None of the patients had had recent vaccinations, notable infections, or any clinical suggestion of myocarditis.

Clinical recovery was corroborated by substantial improvement or normalization of findings on echocardiography, serum biomarker levels, and results of cardiopulmonary exercise tests and scintigraphy.

Serial cardiac MRI scans confirmed near-complete regression of myocardial extracellular volume, coupled with remodeling to near-normal cardiac structure and function without scarring.

The researchers wondered whether the changes in these patients may have been brought about by an antibody response. On further investigation, they found antibodies in the three patients that bound specifically to ATTR amyloid deposits in a transgenic mouse model of the condition, and to synthetic ATTR amyloid. No such antibodies were present in the other 350 patients in the cohort with a typical clinical course.

“The cause and clinical significance of the anti-ATTR amyloid antibodies are intriguing and presently unclear. However, the clinical recovery of these patients establishes the unanticipated potential for reversibility of ATTR-CM and raises expectations for its treatment,” the researchers conclude.

Dr. Gillmore said they didn’t know why these three patients had these antibodies, while all the other patients did not. “There must be something different about these patients. We don’t know what that is at present, but we are looking hard.”

The researchers are hoping that after this publication, other centers caring for patients with ATTR-cardiomyopathy will look in their cohorts and see if they can identify other cases where there has been improvement.

“It is very plausible that they do have such cases, but they will be rare, as we all think of this disease as universally progressive and fatal,” Dr. Gillmore noted.

“We haven’t absolutely proven that the antibodies have caused the clearance of amyloid in these patients, but we strongly suspect this to be the case,” Dr. Gillmore said. The researchers are planning to try to confirm this by isolating the antibodies and treating the transgenic mice.

Dr. Gillmore attributed the current discovery to the development of novel imaging cardiac MRI techniques. “This allowed us to monitor closely the amyloid burden in the heart. The observation that this had diminished in these three patients was the breakthrough that led us to look for antibodies.”

Another antibody product directed against ATTR cardiomyopathy is also in development by Neurimmune, a Swiss biopharmaceutical company. A phase 1 study of this agent was recently published, suggesting that it appeared to reduce the amount of amyloid protein deposited in the heart.

Dr. Gillmore said the antibody they have detected is different from the Neurimmune product.

The research was supported by a British Heart Foundation Intermediate Clinical Research Fellowship, a Medical Research Council Career Development Award, and a project grant from the British Heart Foundation. Dr. Gillmore reports being a consultant or expert advisory board member for Alnylam Pharmaceuticals, AstraZeneca, ATTRalus, Eidos Therapeutics, Intellia Therapeutics, Ionis Pharmaceuticals, and Pfizer.

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

The identification of an antibody linked to spontaneous reversal of cardiac transthyretin amyloidosis may represent a novel approach to treatment of this normally universally progressive and fatal condition.

Cardiac transthyretin amyloidosis (also called ATTR amyloidosis cardiomyopathy or ATTR-CM) is a progressive disease and a cause of heart failure resulting from accumulation of the protein transthyretin, which misfolds and forms amyloid deposits on the walls of the heart, causing both systolic and diastolic dysfunction.

The condition is progressive and normally fatal within a few years of diagnosis. Treatment options are limited and aimed at slowing progression; nothing has been shown to reverse the course of the disease.

However, an international team of researchers is now reporting the discovery of three patients with ATTR-CM–associated heart failure in whom the condition resolved spontaneously, with reversion to near normal cardiac structure and function. On further investigation, it was found that these three patients had developed circulating polyclonal IgG antibodies to human ATTR amyloid.

They are hopeful that a monoclonal form of these antibodies could be developed and may represent a novel treatment, or even a cure, for the condition.

The researchers report their findings in a letter to the New England Journal of Medicine.

“We are very optimistic about this discovery of these antibodies. They could become the first treatment to clear the amyloid that causes this horribly progressive and fatal condition,” senior author Julian Gillmore, MD, head of the University College London Centre for Amyloidosis, based at the Royal Free Hospital, said in an interview.

“Obviously, there is a lot of work to do before we can say this is the case, but it is very exciting,” he added.

Dr. Gillmore explained how the antibodies were discovered. “This disease has a universally progressive course, but we had one patient who on a repeat appointment said he felt better and on detailed cardiac MRI imaging, we found that the amyloid in his heart had reduced. That is totally unheard of,” he said.

“We then looked back at our cohort of 1,663 patients with ATTR-cardiomyopathy, and we discovered two others who had also improved both on imaging and clinically,” Dr. Gillmore said.

Each of these three patients reported a reduction in symptoms, although they had not received any new or potentially disease-modifying treatments. None of the patients had had recent vaccinations, notable infections, or any clinical suggestion of myocarditis.

Clinical recovery was corroborated by substantial improvement or normalization of findings on echocardiography, serum biomarker levels, and results of cardiopulmonary exercise tests and scintigraphy.

Serial cardiac MRI scans confirmed near-complete regression of myocardial extracellular volume, coupled with remodeling to near-normal cardiac structure and function without scarring.

The researchers wondered whether the changes in these patients may have been brought about by an antibody response. On further investigation, they found antibodies in the three patients that bound specifically to ATTR amyloid deposits in a transgenic mouse model of the condition, and to synthetic ATTR amyloid. No such antibodies were present in the other 350 patients in the cohort with a typical clinical course.

“The cause and clinical significance of the anti-ATTR amyloid antibodies are intriguing and presently unclear. However, the clinical recovery of these patients establishes the unanticipated potential for reversibility of ATTR-CM and raises expectations for its treatment,” the researchers conclude.

Dr. Gillmore said they didn’t know why these three patients had these antibodies, while all the other patients did not. “There must be something different about these patients. We don’t know what that is at present, but we are looking hard.”

The researchers are hoping that after this publication, other centers caring for patients with ATTR-cardiomyopathy will look in their cohorts and see if they can identify other cases where there has been improvement.

“It is very plausible that they do have such cases, but they will be rare, as we all think of this disease as universally progressive and fatal,” Dr. Gillmore noted.

“We haven’t absolutely proven that the antibodies have caused the clearance of amyloid in these patients, but we strongly suspect this to be the case,” Dr. Gillmore said. The researchers are planning to try to confirm this by isolating the antibodies and treating the transgenic mice.

Dr. Gillmore attributed the current discovery to the development of novel imaging cardiac MRI techniques. “This allowed us to monitor closely the amyloid burden in the heart. The observation that this had diminished in these three patients was the breakthrough that led us to look for antibodies.”

Another antibody product directed against ATTR cardiomyopathy is also in development by Neurimmune, a Swiss biopharmaceutical company. A phase 1 study of this agent was recently published, suggesting that it appeared to reduce the amount of amyloid protein deposited in the heart.

Dr. Gillmore said the antibody they have detected is different from the Neurimmune product.

The research was supported by a British Heart Foundation Intermediate Clinical Research Fellowship, a Medical Research Council Career Development Award, and a project grant from the British Heart Foundation. Dr. Gillmore reports being a consultant or expert advisory board member for Alnylam Pharmaceuticals, AstraZeneca, ATTRalus, Eidos Therapeutics, Intellia Therapeutics, Ionis Pharmaceuticals, and Pfizer.

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

The identification of an antibody linked to spontaneous reversal of cardiac transthyretin amyloidosis may represent a novel approach to treatment of this normally universally progressive and fatal condition.

Cardiac transthyretin amyloidosis (also called ATTR amyloidosis cardiomyopathy or ATTR-CM) is a progressive disease and a cause of heart failure resulting from accumulation of the protein transthyretin, which misfolds and forms amyloid deposits on the walls of the heart, causing both systolic and diastolic dysfunction.

The condition is progressive and normally fatal within a few years of diagnosis. Treatment options are limited and aimed at slowing progression; nothing has been shown to reverse the course of the disease.

However, an international team of researchers is now reporting the discovery of three patients with ATTR-CM–associated heart failure in whom the condition resolved spontaneously, with reversion to near normal cardiac structure and function. On further investigation, it was found that these three patients had developed circulating polyclonal IgG antibodies to human ATTR amyloid.

They are hopeful that a monoclonal form of these antibodies could be developed and may represent a novel treatment, or even a cure, for the condition.

The researchers report their findings in a letter to the New England Journal of Medicine.

“We are very optimistic about this discovery of these antibodies. They could become the first treatment to clear the amyloid that causes this horribly progressive and fatal condition,” senior author Julian Gillmore, MD, head of the University College London Centre for Amyloidosis, based at the Royal Free Hospital, said in an interview.

“Obviously, there is a lot of work to do before we can say this is the case, but it is very exciting,” he added.

Dr. Gillmore explained how the antibodies were discovered. “This disease has a universally progressive course, but we had one patient who on a repeat appointment said he felt better and on detailed cardiac MRI imaging, we found that the amyloid in his heart had reduced. That is totally unheard of,” he said.

“We then looked back at our cohort of 1,663 patients with ATTR-cardiomyopathy, and we discovered two others who had also improved both on imaging and clinically,” Dr. Gillmore said.

Each of these three patients reported a reduction in symptoms, although they had not received any new or potentially disease-modifying treatments. None of the patients had had recent vaccinations, notable infections, or any clinical suggestion of myocarditis.

Clinical recovery was corroborated by substantial improvement or normalization of findings on echocardiography, serum biomarker levels, and results of cardiopulmonary exercise tests and scintigraphy.

Serial cardiac MRI scans confirmed near-complete regression of myocardial extracellular volume, coupled with remodeling to near-normal cardiac structure and function without scarring.

The researchers wondered whether the changes in these patients may have been brought about by an antibody response. On further investigation, they found antibodies in the three patients that bound specifically to ATTR amyloid deposits in a transgenic mouse model of the condition, and to synthetic ATTR amyloid. No such antibodies were present in the other 350 patients in the cohort with a typical clinical course.

“The cause and clinical significance of the anti-ATTR amyloid antibodies are intriguing and presently unclear. However, the clinical recovery of these patients establishes the unanticipated potential for reversibility of ATTR-CM and raises expectations for its treatment,” the researchers conclude.

Dr. Gillmore said they didn’t know why these three patients had these antibodies, while all the other patients did not. “There must be something different about these patients. We don’t know what that is at present, but we are looking hard.”

The researchers are hoping that after this publication, other centers caring for patients with ATTR-cardiomyopathy will look in their cohorts and see if they can identify other cases where there has been improvement.

“It is very plausible that they do have such cases, but they will be rare, as we all think of this disease as universally progressive and fatal,” Dr. Gillmore noted.

“We haven’t absolutely proven that the antibodies have caused the clearance of amyloid in these patients, but we strongly suspect this to be the case,” Dr. Gillmore said. The researchers are planning to try to confirm this by isolating the antibodies and treating the transgenic mice.

Dr. Gillmore attributed the current discovery to the development of novel imaging cardiac MRI techniques. “This allowed us to monitor closely the amyloid burden in the heart. The observation that this had diminished in these three patients was the breakthrough that led us to look for antibodies.”

Another antibody product directed against ATTR cardiomyopathy is also in development by Neurimmune, a Swiss biopharmaceutical company. A phase 1 study of this agent was recently published, suggesting that it appeared to reduce the amount of amyloid protein deposited in the heart.

Dr. Gillmore said the antibody they have detected is different from the Neurimmune product.

The research was supported by a British Heart Foundation Intermediate Clinical Research Fellowship, a Medical Research Council Career Development Award, and a project grant from the British Heart Foundation. Dr. Gillmore reports being a consultant or expert advisory board member for Alnylam Pharmaceuticals, AstraZeneca, ATTRalus, Eidos Therapeutics, Intellia Therapeutics, Ionis Pharmaceuticals, and Pfizer.

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

When I speak with parents and colleagues about the well-being of today’s youth, the nearly unanimous cry is the negative effects of social media. But then, after a few moments of silence they say, “I don’t know how we can stop it. The genie is out of the bottle.”

The helplessness we as responsible adults and professionals feel about our inability to change this cultural shift to youth fixation on social media and its increasingly clear impact on depression, anxiety, self-esteem, and even suicide is profound. In China the country has “simply” regulated access to the Internet for children to 2 hours per day and blocked many websites. But such universal restriction is not likely in the United States. We need some other solutions.
 

A solution for all ages

Reach Out and Read, an international program promoting early relational health and literacy by encouraging and modeling reading and handing out books to families with children aged 0-5 years, has significant evidence for improving child development and parent-child interaction.

But why stop promoting reading and the associated parent-child bonding at 5 years old? Academic progress, child mental health and well-being, and family relationships are all currently in trouble and could all benefit from more reading. As pediatric providers for all ages of children and youth we can effectively promote reading as part of preventive care, not just for the youngest.

Reading fluency is a key factor in academic success. A study from 2019, before the pandemic, found that by the end of high school, students were reading 19% slower than were students of a similar age 50 years ago. The possible reasons, among many, include poverty with its effect on vocabulary, modeling and access to books, hours on social media, and less unstructured time to read for pleasure. With less reading comes less practice. Reading then doesn’t feel as comfortable and is avoided.

The pandemic made measures of academic level even worse, with reading fluency in second and third grade now about 30% behind what would be expected. Reading fluency and comprehension become more critical for future academic progress beginning in third grade when “learning to read” shifts to “reading to learn.” Educators are doing their best to catch children up but with limited support resources, and families need strategies to help their children.

Early strategies to promote reading by discussing the benefits with parents of bedtime stories and sharing books seems easy in comparison to encouraging school-aged children and older youth to read. But there are good reasons and strategies to persist.

Reading can help a child’s mental health as well as development. After a day at school, picking up another book may seem to the parent like more homework. But “reading for pleasure” is different. Reading has been shown to lower heart rate and muscle tension and reduce stress by as much as 68% in minutes, even lowering cortisol and activating pleasure centers of the brain. An immersive story can distract one from worries and be a real escape; the opposite of looking at social media online where peer comparisons and a constant stream of nasty comments 24/7 are culprits producing anxiety, depression, eating disorders, and suicide. Books that have characters going through similar struggles as those of the youth provide a sense of not being alone with these stresses and generally include models of problem solving and resolution that can inspire hopefulness. Joining (or starting) a kids’ or parent-child book club offers a chance to socialize with a nonjudgmental shared focus. There are books with content about all sorts of topics that may be areas the child or youth have as life and career goals that may help them gain new ideas and confidence as well as knowledge and skills. Having clear ideas about future roles is a one way to reduce the chance of developing depression and even suicide.

Reading a book, ideally illuminated by a warm colored light, assists in falling asleep, a huge issue for many youth. This is valuable in itself as inadequate sleep is a large contributor to worsening of many mental conditions. In contrast, the blue light from computer screens makes it harder to fall asleep. When reading a book is a bedtime habit, just as for babies and toddlers and whether read to by a parent (no age is too old!) or reading alone, the routine itself helps prepare the brain to transition into sleep.
 

Encouraging good habits

But how can parents get their children away from scanning the Internet to reading books? The American Academy of Pediatrics suggests setting time blocks for the day designated for school, exercise, homework, media, and sleep with a goal of a healthy balance. Reading could be added to the family’s plan. Making reading in the same room with parents as a regular habit both models reading (as parents have to get offline, too!) and sets up an opportunity to ask questions and converse about the reading materials, thereby building family relationships. Children are notorious for being recalcitrant about talking “about their day” when coming home from school. Having a less personal and intrusive subject to talk about creates a favorable setting for precious parent-child discussions. Some families read aloud to each other. This comes up naturally when reading a clip from a newspaper or magazine. It is especially valuable and inclusive for younger children who may not yet be able to read that level of material.

Getting creative

Some other strategies to promote reading include bringing books, magazines, or even comics with subjects that interest the child or youth into the house and leaving them around without comment. Getting started on a book series (Nancy Drew, Harry Potter, etc.) that is captivating provides extra incentive. Parents can talk about their favorites from their childhood, some of which are timeless! Families may need to be creative and find literature about the online characters from video games or movies that already interest their child, even if those are not seen as ideal learning material. Not commenting on the presence of the reading material takes the pressure off and makes it clear that it is their choice whether to read them or not.

Books need to be seen as a gift rather than a “penalty” for being online. Visiting a bookstore together or giving a gift certificate for books are other ways a parent can support reading while indicating that the youth has choice. There are now more than 150,000 Little Free Library locations worldwide (visible on the app) where books can be obtained 24/7 at no cost. Bringing books to donate or even joining the cause and becoming a steward of one of these pop-up libraries models high valuation of reading but is also a volunteer activity of which the child can be proud. We brought our children’s old books to our pediatric practice and encouraged patients to “bring one and take one.” Of course, the public library is often an option and is free. Another advantage of the library is that librarians and other children there may make suggestions of books that are popular with children their age. There are lots of specific suggestions online as well.

We need to be aware that children who resist reading books may have reading weaknesses. We can assess reading fluency with standard Gray Oral Reading paragraphs or the Wide Range Achievement test in the office or recommend a reading assessment by the school. Parents who already know that their child has a reading problem may be getting advice from teachers or tutors on how to help. But to promote reading that is not onerous for a child with a reading disability, parents can do more reading aloud at home, offer audiobooks or podcasts at home or play them while driving, and aim for books with a lower reading level. Teachers or librarians can make suggestions. It is important for family members to not be judgmental about a child’s choice of reading materials.

We do not need to feel helpless in the face of the Internet – we can recommend more reading!
 

Dr. Howard is assistant professor of pediatrics at The Johns Hopkins University, Baltimore, and creator of CHADIS. She had no other relevant disclosures. Dr. Howard’s contribution to this publication was as a paid expert to MDedge News. E-mail her at [email protected].

When I speak with parents and colleagues about the well-being of today’s youth, the nearly unanimous cry is the negative effects of social media. But then, after a few moments of silence they say, “I don’t know how we can stop it. The genie is out of the bottle.”

The helplessness we as responsible adults and professionals feel about our inability to change this cultural shift to youth fixation on social media and its increasingly clear impact on depression, anxiety, self-esteem, and even suicide is profound. In China the country has “simply” regulated access to the Internet for children to 2 hours per day and blocked many websites. But such universal restriction is not likely in the United States. We need some other solutions.
 

A solution for all ages

Reach Out and Read, an international program promoting early relational health and literacy by encouraging and modeling reading and handing out books to families with children aged 0-5 years, has significant evidence for improving child development and parent-child interaction.

But why stop promoting reading and the associated parent-child bonding at 5 years old? Academic progress, child mental health and well-being, and family relationships are all currently in trouble and could all benefit from more reading. As pediatric providers for all ages of children and youth we can effectively promote reading as part of preventive care, not just for the youngest.

Reading fluency is a key factor in academic success. A study from 2019, before the pandemic, found that by the end of high school, students were reading 19% slower than were students of a similar age 50 years ago. The possible reasons, among many, include poverty with its effect on vocabulary, modeling and access to books, hours on social media, and less unstructured time to read for pleasure. With less reading comes less practice. Reading then doesn’t feel as comfortable and is avoided.

The pandemic made measures of academic level even worse, with reading fluency in second and third grade now about 30% behind what would be expected. Reading fluency and comprehension become more critical for future academic progress beginning in third grade when “learning to read” shifts to “reading to learn.” Educators are doing their best to catch children up but with limited support resources, and families need strategies to help their children.

Early strategies to promote reading by discussing the benefits with parents of bedtime stories and sharing books seems easy in comparison to encouraging school-aged children and older youth to read. But there are good reasons and strategies to persist.

Reading can help a child’s mental health as well as development. After a day at school, picking up another book may seem to the parent like more homework. But “reading for pleasure” is different. Reading has been shown to lower heart rate and muscle tension and reduce stress by as much as 68% in minutes, even lowering cortisol and activating pleasure centers of the brain. An immersive story can distract one from worries and be a real escape; the opposite of looking at social media online where peer comparisons and a constant stream of nasty comments 24/7 are culprits producing anxiety, depression, eating disorders, and suicide. Books that have characters going through similar struggles as those of the youth provide a sense of not being alone with these stresses and generally include models of problem solving and resolution that can inspire hopefulness. Joining (or starting) a kids’ or parent-child book club offers a chance to socialize with a nonjudgmental shared focus. There are books with content about all sorts of topics that may be areas the child or youth have as life and career goals that may help them gain new ideas and confidence as well as knowledge and skills. Having clear ideas about future roles is a one way to reduce the chance of developing depression and even suicide.

Reading a book, ideally illuminated by a warm colored light, assists in falling asleep, a huge issue for many youth. This is valuable in itself as inadequate sleep is a large contributor to worsening of many mental conditions. In contrast, the blue light from computer screens makes it harder to fall asleep. When reading a book is a bedtime habit, just as for babies and toddlers and whether read to by a parent (no age is too old!) or reading alone, the routine itself helps prepare the brain to transition into sleep.
 

Encouraging good habits

But how can parents get their children away from scanning the Internet to reading books? The American Academy of Pediatrics suggests setting time blocks for the day designated for school, exercise, homework, media, and sleep with a goal of a healthy balance. Reading could be added to the family’s plan. Making reading in the same room with parents as a regular habit both models reading (as parents have to get offline, too!) and sets up an opportunity to ask questions and converse about the reading materials, thereby building family relationships. Children are notorious for being recalcitrant about talking “about their day” when coming home from school. Having a less personal and intrusive subject to talk about creates a favorable setting for precious parent-child discussions. Some families read aloud to each other. This comes up naturally when reading a clip from a newspaper or magazine. It is especially valuable and inclusive for younger children who may not yet be able to read that level of material.

Getting creative

Some other strategies to promote reading include bringing books, magazines, or even comics with subjects that interest the child or youth into the house and leaving them around without comment. Getting started on a book series (Nancy Drew, Harry Potter, etc.) that is captivating provides extra incentive. Parents can talk about their favorites from their childhood, some of which are timeless! Families may need to be creative and find literature about the online characters from video games or movies that already interest their child, even if those are not seen as ideal learning material. Not commenting on the presence of the reading material takes the pressure off and makes it clear that it is their choice whether to read them or not.

Books need to be seen as a gift rather than a “penalty” for being online. Visiting a bookstore together or giving a gift certificate for books are other ways a parent can support reading while indicating that the youth has choice. There are now more than 150,000 Little Free Library locations worldwide (visible on the app) where books can be obtained 24/7 at no cost. Bringing books to donate or even joining the cause and becoming a steward of one of these pop-up libraries models high valuation of reading but is also a volunteer activity of which the child can be proud. We brought our children’s old books to our pediatric practice and encouraged patients to “bring one and take one.” Of course, the public library is often an option and is free. Another advantage of the library is that librarians and other children there may make suggestions of books that are popular with children their age. There are lots of specific suggestions online as well.

We need to be aware that children who resist reading books may have reading weaknesses. We can assess reading fluency with standard Gray Oral Reading paragraphs or the Wide Range Achievement test in the office or recommend a reading assessment by the school. Parents who already know that their child has a reading problem may be getting advice from teachers or tutors on how to help. But to promote reading that is not onerous for a child with a reading disability, parents can do more reading aloud at home, offer audiobooks or podcasts at home or play them while driving, and aim for books with a lower reading level. Teachers or librarians can make suggestions. It is important for family members to not be judgmental about a child’s choice of reading materials.

We do not need to feel helpless in the face of the Internet – we can recommend more reading!
 

Dr. Howard is assistant professor of pediatrics at The Johns Hopkins University, Baltimore, and creator of CHADIS. She had no other relevant disclosures. Dr. Howard’s contribution to this publication was as a paid expert to MDedge News. E-mail her at [email protected].

When I speak with parents and colleagues about the well-being of today’s youth, the nearly unanimous cry is the negative effects of social media. But then, after a few moments of silence they say, “I don’t know how we can stop it. The genie is out of the bottle.”

The helplessness we as responsible adults and professionals feel about our inability to change this cultural shift to youth fixation on social media and its increasingly clear impact on depression, anxiety, self-esteem, and even suicide is profound. In China the country has “simply” regulated access to the Internet for children to 2 hours per day and blocked many websites. But such universal restriction is not likely in the United States. We need some other solutions.
 

A solution for all ages

Reach Out and Read, an international program promoting early relational health and literacy by encouraging and modeling reading and handing out books to families with children aged 0-5 years, has significant evidence for improving child development and parent-child interaction.

But why stop promoting reading and the associated parent-child bonding at 5 years old? Academic progress, child mental health and well-being, and family relationships are all currently in trouble and could all benefit from more reading. As pediatric providers for all ages of children and youth we can effectively promote reading as part of preventive care, not just for the youngest.

Reading fluency is a key factor in academic success. A study from 2019, before the pandemic, found that by the end of high school, students were reading 19% slower than were students of a similar age 50 years ago. The possible reasons, among many, include poverty with its effect on vocabulary, modeling and access to books, hours on social media, and less unstructured time to read for pleasure. With less reading comes less practice. Reading then doesn’t feel as comfortable and is avoided.

The pandemic made measures of academic level even worse, with reading fluency in second and third grade now about 30% behind what would be expected. Reading fluency and comprehension become more critical for future academic progress beginning in third grade when “learning to read” shifts to “reading to learn.” Educators are doing their best to catch children up but with limited support resources, and families need strategies to help their children.

Early strategies to promote reading by discussing the benefits with parents of bedtime stories and sharing books seems easy in comparison to encouraging school-aged children and older youth to read. But there are good reasons and strategies to persist.

Reading can help a child’s mental health as well as development. After a day at school, picking up another book may seem to the parent like more homework. But “reading for pleasure” is different. Reading has been shown to lower heart rate and muscle tension and reduce stress by as much as 68% in minutes, even lowering cortisol and activating pleasure centers of the brain. An immersive story can distract one from worries and be a real escape; the opposite of looking at social media online where peer comparisons and a constant stream of nasty comments 24/7 are culprits producing anxiety, depression, eating disorders, and suicide. Books that have characters going through similar struggles as those of the youth provide a sense of not being alone with these stresses and generally include models of problem solving and resolution that can inspire hopefulness. Joining (or starting) a kids’ or parent-child book club offers a chance to socialize with a nonjudgmental shared focus. There are books with content about all sorts of topics that may be areas the child or youth have as life and career goals that may help them gain new ideas and confidence as well as knowledge and skills. Having clear ideas about future roles is a one way to reduce the chance of developing depression and even suicide.

Reading a book, ideally illuminated by a warm colored light, assists in falling asleep, a huge issue for many youth. This is valuable in itself as inadequate sleep is a large contributor to worsening of many mental conditions. In contrast, the blue light from computer screens makes it harder to fall asleep. When reading a book is a bedtime habit, just as for babies and toddlers and whether read to by a parent (no age is too old!) or reading alone, the routine itself helps prepare the brain to transition into sleep.
 

Encouraging good habits

But how can parents get their children away from scanning the Internet to reading books? The American Academy of Pediatrics suggests setting time blocks for the day designated for school, exercise, homework, media, and sleep with a goal of a healthy balance. Reading could be added to the family’s plan. Making reading in the same room with parents as a regular habit both models reading (as parents have to get offline, too!) and sets up an opportunity to ask questions and converse about the reading materials, thereby building family relationships. Children are notorious for being recalcitrant about talking “about their day” when coming home from school. Having a less personal and intrusive subject to talk about creates a favorable setting for precious parent-child discussions. Some families read aloud to each other. This comes up naturally when reading a clip from a newspaper or magazine. It is especially valuable and inclusive for younger children who may not yet be able to read that level of material.

Getting creative

Some other strategies to promote reading include bringing books, magazines, or even comics with subjects that interest the child or youth into the house and leaving them around without comment. Getting started on a book series (Nancy Drew, Harry Potter, etc.) that is captivating provides extra incentive. Parents can talk about their favorites from their childhood, some of which are timeless! Families may need to be creative and find literature about the online characters from video games or movies that already interest their child, even if those are not seen as ideal learning material. Not commenting on the presence of the reading material takes the pressure off and makes it clear that it is their choice whether to read them or not.

Books need to be seen as a gift rather than a “penalty” for being online. Visiting a bookstore together or giving a gift certificate for books are other ways a parent can support reading while indicating that the youth has choice. There are now more than 150,000 Little Free Library locations worldwide (visible on the app) where books can be obtained 24/7 at no cost. Bringing books to donate or even joining the cause and becoming a steward of one of these pop-up libraries models high valuation of reading but is also a volunteer activity of which the child can be proud. We brought our children’s old books to our pediatric practice and encouraged patients to “bring one and take one.” Of course, the public library is often an option and is free. Another advantage of the library is that librarians and other children there may make suggestions of books that are popular with children their age. There are lots of specific suggestions online as well.

We need to be aware that children who resist reading books may have reading weaknesses. We can assess reading fluency with standard Gray Oral Reading paragraphs or the Wide Range Achievement test in the office or recommend a reading assessment by the school. Parents who already know that their child has a reading problem may be getting advice from teachers or tutors on how to help. But to promote reading that is not onerous for a child with a reading disability, parents can do more reading aloud at home, offer audiobooks or podcasts at home or play them while driving, and aim for books with a lower reading level. Teachers or librarians can make suggestions. It is important for family members to not be judgmental about a child’s choice of reading materials.

We do not need to feel helpless in the face of the Internet – we can recommend more reading!
 

Dr. Howard is assistant professor of pediatrics at The Johns Hopkins University, Baltimore, and creator of CHADIS. She had no other relevant disclosures. Dr. Howard’s contribution to this publication was as a paid expert to MDedge News. E-mail her at [email protected].

Women with moderate to severe psoriasis had a lower fertility rate, compared with age-matched peers without psoriasis, and overall, those with psoriasis had a slightly higher risk of pregnancy loss, compared with those who did not have the disease, in a U.K. cohort study.

Those are key findings from what is believed to be one of the largest studies to investigate fertility and obstetric outcomes in patients with psoriasis.

“Studies that have examined fertility and pregnancy outcomes in women with psoriasis have reported conflicting findings,” lead author Teng-Chou Chen, PhD, of the Centre for Pharmacoepidemiology and Drug Safety at the University of Manchester (England), and colleagues from the Global Psoriasis Atlas wrote in the study, published in JAMA Dermatology. Most of the studies were small, with under 100 women, “and are thus likely underpowered to detect a difference in pregnancy outcomes. The majority of those studies used disease registry data or lacked a matched comparison group and hence were unable to estimate the association of fertility and adverse pregnancy outcomes in women with psoriasis when compared with the general population.”

To determine fertility rates and birth outcomes in female patients with psoriasis, compared with age- and practice-matched patients without psoriasis, the researchers evaluated EHR data from a large U.K. primary care database, the Clinical Practice Research Datalink GOLD, from 1998 to 2019. They limited the analysis to patients aged 15-44 years and used relevant codes from clinical consultations to identify those with psoriasis. Then, for each patient with psoriasis, the researchers selected five comparators without psoriasis from the same primary care practice and matched for year of birth.

Both sets of patients were followed from the index date to age 45 years, death, transfer out of practice, last date of data collection, or end of the study period (Dec. 31, 2019), whichever came first. Pregnancy records were extracted for both sets of patients, and birth outcomes were categorized as pregnancy loss, live birth, stillbirth, and preterm birth. Adverse pregnancy outcomes were also collected. Finally, Dr. Chen and colleagues used a negative binomial model to examine the association between psoriasis and the fertility rate, and they applied logistic regression to compare the association between psoriasis and obstetric outcomes.

The analysis included 63,681 patients with psoriasis and 318,405 comparators whose median age on the index date was 30 years and who were followed for a median of 4.1 years. Among patients with psoriasis, 5.1% met criteria for moderate to severe disease in the follow-up period. The researchers observed that, compared with their age- and practice-matched counterparts, patients with psoriasis were more likely to be current smokers, alcohol drinkers, or overweight on the index date. They were also more often diagnosed with diabetes, hypertension, inflammatory bowel disease, thyroid disorders, and respiratory diseases such as asthma and chronic obstructive pulmonary disease.

Fertility, birth outcomes

When they looked at fertility outcomes, the researchers found that, compared with their matched peers without psoriasis, those with psoriasis had higher rates of fertility (risk ratio, 1.30; 95% confidence interval, 1.27-1.33; P < .001). But after the researchers stratified patients based on psoriasis severity, those with moderate to severe disease had significantly lower rates of fertility (RR, 0.75; 95% CI, 0.69-0.83; P < .001), compared those who did not have psoriasis.

As for adverse birth outcomes, compared with their matched comparators, pregnancies in patients with psoriasis were less likely to end in a live birth (odds ratio, 0.91; 95% CI, 0.88-0.93; P < .001). They also had a higher risk of pregnancy loss (OR, 1.06; 95% CI, 1.03-1.10; P < .001), most during the first trimester, at a gestation period of under 91 days.

In addition to psoriasis, patients younger than age 20 (OR, 2.04; 95% CI, 1.94-2.15; P < .011) and those aged between 20 and 24 years (OR, 1.35; 95% CI, 1.31-1.40; P < .001) had a higher risk of pregnancy loss, compared with those aged between 25 and 34 years.

However, no increases in the risks of antenatal hemorrhage, preeclampsia, or gestational diabetes were observed in patients with psoriasis, and no statistically significant differences in the odds of stillbirth and preterm birth were found between patients with psoriasis and matched comparators who did not have psoriasis.

“The mechanism to link the higher risk of pregnancy loss in patients with psoriasis is not clear, but there might be potential explanations,” the researchers wrote. “Psoriasis is characterized by the increased activity of [interleukin]-17, IL-23, and tumor necrosis factor–alpha. Those proinflammatory cytokines may negatively affect the placenta and cause impaired fetal growth.”

They recommended that further studies “evaluate the effects of better management of psoriasis and close monitoring during pregnancy on pregnancy loss.” In particular, “patients with psoriasis were more likely to have comorbidities that may be related to poor pregnancy outcomes, and hence increased emphasis of managing comorbidities as part of the routine management plan is also warranted.”

Asked to comment on the study, Alexa B. Kimball, MD, MPH, who has been involved with research on this topic, said that she and other investigators had observed some years ago that fertility rates for women with moderate to severe psoriasis might be lower than expected.

This trend was observed in some psoriasis registries, some pregnancy registries, and in clinical practice, Dr. Kimball, professor of dermatology at Harvard Medical School, Boston, said in an interview. “This study clearly demonstrates that lower fertility rates in the moderate to severe psoriasis population occurs and compels further exploration of the reason why.” The reasons could be biologic, she continued, including difficulty conceiving or an increased risk of miscarriage, sociobehavioral issues, or a combination.

“Behavioral examples could include that some women with moderate to severe psoriasis can flare during pregnancy, which might affect their choice” to become pregnant, Dr. Kimball said. “Stigma may also play a role in how women with moderate to severe psoriasis form relationships. Now that there are much better treatments for moderate to severe psoriasis and better knowledge about managing psoriasis during pregnancy, it will also be important to explore whether these trends change over time.”

The study was funded by the International League of Dermatological Societies on behalf of the Global Psoriasis Atlas. Two of the study authors reported receiving consulting fees and grant support from many pharmaceutical companies. Dr. Kimball disclosed that she serves or has served on several Organization of Teratology Information Specialists advisory board pregnancy registries, is a consultant and investigator for Abbvie, Janssen, Lilly, Bristol-Myers Squibb, Moonlake, UCB, and Amgen; has fellowship funding from Janssen; and serves on the board of Almirall.

Women with moderate to severe psoriasis had a lower fertility rate, compared with age-matched peers without psoriasis, and overall, those with psoriasis had a slightly higher risk of pregnancy loss, compared with those who did not have the disease, in a U.K. cohort study.

Those are key findings from what is believed to be one of the largest studies to investigate fertility and obstetric outcomes in patients with psoriasis.

“Studies that have examined fertility and pregnancy outcomes in women with psoriasis have reported conflicting findings,” lead author Teng-Chou Chen, PhD, of the Centre for Pharmacoepidemiology and Drug Safety at the University of Manchester (England), and colleagues from the Global Psoriasis Atlas wrote in the study, published in JAMA Dermatology. Most of the studies were small, with under 100 women, “and are thus likely underpowered to detect a difference in pregnancy outcomes. The majority of those studies used disease registry data or lacked a matched comparison group and hence were unable to estimate the association of fertility and adverse pregnancy outcomes in women with psoriasis when compared with the general population.”

To determine fertility rates and birth outcomes in female patients with psoriasis, compared with age- and practice-matched patients without psoriasis, the researchers evaluated EHR data from a large U.K. primary care database, the Clinical Practice Research Datalink GOLD, from 1998 to 2019. They limited the analysis to patients aged 15-44 years and used relevant codes from clinical consultations to identify those with psoriasis. Then, for each patient with psoriasis, the researchers selected five comparators without psoriasis from the same primary care practice and matched for year of birth.

Both sets of patients were followed from the index date to age 45 years, death, transfer out of practice, last date of data collection, or end of the study period (Dec. 31, 2019), whichever came first. Pregnancy records were extracted for both sets of patients, and birth outcomes were categorized as pregnancy loss, live birth, stillbirth, and preterm birth. Adverse pregnancy outcomes were also collected. Finally, Dr. Chen and colleagues used a negative binomial model to examine the association between psoriasis and the fertility rate, and they applied logistic regression to compare the association between psoriasis and obstetric outcomes.

The analysis included 63,681 patients with psoriasis and 318,405 comparators whose median age on the index date was 30 years and who were followed for a median of 4.1 years. Among patients with psoriasis, 5.1% met criteria for moderate to severe disease in the follow-up period. The researchers observed that, compared with their age- and practice-matched counterparts, patients with psoriasis were more likely to be current smokers, alcohol drinkers, or overweight on the index date. They were also more often diagnosed with diabetes, hypertension, inflammatory bowel disease, thyroid disorders, and respiratory diseases such as asthma and chronic obstructive pulmonary disease.

Fertility, birth outcomes

When they looked at fertility outcomes, the researchers found that, compared with their matched peers without psoriasis, those with psoriasis had higher rates of fertility (risk ratio, 1.30; 95% confidence interval, 1.27-1.33; P < .001). But after the researchers stratified patients based on psoriasis severity, those with moderate to severe disease had significantly lower rates of fertility (RR, 0.75; 95% CI, 0.69-0.83; P < .001), compared those who did not have psoriasis.

As for adverse birth outcomes, compared with their matched comparators, pregnancies in patients with psoriasis were less likely to end in a live birth (odds ratio, 0.91; 95% CI, 0.88-0.93; P < .001). They also had a higher risk of pregnancy loss (OR, 1.06; 95% CI, 1.03-1.10; P < .001), most during the first trimester, at a gestation period of under 91 days.

In addition to psoriasis, patients younger than age 20 (OR, 2.04; 95% CI, 1.94-2.15; P < .011) and those aged between 20 and 24 years (OR, 1.35; 95% CI, 1.31-1.40; P < .001) had a higher risk of pregnancy loss, compared with those aged between 25 and 34 years.

However, no increases in the risks of antenatal hemorrhage, preeclampsia, or gestational diabetes were observed in patients with psoriasis, and no statistically significant differences in the odds of stillbirth and preterm birth were found between patients with psoriasis and matched comparators who did not have psoriasis.

“The mechanism to link the higher risk of pregnancy loss in patients with psoriasis is not clear, but there might be potential explanations,” the researchers wrote. “Psoriasis is characterized by the increased activity of [interleukin]-17, IL-23, and tumor necrosis factor–alpha. Those proinflammatory cytokines may negatively affect the placenta and cause impaired fetal growth.”

They recommended that further studies “evaluate the effects of better management of psoriasis and close monitoring during pregnancy on pregnancy loss.” In particular, “patients with psoriasis were more likely to have comorbidities that may be related to poor pregnancy outcomes, and hence increased emphasis of managing comorbidities as part of the routine management plan is also warranted.”

Asked to comment on the study, Alexa B. Kimball, MD, MPH, who has been involved with research on this topic, said that she and other investigators had observed some years ago that fertility rates for women with moderate to severe psoriasis might be lower than expected.

This trend was observed in some psoriasis registries, some pregnancy registries, and in clinical practice, Dr. Kimball, professor of dermatology at Harvard Medical School, Boston, said in an interview. “This study clearly demonstrates that lower fertility rates in the moderate to severe psoriasis population occurs and compels further exploration of the reason why.” The reasons could be biologic, she continued, including difficulty conceiving or an increased risk of miscarriage, sociobehavioral issues, or a combination.

“Behavioral examples could include that some women with moderate to severe psoriasis can flare during pregnancy, which might affect their choice” to become pregnant, Dr. Kimball said. “Stigma may also play a role in how women with moderate to severe psoriasis form relationships. Now that there are much better treatments for moderate to severe psoriasis and better knowledge about managing psoriasis during pregnancy, it will also be important to explore whether these trends change over time.”

The study was funded by the International League of Dermatological Societies on behalf of the Global Psoriasis Atlas. Two of the study authors reported receiving consulting fees and grant support from many pharmaceutical companies. Dr. Kimball disclosed that she serves or has served on several Organization of Teratology Information Specialists advisory board pregnancy registries, is a consultant and investigator for Abbvie, Janssen, Lilly, Bristol-Myers Squibb, Moonlake, UCB, and Amgen; has fellowship funding from Janssen; and serves on the board of Almirall.

Women with moderate to severe psoriasis had a lower fertility rate, compared with age-matched peers without psoriasis, and overall, those with psoriasis had a slightly higher risk of pregnancy loss, compared with those who did not have the disease, in a U.K. cohort study.

Those are key findings from what is believed to be one of the largest studies to investigate fertility and obstetric outcomes in patients with psoriasis.

“Studies that have examined fertility and pregnancy outcomes in women with psoriasis have reported conflicting findings,” lead author Teng-Chou Chen, PhD, of the Centre for Pharmacoepidemiology and Drug Safety at the University of Manchester (England), and colleagues from the Global Psoriasis Atlas wrote in the study, published in JAMA Dermatology. Most of the studies were small, with under 100 women, “and are thus likely underpowered to detect a difference in pregnancy outcomes. The majority of those studies used disease registry data or lacked a matched comparison group and hence were unable to estimate the association of fertility and adverse pregnancy outcomes in women with psoriasis when compared with the general population.”

To determine fertility rates and birth outcomes in female patients with psoriasis, compared with age- and practice-matched patients without psoriasis, the researchers evaluated EHR data from a large U.K. primary care database, the Clinical Practice Research Datalink GOLD, from 1998 to 2019. They limited the analysis to patients aged 15-44 years and used relevant codes from clinical consultations to identify those with psoriasis. Then, for each patient with psoriasis, the researchers selected five comparators without psoriasis from the same primary care practice and matched for year of birth.

Both sets of patients were followed from the index date to age 45 years, death, transfer out of practice, last date of data collection, or end of the study period (Dec. 31, 2019), whichever came first. Pregnancy records were extracted for both sets of patients, and birth outcomes were categorized as pregnancy loss, live birth, stillbirth, and preterm birth. Adverse pregnancy outcomes were also collected. Finally, Dr. Chen and colleagues used a negative binomial model to examine the association between psoriasis and the fertility rate, and they applied logistic regression to compare the association between psoriasis and obstetric outcomes.

The analysis included 63,681 patients with psoriasis and 318,405 comparators whose median age on the index date was 30 years and who were followed for a median of 4.1 years. Among patients with psoriasis, 5.1% met criteria for moderate to severe disease in the follow-up period. The researchers observed that, compared with their age- and practice-matched counterparts, patients with psoriasis were more likely to be current smokers, alcohol drinkers, or overweight on the index date. They were also more often diagnosed with diabetes, hypertension, inflammatory bowel disease, thyroid disorders, and respiratory diseases such as asthma and chronic obstructive pulmonary disease.

Fertility, birth outcomes

When they looked at fertility outcomes, the researchers found that, compared with their matched peers without psoriasis, those with psoriasis had higher rates of fertility (risk ratio, 1.30; 95% confidence interval, 1.27-1.33; P < .001). But after the researchers stratified patients based on psoriasis severity, those with moderate to severe disease had significantly lower rates of fertility (RR, 0.75; 95% CI, 0.69-0.83; P < .001), compared those who did not have psoriasis.

As for adverse birth outcomes, compared with their matched comparators, pregnancies in patients with psoriasis were less likely to end in a live birth (odds ratio, 0.91; 95% CI, 0.88-0.93; P < .001). They also had a higher risk of pregnancy loss (OR, 1.06; 95% CI, 1.03-1.10; P < .001), most during the first trimester, at a gestation period of under 91 days.

In addition to psoriasis, patients younger than age 20 (OR, 2.04; 95% CI, 1.94-2.15; P < .011) and those aged between 20 and 24 years (OR, 1.35; 95% CI, 1.31-1.40; P < .001) had a higher risk of pregnancy loss, compared with those aged between 25 and 34 years.

However, no increases in the risks of antenatal hemorrhage, preeclampsia, or gestational diabetes were observed in patients with psoriasis, and no statistically significant differences in the odds of stillbirth and preterm birth were found between patients with psoriasis and matched comparators who did not have psoriasis.

“The mechanism to link the higher risk of pregnancy loss in patients with psoriasis is not clear, but there might be potential explanations,” the researchers wrote. “Psoriasis is characterized by the increased activity of [interleukin]-17, IL-23, and tumor necrosis factor–alpha. Those proinflammatory cytokines may negatively affect the placenta and cause impaired fetal growth.”

They recommended that further studies “evaluate the effects of better management of psoriasis and close monitoring during pregnancy on pregnancy loss.” In particular, “patients with psoriasis were more likely to have comorbidities that may be related to poor pregnancy outcomes, and hence increased emphasis of managing comorbidities as part of the routine management plan is also warranted.”

Asked to comment on the study, Alexa B. Kimball, MD, MPH, who has been involved with research on this topic, said that she and other investigators had observed some years ago that fertility rates for women with moderate to severe psoriasis might be lower than expected.

This trend was observed in some psoriasis registries, some pregnancy registries, and in clinical practice, Dr. Kimball, professor of dermatology at Harvard Medical School, Boston, said in an interview. “This study clearly demonstrates that lower fertility rates in the moderate to severe psoriasis population occurs and compels further exploration of the reason why.” The reasons could be biologic, she continued, including difficulty conceiving or an increased risk of miscarriage, sociobehavioral issues, or a combination.

“Behavioral examples could include that some women with moderate to severe psoriasis can flare during pregnancy, which might affect their choice” to become pregnant, Dr. Kimball said. “Stigma may also play a role in how women with moderate to severe psoriasis form relationships. Now that there are much better treatments for moderate to severe psoriasis and better knowledge about managing psoriasis during pregnancy, it will also be important to explore whether these trends change over time.”

The study was funded by the International League of Dermatological Societies on behalf of the Global Psoriasis Atlas. Two of the study authors reported receiving consulting fees and grant support from many pharmaceutical companies. Dr. Kimball disclosed that she serves or has served on several Organization of Teratology Information Specialists advisory board pregnancy registries, is a consultant and investigator for Abbvie, Janssen, Lilly, Bristol-Myers Squibb, Moonlake, UCB, and Amgen; has fellowship funding from Janssen; and serves on the board of Almirall.

Frailty is an age-associated, nonspecific vulnerability to adverse health outcomes. Frailty can also be described as a complex of symptoms characterized by impaired stress tolerance due to a decline in the functionality of different organs.¹ The prevalence of frailty varies widely depending on the method of measurement and the population studied.^2-4 It is a nonconstant factor that increases with age. A deficit accumulation frailty index (FI) is one method used to measure frailty.⁵ This approach sees frailty as a multidimensional risk state measured by quantity rather than the nature of health concerns. A deficit accumulation FI does not require physical testing but correlates well with other phenotypic FIs.⁶ It is, however, time consuming, as ≥ 30 deficits need to be measured to offer greater stability to the frailty estimate.

Health care is seeing increasing utilization of big data analytics to derive predictive models and help with resource allocation. There are currently 2 existing automated tools to predict health care utilization and mortality at the US Department of Veterans Affairs (VA): the VA Frailty Index (VA-FI-10) and the Care Assessment Need (CAN). VA-FI-10 is an International Statistical Classification of Diseases, Tenth Revision (ICD-10) update of the VA-FI that was created in March 2021. The VA-FI-10 is a claims-based frailty assessment tool using 31 health deficits. Calculating the VA-FI-10 requires defining an index date and lookback period (typically 3 years) relative to which it will be calculated.⁷

CAN is a set of risk-stratifying statistical models run on veterans receiving VA primary care services as part of a patient aligned care team (PACT) using electronic health record data.⁸ Each veteran is stratified based on the individual’s risks of hospitalization, death, and hospitalization or death. These 3 events are predicted for 90-day and 1-year time periods for a total of 6 distinct outcomes. CAN is currently on its third iteration (CAN 2.5) and scores range from 0 (low) to 99 (high). CAN scores are updated weekly. The 1-year hospitalization probabilities for all patients range from 0.8% to 93.1%. For patients with a CAN score of 50, the probability of being hospitalized within a year ranges from 4.5% to 5.2%, which increases to 32.2% to 36% for veterans with a CAN score of 95. The probability range widens significantly (32.2%-93.1%) for patients in the top 5 CAN scores (95-99).

CAN scores are a potential screening tool for frailty among older adults; they are generated automatically and provide acceptable diagnostic accuracy. Hence, the CAN score may be a useful tool for primary care practitioners for the detection of frailty in their patients. The CAN score has shown a moderate positive association with the FRAIL Scale.^9,10 The population-based studies that have used the FI approach (differing FIs, depending on the data available) give robust results: People accumulate an average of 0.03 deficits per year after the age of 70 years.¹¹ Interventions to delay or reverse frailty have not been clearly defined with heterogeneity in the definition of frailty and measurement of frailty outcomes.^12,13 The prevalence of frailty in the veteran population is substantially higher than the prevalence in community populations with a similar age distribution. There is also mounting evidence that veterans accumulate deficits more rapidly than their civilian counterparts.¹⁴

COVID-19 was declared a pandemic in March 2020 and had many impacts on global health that were most marked in the first year. These included reductions in hospital visits for non-COVID-19 health concerns, a reduction in completed screening tests, an initial reduction in other infectious diseases (attributable to quarantines), and an increase or worsening of mental health concerns.^15,16

We aimed to investigate whether frailty increased disproportionately in a subset of older veterans in the first year of the COVID-19 pandemic when compared with the previous year using CAN scores. This single institution, longitudinal cohort study was determined to be exempt from institutional review board review but was approved by the Phoenix VA Health Care System (PVAHCS) Research and Development Committee.

Methods

The Office of Clinical Systems Development and Evaluation (CSDE–10E2A) produces a weekly CAN Score Report to help identify the highest-risk patients in a primary care panel or cohort. CAN scores range from 0 (lowest risk) to 99 (highest risk), indicating how likely a patient is to experience hospitalization or death compared with other VA patients. CAN scores are calculated with statistical prediction models that use data elements from the following Corporate Data Warehouse (CDW) domains: demographics, health care utilization, laboratory tests, medical conditions, medications, and vital signs (eAppendix available online at 10.12788/fp.0385).

The CAN Score Report is generated weekly and stored on a CDW server. A patient will receive all 6 distinct CAN scores if they are: (1) assigned to a primary care PACT on the risk date; (2) a veteran; (3) not hospitalized in a VA facility on the risk date; and (4) alive as of the risk date. New to CAN 2.5 is that patients who meet criteria 1, 2, and 4 but are hospitalized in a VA facility on the risk date will receive CAN scores for the 1-year and 90-day mortality models.

Utilizing VA Informatics and Computing Infrastructure (VA HSR RES 13-457, US Department of Veterans Affairs [2008]), we obtained 2 lists of veterans aged 70 to 75 years on February 8, 2019, with a calculated CAN score of ≥ 75 for 1-year mortality and 1-year hospitalization on that date. A veteran with a CAN score of ≥ 75 is likely to be prefrail or frail.^9,10 Veterans who did not have a corresponding calculated CAN score on February 7, 2020, and February 12, 2021, were excluded. COVID-19 was declared a public health emergency in the United States on January 31, 2020, and the World Health Organization declared COVID-19 a pandemic on March 11, 2020.¹⁷ We picked February 7, 2020, within this time frame and without any other special significance. We picked additional CAN score calculation dates approximately 1 year prior and 1 year after this date. Veterans had to be alive on February 12, 2021, (the last date of the CAN score) to be included in the cohorts.

Statistical Analyses

The difference in CAN score from one year to the next was calculated for each patient. The difference between 2019 and 2020 was compared with the difference between 2020 to 2021 using a paired t test. Yearly CAN score values were analyzed using repeated measures analysis of variance. The number of patients that showed an increase in CAN score (ie, increased risk of either mortality or hospitalization within the year) or a decrease (lower risk) was compared using the χ² test. IBM SPSS v26 and GraphPad Prism v18 were used for statistical analysis. P < .05 was considered statistically significant.

Results

There were 3538 veterans at PVAHCS who met the inclusion criteria and had a 1-year mortality CAN score ≥ 75 on February 8, 2019.

In the hospitalization group, there were 6046 veterans in the analysis; 57 veterans missing a 1-year hospitalization CAN score that were excluded. The mean age was 71.7 (1.3) years and included 5874 male (97.2%) and 172 female (2.8%) veterans. There was a decline in mean 1-year hospitalization CAN scores in our subset of frail older veterans by 2.8 (95% CI, -3.1 to -2.6) in the year preceding the COVID-19 pandemic. This mean decline slowed significantly to 1.5 (95% CI, -1.8 to -1.2; P < .0001) after the first year of the COVID-19 pandemic. Mean CAN scores for 1-year hospitalization were 84.6 (95% CI, 84.4 to 84.8), 81.8 (95% CI, 81.5 to 82.1), and 80.2 (95% CI, 79.9 to 80.6) for 2019, 2020, and 2021, respectively.

We also calculated the number of veterans with increasing, stable, and decreasing CAN scores across each of our defined periods in both the 1-year mortality and hospitalization groups.

Discussion

We studied frailty trends in an older veteran subpopulation enrolled at the PVAHCS 1 year prior and into the COVID-19 pandemic using CAN scores. Frailty is a dynamic state. Previous frailty assessments aimed to identify patients at the highest risk of death. With the advent of advanced therapeutics for several diseases, the number of medical conditions that are now managed as chronic illnesses continues to grow. There is a role for repeated measures of frailty to try to identify frailty trends.¹⁹ These trends may assist us in resource allocation, identifying interventions that work and those that do not.

Some studies have shown an overall declining lethality of frailty. This may reflect improvements in the care and management of chronic conditions, screening tests, and increased awareness of healthy lifestyles.²⁰ Another study of frailty trajectories in a veteran population in the 5 years preceding death showed multiple trajectories (stable, gradually increasing, rapidly increasing, and recovering).¹⁹

The PACT is a primary care model implemented at VA medical centers in April 2010. It is a patient-centered medical home model (PCMH) with several components. The VA treats a population of socioeconomically vulnerable patients with complex chronic illness management needs. Some of the components of a PACT model relevant to our study include facilitated self-management support for veterans in between practitioner visits via care partners, peer-to-peer and transitional care programs, physical activity and diet programs, primary care mental health, integration between primary and specialty care, and telehealth.²¹ A previous study has shown that VA primary care clinics with the most PCMH components in place had greater improvements in several chronic disease quality measures than in clinics with a lower number of PCMH components.²²

Limitations

Our study is limited by our older veteran population demographics. We chose only a subset of older veterans at a single VA center for this study and cannot extrapolate the results to all older frail veterans or community dwelling older adults. Robust individuals may also transition to prefrailty and frailty over longer periods; our study monitored frailty trends over 2 years.

CAN scores are not quality measures to improve upon. Allocation and utilization of additional resources may clinically benefit a patient but increase their CAN scores. Although our results are statistically significant, we are unable to make any conclusions about clinical significance.

Conclusions

Our study results indicate frailty as determined by 1-year mortality CAN scores significantly increased in a subset of older veterans during the first year of the COVID-19 pandemic when compared with the previous year. Whether this change in frailty is temporary or long lasting remains to be seen. Automated CAN scores can be effectively utilized to monitor frailty trends in certain veteran populations over longer periods.

Acknowledgments

This material is the result of work supported with resources and the use of facilities at the Phoenix Veterans Affairs Health Care System.

Frailty is an age-associated, nonspecific vulnerability to adverse health outcomes. Frailty can also be described as a complex of symptoms characterized by impaired stress tolerance due to a decline in the functionality of different organs.¹ The prevalence of frailty varies widely depending on the method of measurement and the population studied.^2-4 It is a nonconstant factor that increases with age. A deficit accumulation frailty index (FI) is one method used to measure frailty.⁵ This approach sees frailty as a multidimensional risk state measured by quantity rather than the nature of health concerns. A deficit accumulation FI does not require physical testing but correlates well with other phenotypic FIs.⁶ It is, however, time consuming, as ≥ 30 deficits need to be measured to offer greater stability to the frailty estimate.

Health care is seeing increasing utilization of big data analytics to derive predictive models and help with resource allocation. There are currently 2 existing automated tools to predict health care utilization and mortality at the US Department of Veterans Affairs (VA): the VA Frailty Index (VA-FI-10) and the Care Assessment Need (CAN). VA-FI-10 is an International Statistical Classification of Diseases, Tenth Revision (ICD-10) update of the VA-FI that was created in March 2021. The VA-FI-10 is a claims-based frailty assessment tool using 31 health deficits. Calculating the VA-FI-10 requires defining an index date and lookback period (typically 3 years) relative to which it will be calculated.⁷

CAN is a set of risk-stratifying statistical models run on veterans receiving VA primary care services as part of a patient aligned care team (PACT) using electronic health record data.⁸ Each veteran is stratified based on the individual’s risks of hospitalization, death, and hospitalization or death. These 3 events are predicted for 90-day and 1-year time periods for a total of 6 distinct outcomes. CAN is currently on its third iteration (CAN 2.5) and scores range from 0 (low) to 99 (high). CAN scores are updated weekly. The 1-year hospitalization probabilities for all patients range from 0.8% to 93.1%. For patients with a CAN score of 50, the probability of being hospitalized within a year ranges from 4.5% to 5.2%, which increases to 32.2% to 36% for veterans with a CAN score of 95. The probability range widens significantly (32.2%-93.1%) for patients in the top 5 CAN scores (95-99).

CAN scores are a potential screening tool for frailty among older adults; they are generated automatically and provide acceptable diagnostic accuracy. Hence, the CAN score may be a useful tool for primary care practitioners for the detection of frailty in their patients. The CAN score has shown a moderate positive association with the FRAIL Scale.^9,10 The population-based studies that have used the FI approach (differing FIs, depending on the data available) give robust results: People accumulate an average of 0.03 deficits per year after the age of 70 years.¹¹ Interventions to delay or reverse frailty have not been clearly defined with heterogeneity in the definition of frailty and measurement of frailty outcomes.^12,13 The prevalence of frailty in the veteran population is substantially higher than the prevalence in community populations with a similar age distribution. There is also mounting evidence that veterans accumulate deficits more rapidly than their civilian counterparts.¹⁴

COVID-19 was declared a pandemic in March 2020 and had many impacts on global health that were most marked in the first year. These included reductions in hospital visits for non-COVID-19 health concerns, a reduction in completed screening tests, an initial reduction in other infectious diseases (attributable to quarantines), and an increase or worsening of mental health concerns.^15,16

We aimed to investigate whether frailty increased disproportionately in a subset of older veterans in the first year of the COVID-19 pandemic when compared with the previous year using CAN scores. This single institution, longitudinal cohort study was determined to be exempt from institutional review board review but was approved by the Phoenix VA Health Care System (PVAHCS) Research and Development Committee.

Methods

The Office of Clinical Systems Development and Evaluation (CSDE–10E2A) produces a weekly CAN Score Report to help identify the highest-risk patients in a primary care panel or cohort. CAN scores range from 0 (lowest risk) to 99 (highest risk), indicating how likely a patient is to experience hospitalization or death compared with other VA patients. CAN scores are calculated with statistical prediction models that use data elements from the following Corporate Data Warehouse (CDW) domains: demographics, health care utilization, laboratory tests, medical conditions, medications, and vital signs (eAppendix available online at 10.12788/fp.0385).

The CAN Score Report is generated weekly and stored on a CDW server. A patient will receive all 6 distinct CAN scores if they are: (1) assigned to a primary care PACT on the risk date; (2) a veteran; (3) not hospitalized in a VA facility on the risk date; and (4) alive as of the risk date. New to CAN 2.5 is that patients who meet criteria 1, 2, and 4 but are hospitalized in a VA facility on the risk date will receive CAN scores for the 1-year and 90-day mortality models.

Utilizing VA Informatics and Computing Infrastructure (VA HSR RES 13-457, US Department of Veterans Affairs [2008]), we obtained 2 lists of veterans aged 70 to 75 years on February 8, 2019, with a calculated CAN score of ≥ 75 for 1-year mortality and 1-year hospitalization on that date. A veteran with a CAN score of ≥ 75 is likely to be prefrail or frail.^9,10 Veterans who did not have a corresponding calculated CAN score on February 7, 2020, and February 12, 2021, were excluded. COVID-19 was declared a public health emergency in the United States on January 31, 2020, and the World Health Organization declared COVID-19 a pandemic on March 11, 2020.¹⁷ We picked February 7, 2020, within this time frame and without any other special significance. We picked additional CAN score calculation dates approximately 1 year prior and 1 year after this date. Veterans had to be alive on February 12, 2021, (the last date of the CAN score) to be included in the cohorts.

Statistical Analyses

The difference in CAN score from one year to the next was calculated for each patient. The difference between 2019 and 2020 was compared with the difference between 2020 to 2021 using a paired t test. Yearly CAN score values were analyzed using repeated measures analysis of variance. The number of patients that showed an increase in CAN score (ie, increased risk of either mortality or hospitalization within the year) or a decrease (lower risk) was compared using the χ² test. IBM SPSS v26 and GraphPad Prism v18 were used for statistical analysis. P < .05 was considered statistically significant.

Results

There were 3538 veterans at PVAHCS who met the inclusion criteria and had a 1-year mortality CAN score ≥ 75 on February 8, 2019.

In the hospitalization group, there were 6046 veterans in the analysis; 57 veterans missing a 1-year hospitalization CAN score that were excluded. The mean age was 71.7 (1.3) years and included 5874 male (97.2%) and 172 female (2.8%) veterans. There was a decline in mean 1-year hospitalization CAN scores in our subset of frail older veterans by 2.8 (95% CI, -3.1 to -2.6) in the year preceding the COVID-19 pandemic. This mean decline slowed significantly to 1.5 (95% CI, -1.8 to -1.2; P < .0001) after the first year of the COVID-19 pandemic. Mean CAN scores for 1-year hospitalization were 84.6 (95% CI, 84.4 to 84.8), 81.8 (95% CI, 81.5 to 82.1), and 80.2 (95% CI, 79.9 to 80.6) for 2019, 2020, and 2021, respectively.

We also calculated the number of veterans with increasing, stable, and decreasing CAN scores across each of our defined periods in both the 1-year mortality and hospitalization groups.

Discussion

We studied frailty trends in an older veteran subpopulation enrolled at the PVAHCS 1 year prior and into the COVID-19 pandemic using CAN scores. Frailty is a dynamic state. Previous frailty assessments aimed to identify patients at the highest risk of death. With the advent of advanced therapeutics for several diseases, the number of medical conditions that are now managed as chronic illnesses continues to grow. There is a role for repeated measures of frailty to try to identify frailty trends.¹⁹ These trends may assist us in resource allocation, identifying interventions that work and those that do not.

Some studies have shown an overall declining lethality of frailty. This may reflect improvements in the care and management of chronic conditions, screening tests, and increased awareness of healthy lifestyles.²⁰ Another study of frailty trajectories in a veteran population in the 5 years preceding death showed multiple trajectories (stable, gradually increasing, rapidly increasing, and recovering).¹⁹

The PACT is a primary care model implemented at VA medical centers in April 2010. It is a patient-centered medical home model (PCMH) with several components. The VA treats a population of socioeconomically vulnerable patients with complex chronic illness management needs. Some of the components of a PACT model relevant to our study include facilitated self-management support for veterans in between practitioner visits via care partners, peer-to-peer and transitional care programs, physical activity and diet programs, primary care mental health, integration between primary and specialty care, and telehealth.²¹ A previous study has shown that VA primary care clinics with the most PCMH components in place had greater improvements in several chronic disease quality measures than in clinics with a lower number of PCMH components.²²

Limitations

Our study is limited by our older veteran population demographics. We chose only a subset of older veterans at a single VA center for this study and cannot extrapolate the results to all older frail veterans or community dwelling older adults. Robust individuals may also transition to prefrailty and frailty over longer periods; our study monitored frailty trends over 2 years.

CAN scores are not quality measures to improve upon. Allocation and utilization of additional resources may clinically benefit a patient but increase their CAN scores. Although our results are statistically significant, we are unable to make any conclusions about clinical significance.

Conclusions

Our study results indicate frailty as determined by 1-year mortality CAN scores significantly increased in a subset of older veterans during the first year of the COVID-19 pandemic when compared with the previous year. Whether this change in frailty is temporary or long lasting remains to be seen. Automated CAN scores can be effectively utilized to monitor frailty trends in certain veteran populations over longer periods.

Acknowledgments

This material is the result of work supported with resources and the use of facilities at the Phoenix Veterans Affairs Health Care System.

Frailty is an age-associated, nonspecific vulnerability to adverse health outcomes. Frailty can also be described as a complex of symptoms characterized by impaired stress tolerance due to a decline in the functionality of different organs.¹ The prevalence of frailty varies widely depending on the method of measurement and the population studied.^2-4 It is a nonconstant factor that increases with age. A deficit accumulation frailty index (FI) is one method used to measure frailty.⁵ This approach sees frailty as a multidimensional risk state measured by quantity rather than the nature of health concerns. A deficit accumulation FI does not require physical testing but correlates well with other phenotypic FIs.⁶ It is, however, time consuming, as ≥ 30 deficits need to be measured to offer greater stability to the frailty estimate.

Health care is seeing increasing utilization of big data analytics to derive predictive models and help with resource allocation. There are currently 2 existing automated tools to predict health care utilization and mortality at the US Department of Veterans Affairs (VA): the VA Frailty Index (VA-FI-10) and the Care Assessment Need (CAN). VA-FI-10 is an International Statistical Classification of Diseases, Tenth Revision (ICD-10) update of the VA-FI that was created in March 2021. The VA-FI-10 is a claims-based frailty assessment tool using 31 health deficits. Calculating the VA-FI-10 requires defining an index date and lookback period (typically 3 years) relative to which it will be calculated.⁷

CAN is a set of risk-stratifying statistical models run on veterans receiving VA primary care services as part of a patient aligned care team (PACT) using electronic health record data.⁸ Each veteran is stratified based on the individual’s risks of hospitalization, death, and hospitalization or death. These 3 events are predicted for 90-day and 1-year time periods for a total of 6 distinct outcomes. CAN is currently on its third iteration (CAN 2.5) and scores range from 0 (low) to 99 (high). CAN scores are updated weekly. The 1-year hospitalization probabilities for all patients range from 0.8% to 93.1%. For patients with a CAN score of 50, the probability of being hospitalized within a year ranges from 4.5% to 5.2%, which increases to 32.2% to 36% for veterans with a CAN score of 95. The probability range widens significantly (32.2%-93.1%) for patients in the top 5 CAN scores (95-99).

CAN scores are a potential screening tool for frailty among older adults; they are generated automatically and provide acceptable diagnostic accuracy. Hence, the CAN score may be a useful tool for primary care practitioners for the detection of frailty in their patients. The CAN score has shown a moderate positive association with the FRAIL Scale.^9,10 The population-based studies that have used the FI approach (differing FIs, depending on the data available) give robust results: People accumulate an average of 0.03 deficits per year after the age of 70 years.¹¹ Interventions to delay or reverse frailty have not been clearly defined with heterogeneity in the definition of frailty and measurement of frailty outcomes.^12,13 The prevalence of frailty in the veteran population is substantially higher than the prevalence in community populations with a similar age distribution. There is also mounting evidence that veterans accumulate deficits more rapidly than their civilian counterparts.¹⁴

COVID-19 was declared a pandemic in March 2020 and had many impacts on global health that were most marked in the first year. These included reductions in hospital visits for non-COVID-19 health concerns, a reduction in completed screening tests, an initial reduction in other infectious diseases (attributable to quarantines), and an increase or worsening of mental health concerns.^15,16

We aimed to investigate whether frailty increased disproportionately in a subset of older veterans in the first year of the COVID-19 pandemic when compared with the previous year using CAN scores. This single institution, longitudinal cohort study was determined to be exempt from institutional review board review but was approved by the Phoenix VA Health Care System (PVAHCS) Research and Development Committee.

Methods

The Office of Clinical Systems Development and Evaluation (CSDE–10E2A) produces a weekly CAN Score Report to help identify the highest-risk patients in a primary care panel or cohort. CAN scores range from 0 (lowest risk) to 99 (highest risk), indicating how likely a patient is to experience hospitalization or death compared with other VA patients. CAN scores are calculated with statistical prediction models that use data elements from the following Corporate Data Warehouse (CDW) domains: demographics, health care utilization, laboratory tests, medical conditions, medications, and vital signs (eAppendix available online at 10.12788/fp.0385).

The CAN Score Report is generated weekly and stored on a CDW server. A patient will receive all 6 distinct CAN scores if they are: (1) assigned to a primary care PACT on the risk date; (2) a veteran; (3) not hospitalized in a VA facility on the risk date; and (4) alive as of the risk date. New to CAN 2.5 is that patients who meet criteria 1, 2, and 4 but are hospitalized in a VA facility on the risk date will receive CAN scores for the 1-year and 90-day mortality models.

Utilizing VA Informatics and Computing Infrastructure (VA HSR RES 13-457, US Department of Veterans Affairs [2008]), we obtained 2 lists of veterans aged 70 to 75 years on February 8, 2019, with a calculated CAN score of ≥ 75 for 1-year mortality and 1-year hospitalization on that date. A veteran with a CAN score of ≥ 75 is likely to be prefrail or frail.^9,10 Veterans who did not have a corresponding calculated CAN score on February 7, 2020, and February 12, 2021, were excluded. COVID-19 was declared a public health emergency in the United States on January 31, 2020, and the World Health Organization declared COVID-19 a pandemic on March 11, 2020.¹⁷ We picked February 7, 2020, within this time frame and without any other special significance. We picked additional CAN score calculation dates approximately 1 year prior and 1 year after this date. Veterans had to be alive on February 12, 2021, (the last date of the CAN score) to be included in the cohorts.

Statistical Analyses

The difference in CAN score from one year to the next was calculated for each patient. The difference between 2019 and 2020 was compared with the difference between 2020 to 2021 using a paired t test. Yearly CAN score values were analyzed using repeated measures analysis of variance. The number of patients that showed an increase in CAN score (ie, increased risk of either mortality or hospitalization within the year) or a decrease (lower risk) was compared using the χ² test. IBM SPSS v26 and GraphPad Prism v18 were used for statistical analysis. P < .05 was considered statistically significant.

Results

There were 3538 veterans at PVAHCS who met the inclusion criteria and had a 1-year mortality CAN score ≥ 75 on February 8, 2019.

In the hospitalization group, there were 6046 veterans in the analysis; 57 veterans missing a 1-year hospitalization CAN score that were excluded. The mean age was 71.7 (1.3) years and included 5874 male (97.2%) and 172 female (2.8%) veterans. There was a decline in mean 1-year hospitalization CAN scores in our subset of frail older veterans by 2.8 (95% CI, -3.1 to -2.6) in the year preceding the COVID-19 pandemic. This mean decline slowed significantly to 1.5 (95% CI, -1.8 to -1.2; P < .0001) after the first year of the COVID-19 pandemic. Mean CAN scores for 1-year hospitalization were 84.6 (95% CI, 84.4 to 84.8), 81.8 (95% CI, 81.5 to 82.1), and 80.2 (95% CI, 79.9 to 80.6) for 2019, 2020, and 2021, respectively.

We also calculated the number of veterans with increasing, stable, and decreasing CAN scores across each of our defined periods in both the 1-year mortality and hospitalization groups.

Discussion

We studied frailty trends in an older veteran subpopulation enrolled at the PVAHCS 1 year prior and into the COVID-19 pandemic using CAN scores. Frailty is a dynamic state. Previous frailty assessments aimed to identify patients at the highest risk of death. With the advent of advanced therapeutics for several diseases, the number of medical conditions that are now managed as chronic illnesses continues to grow. There is a role for repeated measures of frailty to try to identify frailty trends.¹⁹ These trends may assist us in resource allocation, identifying interventions that work and those that do not.

Some studies have shown an overall declining lethality of frailty. This may reflect improvements in the care and management of chronic conditions, screening tests, and increased awareness of healthy lifestyles.²⁰ Another study of frailty trajectories in a veteran population in the 5 years preceding death showed multiple trajectories (stable, gradually increasing, rapidly increasing, and recovering).¹⁹

The PACT is a primary care model implemented at VA medical centers in April 2010. It is a patient-centered medical home model (PCMH) with several components. The VA treats a population of socioeconomically vulnerable patients with complex chronic illness management needs. Some of the components of a PACT model relevant to our study include facilitated self-management support for veterans in between practitioner visits via care partners, peer-to-peer and transitional care programs, physical activity and diet programs, primary care mental health, integration between primary and specialty care, and telehealth.²¹ A previous study has shown that VA primary care clinics with the most PCMH components in place had greater improvements in several chronic disease quality measures than in clinics with a lower number of PCMH components.²²

Limitations

Our study is limited by our older veteran population demographics. We chose only a subset of older veterans at a single VA center for this study and cannot extrapolate the results to all older frail veterans or community dwelling older adults. Robust individuals may also transition to prefrailty and frailty over longer periods; our study monitored frailty trends over 2 years.

CAN scores are not quality measures to improve upon. Allocation and utilization of additional resources may clinically benefit a patient but increase their CAN scores. Although our results are statistically significant, we are unable to make any conclusions about clinical significance.

Conclusions

Our study results indicate frailty as determined by 1-year mortality CAN scores significantly increased in a subset of older veterans during the first year of the COVID-19 pandemic when compared with the previous year. Whether this change in frailty is temporary or long lasting remains to be seen. Automated CAN scores can be effectively utilized to monitor frailty trends in certain veteran populations over longer periods.

Acknowledgments

This material is the result of work supported with resources and the use of facilities at the Phoenix Veterans Affairs Health Care System.