Key clinical point: Resistance training (RT) effectively reduces glycosylated hemoglobin (HbA1c) in patients with type 2 diabetes mellitus (T2D), with RT interventions triggering a larger vs. medium or smaller improvement in muscular strength leading to a greater reduction in HbA1c.

Major finding: RT intervention vs. control treatment significantly decreased HbA1c (weighted mean difference −0.39; P < .001), with a larger vs. medium or small effect on muscular strength leading to a greater reduction in HbA1c (β −0.99; P = .0470).

Study details: Findings are from a meta-analysis of 20 trials including 1172 patients with T2DM.

Disclosures: The study received no specific funding. The authors declared no competing interests.

Source: Jansson AK et al. Effect of resistance training on HbA1c in adults with type 2 diabetes mellitus and the moderating effect of changes in muscular strength: a systematic review and meta-analysis. BMJ Open Diabetes Res Care. 2022;10:e002595 (Mar 10). Doi: 10.1136/bmjdrc-2021-002595

Key clinical point: Resistance training (RT) effectively reduces glycosylated hemoglobin (HbA1c) in patients with type 2 diabetes mellitus (T2D), with RT interventions triggering a larger vs. medium or smaller improvement in muscular strength leading to a greater reduction in HbA1c.

Major finding: RT intervention vs. control treatment significantly decreased HbA1c (weighted mean difference −0.39; P < .001), with a larger vs. medium or small effect on muscular strength leading to a greater reduction in HbA1c (β −0.99; P = .0470).

Study details: Findings are from a meta-analysis of 20 trials including 1172 patients with T2DM.

Disclosures: The study received no specific funding. The authors declared no competing interests.

Source: Jansson AK et al. Effect of resistance training on HbA1c in adults with type 2 diabetes mellitus and the moderating effect of changes in muscular strength: a systematic review and meta-analysis. BMJ Open Diabetes Res Care. 2022;10:e002595 (Mar 10). Doi: 10.1136/bmjdrc-2021-002595

Key clinical point: Resistance training (RT) effectively reduces glycosylated hemoglobin (HbA1c) in patients with type 2 diabetes mellitus (T2D), with RT interventions triggering a larger vs. medium or smaller improvement in muscular strength leading to a greater reduction in HbA1c.

Major finding: RT intervention vs. control treatment significantly decreased HbA1c (weighted mean difference −0.39; P < .001), with a larger vs. medium or small effect on muscular strength leading to a greater reduction in HbA1c (β −0.99; P = .0470).

Study details: Findings are from a meta-analysis of 20 trials including 1172 patients with T2DM.

Disclosures: The study received no specific funding. The authors declared no competing interests.

Source: Jansson AK et al. Effect of resistance training on HbA1c in adults with type 2 diabetes mellitus and the moderating effect of changes in muscular strength: a systematic review and meta-analysis. BMJ Open Diabetes Res Care. 2022;10:e002595 (Mar 10). Doi: 10.1136/bmjdrc-2021-002595

Key clinical point: Fenofibrate reduced the composite outcome of heart failure (HF) hospitalizations or cardiovascular death in patients with type 2 diabetes (T2D) treated with simvastatin, predominantly in those who received the standard background glucose-lowering therapy.

Major finding: The composite outcome of HF hospitalization or cardiovascular death was significantly lower with fenofibrate vs. placebo (hazard ratio [HR] 0.82; P = .048), with reduction primarily observed with the standard glucose-lowering strategy (HR 0.64; 95% CI 0.48-0.85), but not with the intensive glucose-lowering strategy (HR 1.02; 95% CI 0.79-1.33; P_interaction = .017).

Study details: Findings are from the ACCORD Lipid trial including 5518 patients with T2D who were randomly assigned to receive simvastatin plus fenofibrate (n = 2765) or simvastatin plus placebo (n = 2753).

Disclosures: The study was funded by national funds through FCT-Portuguese Foundation for

Science and Technology, under the scope of the Cardiovascular R&D Center-UnIC. Some authors declared being consultants and receiving research support or personal fees from various sources.

Source: Ferreira JP et al. Fenofibrate and heart failure outcomes in patients with type 2 diabetes: analysis from ACCORD. Diabetes Care. 2022 (Mar 23). Doi: 10.2337/dc21-1977

Key clinical point: Fenofibrate reduced the composite outcome of heart failure (HF) hospitalizations or cardiovascular death in patients with type 2 diabetes (T2D) treated with simvastatin, predominantly in those who received the standard background glucose-lowering therapy.

Major finding: The composite outcome of HF hospitalization or cardiovascular death was significantly lower with fenofibrate vs. placebo (hazard ratio [HR] 0.82; P = .048), with reduction primarily observed with the standard glucose-lowering strategy (HR 0.64; 95% CI 0.48-0.85), but not with the intensive glucose-lowering strategy (HR 1.02; 95% CI 0.79-1.33; P_interaction = .017).

Study details: Findings are from the ACCORD Lipid trial including 5518 patients with T2D who were randomly assigned to receive simvastatin plus fenofibrate (n = 2765) or simvastatin plus placebo (n = 2753).

Disclosures: The study was funded by national funds through FCT-Portuguese Foundation for

Science and Technology, under the scope of the Cardiovascular R&D Center-UnIC. Some authors declared being consultants and receiving research support or personal fees from various sources.

Source: Ferreira JP et al. Fenofibrate and heart failure outcomes in patients with type 2 diabetes: analysis from ACCORD. Diabetes Care. 2022 (Mar 23). Doi: 10.2337/dc21-1977

Key clinical point: Fenofibrate reduced the composite outcome of heart failure (HF) hospitalizations or cardiovascular death in patients with type 2 diabetes (T2D) treated with simvastatin, predominantly in those who received the standard background glucose-lowering therapy.

Major finding: The composite outcome of HF hospitalization or cardiovascular death was significantly lower with fenofibrate vs. placebo (hazard ratio [HR] 0.82; P = .048), with reduction primarily observed with the standard glucose-lowering strategy (HR 0.64; 95% CI 0.48-0.85), but not with the intensive glucose-lowering strategy (HR 1.02; 95% CI 0.79-1.33; P_interaction = .017).

Study details: Findings are from the ACCORD Lipid trial including 5518 patients with T2D who were randomly assigned to receive simvastatin plus fenofibrate (n = 2765) or simvastatin plus placebo (n = 2753).

Disclosures: The study was funded by national funds through FCT-Portuguese Foundation for

Science and Technology, under the scope of the Cardiovascular R&D Center-UnIC. Some authors declared being consultants and receiving research support or personal fees from various sources.

Source: Ferreira JP et al. Fenofibrate and heart failure outcomes in patients with type 2 diabetes: analysis from ACCORD. Diabetes Care. 2022 (Mar 23). Doi: 10.2337/dc21-1977

Key clinical point: Empagliflozin showed a beneficial effect on cognitive and physical impairment in frail older patients with type 2 diabetes (T2D) and heart failure with preserved ejection fraction (HFpEF).

Major finding: The mean Montreal Cognitive Assessment score significantly improved from baseline to 1 month in the empagliflozin group (19.80 vs. 22.25; P < .001) but not in the metformin (P = .26) and insulin (P = .81) groups, with empagliflozin showing a significant effect on amelioration of cognitive impairment (odds ratio 3.609; P = .03). The 5-meter gait speed improved significantly in the empagliflozin and metformin groups (both P < .05), but not in the insulin group.

Study details: This prospective observational study included 162 frail older patients aged >65 years who had T2D and HFpEF and were treated with empagliflozin (n = 52), metformin (n = 56), or insulin (n = 54).

Disclosures: The study was partly supported by the US National Institute of Diabetes and Digestive and Kidney Diseases, US National Heart, Lung, and Blood Institute, and US National Institute on Aging, among others. The authors declared no conflicts of interest.

Source: Mone P et al. Empagliflozin improves cognitive impairment in frail older adults with type 2 diabetes and heart failure with preserved ejection fraction. Diabetes Care. 2022 (Mar 21). Doi: 10.2337/dc21-2434

Key clinical point: Empagliflozin showed a beneficial effect on cognitive and physical impairment in frail older patients with type 2 diabetes (T2D) and heart failure with preserved ejection fraction (HFpEF).

Major finding: The mean Montreal Cognitive Assessment score significantly improved from baseline to 1 month in the empagliflozin group (19.80 vs. 22.25; P < .001) but not in the metformin (P = .26) and insulin (P = .81) groups, with empagliflozin showing a significant effect on amelioration of cognitive impairment (odds ratio 3.609; P = .03). The 5-meter gait speed improved significantly in the empagliflozin and metformin groups (both P < .05), but not in the insulin group.

Study details: This prospective observational study included 162 frail older patients aged >65 years who had T2D and HFpEF and were treated with empagliflozin (n = 52), metformin (n = 56), or insulin (n = 54).

Disclosures: The study was partly supported by the US National Institute of Diabetes and Digestive and Kidney Diseases, US National Heart, Lung, and Blood Institute, and US National Institute on Aging, among others. The authors declared no conflicts of interest.

Source: Mone P et al. Empagliflozin improves cognitive impairment in frail older adults with type 2 diabetes and heart failure with preserved ejection fraction. Diabetes Care. 2022 (Mar 21). Doi: 10.2337/dc21-2434

Key clinical point: Empagliflozin showed a beneficial effect on cognitive and physical impairment in frail older patients with type 2 diabetes (T2D) and heart failure with preserved ejection fraction (HFpEF).

Major finding: The mean Montreal Cognitive Assessment score significantly improved from baseline to 1 month in the empagliflozin group (19.80 vs. 22.25; P < .001) but not in the metformin (P = .26) and insulin (P = .81) groups, with empagliflozin showing a significant effect on amelioration of cognitive impairment (odds ratio 3.609; P = .03). The 5-meter gait speed improved significantly in the empagliflozin and metformin groups (both P < .05), but not in the insulin group.

Study details: This prospective observational study included 162 frail older patients aged >65 years who had T2D and HFpEF and were treated with empagliflozin (n = 52), metformin (n = 56), or insulin (n = 54).

Disclosures: The study was partly supported by the US National Institute of Diabetes and Digestive and Kidney Diseases, US National Heart, Lung, and Blood Institute, and US National Institute on Aging, among others. The authors declared no conflicts of interest.

Source: Mone P et al. Empagliflozin improves cognitive impairment in frail older adults with type 2 diabetes and heart failure with preserved ejection fraction. Diabetes Care. 2022 (Mar 21). Doi: 10.2337/dc21-2434

Key clinical point: Dapagliflozin in addition to standard-of-care treatment demonstrated a clinically relevant decrease in glycated hemoglobin (HbA1c) and an acceptable safety profile in young people with type 2 diabetes (T2D).

Major finding: At 24 weeks, the adjusted mean change in HbA1c was not significantly different between the dapagliflozin and placebo groups in the intention-to-treat analysis (between-group difference [Δ] −0.75%; P = .10), but was significantly different in the sensitivity analysis in the per-protocol population (Δ −1.13%; P = .012). No new safety signals or episodes of death or diabetic ketoacidosis were recorded.

Study details: The data come from a phase 3 trial including 72 participants aged 10-24 years with T2D and HbA1c concentration of 6.5%-11% who were randomly assigned to receive oral dapagliflozin (10 mg) or placebo in addition to standard-of-care treatment for 24 weeks followed by dapagliflozin for 28 weeks

Disclosures: The study was funded by AstraZeneca. Some authors declared receiving consulting fees or research grants or serving on advisory boards for various sources, including AstraZeneca. Three authors declared being stockholders or employees of AstraZeneca.

Source: Tamborlane WV, Laffel LM et al. Efficacy and safety of dapagliflozin in children and young adults with type 2 diabetes: a prospective, multicentre, randomised, parallel group, phase 3 study. Lancet Diabetes Endocrinol. 2022 (Apr 1). Doi: 10.1016/S2213-8587(22)00052-3

Key clinical point: Dapagliflozin in addition to standard-of-care treatment demonstrated a clinically relevant decrease in glycated hemoglobin (HbA1c) and an acceptable safety profile in young people with type 2 diabetes (T2D).

Major finding: At 24 weeks, the adjusted mean change in HbA1c was not significantly different between the dapagliflozin and placebo groups in the intention-to-treat analysis (between-group difference [Δ] −0.75%; P = .10), but was significantly different in the sensitivity analysis in the per-protocol population (Δ −1.13%; P = .012). No new safety signals or episodes of death or diabetic ketoacidosis were recorded.

Study details: The data come from a phase 3 trial including 72 participants aged 10-24 years with T2D and HbA1c concentration of 6.5%-11% who were randomly assigned to receive oral dapagliflozin (10 mg) or placebo in addition to standard-of-care treatment for 24 weeks followed by dapagliflozin for 28 weeks

Disclosures: The study was funded by AstraZeneca. Some authors declared receiving consulting fees or research grants or serving on advisory boards for various sources, including AstraZeneca. Three authors declared being stockholders or employees of AstraZeneca.

Source: Tamborlane WV, Laffel LM et al. Efficacy and safety of dapagliflozin in children and young adults with type 2 diabetes: a prospective, multicentre, randomised, parallel group, phase 3 study. Lancet Diabetes Endocrinol. 2022 (Apr 1). Doi: 10.1016/S2213-8587(22)00052-3

Key clinical point: Dapagliflozin in addition to standard-of-care treatment demonstrated a clinically relevant decrease in glycated hemoglobin (HbA1c) and an acceptable safety profile in young people with type 2 diabetes (T2D).

Major finding: At 24 weeks, the adjusted mean change in HbA1c was not significantly different between the dapagliflozin and placebo groups in the intention-to-treat analysis (between-group difference [Δ] −0.75%; P = .10), but was significantly different in the sensitivity analysis in the per-protocol population (Δ −1.13%; P = .012). No new safety signals or episodes of death or diabetic ketoacidosis were recorded.

Study details: The data come from a phase 3 trial including 72 participants aged 10-24 years with T2D and HbA1c concentration of 6.5%-11% who were randomly assigned to receive oral dapagliflozin (10 mg) or placebo in addition to standard-of-care treatment for 24 weeks followed by dapagliflozin for 28 weeks

Disclosures: The study was funded by AstraZeneca. Some authors declared receiving consulting fees or research grants or serving on advisory boards for various sources, including AstraZeneca. Three authors declared being stockholders or employees of AstraZeneca.

Source: Tamborlane WV, Laffel LM et al. Efficacy and safety of dapagliflozin in children and young adults with type 2 diabetes: a prospective, multicentre, randomised, parallel group, phase 3 study. Lancet Diabetes Endocrinol. 2022 (Apr 1). Doi: 10.1016/S2213-8587(22)00052-3

The data on cross-protection against gonorrhea by outer membrane vesicle (OMV)–based meningococcal B vaccine continue to look encouraging from a recent study in Clinical Infectious Diseases (2022; doi: 10.1093/cid/ciac436). The authors report matched-cohort study data involving over 33,000 teens/young adults followed at Kaiser Permanente Southern California during 2016-2020. Like the studies above, chlamydia-infected patients (n = 26,471) served as negative controls for the 6,641 gonorrhea patients. The researchers compared chances of getting gonorrhea vs. getting chlamydia in light of having previously gotten C4MenB vaccine (OMV-based) or MenACWY vaccine (not OMV-based). The authors reported gonorrhea incidence rates of 2.0/1,000 person-years (95% CI, 1.3–2.8) in 4CMenB vaccinees vs. 5.2 (4.6–5.8) for MenACWY recipients. An adjusted analysis revealed 46% lower gonorrhea rates in 4CMenB vs. MenACWY vaccinees. There was no difference in chlamydia rates.

We await prospective controlled data to validate these observational studies. However, it is intriguing that OMV-based meningococcal vaccine may be a two-fer vaccine with partial cross protection against gonorrhea because of outer membrane protein similarities between the two pathogens. These data seem worth sharing with families who are making decisions about whether to vaccinate their children against B strains of meningococcus whether or not the child has already had conjugate MenACWY.

Christopher J. Harrison, MD, is professor, University of Missouri Kansas City School of Medicine, department of medicine, infectious diseases section, Kansas City. He has no financial conflicts of interest.

The data on cross-protection against gonorrhea by outer membrane vesicle (OMV)–based meningococcal B vaccine continue to look encouraging from a recent study in Clinical Infectious Diseases (2022; doi: 10.1093/cid/ciac436). The authors report matched-cohort study data involving over 33,000 teens/young adults followed at Kaiser Permanente Southern California during 2016-2020. Like the studies above, chlamydia-infected patients (n = 26,471) served as negative controls for the 6,641 gonorrhea patients. The researchers compared chances of getting gonorrhea vs. getting chlamydia in light of having previously gotten C4MenB vaccine (OMV-based) or MenACWY vaccine (not OMV-based). The authors reported gonorrhea incidence rates of 2.0/1,000 person-years (95% CI, 1.3–2.8) in 4CMenB vaccinees vs. 5.2 (4.6–5.8) for MenACWY recipients. An adjusted analysis revealed 46% lower gonorrhea rates in 4CMenB vs. MenACWY vaccinees. There was no difference in chlamydia rates.

We await prospective controlled data to validate these observational studies. However, it is intriguing that OMV-based meningococcal vaccine may be a two-fer vaccine with partial cross protection against gonorrhea because of outer membrane protein similarities between the two pathogens. These data seem worth sharing with families who are making decisions about whether to vaccinate their children against B strains of meningococcus whether or not the child has already had conjugate MenACWY.

Christopher J. Harrison, MD, is professor, University of Missouri Kansas City School of Medicine, department of medicine, infectious diseases section, Kansas City. He has no financial conflicts of interest.

The data on cross-protection against gonorrhea by outer membrane vesicle (OMV)–based meningococcal B vaccine continue to look encouraging from a recent study in Clinical Infectious Diseases (2022; doi: 10.1093/cid/ciac436). The authors report matched-cohort study data involving over 33,000 teens/young adults followed at Kaiser Permanente Southern California during 2016-2020. Like the studies above, chlamydia-infected patients (n = 26,471) served as negative controls for the 6,641 gonorrhea patients. The researchers compared chances of getting gonorrhea vs. getting chlamydia in light of having previously gotten C4MenB vaccine (OMV-based) or MenACWY vaccine (not OMV-based). The authors reported gonorrhea incidence rates of 2.0/1,000 person-years (95% CI, 1.3–2.8) in 4CMenB vaccinees vs. 5.2 (4.6–5.8) for MenACWY recipients. An adjusted analysis revealed 46% lower gonorrhea rates in 4CMenB vs. MenACWY vaccinees. There was no difference in chlamydia rates.

We await prospective controlled data to validate these observational studies. However, it is intriguing that OMV-based meningococcal vaccine may be a two-fer vaccine with partial cross protection against gonorrhea because of outer membrane protein similarities between the two pathogens. These data seem worth sharing with families who are making decisions about whether to vaccinate their children against B strains of meningococcus whether or not the child has already had conjugate MenACWY.

Christopher J. Harrison, MD, is professor, University of Missouri Kansas City School of Medicine, department of medicine, infectious diseases section, Kansas City. He has no financial conflicts of interest.

An experimental drug that combines fixed doses of extended-release (ER) formulations of existing medications can significantly reduce symptoms in patients with untreated early-stage Parkinson’s disease, new research suggests. Results from a phase 3 trial of P2B001, a combination of pramipexole and rasagiline at currently unavailable low doses, showed the drug was more effective than its individual components and as effective as higher-dose pramipexole ER – with far less daytime sleepiness.

The combination drug is taken once per day and does not require titration, which investigators say make it a good option for first-line treatment of Parkinson’s disease.

“I don’t think people, including me, expected intuitively that if you used small doses and combined it with a little rasagiline it would be equal to full doses of pramipexole, but it appears that it is,” said lead investigator Warren Olanow, MD, professor and chair emeritus of neurology and professor emeritus of neuroscience at Icahn School of Medicine at Mount Sinai, New York.

The findings were presented at the 2022 annual meeting of the American Academy of Neurology.
 

‘Synergistic effects’

Levodopa is considered to be the most effective treatment for Parkinson’s disease, but long-term use is associated with increased risk for motor complications, such as dyskinesia. Dopamine agonists such as pramipexole have been linked in previous research to excessive daytime sleepiness and impulse control disorders. In addition, monoamine oxidase-B inhibitors such as rasagiline are not as effective at controlling Parkinson’s disease as other treatment options.

“There is no consistent agreement on how to initiate treatment because no one treatment is ideal,” Dr. Olanow said.

P2B001, developed by Pharma Two B, is a combination of 0.6 mg of pramipexole and 0.75 mg of rasagiline. The drugs work by dual mechanisms, which investigators suspected might have “synergistic effects.”

Following promising results from an earlier trial, researches launched a phase 3, 12-week, international, randomized, double-blind trial to study the efficacy, safety, and tolerability of P2B001, compared with its individual components and with a calibration arm of pramipexole ER in 519 patients with early Parkinson’s disease.

Participants received P2B001, 0.6 mg of pramipexole ER, 0.75 mg of rasagiline ER, or pramipexole ER titrated to an optimal dose for each patient (1.5-4.5 mg).
 

New first-line treatment?

Results showed that the adjusted mean change from baseline in total Unified Parkinson’s Disease Rating Scale (UPDRS) score was -2.66 points for P2B001 versus pramipexole (P = .0018) and -3.30 points for P2B001 versus rasagiline (P = .0001).

There was no significant difference in UPDRS scores between P2B001 and pramipexole ER, but patients who received P2B001 reported significantly less daytime sleepiness.

The adjusted mean change from baseline in Epworth Sleepiness Scale score for P2B001 versus pramipexole ER was -2.66 points (P < .0001).

In addition, fewer dopaminergic adverse events were reported with the combination drug versus pramipexole ER (44.7% vs. 66.2%), including somnolence (14.7% vs. 31.1%) and orthostatic hypotension (2.7% vs. 12.2%).

As a first-line treatment, P2B001 could offer an effective option instead of levodopa, Dr. Olanow said. “It could be really good for patients because it would delay the introduction of levodopa and allow levodopa to be used in lower doses when the time comes and hopefully reduce the risk of complications,” he added.
 

Questions, cost concerns

Commenting on the study, Alfonso Fasano, MD, PhD, professor of neurology and chair in neuromodulation, University of Toronto, agreed that better therapeutic options are needed for Parkinson’s disease.

Combining available treatments into one pill “might help patients’ adherence, although this can compromise our ability to dose each compound individually,” said Dr. Fasano, who was not involved with the research.

He added that there are also questions about dosage modification as a patient’s disease progresses and whether a higher dose might pose safety problems. There is also the issue of cost. “Conducting large clinical trials like this one is expensive, and I wonder about the cost of the drug when approved,” Dr. Fasano noted. “Do we really need to invest in combination pills containing two already well-known compounds?”

Dr. Olanow, who is not directly involved with Pharma Two B, the developer of P2B001, said he has no information on what the drug might cost or how it might be marketed if approved for use.

“The advantage of the combination is the component doses are not replicable, they are both in an extended-release formulation, it doesn’t require titration, and it has been tested and proven to work,” he said.

The study was funded by Pharma Two B. Dr. Olanow is employed by Clintrex Research Corporation and owns stock in Clintrex Research Corporation. Dr. Fasano reported no relevant financial relationships.

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

An experimental drug that combines fixed doses of extended-release (ER) formulations of existing medications can significantly reduce symptoms in patients with untreated early-stage Parkinson’s disease, new research suggests. Results from a phase 3 trial of P2B001, a combination of pramipexole and rasagiline at currently unavailable low doses, showed the drug was more effective than its individual components and as effective as higher-dose pramipexole ER – with far less daytime sleepiness.

The combination drug is taken once per day and does not require titration, which investigators say make it a good option for first-line treatment of Parkinson’s disease.

“I don’t think people, including me, expected intuitively that if you used small doses and combined it with a little rasagiline it would be equal to full doses of pramipexole, but it appears that it is,” said lead investigator Warren Olanow, MD, professor and chair emeritus of neurology and professor emeritus of neuroscience at Icahn School of Medicine at Mount Sinai, New York.

The findings were presented at the 2022 annual meeting of the American Academy of Neurology.
 

‘Synergistic effects’

Levodopa is considered to be the most effective treatment for Parkinson’s disease, but long-term use is associated with increased risk for motor complications, such as dyskinesia. Dopamine agonists such as pramipexole have been linked in previous research to excessive daytime sleepiness and impulse control disorders. In addition, monoamine oxidase-B inhibitors such as rasagiline are not as effective at controlling Parkinson’s disease as other treatment options.

“There is no consistent agreement on how to initiate treatment because no one treatment is ideal,” Dr. Olanow said.

P2B001, developed by Pharma Two B, is a combination of 0.6 mg of pramipexole and 0.75 mg of rasagiline. The drugs work by dual mechanisms, which investigators suspected might have “synergistic effects.”

Following promising results from an earlier trial, researches launched a phase 3, 12-week, international, randomized, double-blind trial to study the efficacy, safety, and tolerability of P2B001, compared with its individual components and with a calibration arm of pramipexole ER in 519 patients with early Parkinson’s disease.

Participants received P2B001, 0.6 mg of pramipexole ER, 0.75 mg of rasagiline ER, or pramipexole ER titrated to an optimal dose for each patient (1.5-4.5 mg).
 

New first-line treatment?

Results showed that the adjusted mean change from baseline in total Unified Parkinson’s Disease Rating Scale (UPDRS) score was -2.66 points for P2B001 versus pramipexole (P = .0018) and -3.30 points for P2B001 versus rasagiline (P = .0001).

There was no significant difference in UPDRS scores between P2B001 and pramipexole ER, but patients who received P2B001 reported significantly less daytime sleepiness.

The adjusted mean change from baseline in Epworth Sleepiness Scale score for P2B001 versus pramipexole ER was -2.66 points (P < .0001).

In addition, fewer dopaminergic adverse events were reported with the combination drug versus pramipexole ER (44.7% vs. 66.2%), including somnolence (14.7% vs. 31.1%) and orthostatic hypotension (2.7% vs. 12.2%).

As a first-line treatment, P2B001 could offer an effective option instead of levodopa, Dr. Olanow said. “It could be really good for patients because it would delay the introduction of levodopa and allow levodopa to be used in lower doses when the time comes and hopefully reduce the risk of complications,” he added.
 

Questions, cost concerns

Commenting on the study, Alfonso Fasano, MD, PhD, professor of neurology and chair in neuromodulation, University of Toronto, agreed that better therapeutic options are needed for Parkinson’s disease.

Combining available treatments into one pill “might help patients’ adherence, although this can compromise our ability to dose each compound individually,” said Dr. Fasano, who was not involved with the research.

He added that there are also questions about dosage modification as a patient’s disease progresses and whether a higher dose might pose safety problems. There is also the issue of cost. “Conducting large clinical trials like this one is expensive, and I wonder about the cost of the drug when approved,” Dr. Fasano noted. “Do we really need to invest in combination pills containing two already well-known compounds?”

Dr. Olanow, who is not directly involved with Pharma Two B, the developer of P2B001, said he has no information on what the drug might cost or how it might be marketed if approved for use.

“The advantage of the combination is the component doses are not replicable, they are both in an extended-release formulation, it doesn’t require titration, and it has been tested and proven to work,” he said.

The study was funded by Pharma Two B. Dr. Olanow is employed by Clintrex Research Corporation and owns stock in Clintrex Research Corporation. Dr. Fasano reported no relevant financial relationships.

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

An experimental drug that combines fixed doses of extended-release (ER) formulations of existing medications can significantly reduce symptoms in patients with untreated early-stage Parkinson’s disease, new research suggests. Results from a phase 3 trial of P2B001, a combination of pramipexole and rasagiline at currently unavailable low doses, showed the drug was more effective than its individual components and as effective as higher-dose pramipexole ER – with far less daytime sleepiness.

The combination drug is taken once per day and does not require titration, which investigators say make it a good option for first-line treatment of Parkinson’s disease.

“I don’t think people, including me, expected intuitively that if you used small doses and combined it with a little rasagiline it would be equal to full doses of pramipexole, but it appears that it is,” said lead investigator Warren Olanow, MD, professor and chair emeritus of neurology and professor emeritus of neuroscience at Icahn School of Medicine at Mount Sinai, New York.

The findings were presented at the 2022 annual meeting of the American Academy of Neurology.
 

‘Synergistic effects’

Levodopa is considered to be the most effective treatment for Parkinson’s disease, but long-term use is associated with increased risk for motor complications, such as dyskinesia. Dopamine agonists such as pramipexole have been linked in previous research to excessive daytime sleepiness and impulse control disorders. In addition, monoamine oxidase-B inhibitors such as rasagiline are not as effective at controlling Parkinson’s disease as other treatment options.

“There is no consistent agreement on how to initiate treatment because no one treatment is ideal,” Dr. Olanow said.

P2B001, developed by Pharma Two B, is a combination of 0.6 mg of pramipexole and 0.75 mg of rasagiline. The drugs work by dual mechanisms, which investigators suspected might have “synergistic effects.”

Following promising results from an earlier trial, researches launched a phase 3, 12-week, international, randomized, double-blind trial to study the efficacy, safety, and tolerability of P2B001, compared with its individual components and with a calibration arm of pramipexole ER in 519 patients with early Parkinson’s disease.

Participants received P2B001, 0.6 mg of pramipexole ER, 0.75 mg of rasagiline ER, or pramipexole ER titrated to an optimal dose for each patient (1.5-4.5 mg).
 

New first-line treatment?

Results showed that the adjusted mean change from baseline in total Unified Parkinson’s Disease Rating Scale (UPDRS) score was -2.66 points for P2B001 versus pramipexole (P = .0018) and -3.30 points for P2B001 versus rasagiline (P = .0001).

There was no significant difference in UPDRS scores between P2B001 and pramipexole ER, but patients who received P2B001 reported significantly less daytime sleepiness.

The adjusted mean change from baseline in Epworth Sleepiness Scale score for P2B001 versus pramipexole ER was -2.66 points (P < .0001).

In addition, fewer dopaminergic adverse events were reported with the combination drug versus pramipexole ER (44.7% vs. 66.2%), including somnolence (14.7% vs. 31.1%) and orthostatic hypotension (2.7% vs. 12.2%).

As a first-line treatment, P2B001 could offer an effective option instead of levodopa, Dr. Olanow said. “It could be really good for patients because it would delay the introduction of levodopa and allow levodopa to be used in lower doses when the time comes and hopefully reduce the risk of complications,” he added.
 

Questions, cost concerns

Commenting on the study, Alfonso Fasano, MD, PhD, professor of neurology and chair in neuromodulation, University of Toronto, agreed that better therapeutic options are needed for Parkinson’s disease.

Combining available treatments into one pill “might help patients’ adherence, although this can compromise our ability to dose each compound individually,” said Dr. Fasano, who was not involved with the research.

He added that there are also questions about dosage modification as a patient’s disease progresses and whether a higher dose might pose safety problems. There is also the issue of cost. “Conducting large clinical trials like this one is expensive, and I wonder about the cost of the drug when approved,” Dr. Fasano noted. “Do we really need to invest in combination pills containing two already well-known compounds?”

Dr. Olanow, who is not directly involved with Pharma Two B, the developer of P2B001, said he has no information on what the drug might cost or how it might be marketed if approved for use.

“The advantage of the combination is the component doses are not replicable, they are both in an extended-release formulation, it doesn’t require titration, and it has been tested and proven to work,” he said.

The study was funded by Pharma Two B. Dr. Olanow is employed by Clintrex Research Corporation and owns stock in Clintrex Research Corporation. Dr. Fasano reported no relevant financial relationships.

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

BOSTON – The use of carbon dioxide (CO2) laser excision therapy for hidradenitis suppurativa (HS) is not associated with an increased risk for the development of keloids, new research shows.

“With keloids disproportionately affecting Black and other skin of color patients, denying treatment on a notion that lacks evidentiary support further potentiates the health disparities experienced by these marginalized groups,” the researchers reported at the Annual Meeting of the Skin of Color Society Scientific Symposium (SOCS) 2022. In their retrospective study of 129 patients with HS treated with CO2 laser, “there were no cases of keloid formation,” they say.

HS, a potentially debilitating chronic inflammatory condition that involves painful nodules, boils, and abscesses, is often refractory to standard treatment. CO2 laser excision therapy has yielded favorable outcomes in some studies.

Although CO2 laser therapy is also used to treat keloids, some clinicians hesitate to use this treatment in these patients because of concerns that its use for treating HS could trigger the development of keloids.

“Many patients come in telling us they were denied [CO2 laser] surgery due to keloids,” senior author Iltefat Hamzavi, MD, a senior staff physician in the Department of Dermatology at the Henry Ford Health System, Detroit, told this news organization.

Regarding patient selection, he noted that “the disease should be medically stable with reduction in drainage to help control postop bleeding risk.”

The findings of the study are supported by a recent systematic review that compared outcomes and adverse effects of treatment with ablative laser therapies with nonablative lasers for skin resurfacing. The review included 34 studies and involved 1,093 patients. The conditions that were treated ranged from photodamage and acne scars to HS and post-traumatic scarring from basal cell carcinoma excision.

That review found that overall, rates of adverse events were higher with nonablative therapies (12.2%, 31 events), compared with ablative laser therapy, such as with CO2 laser (8.28%, 81 events). In addition, when transient events were excluded, ablative lasers were associated with fewer complications overall, compared with nonablative lasers (2.56% vs. 7.48%).

The authors conclude: “It is our hope that this study will facilitate continued research in this domain in an effort to combat these inequities and improve access to CO2 excision or standardized excisional therapy for hidradenitis suppurativa treatment.”

Dr. Hamzavi and the other authors have disclosed no relevant financial relationships.

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

BOSTON – The use of carbon dioxide (CO2) laser excision therapy for hidradenitis suppurativa (HS) is not associated with an increased risk for the development of keloids, new research shows.

“With keloids disproportionately affecting Black and other skin of color patients, denying treatment on a notion that lacks evidentiary support further potentiates the health disparities experienced by these marginalized groups,” the researchers reported at the Annual Meeting of the Skin of Color Society Scientific Symposium (SOCS) 2022. In their retrospective study of 129 patients with HS treated with CO2 laser, “there were no cases of keloid formation,” they say.

HS, a potentially debilitating chronic inflammatory condition that involves painful nodules, boils, and abscesses, is often refractory to standard treatment. CO2 laser excision therapy has yielded favorable outcomes in some studies.

Although CO2 laser therapy is also used to treat keloids, some clinicians hesitate to use this treatment in these patients because of concerns that its use for treating HS could trigger the development of keloids.

“Many patients come in telling us they were denied [CO2 laser] surgery due to keloids,” senior author Iltefat Hamzavi, MD, a senior staff physician in the Department of Dermatology at the Henry Ford Health System, Detroit, told this news organization.

Regarding patient selection, he noted that “the disease should be medically stable with reduction in drainage to help control postop bleeding risk.”

The findings of the study are supported by a recent systematic review that compared outcomes and adverse effects of treatment with ablative laser therapies with nonablative lasers for skin resurfacing. The review included 34 studies and involved 1,093 patients. The conditions that were treated ranged from photodamage and acne scars to HS and post-traumatic scarring from basal cell carcinoma excision.

That review found that overall, rates of adverse events were higher with nonablative therapies (12.2%, 31 events), compared with ablative laser therapy, such as with CO2 laser (8.28%, 81 events). In addition, when transient events were excluded, ablative lasers were associated with fewer complications overall, compared with nonablative lasers (2.56% vs. 7.48%).

The authors conclude: “It is our hope that this study will facilitate continued research in this domain in an effort to combat these inequities and improve access to CO2 excision or standardized excisional therapy for hidradenitis suppurativa treatment.”

Dr. Hamzavi and the other authors have disclosed no relevant financial relationships.

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

BOSTON – The use of carbon dioxide (CO2) laser excision therapy for hidradenitis suppurativa (HS) is not associated with an increased risk for the development of keloids, new research shows.

“With keloids disproportionately affecting Black and other skin of color patients, denying treatment on a notion that lacks evidentiary support further potentiates the health disparities experienced by these marginalized groups,” the researchers reported at the Annual Meeting of the Skin of Color Society Scientific Symposium (SOCS) 2022. In their retrospective study of 129 patients with HS treated with CO2 laser, “there were no cases of keloid formation,” they say.

HS, a potentially debilitating chronic inflammatory condition that involves painful nodules, boils, and abscesses, is often refractory to standard treatment. CO2 laser excision therapy has yielded favorable outcomes in some studies.

Although CO2 laser therapy is also used to treat keloids, some clinicians hesitate to use this treatment in these patients because of concerns that its use for treating HS could trigger the development of keloids.

“Many patients come in telling us they were denied [CO2 laser] surgery due to keloids,” senior author Iltefat Hamzavi, MD, a senior staff physician in the Department of Dermatology at the Henry Ford Health System, Detroit, told this news organization.

Regarding patient selection, he noted that “the disease should be medically stable with reduction in drainage to help control postop bleeding risk.”

The findings of the study are supported by a recent systematic review that compared outcomes and adverse effects of treatment with ablative laser therapies with nonablative lasers for skin resurfacing. The review included 34 studies and involved 1,093 patients. The conditions that were treated ranged from photodamage and acne scars to HS and post-traumatic scarring from basal cell carcinoma excision.

That review found that overall, rates of adverse events were higher with nonablative therapies (12.2%, 31 events), compared with ablative laser therapy, such as with CO2 laser (8.28%, 81 events). In addition, when transient events were excluded, ablative lasers were associated with fewer complications overall, compared with nonablative lasers (2.56% vs. 7.48%).

The authors conclude: “It is our hope that this study will facilitate continued research in this domain in an effort to combat these inequities and improve access to CO2 excision or standardized excisional therapy for hidradenitis suppurativa treatment.”

Dr. Hamzavi and the other authors have disclosed no relevant financial relationships.

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

The Diagnosis: Cutaneous B-cell Lymphoma

Shave biopsies of 3 lesions revealed a dense, diffuse, atypical lymphoid infiltrate occupying the entirety of the dermis and obscuring the dermoepidermal junction. The infiltrate consisted predominantly of largesized lymphoid cells with fine chromatin and conspicuous nucleoli (Figure). Immunohistochemistry was positive for CD45 and CD20, indicating B-cell lineage. Bcl-2, multiple myeloma oncogene 1, and forkhead box protein P1 also were expressed in the vast majority of lesional cells, distinguishing the lesion from other forms of cutaneous B-cell lymphomas.¹ These findings were consistent with large B-cell lymphoma with a high proliferation index, consistent with primary cutaneous diffuse large B-cell lymphoma, leg type, which often presents on the lower leg.² The patient had a negative systemic workup including bone marrow biopsy. He was started on the R-CEOP (rituximab, cyclophosphamide, etoposide, vincristine, prednisone) chemotherapy regimen.

Primary cutaneous diffuse large B-cell lymphoma, leg type, is an intermediately aggressive and rare form of B-cell lymphoma with a poor prognosis that primarily affects elderly female patients. Primary cutaneous diffuse large B-cell lymphoma, leg type, accounts for only 1% to 3% of cutaneous lymphomas and approximately 10% to 20% of primary cutaneous B-cell lymphomas.² It typically presents as multiple red-brown or bluish nodules on the lower extremities or trunk. Presentation as a solitary nodule also is possible.^1,2 Histologic analysis of primary cutaneous diffuse large B-cell lymphoma, leg type, reveals large cells with round nuclei (immunoblasts and centroblasts), and the immunohistochemical profile shows strong Bcl-2 expression often accompanied by the multiple myeloma oncogene 1 protein.³ The 5-year survival rate is approximately 50%, which is lower than other types of primary cutaneous B-cell lymphomas, and the progression of disease is characterized by frequent relapses and involvement of extracutaneous regions such as the lymph nodes, bone marrow, and central nervous system.^1,2,4 Patients with multiple tumors on the leg have a particularly poor prognosis; in particular, having 1 or more lesions on the leg results in a 43% 3-year survival rate while having multiple lesions has a 36% 3-year survival rate compared with a 77% 3-year survival rate for patients with the non–leg subtype or a single lesion.3 Treatment with rituximab has been shown to be effective in at least short-term control of the disease, and the R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) regimen is the standard of treatment.^3,4

Primary cutaneous diffuse large B-cell lymphoma, leg type, can mimic multiple other cutaneous presentations of disease. Myeloid sarcoma (leukemia cutis) is a rare condition that presents as an extramedullary tumor often simultaneously with the onset or relapse of acute myeloid leukemia.⁵ Our patient had no history of leukemia, but myeloid sarcoma may predate acute myeloid leukemia in about a quarter of cases.⁵ It most commonly presents histologically as a diffuse dermal infiltrate that splays between collagen bundles and often is associated with an overlying Grenz zone. A nodular, or perivascular and periadnexal, pattern also may be seen. Upon closer inspection, the infiltrate is composed of immature myeloid cells (blasts) with background inflammation occasionally containing eosinophils. The immunohistochemical profile varies depending on the type of differentiation and degree of maturity of the cells. The histologic findings in our patient were inconsistent with myeloid sarcoma.

Erythema elevatum diutinum (EED) usually presents as dark red, brown, or violaceous papules or plaques and often is found on the extensor surfaces. It often is associated with hematologic abnormalities as well as recurrent bacterial or viral infections.⁶ Histologically, EED initially manifests as leukocytoclastic vasculitis with a mixed inflammatory infiltrate typically featuring an abundance of neutrophils, making this condition unlikely in this case. As the lesion progresses, fibrosis and scarring ensue as inflammation wanes. The fibrosis often is described as having an onion skin–like pattern, which is characteristic of established EED lesions. Our patient had no history of vasculitis, and the histologic findings were inconsistent with EED.

Angiosarcoma can present as a central nodule surrounded by an erythematous plaque. Although potentially clinically similar to primary cutaneous diffuse large B-cell lymphoma, leg type, angiosarcoma was unlikely in this case because of an absence of lymphedema and no history of radiation to the leg, both of which are key historical features of angiosarcoma.⁷ Additionally, the histology of cutaneous angiosarcoma is marked by vascular proliferation, which was not seen in the lesion biopsied in our patient. The histology of angiosarcoma is that of an atypical vascular proliferation, and a hallmark feature is infiltration between collagen, often referred to as giving the appearance of dissection between collagen bundles. The degree of atypia can vary widely, and epithelioid variants exist, producing a potential diagnostic pitfall. Lesional cells are positive for vascular markers, which can be used for confirmation of the endothelial lineage.

Sarcoidosis is notorious for its mimicry, which can be the case both clinically and histologically. Characteristic pathology of sarcoidosis is that of well-formed epithelioid granulomas with minimal associated inflammation and lack of caseating necrosis. Our patient had no known history of systemic sarcoidosis, and the pathologic features of noncaseating granulomas were not present. As a diagnosis of exclusion, correlation with special stains and culture studies is necessary to exclude an infectious process. The differential diagnosis for sarcoidal granulomatous dermatitis also includes foreign body reaction, inflammatory bowel disease, and granulomatous cheilitis, among others.

The Diagnosis: Cutaneous B-cell Lymphoma

Shave biopsies of 3 lesions revealed a dense, diffuse, atypical lymphoid infiltrate occupying the entirety of the dermis and obscuring the dermoepidermal junction. The infiltrate consisted predominantly of largesized lymphoid cells with fine chromatin and conspicuous nucleoli (Figure). Immunohistochemistry was positive for CD45 and CD20, indicating B-cell lineage. Bcl-2, multiple myeloma oncogene 1, and forkhead box protein P1 also were expressed in the vast majority of lesional cells, distinguishing the lesion from other forms of cutaneous B-cell lymphomas.¹ These findings were consistent with large B-cell lymphoma with a high proliferation index, consistent with primary cutaneous diffuse large B-cell lymphoma, leg type, which often presents on the lower leg.² The patient had a negative systemic workup including bone marrow biopsy. He was started on the R-CEOP (rituximab, cyclophosphamide, etoposide, vincristine, prednisone) chemotherapy regimen.

Primary cutaneous diffuse large B-cell lymphoma, leg type, is an intermediately aggressive and rare form of B-cell lymphoma with a poor prognosis that primarily affects elderly female patients. Primary cutaneous diffuse large B-cell lymphoma, leg type, accounts for only 1% to 3% of cutaneous lymphomas and approximately 10% to 20% of primary cutaneous B-cell lymphomas.² It typically presents as multiple red-brown or bluish nodules on the lower extremities or trunk. Presentation as a solitary nodule also is possible.^1,2 Histologic analysis of primary cutaneous diffuse large B-cell lymphoma, leg type, reveals large cells with round nuclei (immunoblasts and centroblasts), and the immunohistochemical profile shows strong Bcl-2 expression often accompanied by the multiple myeloma oncogene 1 protein.³ The 5-year survival rate is approximately 50%, which is lower than other types of primary cutaneous B-cell lymphomas, and the progression of disease is characterized by frequent relapses and involvement of extracutaneous regions such as the lymph nodes, bone marrow, and central nervous system.^1,2,4 Patients with multiple tumors on the leg have a particularly poor prognosis; in particular, having 1 or more lesions on the leg results in a 43% 3-year survival rate while having multiple lesions has a 36% 3-year survival rate compared with a 77% 3-year survival rate for patients with the non–leg subtype or a single lesion.3 Treatment with rituximab has been shown to be effective in at least short-term control of the disease, and the R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) regimen is the standard of treatment.^3,4

Primary cutaneous diffuse large B-cell lymphoma, leg type, can mimic multiple other cutaneous presentations of disease. Myeloid sarcoma (leukemia cutis) is a rare condition that presents as an extramedullary tumor often simultaneously with the onset or relapse of acute myeloid leukemia.⁵ Our patient had no history of leukemia, but myeloid sarcoma may predate acute myeloid leukemia in about a quarter of cases.⁵ It most commonly presents histologically as a diffuse dermal infiltrate that splays between collagen bundles and often is associated with an overlying Grenz zone. A nodular, or perivascular and periadnexal, pattern also may be seen. Upon closer inspection, the infiltrate is composed of immature myeloid cells (blasts) with background inflammation occasionally containing eosinophils. The immunohistochemical profile varies depending on the type of differentiation and degree of maturity of the cells. The histologic findings in our patient were inconsistent with myeloid sarcoma.

Erythema elevatum diutinum (EED) usually presents as dark red, brown, or violaceous papules or plaques and often is found on the extensor surfaces. It often is associated with hematologic abnormalities as well as recurrent bacterial or viral infections.⁶ Histologically, EED initially manifests as leukocytoclastic vasculitis with a mixed inflammatory infiltrate typically featuring an abundance of neutrophils, making this condition unlikely in this case. As the lesion progresses, fibrosis and scarring ensue as inflammation wanes. The fibrosis often is described as having an onion skin–like pattern, which is characteristic of established EED lesions. Our patient had no history of vasculitis, and the histologic findings were inconsistent with EED.

Angiosarcoma can present as a central nodule surrounded by an erythematous plaque. Although potentially clinically similar to primary cutaneous diffuse large B-cell lymphoma, leg type, angiosarcoma was unlikely in this case because of an absence of lymphedema and no history of radiation to the leg, both of which are key historical features of angiosarcoma.⁷ Additionally, the histology of cutaneous angiosarcoma is marked by vascular proliferation, which was not seen in the lesion biopsied in our patient. The histology of angiosarcoma is that of an atypical vascular proliferation, and a hallmark feature is infiltration between collagen, often referred to as giving the appearance of dissection between collagen bundles. The degree of atypia can vary widely, and epithelioid variants exist, producing a potential diagnostic pitfall. Lesional cells are positive for vascular markers, which can be used for confirmation of the endothelial lineage.

Sarcoidosis is notorious for its mimicry, which can be the case both clinically and histologically. Characteristic pathology of sarcoidosis is that of well-formed epithelioid granulomas with minimal associated inflammation and lack of caseating necrosis. Our patient had no known history of systemic sarcoidosis, and the pathologic features of noncaseating granulomas were not present. As a diagnosis of exclusion, correlation with special stains and culture studies is necessary to exclude an infectious process. The differential diagnosis for sarcoidal granulomatous dermatitis also includes foreign body reaction, inflammatory bowel disease, and granulomatous cheilitis, among others.

The Diagnosis: Cutaneous B-cell Lymphoma

Shave biopsies of 3 lesions revealed a dense, diffuse, atypical lymphoid infiltrate occupying the entirety of the dermis and obscuring the dermoepidermal junction. The infiltrate consisted predominantly of largesized lymphoid cells with fine chromatin and conspicuous nucleoli (Figure). Immunohistochemistry was positive for CD45 and CD20, indicating B-cell lineage. Bcl-2, multiple myeloma oncogene 1, and forkhead box protein P1 also were expressed in the vast majority of lesional cells, distinguishing the lesion from other forms of cutaneous B-cell lymphomas.¹ These findings were consistent with large B-cell lymphoma with a high proliferation index, consistent with primary cutaneous diffuse large B-cell lymphoma, leg type, which often presents on the lower leg.² The patient had a negative systemic workup including bone marrow biopsy. He was started on the R-CEOP (rituximab, cyclophosphamide, etoposide, vincristine, prednisone) chemotherapy regimen.

Primary cutaneous diffuse large B-cell lymphoma, leg type, is an intermediately aggressive and rare form of B-cell lymphoma with a poor prognosis that primarily affects elderly female patients. Primary cutaneous diffuse large B-cell lymphoma, leg type, accounts for only 1% to 3% of cutaneous lymphomas and approximately 10% to 20% of primary cutaneous B-cell lymphomas.² It typically presents as multiple red-brown or bluish nodules on the lower extremities or trunk. Presentation as a solitary nodule also is possible.^1,2 Histologic analysis of primary cutaneous diffuse large B-cell lymphoma, leg type, reveals large cells with round nuclei (immunoblasts and centroblasts), and the immunohistochemical profile shows strong Bcl-2 expression often accompanied by the multiple myeloma oncogene 1 protein.³ The 5-year survival rate is approximately 50%, which is lower than other types of primary cutaneous B-cell lymphomas, and the progression of disease is characterized by frequent relapses and involvement of extracutaneous regions such as the lymph nodes, bone marrow, and central nervous system.^1,2,4 Patients with multiple tumors on the leg have a particularly poor prognosis; in particular, having 1 or more lesions on the leg results in a 43% 3-year survival rate while having multiple lesions has a 36% 3-year survival rate compared with a 77% 3-year survival rate for patients with the non–leg subtype or a single lesion.3 Treatment with rituximab has been shown to be effective in at least short-term control of the disease, and the R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) regimen is the standard of treatment.^3,4

Primary cutaneous diffuse large B-cell lymphoma, leg type, can mimic multiple other cutaneous presentations of disease. Myeloid sarcoma (leukemia cutis) is a rare condition that presents as an extramedullary tumor often simultaneously with the onset or relapse of acute myeloid leukemia.⁵ Our patient had no history of leukemia, but myeloid sarcoma may predate acute myeloid leukemia in about a quarter of cases.⁵ It most commonly presents histologically as a diffuse dermal infiltrate that splays between collagen bundles and often is associated with an overlying Grenz zone. A nodular, or perivascular and periadnexal, pattern also may be seen. Upon closer inspection, the infiltrate is composed of immature myeloid cells (blasts) with background inflammation occasionally containing eosinophils. The immunohistochemical profile varies depending on the type of differentiation and degree of maturity of the cells. The histologic findings in our patient were inconsistent with myeloid sarcoma.

Erythema elevatum diutinum (EED) usually presents as dark red, brown, or violaceous papules or plaques and often is found on the extensor surfaces. It often is associated with hematologic abnormalities as well as recurrent bacterial or viral infections.⁶ Histologically, EED initially manifests as leukocytoclastic vasculitis with a mixed inflammatory infiltrate typically featuring an abundance of neutrophils, making this condition unlikely in this case. As the lesion progresses, fibrosis and scarring ensue as inflammation wanes. The fibrosis often is described as having an onion skin–like pattern, which is characteristic of established EED lesions. Our patient had no history of vasculitis, and the histologic findings were inconsistent with EED.

Angiosarcoma can present as a central nodule surrounded by an erythematous plaque. Although potentially clinically similar to primary cutaneous diffuse large B-cell lymphoma, leg type, angiosarcoma was unlikely in this case because of an absence of lymphedema and no history of radiation to the leg, both of which are key historical features of angiosarcoma.⁷ Additionally, the histology of cutaneous angiosarcoma is marked by vascular proliferation, which was not seen in the lesion biopsied in our patient. The histology of angiosarcoma is that of an atypical vascular proliferation, and a hallmark feature is infiltration between collagen, often referred to as giving the appearance of dissection between collagen bundles. The degree of atypia can vary widely, and epithelioid variants exist, producing a potential diagnostic pitfall. Lesional cells are positive for vascular markers, which can be used for confirmation of the endothelial lineage.

Sarcoidosis is notorious for its mimicry, which can be the case both clinically and histologically. Characteristic pathology of sarcoidosis is that of well-formed epithelioid granulomas with minimal associated inflammation and lack of caseating necrosis. Our patient had no known history of systemic sarcoidosis, and the pathologic features of noncaseating granulomas were not present. As a diagnosis of exclusion, correlation with special stains and culture studies is necessary to exclude an infectious process. The differential diagnosis for sarcoidal granulomatous dermatitis also includes foreign body reaction, inflammatory bowel disease, and granulomatous cheilitis, among others.

U.K. scientists said microplastics may pose even more of a threat than previously thought after confirming their presence in lung tissue taken from living people.

Microplastics were identified in all lung regions, but significantly higher levels were found in the lower lung.

The results supported inhalation as an exposure risk, according to the team from the University of Hull and Hull York Medical School (England), who said their findings could support further investigations into the effects of airborne microplastics on respiratory health.

The study, published in Science of the Total Environment, used lung tissue collected from surgical procedures on patients during routine medical care at Castle Hill Hospital in East Yorkshire.
 

Polypropylene and polyethylene

It found 39 microplastics in 11 of the 13 lung tissue samples tested using micro-Fourier-transform infrared (μFTIR) analysis, which the scientists said was considerably higher than results from previous laboratory tests.

Of microplastics detected, 12 polymer types were identified, of which the most common were polypropylene, (23%) polyethylene terephthalate (18%), and resin (15%). The fibers are commonly found in packaging, bottles, clothing, rope and twine manufacture, and other industries, the scientists said.

Microplastics with dimensions as small as 4 μm were found, but the scientists said they were surprised to discover samples as large as greater than 2 mm within all lung region samples, with the majority being fibrous and fragmented.

The study identified 11 microplastics in the upper part of the lung, seven in the mid part, and 21 in the lower part of the lung.

Laura Sadofsky, the study’s lead author, said: “Microplastics have previously been found in human cadaver autopsy samples. This is the first robust study to show microplastics in lungs from live people. It also shows that they are in the lower parts of the lung. Lung airways are very narrow, so no one thought they could possibly get there, but they clearly have.”

There were also considerably higher levels of microplastics found in male patients, compared with female patients.
 

Future investigations into health implications

“The characterization of types and levels of microplastics we have found can now inform realistic conditions for laboratory exposure experiments with the aim of determining health impacts,” said Laura Sadofsky, who is a senior lecturer in respiratory medicine in the Centre for Atherothrombotic and Metabolic Research at Hull York Medical School.

The latest investigation followed previous research by the medical school and the University of Hull, which found high levels of atmospheric microplastics within the Humber region.

That study, published in Atmosphere, identified resins, which could have originated from degraded roads, paint marking, or tire rubber, as well as polyethylene fibers.

A version of this article first appeared on Medscape UK.

U.K. scientists said microplastics may pose even more of a threat than previously thought after confirming their presence in lung tissue taken from living people.

Microplastics were identified in all lung regions, but significantly higher levels were found in the lower lung.

The results supported inhalation as an exposure risk, according to the team from the University of Hull and Hull York Medical School (England), who said their findings could support further investigations into the effects of airborne microplastics on respiratory health.

The study, published in Science of the Total Environment, used lung tissue collected from surgical procedures on patients during routine medical care at Castle Hill Hospital in East Yorkshire.
 

Polypropylene and polyethylene

It found 39 microplastics in 11 of the 13 lung tissue samples tested using micro-Fourier-transform infrared (μFTIR) analysis, which the scientists said was considerably higher than results from previous laboratory tests.

Of microplastics detected, 12 polymer types were identified, of which the most common were polypropylene, (23%) polyethylene terephthalate (18%), and resin (15%). The fibers are commonly found in packaging, bottles, clothing, rope and twine manufacture, and other industries, the scientists said.

Microplastics with dimensions as small as 4 μm were found, but the scientists said they were surprised to discover samples as large as greater than 2 mm within all lung region samples, with the majority being fibrous and fragmented.

The study identified 11 microplastics in the upper part of the lung, seven in the mid part, and 21 in the lower part of the lung.

Laura Sadofsky, the study’s lead author, said: “Microplastics have previously been found in human cadaver autopsy samples. This is the first robust study to show microplastics in lungs from live people. It also shows that they are in the lower parts of the lung. Lung airways are very narrow, so no one thought they could possibly get there, but they clearly have.”

There were also considerably higher levels of microplastics found in male patients, compared with female patients.
 

Future investigations into health implications

“The characterization of types and levels of microplastics we have found can now inform realistic conditions for laboratory exposure experiments with the aim of determining health impacts,” said Laura Sadofsky, who is a senior lecturer in respiratory medicine in the Centre for Atherothrombotic and Metabolic Research at Hull York Medical School.

The latest investigation followed previous research by the medical school and the University of Hull, which found high levels of atmospheric microplastics within the Humber region.

That study, published in Atmosphere, identified resins, which could have originated from degraded roads, paint marking, or tire rubber, as well as polyethylene fibers.

A version of this article first appeared on Medscape UK.

U.K. scientists said microplastics may pose even more of a threat than previously thought after confirming their presence in lung tissue taken from living people.

Microplastics were identified in all lung regions, but significantly higher levels were found in the lower lung.

The results supported inhalation as an exposure risk, according to the team from the University of Hull and Hull York Medical School (England), who said their findings could support further investigations into the effects of airborne microplastics on respiratory health.

The study, published in Science of the Total Environment, used lung tissue collected from surgical procedures on patients during routine medical care at Castle Hill Hospital in East Yorkshire.
 

Polypropylene and polyethylene

It found 39 microplastics in 11 of the 13 lung tissue samples tested using micro-Fourier-transform infrared (μFTIR) analysis, which the scientists said was considerably higher than results from previous laboratory tests.

Of microplastics detected, 12 polymer types were identified, of which the most common were polypropylene, (23%) polyethylene terephthalate (18%), and resin (15%). The fibers are commonly found in packaging, bottles, clothing, rope and twine manufacture, and other industries, the scientists said.

Microplastics with dimensions as small as 4 μm were found, but the scientists said they were surprised to discover samples as large as greater than 2 mm within all lung region samples, with the majority being fibrous and fragmented.

The study identified 11 microplastics in the upper part of the lung, seven in the mid part, and 21 in the lower part of the lung.

Laura Sadofsky, the study’s lead author, said: “Microplastics have previously been found in human cadaver autopsy samples. This is the first robust study to show microplastics in lungs from live people. It also shows that they are in the lower parts of the lung. Lung airways are very narrow, so no one thought they could possibly get there, but they clearly have.”

There were also considerably higher levels of microplastics found in male patients, compared with female patients.
 

Future investigations into health implications

“The characterization of types and levels of microplastics we have found can now inform realistic conditions for laboratory exposure experiments with the aim of determining health impacts,” said Laura Sadofsky, who is a senior lecturer in respiratory medicine in the Centre for Atherothrombotic and Metabolic Research at Hull York Medical School.

The latest investigation followed previous research by the medical school and the University of Hull, which found high levels of atmospheric microplastics within the Humber region.

That study, published in Atmosphere, identified resins, which could have originated from degraded roads, paint marking, or tire rubber, as well as polyethylene fibers.

A version of this article first appeared on Medscape UK.

When Sigmund Freud claimed that “anatomy is destiny” he was referring to anatomical sex as a determinant of personality traits. Expert consensus statements have previously offered some recommendations for managing these syndromes, but clinical data are scarce, so the present review “is intended to establish a starting point for future research,”

That notion has been widely discredited, but Freud appears to be inadvertently right in one respect: When it comes to chronic obstructive pulmonary disease (COPD), anatomy really is destiny, and sex may be as well, pulmonary researchers say.

There is a growing body of evidence to indicate that COPD affects men and women differently, and that men and women patients with COPD require different clinical management. Yet women are often underdiagnosed or misdiagnosed, partly because of poorly understood sex differences, but also because of cultural biases.

But plunging any farther into the weeds, it’s important to define terms. Although various investigators have used the terms “sex” and “gender” interchangeably, sex is the preferred term when referring to biological attributes of individual patients, while gender refers to personal identity.

These distinctions are important, contended Amik Sodhi, MBBS, MPH, from the division of allergy, pulmonology, and critical care medicine at the University of Wisconsin–Madison.

“Sex is essentially a biologic construct, so it’s got to do with the sex chromosomes, the genetics of that person, and it refers to the anatomic variations that can change susceptibility to different diseases,” she said in an interview.

An example of sex differences or “sexual dimorphism” can be found in a recent meta-analysis of sex-based genetic associations by Megan Hardin, MD, MPH from Brigham & Women’s Hospital in Boston and colleagues.

They reported that CELSR1, a gene involved in fetal lung development, was expressed more among women than among men and that a single nucleotide polymorphism in the gene was associated with COPD among women smokers, but not among men smokers.

The finding points to a potential risk locus for COPD in women, and could help shed light on sexual dimorphism in COPD, Dr. Hardin and colleagues said.

In contrast to sex, “gender is more of a psychosocial construct which can impact how diseases manifest themselves, how they are potentially managed, and what outcomes might occur for that particular disease,” Dr. Sodhi said.

She and her colleagues recently published a review of sex and gender in common lung disorders and sleep in the journal CHEST, where they wrote that the “influence of sex and gender is portrayed in epidemiological data, disease pathogenesis and pathophysiology, clinical manifestations, response to treatment, access to care, and health outcomes. Hence, sex and gender should be considered in all types of research, clinical practice and educational curricula.”

For example, as previously reported at the 2021 annual meeting of the American Thoracic Society, sex-specific differences in the severity of symptoms and prevalence of comorbidities in patients with COPD may point to different criteria for diagnosing cardiac comorbidities in women and men.

Those conclusions came from a retrospective analysis of data on 795 women and 1,251 men with GOLD (Global Initiative for Chronic Obstructive Lung Disease) class 1-3 disease.

The investigators looked at the patients’ clinical history, comorbidities, lung function, COPD Assessment Test scores, and modified Medical Research Council (mMRC) dyspnea score, and found significant differences between men and women for most functional parameters and comorbidities, and for CAT items of cough, phlegm, and energy.

In logistic regression analysis, predictors for cardiac disease in men were energy, mMRC score, smoking status, body mass index, age, and spirometric lung function, but in women only age was significantly predictive for cardiac disease.

An example of gender effects on COPD differences in men and women is the increase in cigarette advertising aimed at women in the 1960s and the advent of women-targeted brands such as Virginia Slims, which in turn lead to increased smoking rates among women. In addition, in the developing world, where the sex/gender gap in COPD is narrowing, women tend to have greater exposure to wood smoke and cooking fuels in unventilated or poorly ventilated spaces, compared with men.
 

Increasing incidence among women

According to the Centers for Disease Control and Prevention, chronic lower respiratory diseases, primarily COPD, were the fourth-leading cause of death in women in the United States in 2018, following only heart disease, cancer, and accidents/injuries.

And as a CDC analysis of data from the 2013 Behavioral Risk Factor Surveillance System showed, women were more likely to report being told by a physician that they had COPD than did men (6.6%, compared with 5.4%).

Dr. Sodhi and colleagues noted that, at all time points examined from 2005 to 2014, women had a higher proportion than men of COPD hospitalizations and in-hospital deaths. They also noted that female sex is associated with a threefold risk for severe early-onset COPD, and that women with COPD have lower diffusion capacity of lungs for carbon monoxide, despite having higher predicted forced expiratory volume in 1 second, compared with men.

“Historically, COPD wasn’t a disease that was so prevalent in women. It’s been in the past 20 years that the trends have changed,” said Patricia Silveyra, MSc, PhD, ATSF, associate professor of environmental and occupational health at Indiana University, Bloomington.

The increasing prevalence of COPD among women cannot be explained by smoking alone, she said in an interview.

“It used to be thought that it was because more women smoked, but actually a lot of women who don’t smoke can develop COPD, so it appears to be probably something environmental, but because it used to be a disease of older men, in the clinic there was also a bias to diagnose men with COPD, and women with asthma, so a lot of women went underdiagnosed,” Dr. Silveyra said.

In their review, Dr. Sodhi and colleagues noted that women with COPD “may be underdiagnosed as a result of having different symptoms from those classically recognized. Reasons for underdiagnosis or a delay in diagnosis may also be due to lack of a formal evaluation with spirometry, women seeking care later in the course of disease, physician bias, or associated fatigue or depression misdirecting diagnostic strategies. Underdiagnosis may be associated with psychological distress and worse health-related quality of life.”

Although the evidence is mixed, women tend to present more frequently with the chronic bronchitis phenotype of COPD, compared with the emphysema phenotype, and women tend to have greater degrees of pulmonary function impairment when exposed to tobacco smoke, even after controlling for differences in height and weight.

“For the same amount of exposure to tobacco smoke, females are likely to develop more severe airflow limitation at an earlier age than males, and have more exacerbation,” Dr. Sodhi and colleagues wrote.

Both Dr. Silveyra and Dr. Sodhi said that reason why men and women differ in their physiological reactions to smoke are still unknown.
 

Sex differences in drug responses

There is only limited evidence to indicate that women and men respond differently to various therapeutic agents, but what is clear is that more research into this area is needed, Dr. Sodhi and Dr. Silveyra said.

For example, among the few studies that have documented sex differences, one showed no sex differences in the efficacy of salmeterol/fluticasone combination therapy for reducing exacerbations or improving quality of life, whereas another showed that women were more likely than men to experience COPD symptoms or exacerbations after stopping inhaled corticosteroids, Dr. Sodhi and colleagues noted.

Both Dr. Sodhi and Dr. Silveyra emphasized the need for clinical trials that study the effects of sex on treatment outcomes in COPD, which could lead to better, more personalized therapeutic regimens that take sex and gender into account.

Dr. Sodhi and colleagues offered the following advice to clinicians: “Interaction with female patients should take into account that their symptoms may not conform to traditionally accepted presentations. Challenges exist for female patients at all levels of health care interaction and as clinicians we need to acknowledge the bias and willfully work toward recognition and elimination of unconscious and conscious bias. Empowering our patients to have frank discussions with their health care team when they perceive bias is another step to help promote equity.”

The review by Dr. Sodhi and colleagues was supported by grants from the National Institutes of Health. Dr. Sodhi and Dr. Silveyra reported having no conflicts of interest to disclose.

When Sigmund Freud claimed that “anatomy is destiny” he was referring to anatomical sex as a determinant of personality traits. Expert consensus statements have previously offered some recommendations for managing these syndromes, but clinical data are scarce, so the present review “is intended to establish a starting point for future research,”

That notion has been widely discredited, but Freud appears to be inadvertently right in one respect: When it comes to chronic obstructive pulmonary disease (COPD), anatomy really is destiny, and sex may be as well, pulmonary researchers say.

There is a growing body of evidence to indicate that COPD affects men and women differently, and that men and women patients with COPD require different clinical management. Yet women are often underdiagnosed or misdiagnosed, partly because of poorly understood sex differences, but also because of cultural biases.

But plunging any farther into the weeds, it’s important to define terms. Although various investigators have used the terms “sex” and “gender” interchangeably, sex is the preferred term when referring to biological attributes of individual patients, while gender refers to personal identity.

These distinctions are important, contended Amik Sodhi, MBBS, MPH, from the division of allergy, pulmonology, and critical care medicine at the University of Wisconsin–Madison.

“Sex is essentially a biologic construct, so it’s got to do with the sex chromosomes, the genetics of that person, and it refers to the anatomic variations that can change susceptibility to different diseases,” she said in an interview.

An example of sex differences or “sexual dimorphism” can be found in a recent meta-analysis of sex-based genetic associations by Megan Hardin, MD, MPH from Brigham & Women’s Hospital in Boston and colleagues.

They reported that CELSR1, a gene involved in fetal lung development, was expressed more among women than among men and that a single nucleotide polymorphism in the gene was associated with COPD among women smokers, but not among men smokers.

The finding points to a potential risk locus for COPD in women, and could help shed light on sexual dimorphism in COPD, Dr. Hardin and colleagues said.

In contrast to sex, “gender is more of a psychosocial construct which can impact how diseases manifest themselves, how they are potentially managed, and what outcomes might occur for that particular disease,” Dr. Sodhi said.

She and her colleagues recently published a review of sex and gender in common lung disorders and sleep in the journal CHEST, where they wrote that the “influence of sex and gender is portrayed in epidemiological data, disease pathogenesis and pathophysiology, clinical manifestations, response to treatment, access to care, and health outcomes. Hence, sex and gender should be considered in all types of research, clinical practice and educational curricula.”

For example, as previously reported at the 2021 annual meeting of the American Thoracic Society, sex-specific differences in the severity of symptoms and prevalence of comorbidities in patients with COPD may point to different criteria for diagnosing cardiac comorbidities in women and men.

Those conclusions came from a retrospective analysis of data on 795 women and 1,251 men with GOLD (Global Initiative for Chronic Obstructive Lung Disease) class 1-3 disease.

The investigators looked at the patients’ clinical history, comorbidities, lung function, COPD Assessment Test scores, and modified Medical Research Council (mMRC) dyspnea score, and found significant differences between men and women for most functional parameters and comorbidities, and for CAT items of cough, phlegm, and energy.

In logistic regression analysis, predictors for cardiac disease in men were energy, mMRC score, smoking status, body mass index, age, and spirometric lung function, but in women only age was significantly predictive for cardiac disease.

An example of gender effects on COPD differences in men and women is the increase in cigarette advertising aimed at women in the 1960s and the advent of women-targeted brands such as Virginia Slims, which in turn lead to increased smoking rates among women. In addition, in the developing world, where the sex/gender gap in COPD is narrowing, women tend to have greater exposure to wood smoke and cooking fuels in unventilated or poorly ventilated spaces, compared with men.
 

Increasing incidence among women

According to the Centers for Disease Control and Prevention, chronic lower respiratory diseases, primarily COPD, were the fourth-leading cause of death in women in the United States in 2018, following only heart disease, cancer, and accidents/injuries.

And as a CDC analysis of data from the 2013 Behavioral Risk Factor Surveillance System showed, women were more likely to report being told by a physician that they had COPD than did men (6.6%, compared with 5.4%).

Dr. Sodhi and colleagues noted that, at all time points examined from 2005 to 2014, women had a higher proportion than men of COPD hospitalizations and in-hospital deaths. They also noted that female sex is associated with a threefold risk for severe early-onset COPD, and that women with COPD have lower diffusion capacity of lungs for carbon monoxide, despite having higher predicted forced expiratory volume in 1 second, compared with men.

“Historically, COPD wasn’t a disease that was so prevalent in women. It’s been in the past 20 years that the trends have changed,” said Patricia Silveyra, MSc, PhD, ATSF, associate professor of environmental and occupational health at Indiana University, Bloomington.

The increasing prevalence of COPD among women cannot be explained by smoking alone, she said in an interview.

“It used to be thought that it was because more women smoked, but actually a lot of women who don’t smoke can develop COPD, so it appears to be probably something environmental, but because it used to be a disease of older men, in the clinic there was also a bias to diagnose men with COPD, and women with asthma, so a lot of women went underdiagnosed,” Dr. Silveyra said.

In their review, Dr. Sodhi and colleagues noted that women with COPD “may be underdiagnosed as a result of having different symptoms from those classically recognized. Reasons for underdiagnosis or a delay in diagnosis may also be due to lack of a formal evaluation with spirometry, women seeking care later in the course of disease, physician bias, or associated fatigue or depression misdirecting diagnostic strategies. Underdiagnosis may be associated with psychological distress and worse health-related quality of life.”

Although the evidence is mixed, women tend to present more frequently with the chronic bronchitis phenotype of COPD, compared with the emphysema phenotype, and women tend to have greater degrees of pulmonary function impairment when exposed to tobacco smoke, even after controlling for differences in height and weight.

“For the same amount of exposure to tobacco smoke, females are likely to develop more severe airflow limitation at an earlier age than males, and have more exacerbation,” Dr. Sodhi and colleagues wrote.

Both Dr. Silveyra and Dr. Sodhi said that reason why men and women differ in their physiological reactions to smoke are still unknown.
 

Sex differences in drug responses

There is only limited evidence to indicate that women and men respond differently to various therapeutic agents, but what is clear is that more research into this area is needed, Dr. Sodhi and Dr. Silveyra said.

For example, among the few studies that have documented sex differences, one showed no sex differences in the efficacy of salmeterol/fluticasone combination therapy for reducing exacerbations or improving quality of life, whereas another showed that women were more likely than men to experience COPD symptoms or exacerbations after stopping inhaled corticosteroids, Dr. Sodhi and colleagues noted.

Both Dr. Sodhi and Dr. Silveyra emphasized the need for clinical trials that study the effects of sex on treatment outcomes in COPD, which could lead to better, more personalized therapeutic regimens that take sex and gender into account.

Dr. Sodhi and colleagues offered the following advice to clinicians: “Interaction with female patients should take into account that their symptoms may not conform to traditionally accepted presentations. Challenges exist for female patients at all levels of health care interaction and as clinicians we need to acknowledge the bias and willfully work toward recognition and elimination of unconscious and conscious bias. Empowering our patients to have frank discussions with their health care team when they perceive bias is another step to help promote equity.”

The review by Dr. Sodhi and colleagues was supported by grants from the National Institutes of Health. Dr. Sodhi and Dr. Silveyra reported having no conflicts of interest to disclose.

When Sigmund Freud claimed that “anatomy is destiny” he was referring to anatomical sex as a determinant of personality traits. Expert consensus statements have previously offered some recommendations for managing these syndromes, but clinical data are scarce, so the present review “is intended to establish a starting point for future research,”

That notion has been widely discredited, but Freud appears to be inadvertently right in one respect: When it comes to chronic obstructive pulmonary disease (COPD), anatomy really is destiny, and sex may be as well, pulmonary researchers say.

There is a growing body of evidence to indicate that COPD affects men and women differently, and that men and women patients with COPD require different clinical management. Yet women are often underdiagnosed or misdiagnosed, partly because of poorly understood sex differences, but also because of cultural biases.

But plunging any farther into the weeds, it’s important to define terms. Although various investigators have used the terms “sex” and “gender” interchangeably, sex is the preferred term when referring to biological attributes of individual patients, while gender refers to personal identity.

These distinctions are important, contended Amik Sodhi, MBBS, MPH, from the division of allergy, pulmonology, and critical care medicine at the University of Wisconsin–Madison.

“Sex is essentially a biologic construct, so it’s got to do with the sex chromosomes, the genetics of that person, and it refers to the anatomic variations that can change susceptibility to different diseases,” she said in an interview.

An example of sex differences or “sexual dimorphism” can be found in a recent meta-analysis of sex-based genetic associations by Megan Hardin, MD, MPH from Brigham & Women’s Hospital in Boston and colleagues.

They reported that CELSR1, a gene involved in fetal lung development, was expressed more among women than among men and that a single nucleotide polymorphism in the gene was associated with COPD among women smokers, but not among men smokers.

The finding points to a potential risk locus for COPD in women, and could help shed light on sexual dimorphism in COPD, Dr. Hardin and colleagues said.

In contrast to sex, “gender is more of a psychosocial construct which can impact how diseases manifest themselves, how they are potentially managed, and what outcomes might occur for that particular disease,” Dr. Sodhi said.

She and her colleagues recently published a review of sex and gender in common lung disorders and sleep in the journal CHEST, where they wrote that the “influence of sex and gender is portrayed in epidemiological data, disease pathogenesis and pathophysiology, clinical manifestations, response to treatment, access to care, and health outcomes. Hence, sex and gender should be considered in all types of research, clinical practice and educational curricula.”

For example, as previously reported at the 2021 annual meeting of the American Thoracic Society, sex-specific differences in the severity of symptoms and prevalence of comorbidities in patients with COPD may point to different criteria for diagnosing cardiac comorbidities in women and men.

Those conclusions came from a retrospective analysis of data on 795 women and 1,251 men with GOLD (Global Initiative for Chronic Obstructive Lung Disease) class 1-3 disease.

The investigators looked at the patients’ clinical history, comorbidities, lung function, COPD Assessment Test scores, and modified Medical Research Council (mMRC) dyspnea score, and found significant differences between men and women for most functional parameters and comorbidities, and for CAT items of cough, phlegm, and energy.

In logistic regression analysis, predictors for cardiac disease in men were energy, mMRC score, smoking status, body mass index, age, and spirometric lung function, but in women only age was significantly predictive for cardiac disease.

An example of gender effects on COPD differences in men and women is the increase in cigarette advertising aimed at women in the 1960s and the advent of women-targeted brands such as Virginia Slims, which in turn lead to increased smoking rates among women. In addition, in the developing world, where the sex/gender gap in COPD is narrowing, women tend to have greater exposure to wood smoke and cooking fuels in unventilated or poorly ventilated spaces, compared with men.
 

Increasing incidence among women

According to the Centers for Disease Control and Prevention, chronic lower respiratory diseases, primarily COPD, were the fourth-leading cause of death in women in the United States in 2018, following only heart disease, cancer, and accidents/injuries.

And as a CDC analysis of data from the 2013 Behavioral Risk Factor Surveillance System showed, women were more likely to report being told by a physician that they had COPD than did men (6.6%, compared with 5.4%).

Dr. Sodhi and colleagues noted that, at all time points examined from 2005 to 2014, women had a higher proportion than men of COPD hospitalizations and in-hospital deaths. They also noted that female sex is associated with a threefold risk for severe early-onset COPD, and that women with COPD have lower diffusion capacity of lungs for carbon monoxide, despite having higher predicted forced expiratory volume in 1 second, compared with men.

“Historically, COPD wasn’t a disease that was so prevalent in women. It’s been in the past 20 years that the trends have changed,” said Patricia Silveyra, MSc, PhD, ATSF, associate professor of environmental and occupational health at Indiana University, Bloomington.

The increasing prevalence of COPD among women cannot be explained by smoking alone, she said in an interview.

“It used to be thought that it was because more women smoked, but actually a lot of women who don’t smoke can develop COPD, so it appears to be probably something environmental, but because it used to be a disease of older men, in the clinic there was also a bias to diagnose men with COPD, and women with asthma, so a lot of women went underdiagnosed,” Dr. Silveyra said.

In their review, Dr. Sodhi and colleagues noted that women with COPD “may be underdiagnosed as a result of having different symptoms from those classically recognized. Reasons for underdiagnosis or a delay in diagnosis may also be due to lack of a formal evaluation with spirometry, women seeking care later in the course of disease, physician bias, or associated fatigue or depression misdirecting diagnostic strategies. Underdiagnosis may be associated with psychological distress and worse health-related quality of life.”

Although the evidence is mixed, women tend to present more frequently with the chronic bronchitis phenotype of COPD, compared with the emphysema phenotype, and women tend to have greater degrees of pulmonary function impairment when exposed to tobacco smoke, even after controlling for differences in height and weight.

“For the same amount of exposure to tobacco smoke, females are likely to develop more severe airflow limitation at an earlier age than males, and have more exacerbation,” Dr. Sodhi and colleagues wrote.

Both Dr. Silveyra and Dr. Sodhi said that reason why men and women differ in their physiological reactions to smoke are still unknown.
 

Sex differences in drug responses

There is only limited evidence to indicate that women and men respond differently to various therapeutic agents, but what is clear is that more research into this area is needed, Dr. Sodhi and Dr. Silveyra said.

For example, among the few studies that have documented sex differences, one showed no sex differences in the efficacy of salmeterol/fluticasone combination therapy for reducing exacerbations or improving quality of life, whereas another showed that women were more likely than men to experience COPD symptoms or exacerbations after stopping inhaled corticosteroids, Dr. Sodhi and colleagues noted.

Both Dr. Sodhi and Dr. Silveyra emphasized the need for clinical trials that study the effects of sex on treatment outcomes in COPD, which could lead to better, more personalized therapeutic regimens that take sex and gender into account.

Dr. Sodhi and colleagues offered the following advice to clinicians: “Interaction with female patients should take into account that their symptoms may not conform to traditionally accepted presentations. Challenges exist for female patients at all levels of health care interaction and as clinicians we need to acknowledge the bias and willfully work toward recognition and elimination of unconscious and conscious bias. Empowering our patients to have frank discussions with their health care team when they perceive bias is another step to help promote equity.”

The review by Dr. Sodhi and colleagues was supported by grants from the National Institutes of Health. Dr. Sodhi and Dr. Silveyra reported having no conflicts of interest to disclose.