Clinical Edge Journal Scan

Key clinical point: Dupilumab led to rapid and significant improvements in atopic dermatitis (AD) signs and symptoms in children, including those who failed to attain clear or almost clear skin according to Investigator's Global Assessment (IGA).

Major finding: At week 16, the composite endpoint, including ≥50% improvement in Eczema Area and Severity Index scores, was achieved by significantly more children receiving dupilumab vs placebo in the overall group (77.7% vs 24.6%; P < .0001) and the subgroup with an IGA score > 1 (68.9% vs 21.5%; P < .0001). Significant improvements were observed as early as week 2.

Study details: This post hoc analysis of LIBERTY AD PRESCHOOL (Part B) included 162 children age 6 months to 5 years with moderate-to-severe AD who were randomized to receive dupilumab or placebo and low-potency topical corticosteroids, of whom 136 had an IGA score > 1.

Disclosures: This study was sponsored by Sanofi and Regeneron Pharmaceuticals Inc. Three authors reported being employees of or owning stocks or stock options in Sanofi or Regeneron. The remaining authors reported receiving grants from or having other ties with Sanofi, Regeneron, or others.

Source: Cork MJ, Lockshin B, Pinter A, et al. Clinically meaningful responses to dupilumab among children aged 6 months to 5 years with moderate-to-severe atopic dermatitis who did not achieve clear or almost clear skin according to the investigator's global assessment: A post hoc analysis of a phase 3 trial. Acta Derm Venereol. 2024 (Feb 12). doi: 10.2340/actadv.v104.13467 Source

Key clinical point: Dupilumab led to rapid and significant improvements in atopic dermatitis (AD) signs and symptoms in children, including those who failed to attain clear or almost clear skin according to Investigator's Global Assessment (IGA).

Major finding: At week 16, the composite endpoint, including ≥50% improvement in Eczema Area and Severity Index scores, was achieved by significantly more children receiving dupilumab vs placebo in the overall group (77.7% vs 24.6%; P < .0001) and the subgroup with an IGA score > 1 (68.9% vs 21.5%; P < .0001). Significant improvements were observed as early as week 2.

Study details: This post hoc analysis of LIBERTY AD PRESCHOOL (Part B) included 162 children age 6 months to 5 years with moderate-to-severe AD who were randomized to receive dupilumab or placebo and low-potency topical corticosteroids, of whom 136 had an IGA score > 1.

Disclosures: This study was sponsored by Sanofi and Regeneron Pharmaceuticals Inc. Three authors reported being employees of or owning stocks or stock options in Sanofi or Regeneron. The remaining authors reported receiving grants from or having other ties with Sanofi, Regeneron, or others.

Source: Cork MJ, Lockshin B, Pinter A, et al. Clinically meaningful responses to dupilumab among children aged 6 months to 5 years with moderate-to-severe atopic dermatitis who did not achieve clear or almost clear skin according to the investigator's global assessment: A post hoc analysis of a phase 3 trial. Acta Derm Venereol. 2024 (Feb 12). doi: 10.2340/actadv.v104.13467 Source

Key clinical point: Dupilumab led to rapid and significant improvements in atopic dermatitis (AD) signs and symptoms in children, including those who failed to attain clear or almost clear skin according to Investigator's Global Assessment (IGA).

Major finding: At week 16, the composite endpoint, including ≥50% improvement in Eczema Area and Severity Index scores, was achieved by significantly more children receiving dupilumab vs placebo in the overall group (77.7% vs 24.6%; P < .0001) and the subgroup with an IGA score > 1 (68.9% vs 21.5%; P < .0001). Significant improvements were observed as early as week 2.

Study details: This post hoc analysis of LIBERTY AD PRESCHOOL (Part B) included 162 children age 6 months to 5 years with moderate-to-severe AD who were randomized to receive dupilumab or placebo and low-potency topical corticosteroids, of whom 136 had an IGA score > 1.

Disclosures: This study was sponsored by Sanofi and Regeneron Pharmaceuticals Inc. Three authors reported being employees of or owning stocks or stock options in Sanofi or Regeneron. The remaining authors reported receiving grants from or having other ties with Sanofi, Regeneron, or others.

Source: Cork MJ, Lockshin B, Pinter A, et al. Clinically meaningful responses to dupilumab among children aged 6 months to 5 years with moderate-to-severe atopic dermatitis who did not achieve clear or almost clear skin according to the investigator's global assessment: A post hoc analysis of a phase 3 trial. Acta Derm Venereol. 2024 (Feb 12). doi: 10.2340/actadv.v104.13467 Source

Key clinical point: Both the age of onset and persistence of atopic dermatitis (AD) are differentially associated with the expression and progression of other atopic diseases during childhood.

Major finding: Children who developed AD at 1 year of age (persistent AD) showed significantly higher rates of food allergy (P = .004), asthma (P < .001), and self-reported rhinitis (P < .001) during childhood compared with children without AD at age 1 year (none/intermittent AD [never had AD or had an intermittent course] or late-onset AD [onset from 4-6 years of age]).

Study details: This study included 285 children from the Childhood Origins of ASThma cohort with a history of physician-diagnosed asthma or respiratory allergies who were followed up to 18 years of age and categorized based on AD phenotypes into none/intermittent (n = 180), late-onset (n = 38), or persistent (n = 67) AD groups.

Disclosures: This study was funded by the US National Institutes of Health (NIH) and the US National Heart, Lung, and Blood Institute. Two authors declared receiving funding from or having other ties with various sources, including NIH.

Source: Taki MH, Lee KE, Gangnon R, et al. Atopic dermatitis phenotypes impact expression of atopic diseases despite similar mononuclear cell cytokine responses. J Allergy Clin Immunol. 2024 (Mar 2). doi: 10.1016/j.jaci.2024.02.015 Source

Key clinical point: Both the age of onset and persistence of atopic dermatitis (AD) are differentially associated with the expression and progression of other atopic diseases during childhood.

Major finding: Children who developed AD at 1 year of age (persistent AD) showed significantly higher rates of food allergy (P = .004), asthma (P < .001), and self-reported rhinitis (P < .001) during childhood compared with children without AD at age 1 year (none/intermittent AD [never had AD or had an intermittent course] or late-onset AD [onset from 4-6 years of age]).

Study details: This study included 285 children from the Childhood Origins of ASThma cohort with a history of physician-diagnosed asthma or respiratory allergies who were followed up to 18 years of age and categorized based on AD phenotypes into none/intermittent (n = 180), late-onset (n = 38), or persistent (n = 67) AD groups.

Disclosures: This study was funded by the US National Institutes of Health (NIH) and the US National Heart, Lung, and Blood Institute. Two authors declared receiving funding from or having other ties with various sources, including NIH.

Source: Taki MH, Lee KE, Gangnon R, et al. Atopic dermatitis phenotypes impact expression of atopic diseases despite similar mononuclear cell cytokine responses. J Allergy Clin Immunol. 2024 (Mar 2). doi: 10.1016/j.jaci.2024.02.015 Source

Key clinical point: Both the age of onset and persistence of atopic dermatitis (AD) are differentially associated with the expression and progression of other atopic diseases during childhood.

Major finding: Children who developed AD at 1 year of age (persistent AD) showed significantly higher rates of food allergy (P = .004), asthma (P < .001), and self-reported rhinitis (P < .001) during childhood compared with children without AD at age 1 year (none/intermittent AD [never had AD or had an intermittent course] or late-onset AD [onset from 4-6 years of age]).

Study details: This study included 285 children from the Childhood Origins of ASThma cohort with a history of physician-diagnosed asthma or respiratory allergies who were followed up to 18 years of age and categorized based on AD phenotypes into none/intermittent (n = 180), late-onset (n = 38), or persistent (n = 67) AD groups.

Disclosures: This study was funded by the US National Institutes of Health (NIH) and the US National Heart, Lung, and Blood Institute. Two authors declared receiving funding from or having other ties with various sources, including NIH.

Source: Taki MH, Lee KE, Gangnon R, et al. Atopic dermatitis phenotypes impact expression of atopic diseases despite similar mononuclear cell cytokine responses. J Allergy Clin Immunol. 2024 (Mar 2). doi: 10.1016/j.jaci.2024.02.015 Source

Key clinical point: Children who later developed atopic dermatitis (AD) had a delayed maturation of the skin microbiome and increased levels of proinflammatory stratum corneum biomarkers before AD onset.

Major finding: Children who did vs did not develop AD later had significantly increased levels of stratum corneum biomarkers (thymus and activation-regulated chemokine, interleukin-18, monocyte chemoattractant protein-1, interleukin-22, etc.; all P ≤ .01) and greater variance over time in the most abundant 14 core amplicon sequence variants (P = .04), indicating delayed establishment of a stable skin microbiome.

Study details: This study longitudinally analyzed the epidermal biomarker levels and microbiome profiles of 50 children who were at a high risk for AD from a previous randomized study, of whom 26% of children developed AD up to month 24.

Disclosures: This study was supported by the BIOMAP project, LA ROCHE-POSAY Laboratoire Pharmaceutique, France, and others. Four authors declared receiving institutional research grants, honoraria for consulting, etc., from or having other ties with various sources.

Source: Fonfara M, Hartmann J, Stölzl D, et al. Stratum corneum and microbial biomarkers precede and characterize childhood atopic dermatitis. J Eur Acad Dermatol Venereol. 2024 (Feb 29). doi: 10.1111/jdv.19932 Source

Key clinical point: Children who later developed atopic dermatitis (AD) had a delayed maturation of the skin microbiome and increased levels of proinflammatory stratum corneum biomarkers before AD onset.

Major finding: Children who did vs did not develop AD later had significantly increased levels of stratum corneum biomarkers (thymus and activation-regulated chemokine, interleukin-18, monocyte chemoattractant protein-1, interleukin-22, etc.; all P ≤ .01) and greater variance over time in the most abundant 14 core amplicon sequence variants (P = .04), indicating delayed establishment of a stable skin microbiome.

Study details: This study longitudinally analyzed the epidermal biomarker levels and microbiome profiles of 50 children who were at a high risk for AD from a previous randomized study, of whom 26% of children developed AD up to month 24.

Disclosures: This study was supported by the BIOMAP project, LA ROCHE-POSAY Laboratoire Pharmaceutique, France, and others. Four authors declared receiving institutional research grants, honoraria for consulting, etc., from or having other ties with various sources.

Source: Fonfara M, Hartmann J, Stölzl D, et al. Stratum corneum and microbial biomarkers precede and characterize childhood atopic dermatitis. J Eur Acad Dermatol Venereol. 2024 (Feb 29). doi: 10.1111/jdv.19932 Source

Key clinical point: Children who later developed atopic dermatitis (AD) had a delayed maturation of the skin microbiome and increased levels of proinflammatory stratum corneum biomarkers before AD onset.

Major finding: Children who did vs did not develop AD later had significantly increased levels of stratum corneum biomarkers (thymus and activation-regulated chemokine, interleukin-18, monocyte chemoattractant protein-1, interleukin-22, etc.; all P ≤ .01) and greater variance over time in the most abundant 14 core amplicon sequence variants (P = .04), indicating delayed establishment of a stable skin microbiome.

Study details: This study longitudinally analyzed the epidermal biomarker levels and microbiome profiles of 50 children who were at a high risk for AD from a previous randomized study, of whom 26% of children developed AD up to month 24.

Disclosures: This study was supported by the BIOMAP project, LA ROCHE-POSAY Laboratoire Pharmaceutique, France, and others. Four authors declared receiving institutional research grants, honoraria for consulting, etc., from or having other ties with various sources.

Source: Fonfara M, Hartmann J, Stölzl D, et al. Stratum corneum and microbial biomarkers precede and characterize childhood atopic dermatitis. J Eur Acad Dermatol Venereol. 2024 (Feb 29). doi: 10.1111/jdv.19932 Source

Key clinical point: The presence of atopic dermatitis (AD) symptoms in children during early life is associated with increased likelihood of pain at 10 years of age, suggesting a prospective influence of AD on pain experiences in children.

Major finding: Children with AD-like symptoms at 6 and 15 months of age had a significantly higher risk of reporting any pain (relative risk [RR] 1.75; 95% CI 1.15-2.66) and multisite pain (RR 1.67; 95% CI 1.18-2.37), respectively, at age 10 years.

Study details: This prospective study analyzed the data of 1302 and 874 children from the Generation XXI birth cohort for AD-like symptoms at ages 6 months and 15 months, respectively, by interviewing parents; data on pain history in the last 3 months at age 10 years was collected using structured questionnaires for parents and children.

Disclosures: This study was funded by the European Regional Development Fund, through COMPETE 2020 Operational Programme 'Competitiveness and Internationalization,' projects at the Univeridade do Porto, Portugal, and others. The authors declared no conflicts of interest.

Source: Gorito V, Brandão M, Azevedo I, et al. Atopic dermatitis in early life and pain at 10 years of age: An exploratory study. Eur J Pediatr. 2024 (Feb 24). doi: 10.1007/s00431-024-05439-0 Source

Key clinical point: The presence of atopic dermatitis (AD) symptoms in children during early life is associated with increased likelihood of pain at 10 years of age, suggesting a prospective influence of AD on pain experiences in children.

Major finding: Children with AD-like symptoms at 6 and 15 months of age had a significantly higher risk of reporting any pain (relative risk [RR] 1.75; 95% CI 1.15-2.66) and multisite pain (RR 1.67; 95% CI 1.18-2.37), respectively, at age 10 years.

Study details: This prospective study analyzed the data of 1302 and 874 children from the Generation XXI birth cohort for AD-like symptoms at ages 6 months and 15 months, respectively, by interviewing parents; data on pain history in the last 3 months at age 10 years was collected using structured questionnaires for parents and children.

Disclosures: This study was funded by the European Regional Development Fund, through COMPETE 2020 Operational Programme 'Competitiveness and Internationalization,' projects at the Univeridade do Porto, Portugal, and others. The authors declared no conflicts of interest.

Source: Gorito V, Brandão M, Azevedo I, et al. Atopic dermatitis in early life and pain at 10 years of age: An exploratory study. Eur J Pediatr. 2024 (Feb 24). doi: 10.1007/s00431-024-05439-0 Source

Key clinical point: The presence of atopic dermatitis (AD) symptoms in children during early life is associated with increased likelihood of pain at 10 years of age, suggesting a prospective influence of AD on pain experiences in children.

Major finding: Children with AD-like symptoms at 6 and 15 months of age had a significantly higher risk of reporting any pain (relative risk [RR] 1.75; 95% CI 1.15-2.66) and multisite pain (RR 1.67; 95% CI 1.18-2.37), respectively, at age 10 years.

Study details: This prospective study analyzed the data of 1302 and 874 children from the Generation XXI birth cohort for AD-like symptoms at ages 6 months and 15 months, respectively, by interviewing parents; data on pain history in the last 3 months at age 10 years was collected using structured questionnaires for parents and children.

Disclosures: This study was funded by the European Regional Development Fund, through COMPETE 2020 Operational Programme 'Competitiveness and Internationalization,' projects at the Univeridade do Porto, Portugal, and others. The authors declared no conflicts of interest.

Source: Gorito V, Brandão M, Azevedo I, et al. Atopic dermatitis in early life and pain at 10 years of age: An exploratory study. Eur J Pediatr. 2024 (Feb 24). doi: 10.1007/s00431-024-05439-0 Source

Key clinical point: Topical Streptococcus postbiotic emollient (strain CX) demonstrated superior efficacy in improving disease activity outcomes and a tolerable safety profile in patients with mild-to-moderate atopic dermatitis (AD).

Major finding: At week 8, a higher percentage of patients in the topical Streptococcus postbiotic emollient vs placebo group (41.5% vs 12.1%; P = .005) achieved an Investigator’s Global Assessment score of 0 or 1 and a reduction of ≥1 point from baseline. No significant safety issues were identified during the study.

Study details: Findings are from a proof-of-concept trial including 98 patients with mild-to-moderate AD (age 12-70 years) who were randomly assigned 2:1 to receive daily topical 1.0% Strain CX postbiotic emollient (n = 65) or placebo (n = 33) for 8 weeks.

Disclosures: This study was supported by the National Research Foundation of Korea grant funded by the Korea government and Cosmax BTI. The authors declared no conflicts of interest.

Source: Kim MS, Kim HJ, Kang SM, Heo YM, Kang J, et al. Efficacy and safety of topical Streptococcus postbiotic emollient in adolescents and adults with mild-to-moderate atopic dermatitis: A randomized, double-blind, vehicle-controlled trial. Allergy. 2024 (Mar 4). doi: 10.1111/all.16077 Source

Key clinical point: Topical Streptococcus postbiotic emollient (strain CX) demonstrated superior efficacy in improving disease activity outcomes and a tolerable safety profile in patients with mild-to-moderate atopic dermatitis (AD).

Major finding: At week 8, a higher percentage of patients in the topical Streptococcus postbiotic emollient vs placebo group (41.5% vs 12.1%; P = .005) achieved an Investigator’s Global Assessment score of 0 or 1 and a reduction of ≥1 point from baseline. No significant safety issues were identified during the study.

Study details: Findings are from a proof-of-concept trial including 98 patients with mild-to-moderate AD (age 12-70 years) who were randomly assigned 2:1 to receive daily topical 1.0% Strain CX postbiotic emollient (n = 65) or placebo (n = 33) for 8 weeks.

Disclosures: This study was supported by the National Research Foundation of Korea grant funded by the Korea government and Cosmax BTI. The authors declared no conflicts of interest.

Source: Kim MS, Kim HJ, Kang SM, Heo YM, Kang J, et al. Efficacy and safety of topical Streptococcus postbiotic emollient in adolescents and adults with mild-to-moderate atopic dermatitis: A randomized, double-blind, vehicle-controlled trial. Allergy. 2024 (Mar 4). doi: 10.1111/all.16077 Source

Key clinical point: Topical Streptococcus postbiotic emollient (strain CX) demonstrated superior efficacy in improving disease activity outcomes and a tolerable safety profile in patients with mild-to-moderate atopic dermatitis (AD).

Major finding: At week 8, a higher percentage of patients in the topical Streptococcus postbiotic emollient vs placebo group (41.5% vs 12.1%; P = .005) achieved an Investigator’s Global Assessment score of 0 or 1 and a reduction of ≥1 point from baseline. No significant safety issues were identified during the study.

Study details: Findings are from a proof-of-concept trial including 98 patients with mild-to-moderate AD (age 12-70 years) who were randomly assigned 2:1 to receive daily topical 1.0% Strain CX postbiotic emollient (n = 65) or placebo (n = 33) for 8 weeks.

Disclosures: This study was supported by the National Research Foundation of Korea grant funded by the Korea government and Cosmax BTI. The authors declared no conflicts of interest.

Source: Kim MS, Kim HJ, Kang SM, Heo YM, Kang J, et al. Efficacy and safety of topical Streptococcus postbiotic emollient in adolescents and adults with mild-to-moderate atopic dermatitis: A randomized, double-blind, vehicle-controlled trial. Allergy. 2024 (Mar 4). doi: 10.1111/all.16077 Source

Key clinical point: Atopic dermatitis (AD) is associated with a higher likelihood of cognitive impairment symptoms involving difficulties in learning or memory, especially in children with neurodevelopmental comorbidities, such as attention-deficit/hyperactivity disorder (ADHD) or learning disability.

Major finding: A significantly greater number of children with vs without AD experienced difficulties with learning (10.8% vs 5.9%) and memory (11.1% vs 5.8%; both P < .001). However, this association was observed only in children with neurodevelopmental disorders (adjusted odds ratio 2.26; 95% CI 1.43-3.57) including ADHD or learning disabilities.

Study details: This cross-sectional study analyzed the data of 7957 children, representing a weighted total of 69,732,807 children without intellectual disabilities from the 2021 US National Health Interview Survey who did (n = 9,223,013) or did not (n = 60,509,794) have AD. The survey randomly selects 1 child per surveyed household for whom a parent or adult caregiver provides information.

Disclosures: This study was supported by a grant to Joy Wan from the US National Institutes of Health. Joy Wan also declared receiving a grant and personal fees from various pharmaceutical companies. The other authors declared no conflicts of interest.

Source: Ma EZ, Chang HR, Radtke S, Wan J. Symptoms of cognitive impairment among children with atopic dermatitis. JAMA Dermatol. 2024 (Mar 6). doi: 10.1001/jamadermatol.2024.0015 Source

Key clinical point: Atopic dermatitis (AD) is associated with a higher likelihood of cognitive impairment symptoms involving difficulties in learning or memory, especially in children with neurodevelopmental comorbidities, such as attention-deficit/hyperactivity disorder (ADHD) or learning disability.

Major finding: A significantly greater number of children with vs without AD experienced difficulties with learning (10.8% vs 5.9%) and memory (11.1% vs 5.8%; both P < .001). However, this association was observed only in children with neurodevelopmental disorders (adjusted odds ratio 2.26; 95% CI 1.43-3.57) including ADHD or learning disabilities.

Study details: This cross-sectional study analyzed the data of 7957 children, representing a weighted total of 69,732,807 children without intellectual disabilities from the 2021 US National Health Interview Survey who did (n = 9,223,013) or did not (n = 60,509,794) have AD. The survey randomly selects 1 child per surveyed household for whom a parent or adult caregiver provides information.

Disclosures: This study was supported by a grant to Joy Wan from the US National Institutes of Health. Joy Wan also declared receiving a grant and personal fees from various pharmaceutical companies. The other authors declared no conflicts of interest.

Source: Ma EZ, Chang HR, Radtke S, Wan J. Symptoms of cognitive impairment among children with atopic dermatitis. JAMA Dermatol. 2024 (Mar 6). doi: 10.1001/jamadermatol.2024.0015 Source

Key clinical point: Atopic dermatitis (AD) is associated with a higher likelihood of cognitive impairment symptoms involving difficulties in learning or memory, especially in children with neurodevelopmental comorbidities, such as attention-deficit/hyperactivity disorder (ADHD) or learning disability.

Major finding: A significantly greater number of children with vs without AD experienced difficulties with learning (10.8% vs 5.9%) and memory (11.1% vs 5.8%; both P < .001). However, this association was observed only in children with neurodevelopmental disorders (adjusted odds ratio 2.26; 95% CI 1.43-3.57) including ADHD or learning disabilities.

Study details: This cross-sectional study analyzed the data of 7957 children, representing a weighted total of 69,732,807 children without intellectual disabilities from the 2021 US National Health Interview Survey who did (n = 9,223,013) or did not (n = 60,509,794) have AD. The survey randomly selects 1 child per surveyed household for whom a parent or adult caregiver provides information.

Disclosures: This study was supported by a grant to Joy Wan from the US National Institutes of Health. Joy Wan also declared receiving a grant and personal fees from various pharmaceutical companies. The other authors declared no conflicts of interest.

Source: Ma EZ, Chang HR, Radtke S, Wan J. Symptoms of cognitive impairment among children with atopic dermatitis. JAMA Dermatol. 2024 (Mar 6). doi: 10.1001/jamadermatol.2024.0015 Source

Additionally, several recently published reviews have examined the risks of comorbidities that are not neurologic or cardiovascular, such as allergies, inflammatory bowel disease, obesity, and diabetes. Although these types of associations are not inherently obvious in terms of migraine pathophysiology, determining whether there is a link may help shed a light on some contributing factors that could play a role in migraine or in the comorbid disorders.

Authors of a study published in the January 2024 issue of the European Journal of Medical Research sought to examine the relationship between allergic rhinitis and migraine. They noted that several studies, as well as a statement from the American Migraine Prevalence and Prevention Study, published in 2013, reported an increased frequency of migraines in patients with allergic rhinitis. The researchers used data extracted from the UK Biobank, comprising 25,486 patients diagnosed with allergic rhinitis and 87,097 controls and 8547 migraine cases and 176,107 controls. They performed statistical analysis using bidirectional two-sample Mendelian randomization with publicly available summary-level statistics of large genome-wide association studies to estimate the possible causal effects. The researchers did not find any clear causal or genetic association between allergic rhinitis and migraine risk. However, the lack of causation between migraine and allergic rhinitis does not contradict previous studies that point to the prevalence of comorbidity of the two conditions. It's also important to note that congestion is a known migraine trigger, and the results of the study do not contradict that relationship. Given the variability of results from different research studies, the authors suggested that more research is warranted to help untangle the complex association between allergic rhinitis and migraine.

Inflammatory bowel disease (IBD) is another condition with a higher prevalence in patients who have migraine. A January 2024 article in Scientific Reports described the results of a nationwide population-based study that was conducted using data from the Korean National Health Insurance Service database. This study included 10,131,193 individuals. The researchers found that the risk for development of IBD in patients with migraine was significantly higher, by 1.3 times, compared with the general population. These results are similar to previous studies, such as a meta-analysis published in May 2023 in the International Journal of Preventive Medicine, which reported a pooled prevalence of migraine in IBD cases of 19%, with 1.5-fold higher odds of developing migraine in IBD cases when compared with controls.^[3] These studies were both aimed at examining epidemiologic data rather than uncovering a physiologic or genetic cause of the link, and neither study described an explanation for this connection.

A Mendelian randomization study published in May 2023 in Headache investigated potential genetic links between migraine and IBD. As with the January 2024 European Journal of Medical Research study that was done to search for a genetic association between migraine and allergic rhinitis, the authors stated that there was no evidence of a shared genetic basis or of a causal association between migraine and either IBD or celiac disease.^[4] Although the evidence doesn't point to a causal relationship, it's important to note that diet plays a role in migraine management, and diet is especially important in managing IBD. Consideration of dietary factors could be beneficial for preventing symptoms — and is even more important for avoiding exacerbation of symptoms.

A high body mass index (BMI) is correlated with migraine. A study published in January 2024 in BMC Geriatrics analyzed data from people who participated in the National Health and Nutrition Examination Survey between 1999 and 2004 by the Centers for Disease Control and the National Center for Health Statistics, comprising a total of 31,126 participants. The researchers found a linear association between BMI and migraine. They also noted that increased BMI was related to a significantly higher risk for migraine in the group with diabetes, but this positive relationship between BMI and migraine seemed to be smaller in the group without diabetes. The authors considered inflammation associated with obesity as a possible contributing factor for this link but acknowledged that the pathophysiologic mechanism is unknown and suggested that there is a high likelihood of confounding factors. Given that diabetes and obesity are both correlated with an increased risk for vascular disease and migraine is associated with a slight increase in cardiovascular risk, it could be especially important to identify these comorbidities in individual patients.

Migraine is common, and many comorbidities have been verified with population studies. Although there are some explanations for the links between migraine and vascular or neurologic conditions, the cause of associations between migraine and other conditions is not known. Some theories that have begun to be investigated include inflammation and genetics. Eventually, further research and understanding of contributing factors could potentially provide explanations that may help in diagnosing migraine or associated disorders at an early stage — and might even be used to help guide treatment.

Additional References

1. Ashina M, Katsarava Z, Do TP, et al. Migraine: Epidemiology and systems of care. Lancet. 2021;397:1485-1495. doi: 10.1016/S0140-6736(20)32160-7 Source

2. Burch RC, Buse DC, Lipton RB. Migraine: Epidemiology, burden, and comorbidity. Neurol Clin. 2019;37:631-649. doi: 10.1016/j.ncl.2019.06.001 Source

3. Olfati H, Mirmosayyeb O, Hosseinabadi AM, Ghajarzadeh M. The prevalence of migraine in inflammatory bowel disease, a systematic review and meta-analysis. Int J Prev Med. 2023;14:66. doi: 10.4103/ijpvm.ijpvm_413_21 Source

4. Welander NZ, Rukh G, Rask-Andersen M, Harder AV, et al and International Headache Genetics Consortium. Migraine, inflammatory bowel disease and celiac disease: A Mendelian randomization study. Headache. 2023;63:642-651. doi: 10.1111/head.14470 Source

Additionally, several recently published reviews have examined the risks of comorbidities that are not neurologic or cardiovascular, such as allergies, inflammatory bowel disease, obesity, and diabetes. Although these types of associations are not inherently obvious in terms of migraine pathophysiology, determining whether there is a link may help shed a light on some contributing factors that could play a role in migraine or in the comorbid disorders.

Authors of a study published in the January 2024 issue of the European Journal of Medical Research sought to examine the relationship between allergic rhinitis and migraine. They noted that several studies, as well as a statement from the American Migraine Prevalence and Prevention Study, published in 2013, reported an increased frequency of migraines in patients with allergic rhinitis. The researchers used data extracted from the UK Biobank, comprising 25,486 patients diagnosed with allergic rhinitis and 87,097 controls and 8547 migraine cases and 176,107 controls. They performed statistical analysis using bidirectional two-sample Mendelian randomization with publicly available summary-level statistics of large genome-wide association studies to estimate the possible causal effects. The researchers did not find any clear causal or genetic association between allergic rhinitis and migraine risk. However, the lack of causation between migraine and allergic rhinitis does not contradict previous studies that point to the prevalence of comorbidity of the two conditions. It's also important to note that congestion is a known migraine trigger, and the results of the study do not contradict that relationship. Given the variability of results from different research studies, the authors suggested that more research is warranted to help untangle the complex association between allergic rhinitis and migraine.

Inflammatory bowel disease (IBD) is another condition with a higher prevalence in patients who have migraine. A January 2024 article in Scientific Reports described the results of a nationwide population-based study that was conducted using data from the Korean National Health Insurance Service database. This study included 10,131,193 individuals. The researchers found that the risk for development of IBD in patients with migraine was significantly higher, by 1.3 times, compared with the general population. These results are similar to previous studies, such as a meta-analysis published in May 2023 in the International Journal of Preventive Medicine, which reported a pooled prevalence of migraine in IBD cases of 19%, with 1.5-fold higher odds of developing migraine in IBD cases when compared with controls.^[3] These studies were both aimed at examining epidemiologic data rather than uncovering a physiologic or genetic cause of the link, and neither study described an explanation for this connection.

A Mendelian randomization study published in May 2023 in Headache investigated potential genetic links between migraine and IBD. As with the January 2024 European Journal of Medical Research study that was done to search for a genetic association between migraine and allergic rhinitis, the authors stated that there was no evidence of a shared genetic basis or of a causal association between migraine and either IBD or celiac disease.^[4] Although the evidence doesn't point to a causal relationship, it's important to note that diet plays a role in migraine management, and diet is especially important in managing IBD. Consideration of dietary factors could be beneficial for preventing symptoms — and is even more important for avoiding exacerbation of symptoms.

A high body mass index (BMI) is correlated with migraine. A study published in January 2024 in BMC Geriatrics analyzed data from people who participated in the National Health and Nutrition Examination Survey between 1999 and 2004 by the Centers for Disease Control and the National Center for Health Statistics, comprising a total of 31,126 participants. The researchers found a linear association between BMI and migraine. They also noted that increased BMI was related to a significantly higher risk for migraine in the group with diabetes, but this positive relationship between BMI and migraine seemed to be smaller in the group without diabetes. The authors considered inflammation associated with obesity as a possible contributing factor for this link but acknowledged that the pathophysiologic mechanism is unknown and suggested that there is a high likelihood of confounding factors. Given that diabetes and obesity are both correlated with an increased risk for vascular disease and migraine is associated with a slight increase in cardiovascular risk, it could be especially important to identify these comorbidities in individual patients.

Migraine is common, and many comorbidities have been verified with population studies. Although there are some explanations for the links between migraine and vascular or neurologic conditions, the cause of associations between migraine and other conditions is not known. Some theories that have begun to be investigated include inflammation and genetics. Eventually, further research and understanding of contributing factors could potentially provide explanations that may help in diagnosing migraine or associated disorders at an early stage — and might even be used to help guide treatment.

Additional References

1. Ashina M, Katsarava Z, Do TP, et al. Migraine: Epidemiology and systems of care. Lancet. 2021;397:1485-1495. doi: 10.1016/S0140-6736(20)32160-7 Source

2. Burch RC, Buse DC, Lipton RB. Migraine: Epidemiology, burden, and comorbidity. Neurol Clin. 2019;37:631-649. doi: 10.1016/j.ncl.2019.06.001 Source

3. Olfati H, Mirmosayyeb O, Hosseinabadi AM, Ghajarzadeh M. The prevalence of migraine in inflammatory bowel disease, a systematic review and meta-analysis. Int J Prev Med. 2023;14:66. doi: 10.4103/ijpvm.ijpvm_413_21 Source

4. Welander NZ, Rukh G, Rask-Andersen M, Harder AV, et al and International Headache Genetics Consortium. Migraine, inflammatory bowel disease and celiac disease: A Mendelian randomization study. Headache. 2023;63:642-651. doi: 10.1111/head.14470 Source

Additionally, several recently published reviews have examined the risks of comorbidities that are not neurologic or cardiovascular, such as allergies, inflammatory bowel disease, obesity, and diabetes. Although these types of associations are not inherently obvious in terms of migraine pathophysiology, determining whether there is a link may help shed a light on some contributing factors that could play a role in migraine or in the comorbid disorders.

Authors of a study published in the January 2024 issue of the European Journal of Medical Research sought to examine the relationship between allergic rhinitis and migraine. They noted that several studies, as well as a statement from the American Migraine Prevalence and Prevention Study, published in 2013, reported an increased frequency of migraines in patients with allergic rhinitis. The researchers used data extracted from the UK Biobank, comprising 25,486 patients diagnosed with allergic rhinitis and 87,097 controls and 8547 migraine cases and 176,107 controls. They performed statistical analysis using bidirectional two-sample Mendelian randomization with publicly available summary-level statistics of large genome-wide association studies to estimate the possible causal effects. The researchers did not find any clear causal or genetic association between allergic rhinitis and migraine risk. However, the lack of causation between migraine and allergic rhinitis does not contradict previous studies that point to the prevalence of comorbidity of the two conditions. It's also important to note that congestion is a known migraine trigger, and the results of the study do not contradict that relationship. Given the variability of results from different research studies, the authors suggested that more research is warranted to help untangle the complex association between allergic rhinitis and migraine.

Inflammatory bowel disease (IBD) is another condition with a higher prevalence in patients who have migraine. A January 2024 article in Scientific Reports described the results of a nationwide population-based study that was conducted using data from the Korean National Health Insurance Service database. This study included 10,131,193 individuals. The researchers found that the risk for development of IBD in patients with migraine was significantly higher, by 1.3 times, compared with the general population. These results are similar to previous studies, such as a meta-analysis published in May 2023 in the International Journal of Preventive Medicine, which reported a pooled prevalence of migraine in IBD cases of 19%, with 1.5-fold higher odds of developing migraine in IBD cases when compared with controls.^[3] These studies were both aimed at examining epidemiologic data rather than uncovering a physiologic or genetic cause of the link, and neither study described an explanation for this connection.

A Mendelian randomization study published in May 2023 in Headache investigated potential genetic links between migraine and IBD. As with the January 2024 European Journal of Medical Research study that was done to search for a genetic association between migraine and allergic rhinitis, the authors stated that there was no evidence of a shared genetic basis or of a causal association between migraine and either IBD or celiac disease.^[4] Although the evidence doesn't point to a causal relationship, it's important to note that diet plays a role in migraine management, and diet is especially important in managing IBD. Consideration of dietary factors could be beneficial for preventing symptoms — and is even more important for avoiding exacerbation of symptoms.

A high body mass index (BMI) is correlated with migraine. A study published in January 2024 in BMC Geriatrics analyzed data from people who participated in the National Health and Nutrition Examination Survey between 1999 and 2004 by the Centers for Disease Control and the National Center for Health Statistics, comprising a total of 31,126 participants. The researchers found a linear association between BMI and migraine. They also noted that increased BMI was related to a significantly higher risk for migraine in the group with diabetes, but this positive relationship between BMI and migraine seemed to be smaller in the group without diabetes. The authors considered inflammation associated with obesity as a possible contributing factor for this link but acknowledged that the pathophysiologic mechanism is unknown and suggested that there is a high likelihood of confounding factors. Given that diabetes and obesity are both correlated with an increased risk for vascular disease and migraine is associated with a slight increase in cardiovascular risk, it could be especially important to identify these comorbidities in individual patients.

Migraine is common, and many comorbidities have been verified with population studies. Although there are some explanations for the links between migraine and vascular or neurologic conditions, the cause of associations between migraine and other conditions is not known. Some theories that have begun to be investigated include inflammation and genetics. Eventually, further research and understanding of contributing factors could potentially provide explanations that may help in diagnosing migraine or associated disorders at an early stage — and might even be used to help guide treatment.

Additional References

1. Ashina M, Katsarava Z, Do TP, et al. Migraine: Epidemiology and systems of care. Lancet. 2021;397:1485-1495. doi: 10.1016/S0140-6736(20)32160-7 Source

2. Burch RC, Buse DC, Lipton RB. Migraine: Epidemiology, burden, and comorbidity. Neurol Clin. 2019;37:631-649. doi: 10.1016/j.ncl.2019.06.001 Source

3. Olfati H, Mirmosayyeb O, Hosseinabadi AM, Ghajarzadeh M. The prevalence of migraine in inflammatory bowel disease, a systematic review and meta-analysis. Int J Prev Med. 2023;14:66. doi: 10.4103/ijpvm.ijpvm_413_21 Source

4. Welander NZ, Rukh G, Rask-Andersen M, Harder AV, et al and International Headache Genetics Consortium. Migraine, inflammatory bowel disease and celiac disease: A Mendelian randomization study. Headache. 2023;63:642-651. doi: 10.1111/head.14470 Source

An important comorbidity of PsA is vascular inflammation leading to accelerated atherosclerosis, and higher risk for cardiovascular and cerebrovascular disease. Previously, vascular imaging modalities have demonstrated vascular inflammation in PsA. In a cross-sectional study that included 75 patients with active PsA and 40 control individuals without PsA, Kleinrensink and colleagues demonstrated that vascular inflammation of the whole aorta was significantly increased in patients with PsA vs control individuals. Of note, the association remained significant after adjusting for gender, age, body mass index, mean arterial pressure, and aortic calcification, but it was not associated with disease-related parameters. Further studies to determine the contributions of PsA per se and its comorbidities to vascular inflammation are required. Nevertheless, the management of PsA should include close monitoring and aggressive treatment of risk factors for atherosclerotic vascular disease.

Psychotic disorders are known to be associated with psoriasis, but their association with PsA is less well known. Using French health administrative data, Brenaut and colleagues showed that the prevalence of psychotic disorders was higher in individuals with psoriasis but surprisingly lower in individuals with PsA, compared with the general population. Moreover, a co-diagnosis of psoriasis/PsA and psychotic disorders was associated with an increased mortality rate and at a lower age.

Clinical trials have demonstrated that Janus kinase (JAK) inhibitors have a remarkable efficacy in the treatment of the musculoskeletal manifestations of PsA. Observational studies are important to evaluate effectiveness in real-world settings. In a study that included 123 patients with PsA from the CorEvitas PsA/Spondyloarthritis Registry who were treated with tofacitinib, Mease and colleagues observed that a quarter of patients achieved a state of low disease activity, based on the Clinical Disease Activity Index for PsA at 6 ± 3 months of follow-up. A substantial proportion of patients also reported the resolution of dactylitis (29.4%) and enthesitis (42.9%). Although these results are remarkable compared with what was seen with older therapies, one must note that only a quarter of patients achieved remission; more effective regimens for improving outcomes in PsA are required.

The safety of newer therapies is always of concern. It is reassuring that a meta-analysis of six randomized controlled trials that included 5038 patients with PsA who received either risankizumab (an anti-interleukin-23 antibody) or placebo by Su and colleagues demonstrated that the incidences of serious adverse events and serious treatment-emergent adverse events were similar between the risankizumab and placebo groups. Given the excellent safety profile of some of the newer therapies for PsA, trials with combinations of newer targeted therapies in treatment-resistant PsA should be conducted.

An important comorbidity of PsA is vascular inflammation leading to accelerated atherosclerosis, and higher risk for cardiovascular and cerebrovascular disease. Previously, vascular imaging modalities have demonstrated vascular inflammation in PsA. In a cross-sectional study that included 75 patients with active PsA and 40 control individuals without PsA, Kleinrensink and colleagues demonstrated that vascular inflammation of the whole aorta was significantly increased in patients with PsA vs control individuals. Of note, the association remained significant after adjusting for gender, age, body mass index, mean arterial pressure, and aortic calcification, but it was not associated with disease-related parameters. Further studies to determine the contributions of PsA per se and its comorbidities to vascular inflammation are required. Nevertheless, the management of PsA should include close monitoring and aggressive treatment of risk factors for atherosclerotic vascular disease.

Psychotic disorders are known to be associated with psoriasis, but their association with PsA is less well known. Using French health administrative data, Brenaut and colleagues showed that the prevalence of psychotic disorders was higher in individuals with psoriasis but surprisingly lower in individuals with PsA, compared with the general population. Moreover, a co-diagnosis of psoriasis/PsA and psychotic disorders was associated with an increased mortality rate and at a lower age.

Clinical trials have demonstrated that Janus kinase (JAK) inhibitors have a remarkable efficacy in the treatment of the musculoskeletal manifestations of PsA. Observational studies are important to evaluate effectiveness in real-world settings. In a study that included 123 patients with PsA from the CorEvitas PsA/Spondyloarthritis Registry who were treated with tofacitinib, Mease and colleagues observed that a quarter of patients achieved a state of low disease activity, based on the Clinical Disease Activity Index for PsA at 6 ± 3 months of follow-up. A substantial proportion of patients also reported the resolution of dactylitis (29.4%) and enthesitis (42.9%). Although these results are remarkable compared with what was seen with older therapies, one must note that only a quarter of patients achieved remission; more effective regimens for improving outcomes in PsA are required.

The safety of newer therapies is always of concern. It is reassuring that a meta-analysis of six randomized controlled trials that included 5038 patients with PsA who received either risankizumab (an anti-interleukin-23 antibody) or placebo by Su and colleagues demonstrated that the incidences of serious adverse events and serious treatment-emergent adverse events were similar between the risankizumab and placebo groups. Given the excellent safety profile of some of the newer therapies for PsA, trials with combinations of newer targeted therapies in treatment-resistant PsA should be conducted.

An important comorbidity of PsA is vascular inflammation leading to accelerated atherosclerosis, and higher risk for cardiovascular and cerebrovascular disease. Previously, vascular imaging modalities have demonstrated vascular inflammation in PsA. In a cross-sectional study that included 75 patients with active PsA and 40 control individuals without PsA, Kleinrensink and colleagues demonstrated that vascular inflammation of the whole aorta was significantly increased in patients with PsA vs control individuals. Of note, the association remained significant after adjusting for gender, age, body mass index, mean arterial pressure, and aortic calcification, but it was not associated with disease-related parameters. Further studies to determine the contributions of PsA per se and its comorbidities to vascular inflammation are required. Nevertheless, the management of PsA should include close monitoring and aggressive treatment of risk factors for atherosclerotic vascular disease.

Psychotic disorders are known to be associated with psoriasis, but their association with PsA is less well known. Using French health administrative data, Brenaut and colleagues showed that the prevalence of psychotic disorders was higher in individuals with psoriasis but surprisingly lower in individuals with PsA, compared with the general population. Moreover, a co-diagnosis of psoriasis/PsA and psychotic disorders was associated with an increased mortality rate and at a lower age.

Clinical trials have demonstrated that Janus kinase (JAK) inhibitors have a remarkable efficacy in the treatment of the musculoskeletal manifestations of PsA. Observational studies are important to evaluate effectiveness in real-world settings. In a study that included 123 patients with PsA from the CorEvitas PsA/Spondyloarthritis Registry who were treated with tofacitinib, Mease and colleagues observed that a quarter of patients achieved a state of low disease activity, based on the Clinical Disease Activity Index for PsA at 6 ± 3 months of follow-up. A substantial proportion of patients also reported the resolution of dactylitis (29.4%) and enthesitis (42.9%). Although these results are remarkable compared with what was seen with older therapies, one must note that only a quarter of patients achieved remission; more effective regimens for improving outcomes in PsA are required.

The safety of newer therapies is always of concern. It is reassuring that a meta-analysis of six randomized controlled trials that included 5038 patients with PsA who received either risankizumab (an anti-interleukin-23 antibody) or placebo by Su and colleagues demonstrated that the incidences of serious adverse events and serious treatment-emergent adverse events were similar between the risankizumab and placebo groups. Given the excellent safety profile of some of the newer therapies for PsA, trials with combinations of newer targeted therapies in treatment-resistant PsA should be conducted.

The phase 3 KEYNOTE-355 trial established the role of chemotherapy in combination with pembrolizumab in the first-line setting for programmed death-ligand 1 (PD-L1)–positive advanced triple-negative breast cancer (TNBC). Patients unselected for PD-L1 status in this trial who received platinum- or taxane-based chemotherapy with placebo had a median progression-free survival of 5.6 months.^[3] Strategies to improve upon efficacy and tolerability are desired in this space, and various trials have evaluated "switch maintenance" that involves receipt of an intensive induction regimen followed by a switch to an alternative/more tolerable regimen after response is achieved.^[4] The phase II DORA trial randomized 45 patients with advanced TNBC and ongoing stable disease or complete or partial response from first- or second-line platinum-based chemotherapy to a maintenance regimen of olaparib (300 mg orally twice daily) with or without durvalumab (1500 mg on day 1 and every 4 weeks) (Tan et al). At a median follow-up of 9.8 months, median progression-free survival was 4.0 months (95% CI 2.6-6.1) with olaparib and 6.1 months (95% CI 3.7-10.1) with the combination; both were significantly longer than the historical control of continued platinum-based therapy (P = .0023 and P < .0001, respectively). Durable disease control appeared more pronounced in patients with complete or partial response to prior platinum therapy, and no new safety signals were observed. Future efforts to study this approach include the phase 2/3 KEYLYNK-009 trial, which is evaluating olaparib plus pembrolizumab maintenance therapy after first-line chemotherapy plus pembrolizumab for TNBC.^[5]

TNBC is a heterogenous subtype, characterized by aggressive biology, and it benefits from chemotherapy and immunotherapy treatment approaches. Presently, the management of early-stage TNBC often involves neoadjuvant systemic therapy; however, a proportion of patients receive treatment in the postoperative setting, highlighting the relevance of time to initiation of adjuvant therapy as well.^[6] Various prior studies have showed that delayed administration of adjuvant chemotherapy for EBC can lead to adverse survival outcomes. Furthermore, this effect is subtype-dependent, with more aggressive tumors (luminal B, triple-negative, human epidermal growth factor receptor 2 [HER2]-positive) exhibiting inferior outcomes with delayed chemotherapy.^[7] A retrospective cohort study that included 245 patients with early TNBC who received adjuvant chemotherapy after surgery evaluated the impact of time to initiation of adjuvant therapy in this population (Hatzipanagiotou et al). Superior survival outcomes were observed for the group receiving systemic therapy 22-28 days after surgery (median overall survival 10.2 years) compared with those receiving adjuvant chemotherapy at later time points (29-35 days, 36-42 days, and >6 weeks after surgery; median overall survival 8.3 years, 7.8 years, and 6.9 years, respectively). Patients receiving chemotherapy 22-28 days after surgery had significantly better survival than those receiving chemotherapy 29-35 days (P = .043) and >6 weeks (P = 0.033) postoperatively. This study emphasizes the importance of timely administration of adjuvant chemotherapy for early TNBC, and efforts aimed to identify potential challenges and propose solutions to optimize outcomes in this space are valuable.

Additional References

1. Gnant M, Frantal S, Pfeiler G, et al, for the Austrian Breast & Colorectal Cancer Study Group. Long-term outcomes of adjuvant denosumab in breast cancer. NEJM Evid. 2022;1:EVIDoa2200162. doi: 10.1056/EVIDoa2200162 Source
2. Fassio A, Idolazzi L, Rossini M, et al. The obesity paradox and osteoporosis. Eating and Weight Disorders - Studies on Anorexia, Bulimia and Obesity. 2018;23:293-30 doi: 10.1007/s40519-018-0505-2 Source
3. Cortes J, Cescon DW, Rugo HS, et al, for the KEYNOTE-355 Investigators. Pembrolizumab plus chemotherapy versus placebo plus chemotherapy for previously untreated locally recurrent inoperable or metastatic triple-negative breast cancer (KEYNOTE-355): A randomised, placebo-controlled, double-blind, phase 3 clinical trial. Lancet. 2020;396:1817-1828. doi: 10.1016/S0140-6736(20)32531-9 Source
4. Bachelot T, Filleron T, Bieche I, et al. Durvalumab compared to maintenance chemotherapy in metastatic breast cancer: The randomized phase II SAFIR02-BREAST IMMUNO trial. Nat Med. 2021;27:250-255. doi: 10.1038/s41591-020-01189-2 Source
5. Saji S, Cussac AL, Andre F, et al. 68TiP KEYLYNK-009: a phase II/III, open-label, randomized study of pembrolizumab (pembro) + olaparib (ola) vs pembro + chemotherapy after induction with first-line (1L) pembro + chemo in patients (pts) with locally recurrent inoperable or metastatic TNBC (abstract). Ann Oncol. 2020;31(Suppl 6):S1268. doi: 10.1016/j.annonc.2020.10.088 Source
6. Ortmann O, Blohmer JU, Sibert NT, et al for 55 breast cancer centers certified by the German Cancer Society. Current clinical practice and outcome of neoadjuvant chemotherapy for early breast cancer: Analysis of individual data from 94,638 patients treated in 55 breast cancer centers. J Cancer Res Clin Oncol. 2023;149:1195-1209. doi: 10.1007/s00432-022-03938-x Source
7. Yu KD, Fan L, Qiu LX, et al. Influence of delayed initiation of adjuvant chemotherapy on breast cancer survival is subtype-dependent. Oncotarget. 2017;8:46549-46556. doi: 10.18632/oncotarget.10551 Source

The phase 3 KEYNOTE-355 trial established the role of chemotherapy in combination with pembrolizumab in the first-line setting for programmed death-ligand 1 (PD-L1)–positive advanced triple-negative breast cancer (TNBC). Patients unselected for PD-L1 status in this trial who received platinum- or taxane-based chemotherapy with placebo had a median progression-free survival of 5.6 months.^[3] Strategies to improve upon efficacy and tolerability are desired in this space, and various trials have evaluated "switch maintenance" that involves receipt of an intensive induction regimen followed by a switch to an alternative/more tolerable regimen after response is achieved.^[4] The phase II DORA trial randomized 45 patients with advanced TNBC and ongoing stable disease or complete or partial response from first- or second-line platinum-based chemotherapy to a maintenance regimen of olaparib (300 mg orally twice daily) with or without durvalumab (1500 mg on day 1 and every 4 weeks) (Tan et al). At a median follow-up of 9.8 months, median progression-free survival was 4.0 months (95% CI 2.6-6.1) with olaparib and 6.1 months (95% CI 3.7-10.1) with the combination; both were significantly longer than the historical control of continued platinum-based therapy (P = .0023 and P < .0001, respectively). Durable disease control appeared more pronounced in patients with complete or partial response to prior platinum therapy, and no new safety signals were observed. Future efforts to study this approach include the phase 2/3 KEYLYNK-009 trial, which is evaluating olaparib plus pembrolizumab maintenance therapy after first-line chemotherapy plus pembrolizumab for TNBC.^[5]

TNBC is a heterogenous subtype, characterized by aggressive biology, and it benefits from chemotherapy and immunotherapy treatment approaches. Presently, the management of early-stage TNBC often involves neoadjuvant systemic therapy; however, a proportion of patients receive treatment in the postoperative setting, highlighting the relevance of time to initiation of adjuvant therapy as well.^[6] Various prior studies have showed that delayed administration of adjuvant chemotherapy for EBC can lead to adverse survival outcomes. Furthermore, this effect is subtype-dependent, with more aggressive tumors (luminal B, triple-negative, human epidermal growth factor receptor 2 [HER2]-positive) exhibiting inferior outcomes with delayed chemotherapy.^[7] A retrospective cohort study that included 245 patients with early TNBC who received adjuvant chemotherapy after surgery evaluated the impact of time to initiation of adjuvant therapy in this population (Hatzipanagiotou et al). Superior survival outcomes were observed for the group receiving systemic therapy 22-28 days after surgery (median overall survival 10.2 years) compared with those receiving adjuvant chemotherapy at later time points (29-35 days, 36-42 days, and >6 weeks after surgery; median overall survival 8.3 years, 7.8 years, and 6.9 years, respectively). Patients receiving chemotherapy 22-28 days after surgery had significantly better survival than those receiving chemotherapy 29-35 days (P = .043) and >6 weeks (P = 0.033) postoperatively. This study emphasizes the importance of timely administration of adjuvant chemotherapy for early TNBC, and efforts aimed to identify potential challenges and propose solutions to optimize outcomes in this space are valuable.

Additional References

1. Gnant M, Frantal S, Pfeiler G, et al, for the Austrian Breast & Colorectal Cancer Study Group. Long-term outcomes of adjuvant denosumab in breast cancer. NEJM Evid. 2022;1:EVIDoa2200162. doi: 10.1056/EVIDoa2200162 Source
2. Fassio A, Idolazzi L, Rossini M, et al. The obesity paradox and osteoporosis. Eating and Weight Disorders - Studies on Anorexia, Bulimia and Obesity. 2018;23:293-30 doi: 10.1007/s40519-018-0505-2 Source
3. Cortes J, Cescon DW, Rugo HS, et al, for the KEYNOTE-355 Investigators. Pembrolizumab plus chemotherapy versus placebo plus chemotherapy for previously untreated locally recurrent inoperable or metastatic triple-negative breast cancer (KEYNOTE-355): A randomised, placebo-controlled, double-blind, phase 3 clinical trial. Lancet. 2020;396:1817-1828. doi: 10.1016/S0140-6736(20)32531-9 Source
4. Bachelot T, Filleron T, Bieche I, et al. Durvalumab compared to maintenance chemotherapy in metastatic breast cancer: The randomized phase II SAFIR02-BREAST IMMUNO trial. Nat Med. 2021;27:250-255. doi: 10.1038/s41591-020-01189-2 Source
5. Saji S, Cussac AL, Andre F, et al. 68TiP KEYLYNK-009: a phase II/III, open-label, randomized study of pembrolizumab (pembro) + olaparib (ola) vs pembro + chemotherapy after induction with first-line (1L) pembro + chemo in patients (pts) with locally recurrent inoperable or metastatic TNBC (abstract). Ann Oncol. 2020;31(Suppl 6):S1268. doi: 10.1016/j.annonc.2020.10.088 Source
6. Ortmann O, Blohmer JU, Sibert NT, et al for 55 breast cancer centers certified by the German Cancer Society. Current clinical practice and outcome of neoadjuvant chemotherapy for early breast cancer: Analysis of individual data from 94,638 patients treated in 55 breast cancer centers. J Cancer Res Clin Oncol. 2023;149:1195-1209. doi: 10.1007/s00432-022-03938-x Source
7. Yu KD, Fan L, Qiu LX, et al. Influence of delayed initiation of adjuvant chemotherapy on breast cancer survival is subtype-dependent. Oncotarget. 2017;8:46549-46556. doi: 10.18632/oncotarget.10551 Source

The phase 3 KEYNOTE-355 trial established the role of chemotherapy in combination with pembrolizumab in the first-line setting for programmed death-ligand 1 (PD-L1)–positive advanced triple-negative breast cancer (TNBC). Patients unselected for PD-L1 status in this trial who received platinum- or taxane-based chemotherapy with placebo had a median progression-free survival of 5.6 months.^[3] Strategies to improve upon efficacy and tolerability are desired in this space, and various trials have evaluated "switch maintenance" that involves receipt of an intensive induction regimen followed by a switch to an alternative/more tolerable regimen after response is achieved.^[4] The phase II DORA trial randomized 45 patients with advanced TNBC and ongoing stable disease or complete or partial response from first- or second-line platinum-based chemotherapy to a maintenance regimen of olaparib (300 mg orally twice daily) with or without durvalumab (1500 mg on day 1 and every 4 weeks) (Tan et al). At a median follow-up of 9.8 months, median progression-free survival was 4.0 months (95% CI 2.6-6.1) with olaparib and 6.1 months (95% CI 3.7-10.1) with the combination; both were significantly longer than the historical control of continued platinum-based therapy (P = .0023 and P < .0001, respectively). Durable disease control appeared more pronounced in patients with complete or partial response to prior platinum therapy, and no new safety signals were observed. Future efforts to study this approach include the phase 2/3 KEYLYNK-009 trial, which is evaluating olaparib plus pembrolizumab maintenance therapy after first-line chemotherapy plus pembrolizumab for TNBC.^[5]

TNBC is a heterogenous subtype, characterized by aggressive biology, and it benefits from chemotherapy and immunotherapy treatment approaches. Presently, the management of early-stage TNBC often involves neoadjuvant systemic therapy; however, a proportion of patients receive treatment in the postoperative setting, highlighting the relevance of time to initiation of adjuvant therapy as well.^[6] Various prior studies have showed that delayed administration of adjuvant chemotherapy for EBC can lead to adverse survival outcomes. Furthermore, this effect is subtype-dependent, with more aggressive tumors (luminal B, triple-negative, human epidermal growth factor receptor 2 [HER2]-positive) exhibiting inferior outcomes with delayed chemotherapy.^[7] A retrospective cohort study that included 245 patients with early TNBC who received adjuvant chemotherapy after surgery evaluated the impact of time to initiation of adjuvant therapy in this population (Hatzipanagiotou et al). Superior survival outcomes were observed for the group receiving systemic therapy 22-28 days after surgery (median overall survival 10.2 years) compared with those receiving adjuvant chemotherapy at later time points (29-35 days, 36-42 days, and >6 weeks after surgery; median overall survival 8.3 years, 7.8 years, and 6.9 years, respectively). Patients receiving chemotherapy 22-28 days after surgery had significantly better survival than those receiving chemotherapy 29-35 days (P = .043) and >6 weeks (P = 0.033) postoperatively. This study emphasizes the importance of timely administration of adjuvant chemotherapy for early TNBC, and efforts aimed to identify potential challenges and propose solutions to optimize outcomes in this space are valuable.

Additional References

1. Gnant M, Frantal S, Pfeiler G, et al, for the Austrian Breast & Colorectal Cancer Study Group. Long-term outcomes of adjuvant denosumab in breast cancer. NEJM Evid. 2022;1:EVIDoa2200162. doi: 10.1056/EVIDoa2200162 Source
2. Fassio A, Idolazzi L, Rossini M, et al. The obesity paradox and osteoporosis. Eating and Weight Disorders - Studies on Anorexia, Bulimia and Obesity. 2018;23:293-30 doi: 10.1007/s40519-018-0505-2 Source
3. Cortes J, Cescon DW, Rugo HS, et al, for the KEYNOTE-355 Investigators. Pembrolizumab plus chemotherapy versus placebo plus chemotherapy for previously untreated locally recurrent inoperable or metastatic triple-negative breast cancer (KEYNOTE-355): A randomised, placebo-controlled, double-blind, phase 3 clinical trial. Lancet. 2020;396:1817-1828. doi: 10.1016/S0140-6736(20)32531-9 Source
4. Bachelot T, Filleron T, Bieche I, et al. Durvalumab compared to maintenance chemotherapy in metastatic breast cancer: The randomized phase II SAFIR02-BREAST IMMUNO trial. Nat Med. 2021;27:250-255. doi: 10.1038/s41591-020-01189-2 Source
5. Saji S, Cussac AL, Andre F, et al. 68TiP KEYLYNK-009: a phase II/III, open-label, randomized study of pembrolizumab (pembro) + olaparib (ola) vs pembro + chemotherapy after induction with first-line (1L) pembro + chemo in patients (pts) with locally recurrent inoperable or metastatic TNBC (abstract). Ann Oncol. 2020;31(Suppl 6):S1268. doi: 10.1016/j.annonc.2020.10.088 Source
6. Ortmann O, Blohmer JU, Sibert NT, et al for 55 breast cancer centers certified by the German Cancer Society. Current clinical practice and outcome of neoadjuvant chemotherapy for early breast cancer: Analysis of individual data from 94,638 patients treated in 55 breast cancer centers. J Cancer Res Clin Oncol. 2023;149:1195-1209. doi: 10.1007/s00432-022-03938-x Source
7. Yu KD, Fan L, Qiu LX, et al. Influence of delayed initiation of adjuvant chemotherapy on breast cancer survival is subtype-dependent. Oncotarget. 2017;8:46549-46556. doi: 10.18632/oncotarget.10551 Source

When skin diseases affect the palm or sole, they can have a disproportionately large negative effect on patients' lives. Hand and foot dermatitis can be disabling. Simpson and colleagues find that dupilumab is an effective treatment for AD of the hands and feet. Having safe and effective treatment for hand and foot dermatitis will be life-changing for many of our patients.

Patients often do very well with biologic treatment. When they do, they often wonder, Do I need to continue taking the medication? Lasheras-Pérez and colleagues found that the great majority of patients doing well taking dupilumab for AD could stretch out their dosing interval. I suspect a lot of our patients are doing this already. I used to worry that stretching out the dosing interval might lead to antidrug antibodies and loss of activity. Such loss of activity doesn't appear common. Because we also have multiple alternative treatments for severe AD, I think it may be quite reasonable for patients to try spreading out their doses after their disease has been well controlled for a good long time.

Superficial skin infections aren't rare in children, particularly children with AD. Paller and colleagues' study is informative about the safety of dupilumab in children. The drug, which blocks a pathway of the immune system, was associated with fewer infections. This is good news. The reduction in infections could be through restoring "immune balance" (whatever that means) or by improving skin barrier function. Perhaps the low rate of infection explains why dupilumab is not considered immunosuppressive.

I love studies of drug survival because I think that knowing the percentage of patients who stay with drug treatment is a good measure of overall safety and efficacy. Pezzolo and colleagues found — perhaps not surprisingly given the extraordinary efficacy of upadacitinib for AD — that almost no one discontinued the drug over 1.5 years due to lack of efficacy. There were patients who discontinued due to adverse events (and additional patients lost to follow-up who perhaps also discontinued the drug), but 80% of patients were still in the study at the end of 1.5 years. Three patients who weren't vaccinated for shingles developed shingles; encouraging patients to get the shingles vaccine may be a prudent measure when starting patients taking upadacitinib. 
 

When skin diseases affect the palm or sole, they can have a disproportionately large negative effect on patients' lives. Hand and foot dermatitis can be disabling. Simpson and colleagues find that dupilumab is an effective treatment for AD of the hands and feet. Having safe and effective treatment for hand and foot dermatitis will be life-changing for many of our patients.

Patients often do very well with biologic treatment. When they do, they often wonder, Do I need to continue taking the medication? Lasheras-Pérez and colleagues found that the great majority of patients doing well taking dupilumab for AD could stretch out their dosing interval. I suspect a lot of our patients are doing this already. I used to worry that stretching out the dosing interval might lead to antidrug antibodies and loss of activity. Such loss of activity doesn't appear common. Because we also have multiple alternative treatments for severe AD, I think it may be quite reasonable for patients to try spreading out their doses after their disease has been well controlled for a good long time.

Superficial skin infections aren't rare in children, particularly children with AD. Paller and colleagues' study is informative about the safety of dupilumab in children. The drug, which blocks a pathway of the immune system, was associated with fewer infections. This is good news. The reduction in infections could be through restoring "immune balance" (whatever that means) or by improving skin barrier function. Perhaps the low rate of infection explains why dupilumab is not considered immunosuppressive.

I love studies of drug survival because I think that knowing the percentage of patients who stay with drug treatment is a good measure of overall safety and efficacy. Pezzolo and colleagues found — perhaps not surprisingly given the extraordinary efficacy of upadacitinib for AD — that almost no one discontinued the drug over 1.5 years due to lack of efficacy. There were patients who discontinued due to adverse events (and additional patients lost to follow-up who perhaps also discontinued the drug), but 80% of patients were still in the study at the end of 1.5 years. Three patients who weren't vaccinated for shingles developed shingles; encouraging patients to get the shingles vaccine may be a prudent measure when starting patients taking upadacitinib. 
 

When skin diseases affect the palm or sole, they can have a disproportionately large negative effect on patients' lives. Hand and foot dermatitis can be disabling. Simpson and colleagues find that dupilumab is an effective treatment for AD of the hands and feet. Having safe and effective treatment for hand and foot dermatitis will be life-changing for many of our patients.

Patients often do very well with biologic treatment. When they do, they often wonder, Do I need to continue taking the medication? Lasheras-Pérez and colleagues found that the great majority of patients doing well taking dupilumab for AD could stretch out their dosing interval. I suspect a lot of our patients are doing this already. I used to worry that stretching out the dosing interval might lead to antidrug antibodies and loss of activity. Such loss of activity doesn't appear common. Because we also have multiple alternative treatments for severe AD, I think it may be quite reasonable for patients to try spreading out their doses after their disease has been well controlled for a good long time.

Superficial skin infections aren't rare in children, particularly children with AD. Paller and colleagues' study is informative about the safety of dupilumab in children. The drug, which blocks a pathway of the immune system, was associated with fewer infections. This is good news. The reduction in infections could be through restoring "immune balance" (whatever that means) or by improving skin barrier function. Perhaps the low rate of infection explains why dupilumab is not considered immunosuppressive.

I love studies of drug survival because I think that knowing the percentage of patients who stay with drug treatment is a good measure of overall safety and efficacy. Pezzolo and colleagues found — perhaps not surprisingly given the extraordinary efficacy of upadacitinib for AD — that almost no one discontinued the drug over 1.5 years due to lack of efficacy. There were patients who discontinued due to adverse events (and additional patients lost to follow-up who perhaps also discontinued the drug), but 80% of patients were still in the study at the end of 1.5 years. Three patients who weren't vaccinated for shingles developed shingles; encouraging patients to get the shingles vaccine may be a prudent measure when starting patients taking upadacitinib.