Clinical Edge Journal Scan Commentary

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. 
 

A significant gap in our understanding of eosinophilic esophagitis (EoE) lies in how environmental factors, such as allergens or food, influence the response to proton pump inhibitor (PPI) therapy. While PPI achieve histologic remission in approximately 50% of patients, the response in the remaining 50% remains unclear. Addressing this, Muftah and colleagues conducted a study to evaluate the relationship between environmental and food allergies and PPI response in newly diagnosed EoE patients.

Between 2012 and 2016, adult patients newly diagnosed with EoE were tested for environmental and food allergies. Following diagnosis, patients participated in an 8-week trial of twice-daily PPI therapy. The treatment's effectiveness was assessed through repeated upper endoscopies with esophageal biopsies.

The study's primary outcome was the histologic remission of EoE, defined as a decrease in eosinophils to < 15 eosinophils/high-powered field (eos/hpf) in all esophageal biopsy samples during repeat endoscopy. Out of 61 patients, 21 achieved histologic remission, while 40 were classified as having PPI-nonresponding EoE. Among PPI-nonresponding EoE patients, positive food allergen testing was significantly more prevalent compared with PPI-responding EoE patients (82.5% vs 42.9%; P = .0003). Additionally, patients with >10 positive environmental allergen tests were significantly less likely to be PPI-responding EoE patients than those with <10 positive results (21% vs 53.9%; P = .03). A similar trend was observed in patients with >5 positive environmental allergens.

This study is not without limitations. It may exhibit a selection bias toward more severe cases and has a relatively small sample size, affecting its statistical power and generalizability.

This research supports the idea of more tailored management for EoE patients, focusing on their allergen profile, potentially leading to more effective treatment strategies and reducing unnecessary PPI trials. The statistically significant results pave the way for further research, providing an additional tool to predict PPI responsiveness and prevent delays in achieving remission.

Clinicians should consider patient characteristics, particularly positive food allergen tests, that might affect treatment response. More studies are needed, however, to understand the effect of environmental allergies on PPI response fully. A notable finding is that specific aeroallergens, such as oak, birch, Hormodendrum mold, dust mite (Dermatophagoides pteronyssinus), tree mix, and grass mix allergens, are associated with a lack of PPI response. This raises questions about whether exposure to these allergens during peak seasons could worsen PPI response in allergic EoE patients.

Key takeaways from this study include: (1) the importance of integrating allergen testing in EoE patients, especially those unresponsive to standard PPI therapy or suspected as having allergic phenotypes; (2) the need to monitor and adjust therapy based on clinical and histologic responses; and (3) the necessity of staying abreast of emerging research in this area.

EoE diagnosis presents unique challenges, particularly when patients exhibit exclusive distal esophageal eosinophilia or when discrepancies arise between endoscopic and histologic findings. Eosinophil-derived neurotoxin (EDN), a molecule previously studied for its role in monitoring allergy-mediated inflammatory diseases such as asthma and eczema, can shed light on these diagnostic difficulties.

Thomas and coworkers conducted a retrospective study in which they reviewed 231 pediatric patients, obtaining a minimum of four biopsies from at least two different levels of the esophagus. The study aimed to evaluate whether EDN concentrations, determined through esophageal epithelial brushing at the time of biopsy, could serve as an adjunctive diagnostic tool for EoE.

EDN levels proved sensitive (84.4%) and specific (94.6%) in evaluating active EoE when several measures of EoE were used in patients with active EoE compared with those with inactive EoE and the control group. Previous studies at the same institution had found EDN useful for differentiating EoE patients from non-EoE patients. Moreover, an EDN concentration > 10 μg/mL, when collected through esophageal epithelial brushing, was highly sensitive (97%) and specific (89%) for active EoE. This finding suggests the potential for using EDN as a biochemical marker, enhancing diagnostic accuracy and reducing the need for additional interventions in complex cases.

EDN as a biomarker could be invaluable for distinguishing difficult cases, such as those involving distal eosinophilia, active vs nonactive EoE, or non-EoE conditions, such as gastroesophageal reflux disease. Of note, lower EDN levels were observed in pediatric EoE patients who responded to PPI, suggesting EDN's potential utility in predicting PPI responsiveness. Incorporating the measurement of eosinophilic activity could add a new dimension to existing criteria, equipping clinicians with more precise diagnostic tools and reducing the reliance on multiple procedures. This approach would strengthen the correlation between symptomatic, endoscopic, and histologic data.

The study by Jensen and colleagues sheds light on a crucial aspect of EoE management: the psychosocial burden. A recent EoE diagnosis can be associated with increased symptom burden, somatization, and anxiety in patients and families, underscoring the need for a multidisciplinary approach to patient care that considers both physical and mental health. To date, numerous studies have focused on understanding the disease, its follow-up, and treatment. However, there has been limited exploration of the psychosocial burden and patient-associated factors in EoE.

In this context, this team aimed to enhance our understanding of the burden of EoE by evaluating psychosocial comorbidities, such as disordered sleep, anxiety, and somatization, in a pediatric population with EoE. The study included 87 patients of age 8-18 years who completed validated assessments during routine clinic visits, encompassing EoE symptoms (Pediatric Eosinophilic Esophagitis Symptom Scores, PEESSv2.0), quality of life (PedsQL-EoE), anxiety state and trait (State-Trait Anxiety Inventory for Children, STAI-C), somatization (Children's Somatic Symptoms Inventory-24, CSSI-24), and sleep-disordered breathing (University of Michigan Pediatric Sleep Questionnaire, PSQ).

The mean age of the participants was 12.8 years, highlighting the importance of addressing psychosocial distress in this age group, which undergoes crucial developmental stages. Most patients (82%, 71) had been diagnosed with EoE at least 12 months prior, and 60% (52) were treated with multiple approaches. Additionally, 34% (29) had undergone seven or more esophagogastroduodenoscopies, and nearly one third (33%, 27) had experienced a gastrointestinal-related emergency department visit. These factors potentially increase patient stress due to the continuous need for repeat procedures and hospital visits. An intriguing finding was that patients with shorter disease durations (6-12 months since diagnosis) experienced higher symptom burdens (P = .03). Patients with public insurance had less favorable scores for sleep-disordered breathing (P = .01).

Significantly, patients with neurodevelopmental comorbidities had higher scores for somatic symptoms, trait anxiety, and sleep-disordered breathing, and lower quality-of-life scores, compared with those without such comorbidities (P < .01 for all), suggesting that patients with neurodevelopmental issues might particularly benefit from tailored treatments addressing these aspects of the disease. Furthermore, patients with shorter disease durations since diagnosis exhibited higher somatic symptoms and trait anxiety (both P < .01). The study also revealed that patients with fewer esophagogastroduodenoscopies (1-3) had higher somatic symptom scores (P < .01), state anxiety (P = .02), and trait anxiety (P = .03). EoE-associated symptom burden was significantly correlated with increased somatic symptoms (0.34; 95% CI 0.23-0.45) and decreased quality of life (-0.42; 95% CI -0.59 to -0.25). Concerns about eating food and EoE-associated symptoms were both linked to the EoE-associated symptom burden.

This study has several limitations, including a relatively small sample size, which decreases the power and limits inferences for smaller groups within the sample. There was also an imbalance in gender distribution, with only 26% of patients being female, potentially limiting the generalizability of the findings. Moreover, the study included only EoE patients, lacking a control group for comparison to the general pediatric population.

Highlighting a significant aspect of pediatric EoE treatment, this study illuminates an area that might affect patients' long-term quality of life. It underscores the need for multidisciplinary care for EoE patients, where mental health professionals, such as psychologists or psychiatrists, can play a vital role in improving mental health through early identification and intervention for anxiety and somatization disorders. They can also provide education for patients and families on coping strategies. Peer support groups for children and adolescents could be another beneficial tool, allowing them to share experiences and reduce feelings of isolation.

Physicians who treat chronic diseases such as EoE should consider psychosocial factors, as they can affect both physical and mental quality of life. Using screening tools (such as PEESSv2.0, PedsQL-EoE, STAI-C, CSSI-24, or PSQ) during clinic visits can facilitate a more comprehensive evaluation.

A significant gap in our understanding of eosinophilic esophagitis (EoE) lies in how environmental factors, such as allergens or food, influence the response to proton pump inhibitor (PPI) therapy. While PPI achieve histologic remission in approximately 50% of patients, the response in the remaining 50% remains unclear. Addressing this, Muftah and colleagues conducted a study to evaluate the relationship between environmental and food allergies and PPI response in newly diagnosed EoE patients.

Between 2012 and 2016, adult patients newly diagnosed with EoE were tested for environmental and food allergies. Following diagnosis, patients participated in an 8-week trial of twice-daily PPI therapy. The treatment's effectiveness was assessed through repeated upper endoscopies with esophageal biopsies.

The study's primary outcome was the histologic remission of EoE, defined as a decrease in eosinophils to < 15 eosinophils/high-powered field (eos/hpf) in all esophageal biopsy samples during repeat endoscopy. Out of 61 patients, 21 achieved histologic remission, while 40 were classified as having PPI-nonresponding EoE. Among PPI-nonresponding EoE patients, positive food allergen testing was significantly more prevalent compared with PPI-responding EoE patients (82.5% vs 42.9%; P = .0003). Additionally, patients with >10 positive environmental allergen tests were significantly less likely to be PPI-responding EoE patients than those with <10 positive results (21% vs 53.9%; P = .03). A similar trend was observed in patients with >5 positive environmental allergens.

This study is not without limitations. It may exhibit a selection bias toward more severe cases and has a relatively small sample size, affecting its statistical power and generalizability.

This research supports the idea of more tailored management for EoE patients, focusing on their allergen profile, potentially leading to more effective treatment strategies and reducing unnecessary PPI trials. The statistically significant results pave the way for further research, providing an additional tool to predict PPI responsiveness and prevent delays in achieving remission.

Clinicians should consider patient characteristics, particularly positive food allergen tests, that might affect treatment response. More studies are needed, however, to understand the effect of environmental allergies on PPI response fully. A notable finding is that specific aeroallergens, such as oak, birch, Hormodendrum mold, dust mite (Dermatophagoides pteronyssinus), tree mix, and grass mix allergens, are associated with a lack of PPI response. This raises questions about whether exposure to these allergens during peak seasons could worsen PPI response in allergic EoE patients.

Key takeaways from this study include: (1) the importance of integrating allergen testing in EoE patients, especially those unresponsive to standard PPI therapy or suspected as having allergic phenotypes; (2) the need to monitor and adjust therapy based on clinical and histologic responses; and (3) the necessity of staying abreast of emerging research in this area.

EoE diagnosis presents unique challenges, particularly when patients exhibit exclusive distal esophageal eosinophilia or when discrepancies arise between endoscopic and histologic findings. Eosinophil-derived neurotoxin (EDN), a molecule previously studied for its role in monitoring allergy-mediated inflammatory diseases such as asthma and eczema, can shed light on these diagnostic difficulties.

Thomas and coworkers conducted a retrospective study in which they reviewed 231 pediatric patients, obtaining a minimum of four biopsies from at least two different levels of the esophagus. The study aimed to evaluate whether EDN concentrations, determined through esophageal epithelial brushing at the time of biopsy, could serve as an adjunctive diagnostic tool for EoE.

EDN levels proved sensitive (84.4%) and specific (94.6%) in evaluating active EoE when several measures of EoE were used in patients with active EoE compared with those with inactive EoE and the control group. Previous studies at the same institution had found EDN useful for differentiating EoE patients from non-EoE patients. Moreover, an EDN concentration > 10 μg/mL, when collected through esophageal epithelial brushing, was highly sensitive (97%) and specific (89%) for active EoE. This finding suggests the potential for using EDN as a biochemical marker, enhancing diagnostic accuracy and reducing the need for additional interventions in complex cases.

EDN as a biomarker could be invaluable for distinguishing difficult cases, such as those involving distal eosinophilia, active vs nonactive EoE, or non-EoE conditions, such as gastroesophageal reflux disease. Of note, lower EDN levels were observed in pediatric EoE patients who responded to PPI, suggesting EDN's potential utility in predicting PPI responsiveness. Incorporating the measurement of eosinophilic activity could add a new dimension to existing criteria, equipping clinicians with more precise diagnostic tools and reducing the reliance on multiple procedures. This approach would strengthen the correlation between symptomatic, endoscopic, and histologic data.

The study by Jensen and colleagues sheds light on a crucial aspect of EoE management: the psychosocial burden. A recent EoE diagnosis can be associated with increased symptom burden, somatization, and anxiety in patients and families, underscoring the need for a multidisciplinary approach to patient care that considers both physical and mental health. To date, numerous studies have focused on understanding the disease, its follow-up, and treatment. However, there has been limited exploration of the psychosocial burden and patient-associated factors in EoE.

In this context, this team aimed to enhance our understanding of the burden of EoE by evaluating psychosocial comorbidities, such as disordered sleep, anxiety, and somatization, in a pediatric population with EoE. The study included 87 patients of age 8-18 years who completed validated assessments during routine clinic visits, encompassing EoE symptoms (Pediatric Eosinophilic Esophagitis Symptom Scores, PEESSv2.0), quality of life (PedsQL-EoE), anxiety state and trait (State-Trait Anxiety Inventory for Children, STAI-C), somatization (Children's Somatic Symptoms Inventory-24, CSSI-24), and sleep-disordered breathing (University of Michigan Pediatric Sleep Questionnaire, PSQ).

The mean age of the participants was 12.8 years, highlighting the importance of addressing psychosocial distress in this age group, which undergoes crucial developmental stages. Most patients (82%, 71) had been diagnosed with EoE at least 12 months prior, and 60% (52) were treated with multiple approaches. Additionally, 34% (29) had undergone seven or more esophagogastroduodenoscopies, and nearly one third (33%, 27) had experienced a gastrointestinal-related emergency department visit. These factors potentially increase patient stress due to the continuous need for repeat procedures and hospital visits. An intriguing finding was that patients with shorter disease durations (6-12 months since diagnosis) experienced higher symptom burdens (P = .03). Patients with public insurance had less favorable scores for sleep-disordered breathing (P = .01).

Significantly, patients with neurodevelopmental comorbidities had higher scores for somatic symptoms, trait anxiety, and sleep-disordered breathing, and lower quality-of-life scores, compared with those without such comorbidities (P < .01 for all), suggesting that patients with neurodevelopmental issues might particularly benefit from tailored treatments addressing these aspects of the disease. Furthermore, patients with shorter disease durations since diagnosis exhibited higher somatic symptoms and trait anxiety (both P < .01). The study also revealed that patients with fewer esophagogastroduodenoscopies (1-3) had higher somatic symptom scores (P < .01), state anxiety (P = .02), and trait anxiety (P = .03). EoE-associated symptom burden was significantly correlated with increased somatic symptoms (0.34; 95% CI 0.23-0.45) and decreased quality of life (-0.42; 95% CI -0.59 to -0.25). Concerns about eating food and EoE-associated symptoms were both linked to the EoE-associated symptom burden.

This study has several limitations, including a relatively small sample size, which decreases the power and limits inferences for smaller groups within the sample. There was also an imbalance in gender distribution, with only 26% of patients being female, potentially limiting the generalizability of the findings. Moreover, the study included only EoE patients, lacking a control group for comparison to the general pediatric population.

Highlighting a significant aspect of pediatric EoE treatment, this study illuminates an area that might affect patients' long-term quality of life. It underscores the need for multidisciplinary care for EoE patients, where mental health professionals, such as psychologists or psychiatrists, can play a vital role in improving mental health through early identification and intervention for anxiety and somatization disorders. They can also provide education for patients and families on coping strategies. Peer support groups for children and adolescents could be another beneficial tool, allowing them to share experiences and reduce feelings of isolation.

Physicians who treat chronic diseases such as EoE should consider psychosocial factors, as they can affect both physical and mental quality of life. Using screening tools (such as PEESSv2.0, PedsQL-EoE, STAI-C, CSSI-24, or PSQ) during clinic visits can facilitate a more comprehensive evaluation.

A significant gap in our understanding of eosinophilic esophagitis (EoE) lies in how environmental factors, such as allergens or food, influence the response to proton pump inhibitor (PPI) therapy. While PPI achieve histologic remission in approximately 50% of patients, the response in the remaining 50% remains unclear. Addressing this, Muftah and colleagues conducted a study to evaluate the relationship between environmental and food allergies and PPI response in newly diagnosed EoE patients.

Between 2012 and 2016, adult patients newly diagnosed with EoE were tested for environmental and food allergies. Following diagnosis, patients participated in an 8-week trial of twice-daily PPI therapy. The treatment's effectiveness was assessed through repeated upper endoscopies with esophageal biopsies.

The study's primary outcome was the histologic remission of EoE, defined as a decrease in eosinophils to < 15 eosinophils/high-powered field (eos/hpf) in all esophageal biopsy samples during repeat endoscopy. Out of 61 patients, 21 achieved histologic remission, while 40 were classified as having PPI-nonresponding EoE. Among PPI-nonresponding EoE patients, positive food allergen testing was significantly more prevalent compared with PPI-responding EoE patients (82.5% vs 42.9%; P = .0003). Additionally, patients with >10 positive environmental allergen tests were significantly less likely to be PPI-responding EoE patients than those with <10 positive results (21% vs 53.9%; P = .03). A similar trend was observed in patients with >5 positive environmental allergens.

This study is not without limitations. It may exhibit a selection bias toward more severe cases and has a relatively small sample size, affecting its statistical power and generalizability.

This research supports the idea of more tailored management for EoE patients, focusing on their allergen profile, potentially leading to more effective treatment strategies and reducing unnecessary PPI trials. The statistically significant results pave the way for further research, providing an additional tool to predict PPI responsiveness and prevent delays in achieving remission.

Clinicians should consider patient characteristics, particularly positive food allergen tests, that might affect treatment response. More studies are needed, however, to understand the effect of environmental allergies on PPI response fully. A notable finding is that specific aeroallergens, such as oak, birch, Hormodendrum mold, dust mite (Dermatophagoides pteronyssinus), tree mix, and grass mix allergens, are associated with a lack of PPI response. This raises questions about whether exposure to these allergens during peak seasons could worsen PPI response in allergic EoE patients.

Key takeaways from this study include: (1) the importance of integrating allergen testing in EoE patients, especially those unresponsive to standard PPI therapy or suspected as having allergic phenotypes; (2) the need to monitor and adjust therapy based on clinical and histologic responses; and (3) the necessity of staying abreast of emerging research in this area.

EoE diagnosis presents unique challenges, particularly when patients exhibit exclusive distal esophageal eosinophilia or when discrepancies arise between endoscopic and histologic findings. Eosinophil-derived neurotoxin (EDN), a molecule previously studied for its role in monitoring allergy-mediated inflammatory diseases such as asthma and eczema, can shed light on these diagnostic difficulties.

Thomas and coworkers conducted a retrospective study in which they reviewed 231 pediatric patients, obtaining a minimum of four biopsies from at least two different levels of the esophagus. The study aimed to evaluate whether EDN concentrations, determined through esophageal epithelial brushing at the time of biopsy, could serve as an adjunctive diagnostic tool for EoE.

EDN levels proved sensitive (84.4%) and specific (94.6%) in evaluating active EoE when several measures of EoE were used in patients with active EoE compared with those with inactive EoE and the control group. Previous studies at the same institution had found EDN useful for differentiating EoE patients from non-EoE patients. Moreover, an EDN concentration > 10 μg/mL, when collected through esophageal epithelial brushing, was highly sensitive (97%) and specific (89%) for active EoE. This finding suggests the potential for using EDN as a biochemical marker, enhancing diagnostic accuracy and reducing the need for additional interventions in complex cases.

EDN as a biomarker could be invaluable for distinguishing difficult cases, such as those involving distal eosinophilia, active vs nonactive EoE, or non-EoE conditions, such as gastroesophageal reflux disease. Of note, lower EDN levels were observed in pediatric EoE patients who responded to PPI, suggesting EDN's potential utility in predicting PPI responsiveness. Incorporating the measurement of eosinophilic activity could add a new dimension to existing criteria, equipping clinicians with more precise diagnostic tools and reducing the reliance on multiple procedures. This approach would strengthen the correlation between symptomatic, endoscopic, and histologic data.

The study by Jensen and colleagues sheds light on a crucial aspect of EoE management: the psychosocial burden. A recent EoE diagnosis can be associated with increased symptom burden, somatization, and anxiety in patients and families, underscoring the need for a multidisciplinary approach to patient care that considers both physical and mental health. To date, numerous studies have focused on understanding the disease, its follow-up, and treatment. However, there has been limited exploration of the psychosocial burden and patient-associated factors in EoE.

In this context, this team aimed to enhance our understanding of the burden of EoE by evaluating psychosocial comorbidities, such as disordered sleep, anxiety, and somatization, in a pediatric population with EoE. The study included 87 patients of age 8-18 years who completed validated assessments during routine clinic visits, encompassing EoE symptoms (Pediatric Eosinophilic Esophagitis Symptom Scores, PEESSv2.0), quality of life (PedsQL-EoE), anxiety state and trait (State-Trait Anxiety Inventory for Children, STAI-C), somatization (Children's Somatic Symptoms Inventory-24, CSSI-24), and sleep-disordered breathing (University of Michigan Pediatric Sleep Questionnaire, PSQ).

The mean age of the participants was 12.8 years, highlighting the importance of addressing psychosocial distress in this age group, which undergoes crucial developmental stages. Most patients (82%, 71) had been diagnosed with EoE at least 12 months prior, and 60% (52) were treated with multiple approaches. Additionally, 34% (29) had undergone seven or more esophagogastroduodenoscopies, and nearly one third (33%, 27) had experienced a gastrointestinal-related emergency department visit. These factors potentially increase patient stress due to the continuous need for repeat procedures and hospital visits. An intriguing finding was that patients with shorter disease durations (6-12 months since diagnosis) experienced higher symptom burdens (P = .03). Patients with public insurance had less favorable scores for sleep-disordered breathing (P = .01).

Significantly, patients with neurodevelopmental comorbidities had higher scores for somatic symptoms, trait anxiety, and sleep-disordered breathing, and lower quality-of-life scores, compared with those without such comorbidities (P < .01 for all), suggesting that patients with neurodevelopmental issues might particularly benefit from tailored treatments addressing these aspects of the disease. Furthermore, patients with shorter disease durations since diagnosis exhibited higher somatic symptoms and trait anxiety (both P < .01). The study also revealed that patients with fewer esophagogastroduodenoscopies (1-3) had higher somatic symptom scores (P < .01), state anxiety (P = .02), and trait anxiety (P = .03). EoE-associated symptom burden was significantly correlated with increased somatic symptoms (0.34; 95% CI 0.23-0.45) and decreased quality of life (-0.42; 95% CI -0.59 to -0.25). Concerns about eating food and EoE-associated symptoms were both linked to the EoE-associated symptom burden.

This study has several limitations, including a relatively small sample size, which decreases the power and limits inferences for smaller groups within the sample. There was also an imbalance in gender distribution, with only 26% of patients being female, potentially limiting the generalizability of the findings. Moreover, the study included only EoE patients, lacking a control group for comparison to the general pediatric population.

Highlighting a significant aspect of pediatric EoE treatment, this study illuminates an area that might affect patients' long-term quality of life. It underscores the need for multidisciplinary care for EoE patients, where mental health professionals, such as psychologists or psychiatrists, can play a vital role in improving mental health through early identification and intervention for anxiety and somatization disorders. They can also provide education for patients and families on coping strategies. Peer support groups for children and adolescents could be another beneficial tool, allowing them to share experiences and reduce feelings of isolation.

Physicians who treat chronic diseases such as EoE should consider psychosocial factors, as they can affect both physical and mental quality of life. Using screening tools (such as PEESSv2.0, PedsQL-EoE, STAI-C, CSSI-24, or PSQ) during clinic visits can facilitate a more comprehensive evaluation.

Another study investigated the persistence of targeted therapies for PsA in women compared with men. In a nationwide cohort study using administrative information from French health insurance, the study looked at 14,778 patients (57% women) with PsA who were new users of targeted therapies. The study showed that women had 20%-40% lower treatment persistence rates than men for tumour necrosis factor (TNF) inhibitors (adjusted hazard ratio [aHR] 1.4; 99% CI 1.3-1.5) and interleukin (IL)-17 inhibitors (aHR 1.2; 99% CI 1.1-1.3). However, the treatment persistence between both sexes was comparable for IL-12/23 inhibitor (aHR 1.1; 99% CI 0.9-1.3), IL-23 inhibitor (aHR 1.1; 99% CI 0.7-1.5), and Janus kinase (JAK) inhibitor (aHR 1.2; 99% CI 0.9-1.6) therapies. The paradigm that women have lower treatment persistence is based on studies done primarily in patients treated with TNF inhibitors. This study and a few other recent studies challenge this paradigm by indicating that other targeted therapies, especially JAK inhibitors, may not have lower persistence in women. Sex should be taken into consideration while choosing and counseling women about PsA therapies.

There are few studies on exercise and its impact on PsA. Functional training (FT) and resistance training (RT) may improve functional capacity and quality of life of patients with PsA. The safety of exercise is also not known, given that (micro)trauma is a risk factor for PsA. To evaluate this, Silva and colleagues conducted a 12-week, single-blind trial including 41 patients with PsA who were randomly assigned to undergo FT with elastic bands or RT with weight machines. They demonstrated that FT and RT led to similar improvements in functional capacity measured by the Bath Ankylosing Spondylitis Functional Index (P = .919), functional status measured by the Health Assessment Questionnaire for Spondyloarthritis (P = .932), disease activity measured by the Bath Ankylosing Spondylitis Disease Activity Index (P = .700), and muscle strength. No adverse events occurred in either group. Thus, FT and RT improved functional capacity, functional status, disease activity, and muscle strength to a comparable extent in patients with PsA, with no adverse events. Both modalities may be recommended for PsA patients.

Finally, a cross-sectional study that included 503 patients with PsA, of whom 160 patients underwent treatment escalation, evaluated whether the patient-reported outcome (PsA Impact of Disease questionnaire [PsAID-12]) affected treatment decisions by the treating rheumatologist. Coyle and colleagues demonstrated that although PsAID-12 scores were higher in patients who did vs did not have a treatment escalation, physicians relied more on their assessment of disease activity rather than the PsAID-12 scores when making treatment-related decisions. Of note, physicians also reported that PsAID-12 scores influenced treatment reduction decisions.

Another study investigated the persistence of targeted therapies for PsA in women compared with men. In a nationwide cohort study using administrative information from French health insurance, the study looked at 14,778 patients (57% women) with PsA who were new users of targeted therapies. The study showed that women had 20%-40% lower treatment persistence rates than men for tumour necrosis factor (TNF) inhibitors (adjusted hazard ratio [aHR] 1.4; 99% CI 1.3-1.5) and interleukin (IL)-17 inhibitors (aHR 1.2; 99% CI 1.1-1.3). However, the treatment persistence between both sexes was comparable for IL-12/23 inhibitor (aHR 1.1; 99% CI 0.9-1.3), IL-23 inhibitor (aHR 1.1; 99% CI 0.7-1.5), and Janus kinase (JAK) inhibitor (aHR 1.2; 99% CI 0.9-1.6) therapies. The paradigm that women have lower treatment persistence is based on studies done primarily in patients treated with TNF inhibitors. This study and a few other recent studies challenge this paradigm by indicating that other targeted therapies, especially JAK inhibitors, may not have lower persistence in women. Sex should be taken into consideration while choosing and counseling women about PsA therapies.

There are few studies on exercise and its impact on PsA. Functional training (FT) and resistance training (RT) may improve functional capacity and quality of life of patients with PsA. The safety of exercise is also not known, given that (micro)trauma is a risk factor for PsA. To evaluate this, Silva and colleagues conducted a 12-week, single-blind trial including 41 patients with PsA who were randomly assigned to undergo FT with elastic bands or RT with weight machines. They demonstrated that FT and RT led to similar improvements in functional capacity measured by the Bath Ankylosing Spondylitis Functional Index (P = .919), functional status measured by the Health Assessment Questionnaire for Spondyloarthritis (P = .932), disease activity measured by the Bath Ankylosing Spondylitis Disease Activity Index (P = .700), and muscle strength. No adverse events occurred in either group. Thus, FT and RT improved functional capacity, functional status, disease activity, and muscle strength to a comparable extent in patients with PsA, with no adverse events. Both modalities may be recommended for PsA patients.

Finally, a cross-sectional study that included 503 patients with PsA, of whom 160 patients underwent treatment escalation, evaluated whether the patient-reported outcome (PsA Impact of Disease questionnaire [PsAID-12]) affected treatment decisions by the treating rheumatologist. Coyle and colleagues demonstrated that although PsAID-12 scores were higher in patients who did vs did not have a treatment escalation, physicians relied more on their assessment of disease activity rather than the PsAID-12 scores when making treatment-related decisions. Of note, physicians also reported that PsAID-12 scores influenced treatment reduction decisions.

Another study investigated the persistence of targeted therapies for PsA in women compared with men. In a nationwide cohort study using administrative information from French health insurance, the study looked at 14,778 patients (57% women) with PsA who were new users of targeted therapies. The study showed that women had 20%-40% lower treatment persistence rates than men for tumour necrosis factor (TNF) inhibitors (adjusted hazard ratio [aHR] 1.4; 99% CI 1.3-1.5) and interleukin (IL)-17 inhibitors (aHR 1.2; 99% CI 1.1-1.3). However, the treatment persistence between both sexes was comparable for IL-12/23 inhibitor (aHR 1.1; 99% CI 0.9-1.3), IL-23 inhibitor (aHR 1.1; 99% CI 0.7-1.5), and Janus kinase (JAK) inhibitor (aHR 1.2; 99% CI 0.9-1.6) therapies. The paradigm that women have lower treatment persistence is based on studies done primarily in patients treated with TNF inhibitors. This study and a few other recent studies challenge this paradigm by indicating that other targeted therapies, especially JAK inhibitors, may not have lower persistence in women. Sex should be taken into consideration while choosing and counseling women about PsA therapies.

There are few studies on exercise and its impact on PsA. Functional training (FT) and resistance training (RT) may improve functional capacity and quality of life of patients with PsA. The safety of exercise is also not known, given that (micro)trauma is a risk factor for PsA. To evaluate this, Silva and colleagues conducted a 12-week, single-blind trial including 41 patients with PsA who were randomly assigned to undergo FT with elastic bands or RT with weight machines. They demonstrated that FT and RT led to similar improvements in functional capacity measured by the Bath Ankylosing Spondylitis Functional Index (P = .919), functional status measured by the Health Assessment Questionnaire for Spondyloarthritis (P = .932), disease activity measured by the Bath Ankylosing Spondylitis Disease Activity Index (P = .700), and muscle strength. No adverse events occurred in either group. Thus, FT and RT improved functional capacity, functional status, disease activity, and muscle strength to a comparable extent in patients with PsA, with no adverse events. Both modalities may be recommended for PsA patients.

Finally, a cross-sectional study that included 503 patients with PsA, of whom 160 patients underwent treatment escalation, evaluated whether the patient-reported outcome (PsA Impact of Disease questionnaire [PsAID-12]) affected treatment decisions by the treating rheumatologist. Coyle and colleagues demonstrated that although PsAID-12 scores were higher in patients who did vs did not have a treatment escalation, physicians relied more on their assessment of disease activity rather than the PsAID-12 scores when making treatment-related decisions. Of note, physicians also reported that PsAID-12 scores influenced treatment reduction decisions.

The benefit of immunotherapy in combination with chemotherapy for programmed death–ligand 1–positive (PD-L1+) metastatic triple-negative breast cancer (mTNBC) has been shown in both the IMpassion130 and KEYNOTE-355 trials.^[2,3] However, the IMpassion131 trial, which evaluated atezolizumab plus paclitaxel, did not show a progression-free survival (PFS) or overall survival (OS) benefit vs paclitaxel alone in PD-L1+ mTNBC.^[4] Various explanations for these divergent results have been proposed, including the inherent properties of the chemotherapy backbone, patient populations, and the heterogenous nature of TNBC, which can affect response to immunotherapy. Of present, the various KEYNOTE-355 regimens (pembrolizumab plus investigator's choice chemotherapy [nab-paclitaxel, paclitaxel, or gemcitabine-carboplatin]) are US Food and Drug Administration approved for PD-L1+ mTNBC in the first-line setting. The phase 2 randomized TBCRC 043 trial investigated the effect of atezolizumab with carboplatin in patients with mTNBC and further looked at clinical and molecular correlates of response (Lehmann et al). A total of 106 patients were randomly assigned to carboplatin or carboplatin plus atezolizumab; the combination improved PFS (median PFS, 4.1 vs 2.2 mo; hazard ratio [HR] 0.66; P = .05) and OS (12.6 vs 8.6 mo; HR 0.60; P = .03). Grade 3/4 serious adverse events were more common with carboplatin-atezolizumab vs carboplatin alone (41% vs 8%). In addition, an association of better responses with PD-L1 immunotherapy was seen in patients with obesity, uncontrolled blood glucose levels, high tumor mutation burden, and increased tumor infiltrating lymphocytes. These data support the role of immunotherapy in mTNBC, highlight tumor heterogeneity within this subtype and encourage correlative studies to better define which patients benefit from immunotherapy.

Various studies have demonstrated the favorable impact of physical activity on breast cancer risk in postmenopausal women.^[5] However, data in premenopausal women is less clear. Various mechanisms connecting physical activity to premenopausal breast cancer risk have been proposed including the effect of exercise on sex steroid hormones, fasting insulin levels, and inflammation.^[6] A pooled analysis from 19 cohort studies including 547,601 premenopausal women, with 10,231 incident cases of breast cancer, aimed to examine the relationship between leisure-time physical activity (sports, exercise, recreational walking) and breast cancer risk in young women (Timmins et al). Higher (90th percentile) vs lower (10th percentile) levels of leisure-time physical activity were associated with a 10% reduction in breast cancer risk after adjustment for body mass index (BMI; adjusted HR 0.90; 95% CI 0.85-0.95; P < .001). They also found a significant reduction in risk: 32% (HR 0.68; P = .01) and 9% (HR 0.91; P = .005) for women with underweight (BMI < 18.5) and with average weight (BMI 18.5-24.9), respectively. Further, the effect of physical activity was most pronounced in the human epidermal growth factor receptor 2 (HER2)–enriched breast cancer subtype, wherein higher vs lower levels of activity were associated with an estimated 45% reduction in breast cancer risk (adjusted HR 0.55; 95% CI 0.37-0.82). These findings support the beneficial role of aerobic exercise and healthy body weight on breast cancer risk among premenopausal women and highlight the value of incorporating this information into counseling for our patients.

Additional References

1. Figueroa JD, Gierach GL, Duggan MA, et al. Risk factors for breast cancer development by tumor characteristics among women with benign breast disease. Breast Cancer Res. 2021;23:34. doi: 10.1186/s13058-021-01410-1 Source
2. Schmid P, Adams S, Rugo HS, et al, for the IMpassion130 Trial Investigators. Atezolizumab and nab-paclitaxel in advanced triple-negative breast cancer. N Engl J Med. 2018;379:2108-2121. doi: 10.1056/nejmoa1809615 Source
3. Cortes J, Rugo HS, Cescon DW, et al, for the KEYNOTE-355 Investigators. Pembrolizumab plus chemotherapy in advanced triple-negative breast cancer. N Engl J Med. 2022;387:217-226. doi: 10.1056/NEJMoa2202809 Source
4. Miles D, Gligorov J, André F, et al, on behalf of the IMpassion131 investigators. Primary results from IMpassion131, a double-blind, placebo-controlled, randomised phase III trial of first-line paclitaxel with or without atezolizumab for unresectable locally advanced/metastatic triple-negative breast cancer. Ann Oncol. 2021;32:994-1004. doi: 10.1016/j.annonc.2021.05.801 Source
5. Eliassen AH, Hankinson SE, Rosner B, et al. Physical activity and risk of breast cancer among postmenopausal women. Arch Intern Med. 2010;170:1758-1764. doi: 10.1001/archinternmed.2010.363 Source
6. Swain CTV, Drummond AE, Boing L, et al. Linking physical activity to breast cancer via sex hormones, part 1: The effect of physical activity on sex steroid hormones. Cancer Epidemiol Biomarkers Prev. 2022;31:16-27. doi: 10.1158/1055-9965.EPI-21-0437 Source

The benefit of immunotherapy in combination with chemotherapy for programmed death–ligand 1–positive (PD-L1+) metastatic triple-negative breast cancer (mTNBC) has been shown in both the IMpassion130 and KEYNOTE-355 trials.^[2,3] However, the IMpassion131 trial, which evaluated atezolizumab plus paclitaxel, did not show a progression-free survival (PFS) or overall survival (OS) benefit vs paclitaxel alone in PD-L1+ mTNBC.^[4] Various explanations for these divergent results have been proposed, including the inherent properties of the chemotherapy backbone, patient populations, and the heterogenous nature of TNBC, which can affect response to immunotherapy. Of present, the various KEYNOTE-355 regimens (pembrolizumab plus investigator's choice chemotherapy [nab-paclitaxel, paclitaxel, or gemcitabine-carboplatin]) are US Food and Drug Administration approved for PD-L1+ mTNBC in the first-line setting. The phase 2 randomized TBCRC 043 trial investigated the effect of atezolizumab with carboplatin in patients with mTNBC and further looked at clinical and molecular correlates of response (Lehmann et al). A total of 106 patients were randomly assigned to carboplatin or carboplatin plus atezolizumab; the combination improved PFS (median PFS, 4.1 vs 2.2 mo; hazard ratio [HR] 0.66; P = .05) and OS (12.6 vs 8.6 mo; HR 0.60; P = .03). Grade 3/4 serious adverse events were more common with carboplatin-atezolizumab vs carboplatin alone (41% vs 8%). In addition, an association of better responses with PD-L1 immunotherapy was seen in patients with obesity, uncontrolled blood glucose levels, high tumor mutation burden, and increased tumor infiltrating lymphocytes. These data support the role of immunotherapy in mTNBC, highlight tumor heterogeneity within this subtype and encourage correlative studies to better define which patients benefit from immunotherapy.

Various studies have demonstrated the favorable impact of physical activity on breast cancer risk in postmenopausal women.^[5] However, data in premenopausal women is less clear. Various mechanisms connecting physical activity to premenopausal breast cancer risk have been proposed including the effect of exercise on sex steroid hormones, fasting insulin levels, and inflammation.^[6] A pooled analysis from 19 cohort studies including 547,601 premenopausal women, with 10,231 incident cases of breast cancer, aimed to examine the relationship between leisure-time physical activity (sports, exercise, recreational walking) and breast cancer risk in young women (Timmins et al). Higher (90th percentile) vs lower (10th percentile) levels of leisure-time physical activity were associated with a 10% reduction in breast cancer risk after adjustment for body mass index (BMI; adjusted HR 0.90; 95% CI 0.85-0.95; P < .001). They also found a significant reduction in risk: 32% (HR 0.68; P = .01) and 9% (HR 0.91; P = .005) for women with underweight (BMI < 18.5) and with average weight (BMI 18.5-24.9), respectively. Further, the effect of physical activity was most pronounced in the human epidermal growth factor receptor 2 (HER2)–enriched breast cancer subtype, wherein higher vs lower levels of activity were associated with an estimated 45% reduction in breast cancer risk (adjusted HR 0.55; 95% CI 0.37-0.82). These findings support the beneficial role of aerobic exercise and healthy body weight on breast cancer risk among premenopausal women and highlight the value of incorporating this information into counseling for our patients.

Additional References

1. Figueroa JD, Gierach GL, Duggan MA, et al. Risk factors for breast cancer development by tumor characteristics among women with benign breast disease. Breast Cancer Res. 2021;23:34. doi: 10.1186/s13058-021-01410-1 Source
2. Schmid P, Adams S, Rugo HS, et al, for the IMpassion130 Trial Investigators. Atezolizumab and nab-paclitaxel in advanced triple-negative breast cancer. N Engl J Med. 2018;379:2108-2121. doi: 10.1056/nejmoa1809615 Source
3. Cortes J, Rugo HS, Cescon DW, et al, for the KEYNOTE-355 Investigators. Pembrolizumab plus chemotherapy in advanced triple-negative breast cancer. N Engl J Med. 2022;387:217-226. doi: 10.1056/NEJMoa2202809 Source
4. Miles D, Gligorov J, André F, et al, on behalf of the IMpassion131 investigators. Primary results from IMpassion131, a double-blind, placebo-controlled, randomised phase III trial of first-line paclitaxel with or without atezolizumab for unresectable locally advanced/metastatic triple-negative breast cancer. Ann Oncol. 2021;32:994-1004. doi: 10.1016/j.annonc.2021.05.801 Source
5. Eliassen AH, Hankinson SE, Rosner B, et al. Physical activity and risk of breast cancer among postmenopausal women. Arch Intern Med. 2010;170:1758-1764. doi: 10.1001/archinternmed.2010.363 Source
6. Swain CTV, Drummond AE, Boing L, et al. Linking physical activity to breast cancer via sex hormones, part 1: The effect of physical activity on sex steroid hormones. Cancer Epidemiol Biomarkers Prev. 2022;31:16-27. doi: 10.1158/1055-9965.EPI-21-0437 Source

The benefit of immunotherapy in combination with chemotherapy for programmed death–ligand 1–positive (PD-L1+) metastatic triple-negative breast cancer (mTNBC) has been shown in both the IMpassion130 and KEYNOTE-355 trials.^[2,3] However, the IMpassion131 trial, which evaluated atezolizumab plus paclitaxel, did not show a progression-free survival (PFS) or overall survival (OS) benefit vs paclitaxel alone in PD-L1+ mTNBC.^[4] Various explanations for these divergent results have been proposed, including the inherent properties of the chemotherapy backbone, patient populations, and the heterogenous nature of TNBC, which can affect response to immunotherapy. Of present, the various KEYNOTE-355 regimens (pembrolizumab plus investigator's choice chemotherapy [nab-paclitaxel, paclitaxel, or gemcitabine-carboplatin]) are US Food and Drug Administration approved for PD-L1+ mTNBC in the first-line setting. The phase 2 randomized TBCRC 043 trial investigated the effect of atezolizumab with carboplatin in patients with mTNBC and further looked at clinical and molecular correlates of response (Lehmann et al). A total of 106 patients were randomly assigned to carboplatin or carboplatin plus atezolizumab; the combination improved PFS (median PFS, 4.1 vs 2.2 mo; hazard ratio [HR] 0.66; P = .05) and OS (12.6 vs 8.6 mo; HR 0.60; P = .03). Grade 3/4 serious adverse events were more common with carboplatin-atezolizumab vs carboplatin alone (41% vs 8%). In addition, an association of better responses with PD-L1 immunotherapy was seen in patients with obesity, uncontrolled blood glucose levels, high tumor mutation burden, and increased tumor infiltrating lymphocytes. These data support the role of immunotherapy in mTNBC, highlight tumor heterogeneity within this subtype and encourage correlative studies to better define which patients benefit from immunotherapy.

Various studies have demonstrated the favorable impact of physical activity on breast cancer risk in postmenopausal women.^[5] However, data in premenopausal women is less clear. Various mechanisms connecting physical activity to premenopausal breast cancer risk have been proposed including the effect of exercise on sex steroid hormones, fasting insulin levels, and inflammation.^[6] A pooled analysis from 19 cohort studies including 547,601 premenopausal women, with 10,231 incident cases of breast cancer, aimed to examine the relationship between leisure-time physical activity (sports, exercise, recreational walking) and breast cancer risk in young women (Timmins et al). Higher (90th percentile) vs lower (10th percentile) levels of leisure-time physical activity were associated with a 10% reduction in breast cancer risk after adjustment for body mass index (BMI; adjusted HR 0.90; 95% CI 0.85-0.95; P < .001). They also found a significant reduction in risk: 32% (HR 0.68; P = .01) and 9% (HR 0.91; P = .005) for women with underweight (BMI < 18.5) and with average weight (BMI 18.5-24.9), respectively. Further, the effect of physical activity was most pronounced in the human epidermal growth factor receptor 2 (HER2)–enriched breast cancer subtype, wherein higher vs lower levels of activity were associated with an estimated 45% reduction in breast cancer risk (adjusted HR 0.55; 95% CI 0.37-0.82). These findings support the beneficial role of aerobic exercise and healthy body weight on breast cancer risk among premenopausal women and highlight the value of incorporating this information into counseling for our patients.

Additional References

1. Figueroa JD, Gierach GL, Duggan MA, et al. Risk factors for breast cancer development by tumor characteristics among women with benign breast disease. Breast Cancer Res. 2021;23:34. doi: 10.1186/s13058-021-01410-1 Source
2. Schmid P, Adams S, Rugo HS, et al, for the IMpassion130 Trial Investigators. Atezolizumab and nab-paclitaxel in advanced triple-negative breast cancer. N Engl J Med. 2018;379:2108-2121. doi: 10.1056/nejmoa1809615 Source
3. Cortes J, Rugo HS, Cescon DW, et al, for the KEYNOTE-355 Investigators. Pembrolizumab plus chemotherapy in advanced triple-negative breast cancer. N Engl J Med. 2022;387:217-226. doi: 10.1056/NEJMoa2202809 Source
4. Miles D, Gligorov J, André F, et al, on behalf of the IMpassion131 investigators. Primary results from IMpassion131, a double-blind, placebo-controlled, randomised phase III trial of first-line paclitaxel with or without atezolizumab for unresectable locally advanced/metastatic triple-negative breast cancer. Ann Oncol. 2021;32:994-1004. doi: 10.1016/j.annonc.2021.05.801 Source
5. Eliassen AH, Hankinson SE, Rosner B, et al. Physical activity and risk of breast cancer among postmenopausal women. Arch Intern Med. 2010;170:1758-1764. doi: 10.1001/archinternmed.2010.363 Source
6. Swain CTV, Drummond AE, Boing L, et al. Linking physical activity to breast cancer via sex hormones, part 1: The effect of physical activity on sex steroid hormones. Cancer Epidemiol Biomarkers Prev. 2022;31:16-27. doi: 10.1158/1055-9965.EPI-21-0437 Source

But here's the thing: We should not be making clinical judgments on the basis of differences in relative risk; clinical decisions should be based on absolute risks. Should we worry about VTE risk when treating patients with AD? This paper did not focus on absolute risk, but we can get an idea of the absolute risk by looking at the data presented in the figures in the paper. The risk for VTE in patients without AD was about 1 in 400, whereas with AD the risk was about 1 in 300, even before controlling for risk factors. This rate is sufficiently low for both groups that it doesn't seem like this risk would affect whether we would use a drug that might be associated with some minimal or theoretical increased risk for VTE.

The bottom line is that the findings of this study are reassuring, at least to me.

I'm already convinced that dupilumab is a very safe treatment for our patients with AD. The study by Simpson and colleagues looked at data from a registry of patients followed in real-life practice. The 2-year study showed no new concerns for dupilumab treatment of AD. The most common adverse event was conjunctivitis, and that was seen in only 2.4% of the patients. Perhaps the most interesting finding was that 83% of the patients who started in the study were still on dupilumab treatment at the end of 2 years. Dupilumab has a good level of efficacy and safety such that the great majority of patients who start on it seem to do well.

Dupilumab is a highly effective, very safe treatment for AD. Rademikibart Is another interleukin-4 receptor alpha-chain blocker. Not surprisingly, rademikibart also seems to be an effective, safe treatment for AD (Silverberg et al). Rademikibart may serve as another option for AD, and I imagine that it could be used if a patient on dupilumab were to develop an anti-drug antibody and lose effectiveness.

The very interesting analysis by Silverberg and colleagues looks at a new way to compare the effectiveness of different drugs for AD. They use this new approach to compare upadacitinib and dupilumab. What they found, not surprisingly, was that upadacitinib was generally more effective for AD than dupilumab. I used to think I would never see anything more effective for AD than dupilumab, but, clearly, based on head-to-head trials, upadacitinib is more effective for AD than is dupilumab. But does that greater efficacy mean that we should use upadacitinib first? We need to consider safety, too. Dupilumab works well enough for the great majority of patients and is extremely safe. I think upadacitinib is a great choice for patients who did not respond to dupilumab and could also be considered for those patients who want to take the most effective treatment option.

Trimeche and colleagues' study of contact allergens in patients with AD may change how I practice. In this study, 60% of the AD patients had positive patch test results of which 71% were considered relevant. The most frequent allergens included textile dye mix (25%), nickel (20%), cobalt (13%), isothiazolinone (9%), quanterium-15 (4%), and balsam of Peru (4%). Two patients were allergic to corticosteroids. Avoidance of relevant allergens resulted in improvement. I need to warn my AD patients to be on the lookout for contact allergens that may be causing or exacerbating their skin disease.

But here's the thing: We should not be making clinical judgments on the basis of differences in relative risk; clinical decisions should be based on absolute risks. Should we worry about VTE risk when treating patients with AD? This paper did not focus on absolute risk, but we can get an idea of the absolute risk by looking at the data presented in the figures in the paper. The risk for VTE in patients without AD was about 1 in 400, whereas with AD the risk was about 1 in 300, even before controlling for risk factors. This rate is sufficiently low for both groups that it doesn't seem like this risk would affect whether we would use a drug that might be associated with some minimal or theoretical increased risk for VTE.

The bottom line is that the findings of this study are reassuring, at least to me.

I'm already convinced that dupilumab is a very safe treatment for our patients with AD. The study by Simpson and colleagues looked at data from a registry of patients followed in real-life practice. The 2-year study showed no new concerns for dupilumab treatment of AD. The most common adverse event was conjunctivitis, and that was seen in only 2.4% of the patients. Perhaps the most interesting finding was that 83% of the patients who started in the study were still on dupilumab treatment at the end of 2 years. Dupilumab has a good level of efficacy and safety such that the great majority of patients who start on it seem to do well.

Dupilumab is a highly effective, very safe treatment for AD. Rademikibart Is another interleukin-4 receptor alpha-chain blocker. Not surprisingly, rademikibart also seems to be an effective, safe treatment for AD (Silverberg et al). Rademikibart may serve as another option for AD, and I imagine that it could be used if a patient on dupilumab were to develop an anti-drug antibody and lose effectiveness.

The very interesting analysis by Silverberg and colleagues looks at a new way to compare the effectiveness of different drugs for AD. They use this new approach to compare upadacitinib and dupilumab. What they found, not surprisingly, was that upadacitinib was generally more effective for AD than dupilumab. I used to think I would never see anything more effective for AD than dupilumab, but, clearly, based on head-to-head trials, upadacitinib is more effective for AD than is dupilumab. But does that greater efficacy mean that we should use upadacitinib first? We need to consider safety, too. Dupilumab works well enough for the great majority of patients and is extremely safe. I think upadacitinib is a great choice for patients who did not respond to dupilumab and could also be considered for those patients who want to take the most effective treatment option.

Trimeche and colleagues' study of contact allergens in patients with AD may change how I practice. In this study, 60% of the AD patients had positive patch test results of which 71% were considered relevant. The most frequent allergens included textile dye mix (25%), nickel (20%), cobalt (13%), isothiazolinone (9%), quanterium-15 (4%), and balsam of Peru (4%). Two patients were allergic to corticosteroids. Avoidance of relevant allergens resulted in improvement. I need to warn my AD patients to be on the lookout for contact allergens that may be causing or exacerbating their skin disease.

But here's the thing: We should not be making clinical judgments on the basis of differences in relative risk; clinical decisions should be based on absolute risks. Should we worry about VTE risk when treating patients with AD? This paper did not focus on absolute risk, but we can get an idea of the absolute risk by looking at the data presented in the figures in the paper. The risk for VTE in patients without AD was about 1 in 400, whereas with AD the risk was about 1 in 300, even before controlling for risk factors. This rate is sufficiently low for both groups that it doesn't seem like this risk would affect whether we would use a drug that might be associated with some minimal or theoretical increased risk for VTE.

The bottom line is that the findings of this study are reassuring, at least to me.

I'm already convinced that dupilumab is a very safe treatment for our patients with AD. The study by Simpson and colleagues looked at data from a registry of patients followed in real-life practice. The 2-year study showed no new concerns for dupilumab treatment of AD. The most common adverse event was conjunctivitis, and that was seen in only 2.4% of the patients. Perhaps the most interesting finding was that 83% of the patients who started in the study were still on dupilumab treatment at the end of 2 years. Dupilumab has a good level of efficacy and safety such that the great majority of patients who start on it seem to do well.

Dupilumab is a highly effective, very safe treatment for AD. Rademikibart Is another interleukin-4 receptor alpha-chain blocker. Not surprisingly, rademikibart also seems to be an effective, safe treatment for AD (Silverberg et al). Rademikibart may serve as another option for AD, and I imagine that it could be used if a patient on dupilumab were to develop an anti-drug antibody and lose effectiveness.

The very interesting analysis by Silverberg and colleagues looks at a new way to compare the effectiveness of different drugs for AD. They use this new approach to compare upadacitinib and dupilumab. What they found, not surprisingly, was that upadacitinib was generally more effective for AD than dupilumab. I used to think I would never see anything more effective for AD than dupilumab, but, clearly, based on head-to-head trials, upadacitinib is more effective for AD than is dupilumab. But does that greater efficacy mean that we should use upadacitinib first? We need to consider safety, too. Dupilumab works well enough for the great majority of patients and is extremely safe. I think upadacitinib is a great choice for patients who did not respond to dupilumab and could also be considered for those patients who want to take the most effective treatment option.

Trimeche and colleagues' study of contact allergens in patients with AD may change how I practice. In this study, 60% of the AD patients had positive patch test results of which 71% were considered relevant. The most frequent allergens included textile dye mix (25%), nickel (20%), cobalt (13%), isothiazolinone (9%), quanterium-15 (4%), and balsam of Peru (4%). Two patients were allergic to corticosteroids. Avoidance of relevant allergens resulted in improvement. I need to warn my AD patients to be on the lookout for contact allergens that may be causing or exacerbating their skin disease.

Young women diagnosed with breast cancer have been shown to experience higher rates of symptoms that may adversely affect quality of life (QOL), including depression, weight gain, vasomotor symptoms, and sexual dysfunction; they may also have a harder time managing these issues.³ Chemotherapy-related amenorrhea (CRA) is one of the side effects of breast cancer treatment that can affect premenopausal women, and is associated with both patient- (age, body mass index) and treatment-related (regimen, duration) factors.⁴ A study analyzing data derived from the prospective, longitudinal Cancer Toxicities Study included 1636 premenopausal women ≤ 50 years of age with stage I-III breast cancer treated with chemotherapy but not receiving ovarian suppression (Kabirian et al). A total of 83.0% of women reported CRA at year 1, 72.5% at year 2, and 66.1% at year 4. A higher likelihood of CRA was observed for women of older age vs those age 18-34 years (adjusted odds ratio [aOR] for 35-39 years 1.84; 40-44 years 5.90; and ≥ 45 years 21.29; P < .001 for all), those who received adjuvant tamoxifen (aOR 1.97; P < .001), and those who had hot flashes at baseline (aOR 1.83; P = .01). In the QOL analysis, 57.1% reported no recovery of menses. Persistent CRA was associated with worse insomnia, more systemic therapy–related adverse effects, and worse sexual functioning. These findings highlight the importance of identifying and discussing CRA with our patients, as this can have both physical and psychological effects in the survivorship setting.

The phase 3 KEYNOTE-522 trial has established immunotherapy plus an anthracycline-based chemotherapy backbone for the treatment of stage II-III triple-negative breast cancer (TNBC), with improvements in pathologic complete response (pCR) rates and survival outcomes.⁵ This regimen can present tolerance issues in clinical practice, and rare risks for cardiotoxicity and secondary hematologic malignancies are also relevant to consider. Furthermore, some patients may not be candidates for anthracycline-based treatment due to prior receipt of a drug in this class or cardiac comorbidities. De-escalation strategies are desired to lessen toxicity and maintain (or improve) outcomes. An open-label phase 2 trial (NeoPACT) investigated the efficacy of neoadjuvant carboplatin (AUC 6), docetaxel (75 mg/m²), and pembrolizumab (200 mg) every 21 days for six cycles among 115 patients with stage I-III TNBC (Sharma et al). The overall pCR and residual cancer burden (RCB 0+1) rates were 58% (95% CI 48%-67%) and 69% (95% CI 60%-78%), respectively. Estimated 3-year event-free survival was 86% (95% CI 77%-95%) in all patients, 98% in those with a pCR, and 68% in those with residual disease. This study also demonstrated a positive association of immune biomarkers and pathologic response. The most common grade ≥ 3 treatment-related adverse events were diarrhea (4.3%), anemia (3.5%), and peripheral sensory neuropathy (2.6%). The phase 3 SCARLET (Shorter Anthracycline-Free Chemoimmunotherapy Adapted to Pathologic Response in Early TNBC) trial is comparing the NeoPACT regimen with the standard KEYNOTE-522 regimen in early-stage TNBC and will be critical to further defining this treatment space.⁶ Presently, considering the described efficacy outcomes with the NeoPACT regimen, this regimen would be very reasonable to consider in patients who are not candidates for an anthracycline. Future prospective evaluation of immune biomarkers and additional predictors of response will also be valuable to further individualize treatment for our patients.

Additional References

1. Lambertini M, Blondeaux E, Bruzzone M, et al. Pregnancy after breast cancer: A systematic review and meta-analysis. J Clin Oncol. 2021;39:3293-3305. doi: 10.1200/JCO.21.00535
2. Partridge AH, Niman SM, Ruggeri M, et al, for the International Breast Cancer Study Group and POSITIVE Trial Collaborators. Interrupting endocrine therapy to attempt pregnancy after breast cancer. N Engl J Med. 2023;388:1645-1656. doi: 10.1056/NEJMoa2212856
3. Howard-Anderson J, Ganz PA, Bower JE, Stanton AL. Quality of life, fertility concerns, and behavioral health outcomes in younger breast cancer survivors: A systematic review. J Natl Cancer Inst. 2012;104:386-405. doi: 10.1093/jnci/djr541
4. Turnbull AK, Patel S, Martinez-Perez C, et al. Risk of chemotherapy-related amenorrhoea (CRA) in premenopausal women undergoing chemotherapy for early stage breast cancer. Breast Cancer Res Treat. 2021;186:237-245. doi: 10.1007/s10549-020-05951-5
5. Schmid P, Cortes J, Dent R, et al; KEYNOTE-522 Investigators. Event-free survival with pembrolizumab in early triple-negative breast cancer. N Engl J Med. 2022;386:556-567. doi: 10.1056/NEJMoa2112651
6. US National Cancer Institute, Cancer Therapy Evaluation Program. Shorter anthracycline-free chemoimmunotherapy adapted to pathological response in early TNBC (SCARLET); SWOG S2212. Source

Young women diagnosed with breast cancer have been shown to experience higher rates of symptoms that may adversely affect quality of life (QOL), including depression, weight gain, vasomotor symptoms, and sexual dysfunction; they may also have a harder time managing these issues.³ Chemotherapy-related amenorrhea (CRA) is one of the side effects of breast cancer treatment that can affect premenopausal women, and is associated with both patient- (age, body mass index) and treatment-related (regimen, duration) factors.⁴ A study analyzing data derived from the prospective, longitudinal Cancer Toxicities Study included 1636 premenopausal women ≤ 50 years of age with stage I-III breast cancer treated with chemotherapy but not receiving ovarian suppression (Kabirian et al). A total of 83.0% of women reported CRA at year 1, 72.5% at year 2, and 66.1% at year 4. A higher likelihood of CRA was observed for women of older age vs those age 18-34 years (adjusted odds ratio [aOR] for 35-39 years 1.84; 40-44 years 5.90; and ≥ 45 years 21.29; P < .001 for all), those who received adjuvant tamoxifen (aOR 1.97; P < .001), and those who had hot flashes at baseline (aOR 1.83; P = .01). In the QOL analysis, 57.1% reported no recovery of menses. Persistent CRA was associated with worse insomnia, more systemic therapy–related adverse effects, and worse sexual functioning. These findings highlight the importance of identifying and discussing CRA with our patients, as this can have both physical and psychological effects in the survivorship setting.

The phase 3 KEYNOTE-522 trial has established immunotherapy plus an anthracycline-based chemotherapy backbone for the treatment of stage II-III triple-negative breast cancer (TNBC), with improvements in pathologic complete response (pCR) rates and survival outcomes.⁵ This regimen can present tolerance issues in clinical practice, and rare risks for cardiotoxicity and secondary hematologic malignancies are also relevant to consider. Furthermore, some patients may not be candidates for anthracycline-based treatment due to prior receipt of a drug in this class or cardiac comorbidities. De-escalation strategies are desired to lessen toxicity and maintain (or improve) outcomes. An open-label phase 2 trial (NeoPACT) investigated the efficacy of neoadjuvant carboplatin (AUC 6), docetaxel (75 mg/m²), and pembrolizumab (200 mg) every 21 days for six cycles among 115 patients with stage I-III TNBC (Sharma et al). The overall pCR and residual cancer burden (RCB 0+1) rates were 58% (95% CI 48%-67%) and 69% (95% CI 60%-78%), respectively. Estimated 3-year event-free survival was 86% (95% CI 77%-95%) in all patients, 98% in those with a pCR, and 68% in those with residual disease. This study also demonstrated a positive association of immune biomarkers and pathologic response. The most common grade ≥ 3 treatment-related adverse events were diarrhea (4.3%), anemia (3.5%), and peripheral sensory neuropathy (2.6%). The phase 3 SCARLET (Shorter Anthracycline-Free Chemoimmunotherapy Adapted to Pathologic Response in Early TNBC) trial is comparing the NeoPACT regimen with the standard KEYNOTE-522 regimen in early-stage TNBC and will be critical to further defining this treatment space.⁶ Presently, considering the described efficacy outcomes with the NeoPACT regimen, this regimen would be very reasonable to consider in patients who are not candidates for an anthracycline. Future prospective evaluation of immune biomarkers and additional predictors of response will also be valuable to further individualize treatment for our patients.

Additional References

1. Lambertini M, Blondeaux E, Bruzzone M, et al. Pregnancy after breast cancer: A systematic review and meta-analysis. J Clin Oncol. 2021;39:3293-3305. doi: 10.1200/JCO.21.00535
2. Partridge AH, Niman SM, Ruggeri M, et al, for the International Breast Cancer Study Group and POSITIVE Trial Collaborators. Interrupting endocrine therapy to attempt pregnancy after breast cancer. N Engl J Med. 2023;388:1645-1656. doi: 10.1056/NEJMoa2212856
3. Howard-Anderson J, Ganz PA, Bower JE, Stanton AL. Quality of life, fertility concerns, and behavioral health outcomes in younger breast cancer survivors: A systematic review. J Natl Cancer Inst. 2012;104:386-405. doi: 10.1093/jnci/djr541
4. Turnbull AK, Patel S, Martinez-Perez C, et al. Risk of chemotherapy-related amenorrhoea (CRA) in premenopausal women undergoing chemotherapy for early stage breast cancer. Breast Cancer Res Treat. 2021;186:237-245. doi: 10.1007/s10549-020-05951-5
5. Schmid P, Cortes J, Dent R, et al; KEYNOTE-522 Investigators. Event-free survival with pembrolizumab in early triple-negative breast cancer. N Engl J Med. 2022;386:556-567. doi: 10.1056/NEJMoa2112651
6. US National Cancer Institute, Cancer Therapy Evaluation Program. Shorter anthracycline-free chemoimmunotherapy adapted to pathological response in early TNBC (SCARLET); SWOG S2212. Source

Young women diagnosed with breast cancer have been shown to experience higher rates of symptoms that may adversely affect quality of life (QOL), including depression, weight gain, vasomotor symptoms, and sexual dysfunction; they may also have a harder time managing these issues.³ Chemotherapy-related amenorrhea (CRA) is one of the side effects of breast cancer treatment that can affect premenopausal women, and is associated with both patient- (age, body mass index) and treatment-related (regimen, duration) factors.⁴ A study analyzing data derived from the prospective, longitudinal Cancer Toxicities Study included 1636 premenopausal women ≤ 50 years of age with stage I-III breast cancer treated with chemotherapy but not receiving ovarian suppression (Kabirian et al). A total of 83.0% of women reported CRA at year 1, 72.5% at year 2, and 66.1% at year 4. A higher likelihood of CRA was observed for women of older age vs those age 18-34 years (adjusted odds ratio [aOR] for 35-39 years 1.84; 40-44 years 5.90; and ≥ 45 years 21.29; P < .001 for all), those who received adjuvant tamoxifen (aOR 1.97; P < .001), and those who had hot flashes at baseline (aOR 1.83; P = .01). In the QOL analysis, 57.1% reported no recovery of menses. Persistent CRA was associated with worse insomnia, more systemic therapy–related adverse effects, and worse sexual functioning. These findings highlight the importance of identifying and discussing CRA with our patients, as this can have both physical and psychological effects in the survivorship setting.

The phase 3 KEYNOTE-522 trial has established immunotherapy plus an anthracycline-based chemotherapy backbone for the treatment of stage II-III triple-negative breast cancer (TNBC), with improvements in pathologic complete response (pCR) rates and survival outcomes.⁵ This regimen can present tolerance issues in clinical practice, and rare risks for cardiotoxicity and secondary hematologic malignancies are also relevant to consider. Furthermore, some patients may not be candidates for anthracycline-based treatment due to prior receipt of a drug in this class or cardiac comorbidities. De-escalation strategies are desired to lessen toxicity and maintain (or improve) outcomes. An open-label phase 2 trial (NeoPACT) investigated the efficacy of neoadjuvant carboplatin (AUC 6), docetaxel (75 mg/m²), and pembrolizumab (200 mg) every 21 days for six cycles among 115 patients with stage I-III TNBC (Sharma et al). The overall pCR and residual cancer burden (RCB 0+1) rates were 58% (95% CI 48%-67%) and 69% (95% CI 60%-78%), respectively. Estimated 3-year event-free survival was 86% (95% CI 77%-95%) in all patients, 98% in those with a pCR, and 68% in those with residual disease. This study also demonstrated a positive association of immune biomarkers and pathologic response. The most common grade ≥ 3 treatment-related adverse events were diarrhea (4.3%), anemia (3.5%), and peripheral sensory neuropathy (2.6%). The phase 3 SCARLET (Shorter Anthracycline-Free Chemoimmunotherapy Adapted to Pathologic Response in Early TNBC) trial is comparing the NeoPACT regimen with the standard KEYNOTE-522 regimen in early-stage TNBC and will be critical to further defining this treatment space.⁶ Presently, considering the described efficacy outcomes with the NeoPACT regimen, this regimen would be very reasonable to consider in patients who are not candidates for an anthracycline. Future prospective evaluation of immune biomarkers and additional predictors of response will also be valuable to further individualize treatment for our patients.

Additional References

1. Lambertini M, Blondeaux E, Bruzzone M, et al. Pregnancy after breast cancer: A systematic review and meta-analysis. J Clin Oncol. 2021;39:3293-3305. doi: 10.1200/JCO.21.00535
2. Partridge AH, Niman SM, Ruggeri M, et al, for the International Breast Cancer Study Group and POSITIVE Trial Collaborators. Interrupting endocrine therapy to attempt pregnancy after breast cancer. N Engl J Med. 2023;388:1645-1656. doi: 10.1056/NEJMoa2212856
3. Howard-Anderson J, Ganz PA, Bower JE, Stanton AL. Quality of life, fertility concerns, and behavioral health outcomes in younger breast cancer survivors: A systematic review. J Natl Cancer Inst. 2012;104:386-405. doi: 10.1093/jnci/djr541
4. Turnbull AK, Patel S, Martinez-Perez C, et al. Risk of chemotherapy-related amenorrhoea (CRA) in premenopausal women undergoing chemotherapy for early stage breast cancer. Breast Cancer Res Treat. 2021;186:237-245. doi: 10.1007/s10549-020-05951-5
5. Schmid P, Cortes J, Dent R, et al; KEYNOTE-522 Investigators. Event-free survival with pembrolizumab in early triple-negative breast cancer. N Engl J Med. 2022;386:556-567. doi: 10.1056/NEJMoa2112651
6. US National Cancer Institute, Cancer Therapy Evaluation Program. Shorter anthracycline-free chemoimmunotherapy adapted to pathological response in early TNBC (SCARLET); SWOG S2212. Source

Treatment of enthesitis can be challenging. Head-to-head clinical trials using clinical enthesitis indices have indicated that TNF inhibitors and IL-17 inhibitors have similar efficacy in treating enthesitis. However, clinically determined enthesitis may not be true inflammatory enthesitis. Ultrasonography-confirmed enthesitis probably reflects true enthesitis. Therefore, Elliot and colleagues conducted an observational study that compared the change in MAdrid Sonographic Enthesitis Index (MASEI) at 16 weeks of treatment with either TNF inhibitors or secukinumab. They observed that the mean reduction in MASEI that assesses both active and chronic entheseal disease was not significantly different with TNF inhibitors vs secukinumab treatment. However, TNF inhibitors were significantly more effective than secukinumab when only active entheseal lesions were considered. Thus, TNF inhibitors may be more effective for active enthesitis; randomized trials using ultrasonographic enthesitis indices comparing the two treatments are required.

Serum drug levels have previously been shown to be associated with response to bDMARD therapy, but use of drug-level measurement is not routine in rheumatology practice. Moreover, trough levels are emphasized and may not often be feasible to obtain. Curry and colleagues investigated the relationship between serum non-trough drug levels (SDL) and treatment response at 3 months in patients with PsA who initiated treatment with adalimumab (n = 104) or etanercept (n = 97). They demonstrated that patients with higher etanercept SDL or higher adalimumab SDL were significantly more likely to be responders. A non-trough etanercept SDL of 2.0 µg/mL and adalimumab SDL of 3.6 µg/mL could differentiate between responders and nonresponders with ~50% specificity and > 60% sensitivity. However, the area under the receiver operating characteristic curves were only about 65%; thus, the ability of SDL to discriminate between responders and nonresponders is low.

Treatment of enthesitis can be challenging. Head-to-head clinical trials using clinical enthesitis indices have indicated that TNF inhibitors and IL-17 inhibitors have similar efficacy in treating enthesitis. However, clinically determined enthesitis may not be true inflammatory enthesitis. Ultrasonography-confirmed enthesitis probably reflects true enthesitis. Therefore, Elliot and colleagues conducted an observational study that compared the change in MAdrid Sonographic Enthesitis Index (MASEI) at 16 weeks of treatment with either TNF inhibitors or secukinumab. They observed that the mean reduction in MASEI that assesses both active and chronic entheseal disease was not significantly different with TNF inhibitors vs secukinumab treatment. However, TNF inhibitors were significantly more effective than secukinumab when only active entheseal lesions were considered. Thus, TNF inhibitors may be more effective for active enthesitis; randomized trials using ultrasonographic enthesitis indices comparing the two treatments are required.

Serum drug levels have previously been shown to be associated with response to bDMARD therapy, but use of drug-level measurement is not routine in rheumatology practice. Moreover, trough levels are emphasized and may not often be feasible to obtain. Curry and colleagues investigated the relationship between serum non-trough drug levels (SDL) and treatment response at 3 months in patients with PsA who initiated treatment with adalimumab (n = 104) or etanercept (n = 97). They demonstrated that patients with higher etanercept SDL or higher adalimumab SDL were significantly more likely to be responders. A non-trough etanercept SDL of 2.0 µg/mL and adalimumab SDL of 3.6 µg/mL could differentiate between responders and nonresponders with ~50% specificity and > 60% sensitivity. However, the area under the receiver operating characteristic curves were only about 65%; thus, the ability of SDL to discriminate between responders and nonresponders is low.

Treatment of enthesitis can be challenging. Head-to-head clinical trials using clinical enthesitis indices have indicated that TNF inhibitors and IL-17 inhibitors have similar efficacy in treating enthesitis. However, clinically determined enthesitis may not be true inflammatory enthesitis. Ultrasonography-confirmed enthesitis probably reflects true enthesitis. Therefore, Elliot and colleagues conducted an observational study that compared the change in MAdrid Sonographic Enthesitis Index (MASEI) at 16 weeks of treatment with either TNF inhibitors or secukinumab. They observed that the mean reduction in MASEI that assesses both active and chronic entheseal disease was not significantly different with TNF inhibitors vs secukinumab treatment. However, TNF inhibitors were significantly more effective than secukinumab when only active entheseal lesions were considered. Thus, TNF inhibitors may be more effective for active enthesitis; randomized trials using ultrasonographic enthesitis indices comparing the two treatments are required.

Serum drug levels have previously been shown to be associated with response to bDMARD therapy, but use of drug-level measurement is not routine in rheumatology practice. Moreover, trough levels are emphasized and may not often be feasible to obtain. Curry and colleagues investigated the relationship between serum non-trough drug levels (SDL) and treatment response at 3 months in patients with PsA who initiated treatment with adalimumab (n = 104) or etanercept (n = 97). They demonstrated that patients with higher etanercept SDL or higher adalimumab SDL were significantly more likely to be responders. A non-trough etanercept SDL of 2.0 µg/mL and adalimumab SDL of 3.6 µg/mL could differentiate between responders and nonresponders with ~50% specificity and > 60% sensitivity. However, the area under the receiver operating characteristic curves were only about 65%; thus, the ability of SDL to discriminate between responders and nonresponders is low.

While chimeric antigen receptor (CAR) T-cell therapy has transformed the management of large B-cell lymphoma (LBCL), the majority of patients will ultimately relapse. Efforts to identify predictors of response remain an active area of investigation. One key variable that has been postulated to influence CAR T-cell outcomes is pretreatment bendamustine exposure. Specifically, there has been concern that the lymphodepleting effects of bendamustine could affect T-cell fitness, thus impairing CAR T-cell response. While consensus guidelines have recommended avoiding bendamustine prior to lymphocyte collection, clear data have been lacking. A recent retrospective, multicenter study, which included patients from seven European sites, reported outcomes based on prior bendamustine exposure (Iacoboni et al). In this study, 439 patients with relapsed or refractory LBCL, who received anti-CD19 commercial CAR T-cell therapy after two or more prior treatment lines of therapy, were included. Of these patients, 80 had received prior bendamustine. The authors found that patients recently exposed to bendamustine (< 9 months), vs bendamustine-naive patients, had a significantly lower overall response rate (40% vs 66%; P = .01), overall survival (OS; adjusted hazard ratio [aHR] 2.11; P < .01), and progression-free survival (PFS; aHR 1.82; P < .01) after CAR T-cell infusion. These differences remained significant after inverse probability treatment weighting and propensity score matching. Of note, the authors did not find that the cumulative dose of bendamustine affected outcomes. The authors also identified that, while the risk for cytokine release syndrome and immune effector cell–associated neurotoxicity syndrome was similar between the groups, hematologic toxicity and severe infections were increased in the bendamustine-exposed patients. These data support the recommendation to avoid bendamustine treatment prior to CAR T-cell apheresis. While treatment regimens such as polatuzumab plus bendamustine and rituximab are available in the relapsed setting for LBCL,¹ this regimen should be reserved for post CAR T-cell relapse or for patients not planning to proceed with cellular therapy. The impact of bendamustine exposure on other immune-mediated therapies, such as bispecific antibodies, remains unknown.

Quantitative PET/CT biomarkers have also emerged as predictors of response in diffuse large B-cell lymphoma (DLBCL). A key variable of interest includes total metabolic tumor volume (MTV), which refers to the total volume of tumor with metabolic uptake. While prior studies have demonstrated a correlation of MTV on outcomes following treatment with chemotherapy and CAR T-cell therapy,^2,3 the effect of PET/CT biomarkers on outcomes with other novel agents remains poorly described. A recent study by Alderuccio and colleagues explored the predictive power of PET/CT biomarkers on outcomes in a clinical trial cohort of patients treated with the antibody drug conjugate loncastuximab tesirine. This post hoc analysis reviewed the screening PET/CT scans of 138 patients with relapsed or refractory DLBCL treated with two or more prior systemic therapy lines who received loncastuximab tesirine in LOTIS-2<.⁴ The authors found that an MTV ≥ 96 mL was significantly associated with failure to achieve a complete metabolic response (adjusted odds ratio 5.42; P = .002). Patients with an MTV ≥ 96 mL vs < 96 mL also had a shorter PFS (aHR 2.68; P = .002) and OS (aHR 3.09; P < .0001). In line with prior studies, this analysis demonstrates that baseline MTV has the potential to provide robust risk-stratification and confirms the value of PET/CT biomarkers in DLBCL across treatment types.

This month, the results of the phase 2 TARMAC study, which evaluated treatment with ibrutinib in combination with tisagenlecleucel, were also published. This study included 20 patients with relapsed/refractory mantle cell lymphoma (MCL) who had received one or more prior lines of therapy, including 50% with prior Bruton tyrosine kinase inhibitor (BTKi) exposure. Ibrutinib was initiated prior to leukapheresis and continued through CAR T-cell manufacturing and for at least 6 months post tisagenlecleucel infusion. At 4 months post infusion, the overall and complete response rates were 80% each. Patients without and with prior BTKi exposure had complete response rates of 90% and 70%, respectively. At a median follow-up of 13 months, the estimated 12-month PFS was 75% and OS was 100%. Grades 1-2 and grade 3 cytokine-release syndrome rates were 55% and 20%, respectively, and grade 1-2 immune effector cell–associated neurotoxicity syndrome was seen in 10% of patients. The authors also demonstrated that markers of T-cell exhaustion were decreased in patients with longer ibrutinib exposure prior to leukapheresis. Also of note, the three patients with recent bendamustine therapy did not receive a durable response. Although this is a small study without a control arm, this study provides rationale for the potential advantage of combining BTKi with CAR T-cell therapy, even among patients with prior BTKi exposure.

Additional References

1.       Sehn LH, Hertzberg M, Opat S, et al. Polatuzumab vedotin plus bendamustine and rituximab in relapsed/refractory DLBCL: survival update and new extension cohort data. Blood Adv. 2022;6(2):533-543. doi: 10.1182/bloodadvances.2021005794

2.       Vercellino L, Cottereau AS, Casasnovas O, et al. High total metabolic tumor volume at baseline predicts survival independent of response to therapy. Blood. 2020;135(16):1396-1405. doi: 10.1182/blood.2019003526

3.       Dean EA, Mhaskar RS, Lu H, et al. High metabolic tumor volume is associated with decreased efficacy of axicabtagene ciloleucel in large B-cell lymphoma. Blood Adv. 2020;4(14):3268-3276. doi: 10.1182/bloodadvances.2020001900

4.       Caimi PF, Ai W, Alderuccio JP, et al. Loncastuximab tesirine in relapsed or refractory diffuse large B-cell lymphoma (LOTIS-2): a multicentre, open-label, single-arm, phase 2 trial. Lancet Oncol. 2021;22(6):790-800. doi:

While chimeric antigen receptor (CAR) T-cell therapy has transformed the management of large B-cell lymphoma (LBCL), the majority of patients will ultimately relapse. Efforts to identify predictors of response remain an active area of investigation. One key variable that has been postulated to influence CAR T-cell outcomes is pretreatment bendamustine exposure. Specifically, there has been concern that the lymphodepleting effects of bendamustine could affect T-cell fitness, thus impairing CAR T-cell response. While consensus guidelines have recommended avoiding bendamustine prior to lymphocyte collection, clear data have been lacking. A recent retrospective, multicenter study, which included patients from seven European sites, reported outcomes based on prior bendamustine exposure (Iacoboni et al). In this study, 439 patients with relapsed or refractory LBCL, who received anti-CD19 commercial CAR T-cell therapy after two or more prior treatment lines of therapy, were included. Of these patients, 80 had received prior bendamustine. The authors found that patients recently exposed to bendamustine (< 9 months), vs bendamustine-naive patients, had a significantly lower overall response rate (40% vs 66%; P = .01), overall survival (OS; adjusted hazard ratio [aHR] 2.11; P < .01), and progression-free survival (PFS; aHR 1.82; P < .01) after CAR T-cell infusion. These differences remained significant after inverse probability treatment weighting and propensity score matching. Of note, the authors did not find that the cumulative dose of bendamustine affected outcomes. The authors also identified that, while the risk for cytokine release syndrome and immune effector cell–associated neurotoxicity syndrome was similar between the groups, hematologic toxicity and severe infections were increased in the bendamustine-exposed patients. These data support the recommendation to avoid bendamustine treatment prior to CAR T-cell apheresis. While treatment regimens such as polatuzumab plus bendamustine and rituximab are available in the relapsed setting for LBCL,¹ this regimen should be reserved for post CAR T-cell relapse or for patients not planning to proceed with cellular therapy. The impact of bendamustine exposure on other immune-mediated therapies, such as bispecific antibodies, remains unknown.

Quantitative PET/CT biomarkers have also emerged as predictors of response in diffuse large B-cell lymphoma (DLBCL). A key variable of interest includes total metabolic tumor volume (MTV), which refers to the total volume of tumor with metabolic uptake. While prior studies have demonstrated a correlation of MTV on outcomes following treatment with chemotherapy and CAR T-cell therapy,^2,3 the effect of PET/CT biomarkers on outcomes with other novel agents remains poorly described. A recent study by Alderuccio and colleagues explored the predictive power of PET/CT biomarkers on outcomes in a clinical trial cohort of patients treated with the antibody drug conjugate loncastuximab tesirine. This post hoc analysis reviewed the screening PET/CT scans of 138 patients with relapsed or refractory DLBCL treated with two or more prior systemic therapy lines who received loncastuximab tesirine in LOTIS-2<.⁴ The authors found that an MTV ≥ 96 mL was significantly associated with failure to achieve a complete metabolic response (adjusted odds ratio 5.42; P = .002). Patients with an MTV ≥ 96 mL vs < 96 mL also had a shorter PFS (aHR 2.68; P = .002) and OS (aHR 3.09; P < .0001). In line with prior studies, this analysis demonstrates that baseline MTV has the potential to provide robust risk-stratification and confirms the value of PET/CT biomarkers in DLBCL across treatment types.

This month, the results of the phase 2 TARMAC study, which evaluated treatment with ibrutinib in combination with tisagenlecleucel, were also published. This study included 20 patients with relapsed/refractory mantle cell lymphoma (MCL) who had received one or more prior lines of therapy, including 50% with prior Bruton tyrosine kinase inhibitor (BTKi) exposure. Ibrutinib was initiated prior to leukapheresis and continued through CAR T-cell manufacturing and for at least 6 months post tisagenlecleucel infusion. At 4 months post infusion, the overall and complete response rates were 80% each. Patients without and with prior BTKi exposure had complete response rates of 90% and 70%, respectively. At a median follow-up of 13 months, the estimated 12-month PFS was 75% and OS was 100%. Grades 1-2 and grade 3 cytokine-release syndrome rates were 55% and 20%, respectively, and grade 1-2 immune effector cell–associated neurotoxicity syndrome was seen in 10% of patients. The authors also demonstrated that markers of T-cell exhaustion were decreased in patients with longer ibrutinib exposure prior to leukapheresis. Also of note, the three patients with recent bendamustine therapy did not receive a durable response. Although this is a small study without a control arm, this study provides rationale for the potential advantage of combining BTKi with CAR T-cell therapy, even among patients with prior BTKi exposure.

Additional References

1.       Sehn LH, Hertzberg M, Opat S, et al. Polatuzumab vedotin plus bendamustine and rituximab in relapsed/refractory DLBCL: survival update and new extension cohort data. Blood Adv. 2022;6(2):533-543. doi: 10.1182/bloodadvances.2021005794

2.       Vercellino L, Cottereau AS, Casasnovas O, et al. High total metabolic tumor volume at baseline predicts survival independent of response to therapy. Blood. 2020;135(16):1396-1405. doi: 10.1182/blood.2019003526

3.       Dean EA, Mhaskar RS, Lu H, et al. High metabolic tumor volume is associated with decreased efficacy of axicabtagene ciloleucel in large B-cell lymphoma. Blood Adv. 2020;4(14):3268-3276. doi: 10.1182/bloodadvances.2020001900

4.       Caimi PF, Ai W, Alderuccio JP, et al. Loncastuximab tesirine in relapsed or refractory diffuse large B-cell lymphoma (LOTIS-2): a multicentre, open-label, single-arm, phase 2 trial. Lancet Oncol. 2021;22(6):790-800. doi:

While chimeric antigen receptor (CAR) T-cell therapy has transformed the management of large B-cell lymphoma (LBCL), the majority of patients will ultimately relapse. Efforts to identify predictors of response remain an active area of investigation. One key variable that has been postulated to influence CAR T-cell outcomes is pretreatment bendamustine exposure. Specifically, there has been concern that the lymphodepleting effects of bendamustine could affect T-cell fitness, thus impairing CAR T-cell response. While consensus guidelines have recommended avoiding bendamustine prior to lymphocyte collection, clear data have been lacking. A recent retrospective, multicenter study, which included patients from seven European sites, reported outcomes based on prior bendamustine exposure (Iacoboni et al). In this study, 439 patients with relapsed or refractory LBCL, who received anti-CD19 commercial CAR T-cell therapy after two or more prior treatment lines of therapy, were included. Of these patients, 80 had received prior bendamustine. The authors found that patients recently exposed to bendamustine (< 9 months), vs bendamustine-naive patients, had a significantly lower overall response rate (40% vs 66%; P = .01), overall survival (OS; adjusted hazard ratio [aHR] 2.11; P < .01), and progression-free survival (PFS; aHR 1.82; P < .01) after CAR T-cell infusion. These differences remained significant after inverse probability treatment weighting and propensity score matching. Of note, the authors did not find that the cumulative dose of bendamustine affected outcomes. The authors also identified that, while the risk for cytokine release syndrome and immune effector cell–associated neurotoxicity syndrome was similar between the groups, hematologic toxicity and severe infections were increased in the bendamustine-exposed patients. These data support the recommendation to avoid bendamustine treatment prior to CAR T-cell apheresis. While treatment regimens such as polatuzumab plus bendamustine and rituximab are available in the relapsed setting for LBCL,¹ this regimen should be reserved for post CAR T-cell relapse or for patients not planning to proceed with cellular therapy. The impact of bendamustine exposure on other immune-mediated therapies, such as bispecific antibodies, remains unknown.

Quantitative PET/CT biomarkers have also emerged as predictors of response in diffuse large B-cell lymphoma (DLBCL). A key variable of interest includes total metabolic tumor volume (MTV), which refers to the total volume of tumor with metabolic uptake. While prior studies have demonstrated a correlation of MTV on outcomes following treatment with chemotherapy and CAR T-cell therapy,^2,3 the effect of PET/CT biomarkers on outcomes with other novel agents remains poorly described. A recent study by Alderuccio and colleagues explored the predictive power of PET/CT biomarkers on outcomes in a clinical trial cohort of patients treated with the antibody drug conjugate loncastuximab tesirine. This post hoc analysis reviewed the screening PET/CT scans of 138 patients with relapsed or refractory DLBCL treated with two or more prior systemic therapy lines who received loncastuximab tesirine in LOTIS-2<.⁴ The authors found that an MTV ≥ 96 mL was significantly associated with failure to achieve a complete metabolic response (adjusted odds ratio 5.42; P = .002). Patients with an MTV ≥ 96 mL vs < 96 mL also had a shorter PFS (aHR 2.68; P = .002) and OS (aHR 3.09; P < .0001). In line with prior studies, this analysis demonstrates that baseline MTV has the potential to provide robust risk-stratification and confirms the value of PET/CT biomarkers in DLBCL across treatment types.

This month, the results of the phase 2 TARMAC study, which evaluated treatment with ibrutinib in combination with tisagenlecleucel, were also published. This study included 20 patients with relapsed/refractory mantle cell lymphoma (MCL) who had received one or more prior lines of therapy, including 50% with prior Bruton tyrosine kinase inhibitor (BTKi) exposure. Ibrutinib was initiated prior to leukapheresis and continued through CAR T-cell manufacturing and for at least 6 months post tisagenlecleucel infusion. At 4 months post infusion, the overall and complete response rates were 80% each. Patients without and with prior BTKi exposure had complete response rates of 90% and 70%, respectively. At a median follow-up of 13 months, the estimated 12-month PFS was 75% and OS was 100%. Grades 1-2 and grade 3 cytokine-release syndrome rates were 55% and 20%, respectively, and grade 1-2 immune effector cell–associated neurotoxicity syndrome was seen in 10% of patients. The authors also demonstrated that markers of T-cell exhaustion were decreased in patients with longer ibrutinib exposure prior to leukapheresis. Also of note, the three patients with recent bendamustine therapy did not receive a durable response. Although this is a small study without a control arm, this study provides rationale for the potential advantage of combining BTKi with CAR T-cell therapy, even among patients with prior BTKi exposure.

Additional References

1.       Sehn LH, Hertzberg M, Opat S, et al. Polatuzumab vedotin plus bendamustine and rituximab in relapsed/refractory DLBCL: survival update and new extension cohort data. Blood Adv. 2022;6(2):533-543. doi: 10.1182/bloodadvances.2021005794

2.       Vercellino L, Cottereau AS, Casasnovas O, et al. High total metabolic tumor volume at baseline predicts survival independent of response to therapy. Blood. 2020;135(16):1396-1405. doi: 10.1182/blood.2019003526

3.       Dean EA, Mhaskar RS, Lu H, et al. High metabolic tumor volume is associated with decreased efficacy of axicabtagene ciloleucel in large B-cell lymphoma. Blood Adv. 2020;4(14):3268-3276. doi: 10.1182/bloodadvances.2020001900

4.       Caimi PF, Ai W, Alderuccio JP, et al. Loncastuximab tesirine in relapsed or refractory diffuse large B-cell lymphoma (LOTIS-2): a multicentre, open-label, single-arm, phase 2 trial. Lancet Oncol. 2021;22(6):790-800. doi:

The association of rheumatoid arthritis (RA) with increased cancer risk compared with the general population has long been known, though the balance between risk related to RA disease activity compared with risk related to immunosuppressive medication has not been clear. This increased risk is seen primarily with lymphoma and lung cancer, and prior research has suggested a risk with biological disease-modifying antirheumatic drugs (bDMARD), such as anti–tumor necrosis factor (TNF) agents. Beydon and colleagues performed a cohort study using a French national claims database; they looked at patients seen for at least 1 year with treatment for RA and compared the incidence of cancer by type. In over 257,000 patients, nearly 24,000 cancer cases were found. The most common cancers were breast, colon, lung, and prostate. All-cancer risk was > 1.2 (standardized incidence ratio) compared with those without cancer, higher in men compared with women, and the risk was increased in patients who received conventional synthetic (cs) DMARD, TNF inhibitors (TNFi), abatacept, and rituximab, but not interleukin (IL)-6 inhibitors or Janus kinase inhibitors (JAKi). Given that the risk was most highly associated with exposure to rituximab, this may show a type of bias rendering the study difficult to interpret, as rituximab is considered "safe" in cancer, and treatments such as csDMARD may have been given because they were not contraindicated in patients with cancer. This renders the study’s other results, such as lower risk with JAKi or higher risk with abatacept, hard to interpret.

Hayashi and colleagues performed a "real-world" comparative study using data from the Japanese observational ANSWER registry database to compare effectiveness of different JAKi over 6 months, a question of high interest given the availability of several JAKi currently. Within the database of over 11,000 participants, only 622 patients were exposed to tofacitinib, baricitinib, peficitinib, or upadacitinib, with 361 included in the final analysis due to missing baseline data (later missing data were imputed). Treatment retention rates were similar among all four JAKi, and discontinuation rates due to adverse events and due to lack of efficacy were similar as well. There was no significant difference in Health Assessment Questionnaire (HAQ), Clinical Disease Activity Index (CDAI), or C-reactive protein after 6 months between the four JAKi. Baricitinib had higher rates of CDAI low disease activity and remission at 6 months when used as a first-line biologic/targeted synthetic (b/ts) DMARD. However, this and other specific findings related to individual JAKi may be affected by the relatively small number of patients included and exposed to each JAKi, and the relatively short duration of follow-up (in terms of drug discontinuation), thus countering the initial premise for the study.

Finally, another important real-world study, by Tageldin and colleagues, looked at tapering therapy in the Rheumatoid Arthritis Medication Tapering (RHEUMTAP) cohort of patients with RA in sustained disease remission or low disease activity for at least 6 months on stable medications (infused bDMARD excluded). This 2-year prospective cohort included reducing frequency, reducing dose, and stopping medication according to predefined regimens. Of 131 patients, 40% underwent tapering, with more flares in the taper group over > 400 days of follow-up; flare rates were much higher in those tapering b/tsDMARD compared with csDMARD. Though limited by small numbers in examining the three different tapering groups, this real-world study provides an important counterpoint to the notion that medication can be tapered easily in RA patients doing well. A more stringent definition or longer duration of disease remission may also affect this finding.

The association of rheumatoid arthritis (RA) with increased cancer risk compared with the general population has long been known, though the balance between risk related to RA disease activity compared with risk related to immunosuppressive medication has not been clear. This increased risk is seen primarily with lymphoma and lung cancer, and prior research has suggested a risk with biological disease-modifying antirheumatic drugs (bDMARD), such as anti–tumor necrosis factor (TNF) agents. Beydon and colleagues performed a cohort study using a French national claims database; they looked at patients seen for at least 1 year with treatment for RA and compared the incidence of cancer by type. In over 257,000 patients, nearly 24,000 cancer cases were found. The most common cancers were breast, colon, lung, and prostate. All-cancer risk was > 1.2 (standardized incidence ratio) compared with those without cancer, higher in men compared with women, and the risk was increased in patients who received conventional synthetic (cs) DMARD, TNF inhibitors (TNFi), abatacept, and rituximab, but not interleukin (IL)-6 inhibitors or Janus kinase inhibitors (JAKi). Given that the risk was most highly associated with exposure to rituximab, this may show a type of bias rendering the study difficult to interpret, as rituximab is considered "safe" in cancer, and treatments such as csDMARD may have been given because they were not contraindicated in patients with cancer. This renders the study’s other results, such as lower risk with JAKi or higher risk with abatacept, hard to interpret.

Hayashi and colleagues performed a "real-world" comparative study using data from the Japanese observational ANSWER registry database to compare effectiveness of different JAKi over 6 months, a question of high interest given the availability of several JAKi currently. Within the database of over 11,000 participants, only 622 patients were exposed to tofacitinib, baricitinib, peficitinib, or upadacitinib, with 361 included in the final analysis due to missing baseline data (later missing data were imputed). Treatment retention rates were similar among all four JAKi, and discontinuation rates due to adverse events and due to lack of efficacy were similar as well. There was no significant difference in Health Assessment Questionnaire (HAQ), Clinical Disease Activity Index (CDAI), or C-reactive protein after 6 months between the four JAKi. Baricitinib had higher rates of CDAI low disease activity and remission at 6 months when used as a first-line biologic/targeted synthetic (b/ts) DMARD. However, this and other specific findings related to individual JAKi may be affected by the relatively small number of patients included and exposed to each JAKi, and the relatively short duration of follow-up (in terms of drug discontinuation), thus countering the initial premise for the study.

Finally, another important real-world study, by Tageldin and colleagues, looked at tapering therapy in the Rheumatoid Arthritis Medication Tapering (RHEUMTAP) cohort of patients with RA in sustained disease remission or low disease activity for at least 6 months on stable medications (infused bDMARD excluded). This 2-year prospective cohort included reducing frequency, reducing dose, and stopping medication according to predefined regimens. Of 131 patients, 40% underwent tapering, with more flares in the taper group over > 400 days of follow-up; flare rates were much higher in those tapering b/tsDMARD compared with csDMARD. Though limited by small numbers in examining the three different tapering groups, this real-world study provides an important counterpoint to the notion that medication can be tapered easily in RA patients doing well. A more stringent definition or longer duration of disease remission may also affect this finding.

The association of rheumatoid arthritis (RA) with increased cancer risk compared with the general population has long been known, though the balance between risk related to RA disease activity compared with risk related to immunosuppressive medication has not been clear. This increased risk is seen primarily with lymphoma and lung cancer, and prior research has suggested a risk with biological disease-modifying antirheumatic drugs (bDMARD), such as anti–tumor necrosis factor (TNF) agents. Beydon and colleagues performed a cohort study using a French national claims database; they looked at patients seen for at least 1 year with treatment for RA and compared the incidence of cancer by type. In over 257,000 patients, nearly 24,000 cancer cases were found. The most common cancers were breast, colon, lung, and prostate. All-cancer risk was > 1.2 (standardized incidence ratio) compared with those without cancer, higher in men compared with women, and the risk was increased in patients who received conventional synthetic (cs) DMARD, TNF inhibitors (TNFi), abatacept, and rituximab, but not interleukin (IL)-6 inhibitors or Janus kinase inhibitors (JAKi). Given that the risk was most highly associated with exposure to rituximab, this may show a type of bias rendering the study difficult to interpret, as rituximab is considered "safe" in cancer, and treatments such as csDMARD may have been given because they were not contraindicated in patients with cancer. This renders the study’s other results, such as lower risk with JAKi or higher risk with abatacept, hard to interpret.

Hayashi and colleagues performed a "real-world" comparative study using data from the Japanese observational ANSWER registry database to compare effectiveness of different JAKi over 6 months, a question of high interest given the availability of several JAKi currently. Within the database of over 11,000 participants, only 622 patients were exposed to tofacitinib, baricitinib, peficitinib, or upadacitinib, with 361 included in the final analysis due to missing baseline data (later missing data were imputed). Treatment retention rates were similar among all four JAKi, and discontinuation rates due to adverse events and due to lack of efficacy were similar as well. There was no significant difference in Health Assessment Questionnaire (HAQ), Clinical Disease Activity Index (CDAI), or C-reactive protein after 6 months between the four JAKi. Baricitinib had higher rates of CDAI low disease activity and remission at 6 months when used as a first-line biologic/targeted synthetic (b/ts) DMARD. However, this and other specific findings related to individual JAKi may be affected by the relatively small number of patients included and exposed to each JAKi, and the relatively short duration of follow-up (in terms of drug discontinuation), thus countering the initial premise for the study.

Finally, another important real-world study, by Tageldin and colleagues, looked at tapering therapy in the Rheumatoid Arthritis Medication Tapering (RHEUMTAP) cohort of patients with RA in sustained disease remission or low disease activity for at least 6 months on stable medications (infused bDMARD excluded). This 2-year prospective cohort included reducing frequency, reducing dose, and stopping medication according to predefined regimens. Of 131 patients, 40% underwent tapering, with more flares in the taper group over > 400 days of follow-up; flare rates were much higher in those tapering b/tsDMARD compared with csDMARD. Though limited by small numbers in examining the three different tapering groups, this real-world study provides an important counterpoint to the notion that medication can be tapered easily in RA patients doing well. A more stringent definition or longer duration of disease remission may also affect this finding.

Prior studies show inconsistent outcomes in patients with invasive lobular carcinoma (ILC) and data in premenopausal women is limited. The retrospective cohort study by Yoon and colleagues analyzed the data from three databases and included 225,938 premenopausal women with stage I-III ILC or invasive ductal carcinoma (IDC) in their study to evaluate survival trends in young women with ILC. In the Surveillance, Epidemiology, and End Results (SEER) database, patients with ILC vs IDC showed superior breast cancer severity score (BCSS) outcomes during the first 10 years after diagnosis (HR 0.73; P < .001); similar results were seen in the Asan Medical Center Research (AMCR) database (HR 0.50; 95% CI 0.29-0.86; P = .01). After 10 years, the trend reversed, and BCSS outcomes worsened by 80% in patients with ILC in the SEER database (HR 1.80; P < .001). This was also seen in both the Korean Breast Cancer Registry (HR 2.79; 95% CI 1.32-5.88; P = .007) and AMCR database (HR 2.23; 95% CI 1.04-4.79; P = .04). These findings remained consistent after adjusting for tumor characteristics including age, stage, tumor grade, hormone receptor status, and after controlling for treatment with chemotherapy and radiation. In addition, in the SEER database, the histologic type exerted a statistically significant time-dependent association with BCSS, with ILC showing decreasing BCSS over time (time interaction HR 1.93; 95% CI 1.78-2.10; P < .001). Furthermore, on annual hazard function analysis, the ILC annual peak event of BCSS occurred 5 years after diagnosis, whereas the IDC recurrence events peaked at 5 years before diagnosis, suggesting a higher late recurrence rate for ILC. These findings may have implications on the duration of endocrine therapy used in these patients given concern for worse long-term outcomes in premenopausal patients with ILC.

Oral selective estrogen receptor degraders (SERD) have recently emerged as a new therapeutic mechanism for patients with hormone receptor–positive breast cancer who have developed resistance to other endocrine therapies. Two of these agents, elacestrant and camizestrant, have demonstrated statistically significant progression-free survival benefit in these populations, particularly in tumors with ESR1 mutations. The efficacy of these agents in tumors with ESR1 wild-type subgroup remains uncertain. A meta-analysis by Wong and colleagues of individual patient data from four randomized clinical trials (ACELERA, AMEERA-3, EMERALD, and SERENA-2) included 1290 patients with hormone receptor–positive/human epidermal growth factor receptor 2–negative metastatic breast cancer who received oral SERD or endocrine therapies (ET) of the physician's choice. In the overall cohort, oral SERD showed improved progression-free survival (PFS) outcomes compared with ET of the physician's choice (HR 0.783; 95% CI 0.681-0.900; P < .001). This was also noted in the subgroup of patients with ESR1 mutations (HR 0.557; 95% CI 0.440-0.705; P < .001); although no significant PFS benefit was observed with oral SERD in the ESR1 wild-type subgroup (HR 0.944; 95% CI 0.783-1.138; P = .543). These results suggest that the PFS benefit observed with oral SERD is mainly seen in patients with ESR1-mutated tumors, and, therefore, these drugs should be prescribed accordingly.

Additional Reference

1. Cold S, Cold F, Jensen M-B, et al. Systemic or vaginal hormone therapy after early breast cancer: A Danish observational cohort study. J Natl Cancer Inst. 2022;114:1347–1354. doi: 10.1093/jnci/djac112

Prior studies show inconsistent outcomes in patients with invasive lobular carcinoma (ILC) and data in premenopausal women is limited. The retrospective cohort study by Yoon and colleagues analyzed the data from three databases and included 225,938 premenopausal women with stage I-III ILC or invasive ductal carcinoma (IDC) in their study to evaluate survival trends in young women with ILC. In the Surveillance, Epidemiology, and End Results (SEER) database, patients with ILC vs IDC showed superior breast cancer severity score (BCSS) outcomes during the first 10 years after diagnosis (HR 0.73; P < .001); similar results were seen in the Asan Medical Center Research (AMCR) database (HR 0.50; 95% CI 0.29-0.86; P = .01). After 10 years, the trend reversed, and BCSS outcomes worsened by 80% in patients with ILC in the SEER database (HR 1.80; P < .001). This was also seen in both the Korean Breast Cancer Registry (HR 2.79; 95% CI 1.32-5.88; P = .007) and AMCR database (HR 2.23; 95% CI 1.04-4.79; P = .04). These findings remained consistent after adjusting for tumor characteristics including age, stage, tumor grade, hormone receptor status, and after controlling for treatment with chemotherapy and radiation. In addition, in the SEER database, the histologic type exerted a statistically significant time-dependent association with BCSS, with ILC showing decreasing BCSS over time (time interaction HR 1.93; 95% CI 1.78-2.10; P < .001). Furthermore, on annual hazard function analysis, the ILC annual peak event of BCSS occurred 5 years after diagnosis, whereas the IDC recurrence events peaked at 5 years before diagnosis, suggesting a higher late recurrence rate for ILC. These findings may have implications on the duration of endocrine therapy used in these patients given concern for worse long-term outcomes in premenopausal patients with ILC.

Oral selective estrogen receptor degraders (SERD) have recently emerged as a new therapeutic mechanism for patients with hormone receptor–positive breast cancer who have developed resistance to other endocrine therapies. Two of these agents, elacestrant and camizestrant, have demonstrated statistically significant progression-free survival benefit in these populations, particularly in tumors with ESR1 mutations. The efficacy of these agents in tumors with ESR1 wild-type subgroup remains uncertain. A meta-analysis by Wong and colleagues of individual patient data from four randomized clinical trials (ACELERA, AMEERA-3, EMERALD, and SERENA-2) included 1290 patients with hormone receptor–positive/human epidermal growth factor receptor 2–negative metastatic breast cancer who received oral SERD or endocrine therapies (ET) of the physician's choice. In the overall cohort, oral SERD showed improved progression-free survival (PFS) outcomes compared with ET of the physician's choice (HR 0.783; 95% CI 0.681-0.900; P < .001). This was also noted in the subgroup of patients with ESR1 mutations (HR 0.557; 95% CI 0.440-0.705; P < .001); although no significant PFS benefit was observed with oral SERD in the ESR1 wild-type subgroup (HR 0.944; 95% CI 0.783-1.138; P = .543). These results suggest that the PFS benefit observed with oral SERD is mainly seen in patients with ESR1-mutated tumors, and, therefore, these drugs should be prescribed accordingly.

Additional Reference

1. Cold S, Cold F, Jensen M-B, et al. Systemic or vaginal hormone therapy after early breast cancer: A Danish observational cohort study. J Natl Cancer Inst. 2022;114:1347–1354. doi: 10.1093/jnci/djac112

Prior studies show inconsistent outcomes in patients with invasive lobular carcinoma (ILC) and data in premenopausal women is limited. The retrospective cohort study by Yoon and colleagues analyzed the data from three databases and included 225,938 premenopausal women with stage I-III ILC or invasive ductal carcinoma (IDC) in their study to evaluate survival trends in young women with ILC. In the Surveillance, Epidemiology, and End Results (SEER) database, patients with ILC vs IDC showed superior breast cancer severity score (BCSS) outcomes during the first 10 years after diagnosis (HR 0.73; P < .001); similar results were seen in the Asan Medical Center Research (AMCR) database (HR 0.50; 95% CI 0.29-0.86; P = .01). After 10 years, the trend reversed, and BCSS outcomes worsened by 80% in patients with ILC in the SEER database (HR 1.80; P < .001). This was also seen in both the Korean Breast Cancer Registry (HR 2.79; 95% CI 1.32-5.88; P = .007) and AMCR database (HR 2.23; 95% CI 1.04-4.79; P = .04). These findings remained consistent after adjusting for tumor characteristics including age, stage, tumor grade, hormone receptor status, and after controlling for treatment with chemotherapy and radiation. In addition, in the SEER database, the histologic type exerted a statistically significant time-dependent association with BCSS, with ILC showing decreasing BCSS over time (time interaction HR 1.93; 95% CI 1.78-2.10; P < .001). Furthermore, on annual hazard function analysis, the ILC annual peak event of BCSS occurred 5 years after diagnosis, whereas the IDC recurrence events peaked at 5 years before diagnosis, suggesting a higher late recurrence rate for ILC. These findings may have implications on the duration of endocrine therapy used in these patients given concern for worse long-term outcomes in premenopausal patients with ILC.

Oral selective estrogen receptor degraders (SERD) have recently emerged as a new therapeutic mechanism for patients with hormone receptor–positive breast cancer who have developed resistance to other endocrine therapies. Two of these agents, elacestrant and camizestrant, have demonstrated statistically significant progression-free survival benefit in these populations, particularly in tumors with ESR1 mutations. The efficacy of these agents in tumors with ESR1 wild-type subgroup remains uncertain. A meta-analysis by Wong and colleagues of individual patient data from four randomized clinical trials (ACELERA, AMEERA-3, EMERALD, and SERENA-2) included 1290 patients with hormone receptor–positive/human epidermal growth factor receptor 2–negative metastatic breast cancer who received oral SERD or endocrine therapies (ET) of the physician's choice. In the overall cohort, oral SERD showed improved progression-free survival (PFS) outcomes compared with ET of the physician's choice (HR 0.783; 95% CI 0.681-0.900; P < .001). This was also noted in the subgroup of patients with ESR1 mutations (HR 0.557; 95% CI 0.440-0.705; P < .001); although no significant PFS benefit was observed with oral SERD in the ESR1 wild-type subgroup (HR 0.944; 95% CI 0.783-1.138; P = .543). These results suggest that the PFS benefit observed with oral SERD is mainly seen in patients with ESR1-mutated tumors, and, therefore, these drugs should be prescribed accordingly.

Additional Reference

1. Cold S, Cold F, Jensen M-B, et al. Systemic or vaginal hormone therapy after early breast cancer: A Danish observational cohort study. J Natl Cancer Inst. 2022;114:1347–1354. doi: 10.1093/jnci/djac112