MD

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.

Although there exists a recognized association between IBD and secondary EoE diagnoses, studies focusing on the primary diagnosis of EoE alongside IBD have yielded conflicting results. Dr Amiko Uchida, from the University of Utah Department of Medicine, working with colleagues from the Department of Medical Epidemiology and Biostatistics at Karolinska Institutet in Stockholm, Sweden, led by Dr Jonas F. Ludvigsson, conducted a comprehensive study spanning 1990-2019 to explore the relationship between these two diseases.

Dr Uchida and colleagues assessed the association among Swedish patients diagnosed with biopsy-verified EoE (n = 1587) between 1990 and 2017. These patients were age- and sex-matched with up to five reference individuals from the general population (n = 7808). The primary focus was to discern the relationship between the primary diagnosis of EoE and the subsequent diagnosis of IBD.

The study's findings underscore the importance of heightened awareness among healthcare professionals regarding the potential association between EoE and the development of subsequent IBD. Collaborative efforts between physicians, gastroenterologists, and specialists in allergic diseases are crucial to ensure comprehensive care and timely identification of gastrointestinal complications in patients with EoE.

These results indicate a potential interplay between EoE and the pathogenesis of IBD, particularly Crohn's disease. In patients with EoE, careful consideration of gastrointestinal symptoms suggestive of IBD, such as abdominal pain, diarrhea, and rectal bleeding, is pivotal, necessitating further evaluation and appropriate monitoring for early detection and management of IBD.

Upon diagnosis, clinicians must develop a management plan for this chronic and critical disease. This study aids in planning future screenings for these patients, because one third of those diagnosed with EoE are at risk of developing IBD within a year. Therefore, primary physicians must remain vigilant for the development of gastrointestinal symptoms leading to a diagnosis of Crohn's disease or ulcerative colitis. Additionally, family awareness is crucial owing to observed associations between siblings, suggesting a potential role of genetics or early environmental factors in EoE development and future IBD diagnoses.

Further research is necessary to elucidate the shared pathophysiologic mechanisms connecting EoE and IBD. It is important to consider certain details, however; for instance, 31% of all subsequent IBD cases were diagnosed within the first year after an EoE diagnosis, potentially indicating a role of detection bias in these findings. Using a validated nationwide cohort and comparing study individuals with their siblings helped control for potential intrafamilial confounders as well as some environmental confounders, minimizing such biases as selection bias due to socioeconomic status. This strengthens the observed association in this study.

These insights into the increased risk for IBD, notably Crohn's disease, among patients with EoE underscore the need for thorough clinical evaluation and vigilant monitoring for gastrointestinal complications in this population.

A retrospective study conducted in pediatric patients presenting with an aerodigestive manifestation aimed to assess the factors associated with EoE and the diagnostic role of triple endoscopy. The results suggested a potential association between a family history of eczema and a diet lacking allergenic foods with a future diagnosis of EoE.

This study by Sheila Moran and colleagues, led by Dr Christina J. Yang from the Department of Otorhinolaryngology, Head and Neck Surgery at the Albert Einstein College of Medicine, Bronx, New York, aimed to identify preoperative risk factors linked to an EoE diagnosis in children undergoing triple endoscopy. They evaluated 119 pediatric patients aged 0-21 years who underwent triple endoscopy (including flexible bronchoscopy, rigid direct laryngoscopy and bronchoscopy, and esophagoscopy with biopsy) at the Children's Hospital at Montefiore between January 1, 2015, and December 31, 2019.

The study underscored the significance of both genetic predisposition and dietary influences in EoE development. Understanding the interplay between familial atopic conditions and dietary choices among pediatric patients with aerodigestive dysfunction is crucial for early identification and implementing preventive strategies against EoE.

As clinicians, it's essential to consider rare diseases like EoE when patients present with mixed symptoms, including aerodigestive symptoms, a family history of eczema, and a history of environmental allergies, given the association between these conditions. The potential link between a family history of eczema and increased EoE risk suggests a shared genetic susceptibility among allergic conditions. Therefore, clinicians evaluating children with aerodigestive dysfunction, particularly those with a familial history of eczema, should maintain a high index of suspicion for EoE, prompting vigilant monitoring and appropriate diagnostic assessments.

When contemplating advanced procedures, such as triple endoscopy or biopsy sampling, considering the patient's previous medical history and the effect of dietary modifications, such as incorporating or excluding dairy from the diet, warrants further investigation in the context of EoE prevention. Clinicians should consider providing dietary counseling and personalized nutritional plans based on evidence-based approaches to potentially mitigate EoE risk in susceptible pediatric populations.

Additionally, it's crucial to consider EoE in minority racial groups and underserved communities and encourage the use of diagnostic tests, such as triple endoscopy, to facilitate early diagnosis. Healthcare providers should contemplate integrating family history assessments, particularly regarding eczema, into the evaluation of children with aerodigestive dysfunction. This information can assist in risk assessment and early identification of individuals at a higher risk of developing EoE, enabling prompt intervention and management.

The increasing incidence of EoE across different nations, including the United States, has underscored the need for a deeper understanding of its causes, early diagnosis, and treatment. A novel population-based study conducted in Denmark aimed to explore the relationship between maternal and infant use of antibiotics and acid suppressants in the development of EoE. The study yielded significant results based on a population of 392 cases. Dr Elizabeth T. Jensen, MPH, PhD, from the Department of Epidemiology & Prevention at Wake Forest University School of Medicine, Winston-Salem, North Carolina, conducted a comprehensive study spanning the last 20 years to decipher potential causes contributing to the rising incidence of EoE.

Dr Jensen and her colleagues evaluated the association between maternal and infant use of antibiotics and acid suppressants in Denmark. They used pathology, prescription, birth, inpatient, and outpatient health registry data, ensuring complete ascertainment of all EoE cases among Danish residents born between 1997 and 2018. The research obtained a census of cases from a registered sample of approximately 1.4 million children, matching EoE cases to controls using a 1:10 ratio through incidence density sampling. A total of 392 patients with EoE and 3637 control patients were enrolled. The primary outcome of the study focused on the development of EoE, revealing a dose-response association between maternal and infant antibiotic and acid suppressant use and increased EoE risk.

This study demonstrated a robust correlation between the dosage of antibiotics and acid suppressants and the development of EoE in offspring during childhood. These findings hold significance because these medications represent some of the most common prescriptions in clinical practice. Pregnancy triggers significant physiologic changes in women, including increased hormonal effects and abdominal pressure on the lower esophageal sphincter, making pregnant individuals more prone to esophageal reflux and necessitating the use of gastric acid suppressants. As clinicians, it's crucial to consider lifestyle modifications and dietary adjustments before resorting to acid suppressants, reserving their use for only when absolutely necessary.

Postpregnancy, emphasizing exclusive breastfeeding for the first 6 months and proper feeding techniques can aid in reducing the likelihood of reflux disease in newborns. Acid suppressants have been linked to alterations in infant microbiome colonization, potentially increasing the susceptibility to immunoreactive diseases, such as asthma, atopic dermatitis, and allergic rhinitis. Given that exclusive breastfeeding in the initial 6 months has demonstrated preventive benefits against such diseases, primary physicians play a crucial role in advocating its importance. Although gastric acid suppressants and antibiotics are essential for managing various health conditions, including infections and gastroesophageal reflux disease (GERD), their potential impact on EoE development should not be overlooked.

Though this study had a relatively small sample size, the strong population registry of Denmark significantly reduced recall bias. However, cultural differences and over-the-counter access to drugs, such as acid suppressants, in other countries, including the United States, warrant further research to ascertain their effect on EoE development.

In light of these findings, clinicians should carefully weigh the risks and benefits of prescribing antibiotics and acid suppressants during pregnancy and infancy. Adherence to evidence-based guidelines and considering alternative treatment options, such as lifestyle modifications, should be prioritized. Prescribing antibiotics only when medically necessary and using nonpharmacologic strategies for managing GERD in infants should be considered to mitigate potential risks associated with these medications.

Although there exists a recognized association between IBD and secondary EoE diagnoses, studies focusing on the primary diagnosis of EoE alongside IBD have yielded conflicting results. Dr Amiko Uchida, from the University of Utah Department of Medicine, working with colleagues from the Department of Medical Epidemiology and Biostatistics at Karolinska Institutet in Stockholm, Sweden, led by Dr Jonas F. Ludvigsson, conducted a comprehensive study spanning 1990-2019 to explore the relationship between these two diseases.

Dr Uchida and colleagues assessed the association among Swedish patients diagnosed with biopsy-verified EoE (n = 1587) between 1990 and 2017. These patients were age- and sex-matched with up to five reference individuals from the general population (n = 7808). The primary focus was to discern the relationship between the primary diagnosis of EoE and the subsequent diagnosis of IBD.

The study's findings underscore the importance of heightened awareness among healthcare professionals regarding the potential association between EoE and the development of subsequent IBD. Collaborative efforts between physicians, gastroenterologists, and specialists in allergic diseases are crucial to ensure comprehensive care and timely identification of gastrointestinal complications in patients with EoE.

These results indicate a potential interplay between EoE and the pathogenesis of IBD, particularly Crohn's disease. In patients with EoE, careful consideration of gastrointestinal symptoms suggestive of IBD, such as abdominal pain, diarrhea, and rectal bleeding, is pivotal, necessitating further evaluation and appropriate monitoring for early detection and management of IBD.

Upon diagnosis, clinicians must develop a management plan for this chronic and critical disease. This study aids in planning future screenings for these patients, because one third of those diagnosed with EoE are at risk of developing IBD within a year. Therefore, primary physicians must remain vigilant for the development of gastrointestinal symptoms leading to a diagnosis of Crohn's disease or ulcerative colitis. Additionally, family awareness is crucial owing to observed associations between siblings, suggesting a potential role of genetics or early environmental factors in EoE development and future IBD diagnoses.

Further research is necessary to elucidate the shared pathophysiologic mechanisms connecting EoE and IBD. It is important to consider certain details, however; for instance, 31% of all subsequent IBD cases were diagnosed within the first year after an EoE diagnosis, potentially indicating a role of detection bias in these findings. Using a validated nationwide cohort and comparing study individuals with their siblings helped control for potential intrafamilial confounders as well as some environmental confounders, minimizing such biases as selection bias due to socioeconomic status. This strengthens the observed association in this study.

These insights into the increased risk for IBD, notably Crohn's disease, among patients with EoE underscore the need for thorough clinical evaluation and vigilant monitoring for gastrointestinal complications in this population.

A retrospective study conducted in pediatric patients presenting with an aerodigestive manifestation aimed to assess the factors associated with EoE and the diagnostic role of triple endoscopy. The results suggested a potential association between a family history of eczema and a diet lacking allergenic foods with a future diagnosis of EoE.

This study by Sheila Moran and colleagues, led by Dr Christina J. Yang from the Department of Otorhinolaryngology, Head and Neck Surgery at the Albert Einstein College of Medicine, Bronx, New York, aimed to identify preoperative risk factors linked to an EoE diagnosis in children undergoing triple endoscopy. They evaluated 119 pediatric patients aged 0-21 years who underwent triple endoscopy (including flexible bronchoscopy, rigid direct laryngoscopy and bronchoscopy, and esophagoscopy with biopsy) at the Children's Hospital at Montefiore between January 1, 2015, and December 31, 2019.

The study underscored the significance of both genetic predisposition and dietary influences in EoE development. Understanding the interplay between familial atopic conditions and dietary choices among pediatric patients with aerodigestive dysfunction is crucial for early identification and implementing preventive strategies against EoE.

As clinicians, it's essential to consider rare diseases like EoE when patients present with mixed symptoms, including aerodigestive symptoms, a family history of eczema, and a history of environmental allergies, given the association between these conditions. The potential link between a family history of eczema and increased EoE risk suggests a shared genetic susceptibility among allergic conditions. Therefore, clinicians evaluating children with aerodigestive dysfunction, particularly those with a familial history of eczema, should maintain a high index of suspicion for EoE, prompting vigilant monitoring and appropriate diagnostic assessments.

When contemplating advanced procedures, such as triple endoscopy or biopsy sampling, considering the patient's previous medical history and the effect of dietary modifications, such as incorporating or excluding dairy from the diet, warrants further investigation in the context of EoE prevention. Clinicians should consider providing dietary counseling and personalized nutritional plans based on evidence-based approaches to potentially mitigate EoE risk in susceptible pediatric populations.

Additionally, it's crucial to consider EoE in minority racial groups and underserved communities and encourage the use of diagnostic tests, such as triple endoscopy, to facilitate early diagnosis. Healthcare providers should contemplate integrating family history assessments, particularly regarding eczema, into the evaluation of children with aerodigestive dysfunction. This information can assist in risk assessment and early identification of individuals at a higher risk of developing EoE, enabling prompt intervention and management.

The increasing incidence of EoE across different nations, including the United States, has underscored the need for a deeper understanding of its causes, early diagnosis, and treatment. A novel population-based study conducted in Denmark aimed to explore the relationship between maternal and infant use of antibiotics and acid suppressants in the development of EoE. The study yielded significant results based on a population of 392 cases. Dr Elizabeth T. Jensen, MPH, PhD, from the Department of Epidemiology & Prevention at Wake Forest University School of Medicine, Winston-Salem, North Carolina, conducted a comprehensive study spanning the last 20 years to decipher potential causes contributing to the rising incidence of EoE.

Dr Jensen and her colleagues evaluated the association between maternal and infant use of antibiotics and acid suppressants in Denmark. They used pathology, prescription, birth, inpatient, and outpatient health registry data, ensuring complete ascertainment of all EoE cases among Danish residents born between 1997 and 2018. The research obtained a census of cases from a registered sample of approximately 1.4 million children, matching EoE cases to controls using a 1:10 ratio through incidence density sampling. A total of 392 patients with EoE and 3637 control patients were enrolled. The primary outcome of the study focused on the development of EoE, revealing a dose-response association between maternal and infant antibiotic and acid suppressant use and increased EoE risk.

This study demonstrated a robust correlation between the dosage of antibiotics and acid suppressants and the development of EoE in offspring during childhood. These findings hold significance because these medications represent some of the most common prescriptions in clinical practice. Pregnancy triggers significant physiologic changes in women, including increased hormonal effects and abdominal pressure on the lower esophageal sphincter, making pregnant individuals more prone to esophageal reflux and necessitating the use of gastric acid suppressants. As clinicians, it's crucial to consider lifestyle modifications and dietary adjustments before resorting to acid suppressants, reserving their use for only when absolutely necessary.

Postpregnancy, emphasizing exclusive breastfeeding for the first 6 months and proper feeding techniques can aid in reducing the likelihood of reflux disease in newborns. Acid suppressants have been linked to alterations in infant microbiome colonization, potentially increasing the susceptibility to immunoreactive diseases, such as asthma, atopic dermatitis, and allergic rhinitis. Given that exclusive breastfeeding in the initial 6 months has demonstrated preventive benefits against such diseases, primary physicians play a crucial role in advocating its importance. Although gastric acid suppressants and antibiotics are essential for managing various health conditions, including infections and gastroesophageal reflux disease (GERD), their potential impact on EoE development should not be overlooked.

Though this study had a relatively small sample size, the strong population registry of Denmark significantly reduced recall bias. However, cultural differences and over-the-counter access to drugs, such as acid suppressants, in other countries, including the United States, warrant further research to ascertain their effect on EoE development.

In light of these findings, clinicians should carefully weigh the risks and benefits of prescribing antibiotics and acid suppressants during pregnancy and infancy. Adherence to evidence-based guidelines and considering alternative treatment options, such as lifestyle modifications, should be prioritized. Prescribing antibiotics only when medically necessary and using nonpharmacologic strategies for managing GERD in infants should be considered to mitigate potential risks associated with these medications.

Although there exists a recognized association between IBD and secondary EoE diagnoses, studies focusing on the primary diagnosis of EoE alongside IBD have yielded conflicting results. Dr Amiko Uchida, from the University of Utah Department of Medicine, working with colleagues from the Department of Medical Epidemiology and Biostatistics at Karolinska Institutet in Stockholm, Sweden, led by Dr Jonas F. Ludvigsson, conducted a comprehensive study spanning 1990-2019 to explore the relationship between these two diseases.

Dr Uchida and colleagues assessed the association among Swedish patients diagnosed with biopsy-verified EoE (n = 1587) between 1990 and 2017. These patients were age- and sex-matched with up to five reference individuals from the general population (n = 7808). The primary focus was to discern the relationship between the primary diagnosis of EoE and the subsequent diagnosis of IBD.

The study's findings underscore the importance of heightened awareness among healthcare professionals regarding the potential association between EoE and the development of subsequent IBD. Collaborative efforts between physicians, gastroenterologists, and specialists in allergic diseases are crucial to ensure comprehensive care and timely identification of gastrointestinal complications in patients with EoE.

These results indicate a potential interplay between EoE and the pathogenesis of IBD, particularly Crohn's disease. In patients with EoE, careful consideration of gastrointestinal symptoms suggestive of IBD, such as abdominal pain, diarrhea, and rectal bleeding, is pivotal, necessitating further evaluation and appropriate monitoring for early detection and management of IBD.

Upon diagnosis, clinicians must develop a management plan for this chronic and critical disease. This study aids in planning future screenings for these patients, because one third of those diagnosed with EoE are at risk of developing IBD within a year. Therefore, primary physicians must remain vigilant for the development of gastrointestinal symptoms leading to a diagnosis of Crohn's disease or ulcerative colitis. Additionally, family awareness is crucial owing to observed associations between siblings, suggesting a potential role of genetics or early environmental factors in EoE development and future IBD diagnoses.

Further research is necessary to elucidate the shared pathophysiologic mechanisms connecting EoE and IBD. It is important to consider certain details, however; for instance, 31% of all subsequent IBD cases were diagnosed within the first year after an EoE diagnosis, potentially indicating a role of detection bias in these findings. Using a validated nationwide cohort and comparing study individuals with their siblings helped control for potential intrafamilial confounders as well as some environmental confounders, minimizing such biases as selection bias due to socioeconomic status. This strengthens the observed association in this study.

These insights into the increased risk for IBD, notably Crohn's disease, among patients with EoE underscore the need for thorough clinical evaluation and vigilant monitoring for gastrointestinal complications in this population.

A retrospective study conducted in pediatric patients presenting with an aerodigestive manifestation aimed to assess the factors associated with EoE and the diagnostic role of triple endoscopy. The results suggested a potential association between a family history of eczema and a diet lacking allergenic foods with a future diagnosis of EoE.

This study by Sheila Moran and colleagues, led by Dr Christina J. Yang from the Department of Otorhinolaryngology, Head and Neck Surgery at the Albert Einstein College of Medicine, Bronx, New York, aimed to identify preoperative risk factors linked to an EoE diagnosis in children undergoing triple endoscopy. They evaluated 119 pediatric patients aged 0-21 years who underwent triple endoscopy (including flexible bronchoscopy, rigid direct laryngoscopy and bronchoscopy, and esophagoscopy with biopsy) at the Children's Hospital at Montefiore between January 1, 2015, and December 31, 2019.

The study underscored the significance of both genetic predisposition and dietary influences in EoE development. Understanding the interplay between familial atopic conditions and dietary choices among pediatric patients with aerodigestive dysfunction is crucial for early identification and implementing preventive strategies against EoE.

As clinicians, it's essential to consider rare diseases like EoE when patients present with mixed symptoms, including aerodigestive symptoms, a family history of eczema, and a history of environmental allergies, given the association between these conditions. The potential link between a family history of eczema and increased EoE risk suggests a shared genetic susceptibility among allergic conditions. Therefore, clinicians evaluating children with aerodigestive dysfunction, particularly those with a familial history of eczema, should maintain a high index of suspicion for EoE, prompting vigilant monitoring and appropriate diagnostic assessments.

When contemplating advanced procedures, such as triple endoscopy or biopsy sampling, considering the patient's previous medical history and the effect of dietary modifications, such as incorporating or excluding dairy from the diet, warrants further investigation in the context of EoE prevention. Clinicians should consider providing dietary counseling and personalized nutritional plans based on evidence-based approaches to potentially mitigate EoE risk in susceptible pediatric populations.

Additionally, it's crucial to consider EoE in minority racial groups and underserved communities and encourage the use of diagnostic tests, such as triple endoscopy, to facilitate early diagnosis. Healthcare providers should contemplate integrating family history assessments, particularly regarding eczema, into the evaluation of children with aerodigestive dysfunction. This information can assist in risk assessment and early identification of individuals at a higher risk of developing EoE, enabling prompt intervention and management.

The increasing incidence of EoE across different nations, including the United States, has underscored the need for a deeper understanding of its causes, early diagnosis, and treatment. A novel population-based study conducted in Denmark aimed to explore the relationship between maternal and infant use of antibiotics and acid suppressants in the development of EoE. The study yielded significant results based on a population of 392 cases. Dr Elizabeth T. Jensen, MPH, PhD, from the Department of Epidemiology & Prevention at Wake Forest University School of Medicine, Winston-Salem, North Carolina, conducted a comprehensive study spanning the last 20 years to decipher potential causes contributing to the rising incidence of EoE.

Dr Jensen and her colleagues evaluated the association between maternal and infant use of antibiotics and acid suppressants in Denmark. They used pathology, prescription, birth, inpatient, and outpatient health registry data, ensuring complete ascertainment of all EoE cases among Danish residents born between 1997 and 2018. The research obtained a census of cases from a registered sample of approximately 1.4 million children, matching EoE cases to controls using a 1:10 ratio through incidence density sampling. A total of 392 patients with EoE and 3637 control patients were enrolled. The primary outcome of the study focused on the development of EoE, revealing a dose-response association between maternal and infant antibiotic and acid suppressant use and increased EoE risk.

This study demonstrated a robust correlation between the dosage of antibiotics and acid suppressants and the development of EoE in offspring during childhood. These findings hold significance because these medications represent some of the most common prescriptions in clinical practice. Pregnancy triggers significant physiologic changes in women, including increased hormonal effects and abdominal pressure on the lower esophageal sphincter, making pregnant individuals more prone to esophageal reflux and necessitating the use of gastric acid suppressants. As clinicians, it's crucial to consider lifestyle modifications and dietary adjustments before resorting to acid suppressants, reserving their use for only when absolutely necessary.

Postpregnancy, emphasizing exclusive breastfeeding for the first 6 months and proper feeding techniques can aid in reducing the likelihood of reflux disease in newborns. Acid suppressants have been linked to alterations in infant microbiome colonization, potentially increasing the susceptibility to immunoreactive diseases, such as asthma, atopic dermatitis, and allergic rhinitis. Given that exclusive breastfeeding in the initial 6 months has demonstrated preventive benefits against such diseases, primary physicians play a crucial role in advocating its importance. Although gastric acid suppressants and antibiotics are essential for managing various health conditions, including infections and gastroesophageal reflux disease (GERD), their potential impact on EoE development should not be overlooked.

Though this study had a relatively small sample size, the strong population registry of Denmark significantly reduced recall bias. However, cultural differences and over-the-counter access to drugs, such as acid suppressants, in other countries, including the United States, warrant further research to ascertain their effect on EoE development.

In light of these findings, clinicians should carefully weigh the risks and benefits of prescribing antibiotics and acid suppressants during pregnancy and infancy. Adherence to evidence-based guidelines and considering alternative treatment options, such as lifestyle modifications, should be prioritized. Prescribing antibiotics only when medically necessary and using nonpharmacologic strategies for managing GERD in infants should be considered to mitigate potential risks associated with these medications.

To the Editor:

Biologic medications are increasingly utilized in adults with moderate to severe atopic dermatitis (AD) that is inadequately controlled with topical medication. By targeting the IL-4 receptor alpha subunit, dupilumab inhibits the biologic effects of IL-4 and IL-13, resulting in remarkable improvement in disease and quality of life for many patients with refractory AD.¹

In 2017, the US Food and Drug Administration approved dupilumab for use in AD, asthma, and chronic rhinosinusitis. However, there is evidence of the drug’s off-label efficacy in conditions such as eosinophilic annular erythema.² We present a patient with dyshidrotic eczema treated with dupilumab who experienced contemporaneous secondary improvement in chronic eosinophilic pneumonia (CEP) and interstitial lung disease (ILD).

A 45-year-old man was referred to our dermatology clinic for chronic hand dermatitis refractory to increasing strengths of topical corticosteroids. He had a history of progressive shortness of breath of unknown cause, which began 2 years prior, and he was being followed at our institution’s ILD clinic. Earlier pulmonary function testing revealed a restrictive pattern with interstitial infiltrates seen on chest computed tomography. A lung biopsy demonstrated features of fibrotic nonspecific interstitial pneumonitis with superimposed eosinophilic pneumonia. His pulmonary symptoms had progressively worsened; over a period of several months, the supplemental oxygen requirement had increased to 6 L at rest and 12 L upon exertion. Prednisone therapy was initiated, which alleviated respiratory symptoms; however, the patient was unable to tolerate a gradual wean of the medication, which rendered him steroid dependent at 30 mg/d.

Along with respiratory symptoms, the patient reported symptoms consistent with an autoimmune process, including dry eyes. Muscle weakness and tenderness also were noted. Ultimately, a diagnosis of anti–PL-7 (anti-threonyl-transfer RNA synthetase) antisynthetase syndrome was rendered by identification of anti–PL-7 antibodies and an elevated level of creatinine kinase.

Physical examination at our clinic revealed subtle palmar scaling on the hands and multiple small clear vesicles on the lateral aspects of the digits (Figure, A), consistent with dyshidrotic eczema. He initially was treated with clobetasol propionate ointment 0.05%. Despite adherence to this high-potency topical corticosteroid, he experienced only minimal improvement over a period of 3 months. Dupilumab was started at standard dosing—600 mg at initiation, followed by 300 mg every 2 weeks. The patient reported rapid improvement in dyshidrotic eczema over several months with near-complete resolution (Figure, B).

Concurrent with initiation and continued use of dupilumab, without other changes in his medication regimen, the patient noted gradual improvement in respiratory symptoms. At 6-month follow-up he reported notable improvement in respiratory function and quality of life. He then tolerated a gradual wean of prednisone to 10 mg/d, with a similar reduction in supplemental oxygen.

Off-label use of dupilumab for various eosinophilic conditions has shown promising efficacy. Our patient experienced improvement in CEP shortly after initiation of dupilumab, enabling weaning of prednisone, which has a well established adverse effect profile associated with long term use.^3,4 In comparison, dupilumab generally is well tolerated, with rare ophthalmologic complications and injection-site reactions.⁵

One case report suggested that CEP may represent a potential rare adverse effect of dupilumab initiation.⁶ However, prior to initiation of dupilumab, that patient had poorly controlled asthma requiring frequent oral corticosteroid therapy. It is possible that CEP was subclinical prior to initiation of dupilumab and became more noticeable once the patient was weaned from corticosteroids, which had served as an indirect treatment.⁶ Nonetheless, more research is needed to definitively establish the efficacy of dupilumab in CEP prior to more widespread use.

Irrespective of the potential efficacy of dupilumab for the treatment of CEP, our case highlights the growing body of evidence that dupilumab should be considered in the treatment of dyshidrotic eczema, particularly in cases refractory to topical treatment.⁷ When a systemic medication is preferred, dupilumab likely represents an option with a relatively well-tolerated adverse effect profile compared to traditional systemic treatments for dyshidrotic eczema.

To the Editor:

Biologic medications are increasingly utilized in adults with moderate to severe atopic dermatitis (AD) that is inadequately controlled with topical medication. By targeting the IL-4 receptor alpha subunit, dupilumab inhibits the biologic effects of IL-4 and IL-13, resulting in remarkable improvement in disease and quality of life for many patients with refractory AD.¹

In 2017, the US Food and Drug Administration approved dupilumab for use in AD, asthma, and chronic rhinosinusitis. However, there is evidence of the drug’s off-label efficacy in conditions such as eosinophilic annular erythema.² We present a patient with dyshidrotic eczema treated with dupilumab who experienced contemporaneous secondary improvement in chronic eosinophilic pneumonia (CEP) and interstitial lung disease (ILD).

A 45-year-old man was referred to our dermatology clinic for chronic hand dermatitis refractory to increasing strengths of topical corticosteroids. He had a history of progressive shortness of breath of unknown cause, which began 2 years prior, and he was being followed at our institution’s ILD clinic. Earlier pulmonary function testing revealed a restrictive pattern with interstitial infiltrates seen on chest computed tomography. A lung biopsy demonstrated features of fibrotic nonspecific interstitial pneumonitis with superimposed eosinophilic pneumonia. His pulmonary symptoms had progressively worsened; over a period of several months, the supplemental oxygen requirement had increased to 6 L at rest and 12 L upon exertion. Prednisone therapy was initiated, which alleviated respiratory symptoms; however, the patient was unable to tolerate a gradual wean of the medication, which rendered him steroid dependent at 30 mg/d.

Along with respiratory symptoms, the patient reported symptoms consistent with an autoimmune process, including dry eyes. Muscle weakness and tenderness also were noted. Ultimately, a diagnosis of anti–PL-7 (anti-threonyl-transfer RNA synthetase) antisynthetase syndrome was rendered by identification of anti–PL-7 antibodies and an elevated level of creatinine kinase.

Physical examination at our clinic revealed subtle palmar scaling on the hands and multiple small clear vesicles on the lateral aspects of the digits (Figure, A), consistent with dyshidrotic eczema. He initially was treated with clobetasol propionate ointment 0.05%. Despite adherence to this high-potency topical corticosteroid, he experienced only minimal improvement over a period of 3 months. Dupilumab was started at standard dosing—600 mg at initiation, followed by 300 mg every 2 weeks. The patient reported rapid improvement in dyshidrotic eczema over several months with near-complete resolution (Figure, B).

Concurrent with initiation and continued use of dupilumab, without other changes in his medication regimen, the patient noted gradual improvement in respiratory symptoms. At 6-month follow-up he reported notable improvement in respiratory function and quality of life. He then tolerated a gradual wean of prednisone to 10 mg/d, with a similar reduction in supplemental oxygen.

Off-label use of dupilumab for various eosinophilic conditions has shown promising efficacy. Our patient experienced improvement in CEP shortly after initiation of dupilumab, enabling weaning of prednisone, which has a well established adverse effect profile associated with long term use.^3,4 In comparison, dupilumab generally is well tolerated, with rare ophthalmologic complications and injection-site reactions.⁵

One case report suggested that CEP may represent a potential rare adverse effect of dupilumab initiation.⁶ However, prior to initiation of dupilumab, that patient had poorly controlled asthma requiring frequent oral corticosteroid therapy. It is possible that CEP was subclinical prior to initiation of dupilumab and became more noticeable once the patient was weaned from corticosteroids, which had served as an indirect treatment.⁶ Nonetheless, more research is needed to definitively establish the efficacy of dupilumab in CEP prior to more widespread use.

Irrespective of the potential efficacy of dupilumab for the treatment of CEP, our case highlights the growing body of evidence that dupilumab should be considered in the treatment of dyshidrotic eczema, particularly in cases refractory to topical treatment.⁷ When a systemic medication is preferred, dupilumab likely represents an option with a relatively well-tolerated adverse effect profile compared to traditional systemic treatments for dyshidrotic eczema.

To the Editor:

Biologic medications are increasingly utilized in adults with moderate to severe atopic dermatitis (AD) that is inadequately controlled with topical medication. By targeting the IL-4 receptor alpha subunit, dupilumab inhibits the biologic effects of IL-4 and IL-13, resulting in remarkable improvement in disease and quality of life for many patients with refractory AD.¹

In 2017, the US Food and Drug Administration approved dupilumab for use in AD, asthma, and chronic rhinosinusitis. However, there is evidence of the drug’s off-label efficacy in conditions such as eosinophilic annular erythema.² We present a patient with dyshidrotic eczema treated with dupilumab who experienced contemporaneous secondary improvement in chronic eosinophilic pneumonia (CEP) and interstitial lung disease (ILD).

A 45-year-old man was referred to our dermatology clinic for chronic hand dermatitis refractory to increasing strengths of topical corticosteroids. He had a history of progressive shortness of breath of unknown cause, which began 2 years prior, and he was being followed at our institution’s ILD clinic. Earlier pulmonary function testing revealed a restrictive pattern with interstitial infiltrates seen on chest computed tomography. A lung biopsy demonstrated features of fibrotic nonspecific interstitial pneumonitis with superimposed eosinophilic pneumonia. His pulmonary symptoms had progressively worsened; over a period of several months, the supplemental oxygen requirement had increased to 6 L at rest and 12 L upon exertion. Prednisone therapy was initiated, which alleviated respiratory symptoms; however, the patient was unable to tolerate a gradual wean of the medication, which rendered him steroid dependent at 30 mg/d.

Along with respiratory symptoms, the patient reported symptoms consistent with an autoimmune process, including dry eyes. Muscle weakness and tenderness also were noted. Ultimately, a diagnosis of anti–PL-7 (anti-threonyl-transfer RNA synthetase) antisynthetase syndrome was rendered by identification of anti–PL-7 antibodies and an elevated level of creatinine kinase.

Physical examination at our clinic revealed subtle palmar scaling on the hands and multiple small clear vesicles on the lateral aspects of the digits (Figure, A), consistent with dyshidrotic eczema. He initially was treated with clobetasol propionate ointment 0.05%. Despite adherence to this high-potency topical corticosteroid, he experienced only minimal improvement over a period of 3 months. Dupilumab was started at standard dosing—600 mg at initiation, followed by 300 mg every 2 weeks. The patient reported rapid improvement in dyshidrotic eczema over several months with near-complete resolution (Figure, B).

Concurrent with initiation and continued use of dupilumab, without other changes in his medication regimen, the patient noted gradual improvement in respiratory symptoms. At 6-month follow-up he reported notable improvement in respiratory function and quality of life. He then tolerated a gradual wean of prednisone to 10 mg/d, with a similar reduction in supplemental oxygen.

Off-label use of dupilumab for various eosinophilic conditions has shown promising efficacy. Our patient experienced improvement in CEP shortly after initiation of dupilumab, enabling weaning of prednisone, which has a well established adverse effect profile associated with long term use.^3,4 In comparison, dupilumab generally is well tolerated, with rare ophthalmologic complications and injection-site reactions.⁵

One case report suggested that CEP may represent a potential rare adverse effect of dupilumab initiation.⁶ However, prior to initiation of dupilumab, that patient had poorly controlled asthma requiring frequent oral corticosteroid therapy. It is possible that CEP was subclinical prior to initiation of dupilumab and became more noticeable once the patient was weaned from corticosteroids, which had served as an indirect treatment.⁶ Nonetheless, more research is needed to definitively establish the efficacy of dupilumab in CEP prior to more widespread use.

Irrespective of the potential efficacy of dupilumab for the treatment of CEP, our case highlights the growing body of evidence that dupilumab should be considered in the treatment of dyshidrotic eczema, particularly in cases refractory to topical treatment.⁷ When a systemic medication is preferred, dupilumab likely represents an option with a relatively well-tolerated adverse effect profile compared to traditional systemic treatments for dyshidrotic eczema.

BACKGROUND

In 2017, the Thoracic Tumor Board realized that there were patients whose lung resections had critical review of the slides and reports prior to presentation. Errors were found which resulted in a change of the pathology Tumor Nodal Metastases (pTNM) staging for the patient. The impacts were important for determining appropriate therapy. It was decided to systematically review all lung cancer resections for accuracy before determining definitive therapy recommendations.

METHODS

All lung resections for malignancy were examined prior and up to 2 days of completion for accuracy of tumor type, tumor size, tumor grade, lymph node metastases and pathologic stage (pTNM). Any errors found were given to the original pathologist for a change in the report before release or for a modified report to be issued.

RESULTS

From June 2017 to December 2020, there were 91 lung resections with 28 (30.77%) errors. Errors included: 16 incorrect pathologic staging, 5 missed tumors in lung and lymph nodes, 2 unexamined stapled surgical margins, 1 wrong site, 1 incorrect lymph node number and 2 missed tumor vascular invasion.

IMPLICATIONS

Quality improvement (QI) review of lung resections by a second pathologist is important and may clearly improve pathologic staging for lung cancer patients. It can be added to QI programs currently used in Surgical Pathology. It is important in directing appropriate postsurgical therapies.

BACKGROUND

In 2017, the Thoracic Tumor Board realized that there were patients whose lung resections had critical review of the slides and reports prior to presentation. Errors were found which resulted in a change of the pathology Tumor Nodal Metastases (pTNM) staging for the patient. The impacts were important for determining appropriate therapy. It was decided to systematically review all lung cancer resections for accuracy before determining definitive therapy recommendations.

METHODS

All lung resections for malignancy were examined prior and up to 2 days of completion for accuracy of tumor type, tumor size, tumor grade, lymph node metastases and pathologic stage (pTNM). Any errors found were given to the original pathologist for a change in the report before release or for a modified report to be issued.

RESULTS

From June 2017 to December 2020, there were 91 lung resections with 28 (30.77%) errors. Errors included: 16 incorrect pathologic staging, 5 missed tumors in lung and lymph nodes, 2 unexamined stapled surgical margins, 1 wrong site, 1 incorrect lymph node number and 2 missed tumor vascular invasion.

IMPLICATIONS

Quality improvement (QI) review of lung resections by a second pathologist is important and may clearly improve pathologic staging for lung cancer patients. It can be added to QI programs currently used in Surgical Pathology. It is important in directing appropriate postsurgical therapies.

BACKGROUND

In 2017, the Thoracic Tumor Board realized that there were patients whose lung resections had critical review of the slides and reports prior to presentation. Errors were found which resulted in a change of the pathology Tumor Nodal Metastases (pTNM) staging for the patient. The impacts were important for determining appropriate therapy. It was decided to systematically review all lung cancer resections for accuracy before determining definitive therapy recommendations.

METHODS

All lung resections for malignancy were examined prior and up to 2 days of completion for accuracy of tumor type, tumor size, tumor grade, lymph node metastases and pathologic stage (pTNM). Any errors found were given to the original pathologist for a change in the report before release or for a modified report to be issued.

RESULTS

From June 2017 to December 2020, there were 91 lung resections with 28 (30.77%) errors. Errors included: 16 incorrect pathologic staging, 5 missed tumors in lung and lymph nodes, 2 unexamined stapled surgical margins, 1 wrong site, 1 incorrect lymph node number and 2 missed tumor vascular invasion.

IMPLICATIONS

Quality improvement (QI) review of lung resections by a second pathologist is important and may clearly improve pathologic staging for lung cancer patients. It can be added to QI programs currently used in Surgical Pathology. It is important in directing appropriate postsurgical therapies.

INTRODUCTION

Leptomeningeal metastasis (LM) is an extremely rare complication of gastroesophageal (GE) cancer. Diagnosis is challenging due to frequently nonspecific clinical presentations, limited sensitivity of diagnostic testing, and potential overlap with neurologic immune-related adverse events (irAE). We describe a case of metastatic gastroesophageal cancer on immunotherapy presenting with LM masquerading as polyneuropathy.

CASE REPORT

A 74-year-old male with HER2+ GE junction cancer with peritoneal metastases diagnosed 6 months ago, on maintenance trastuzumab/pembrolizumab and with no previous history of cranial or spinal disease, presented with worsening ataxia, headache, and diplopia for one month with multiple negative outpatient MRIs. Examination showed left abducens nerve palsy, dysmetria and absent deep tendon reflexes in upper and lower extremities. CT head was unremarkable, and MRI showed non-specific mild enhancement of the right optic nerve, symmetrical lumbosacral nerve roots and cauda equina concerning for paraneoplastic versus immunotherapy-related polyneuropathy. He was started on empiric high-dose corticosteroids. PET-CT was negative for FDG-avid lesions. Cerebrospinal fluid (CSF) analysis revealed moderate pleocytosis with many large atypical cells, elevated protein (118 mg/dL) and LDH (28 IU/L). Immunohistochemistry was positive for CDX2, CA 19-9, CK7, and pankeratin, consistent with metastatic adenocarcinoma, negative for HER2 in contrast to the original tumor. He subsequently developed hydrocephalus requiring a ventriculoperitoneal shunt. He received ten fractions of whole brain irradiation before electing to pursue hospice care.

DISCUSSION

LM is an extremely rare complication of GE cancer with an incidence of <0.2% and carries a poor prognosis. Differentiation between LM and irAE in patients on immunotherapy can be challenging. Diagnosis relies mostly on CSF cytology, and lumbar puncture should not be delayed in patients with new neurologic symptoms. Treatment options are intrathecal chemotherapy, radiation and steroids. A recent phase II trial has shown promise for intrathecal trastuzumab in patients with HER2+ cancers, but options for HER2 negative disease remain mostly palliative.

CONCLUSIONS

Our case highlights the need for suspecting this rare metastatic site, as early diagnosis and genetic characterization allow for exploring more treatment options including targeted therapies which may improve overall survival and quality of life.

INTRODUCTION

Leptomeningeal metastasis (LM) is an extremely rare complication of gastroesophageal (GE) cancer. Diagnosis is challenging due to frequently nonspecific clinical presentations, limited sensitivity of diagnostic testing, and potential overlap with neurologic immune-related adverse events (irAE). We describe a case of metastatic gastroesophageal cancer on immunotherapy presenting with LM masquerading as polyneuropathy.

CASE REPORT

A 74-year-old male with HER2+ GE junction cancer with peritoneal metastases diagnosed 6 months ago, on maintenance trastuzumab/pembrolizumab and with no previous history of cranial or spinal disease, presented with worsening ataxia, headache, and diplopia for one month with multiple negative outpatient MRIs. Examination showed left abducens nerve palsy, dysmetria and absent deep tendon reflexes in upper and lower extremities. CT head was unremarkable, and MRI showed non-specific mild enhancement of the right optic nerve, symmetrical lumbosacral nerve roots and cauda equina concerning for paraneoplastic versus immunotherapy-related polyneuropathy. He was started on empiric high-dose corticosteroids. PET-CT was negative for FDG-avid lesions. Cerebrospinal fluid (CSF) analysis revealed moderate pleocytosis with many large atypical cells, elevated protein (118 mg/dL) and LDH (28 IU/L). Immunohistochemistry was positive for CDX2, CA 19-9, CK7, and pankeratin, consistent with metastatic adenocarcinoma, negative for HER2 in contrast to the original tumor. He subsequently developed hydrocephalus requiring a ventriculoperitoneal shunt. He received ten fractions of whole brain irradiation before electing to pursue hospice care.

DISCUSSION

LM is an extremely rare complication of GE cancer with an incidence of <0.2% and carries a poor prognosis. Differentiation between LM and irAE in patients on immunotherapy can be challenging. Diagnosis relies mostly on CSF cytology, and lumbar puncture should not be delayed in patients with new neurologic symptoms. Treatment options are intrathecal chemotherapy, radiation and steroids. A recent phase II trial has shown promise for intrathecal trastuzumab in patients with HER2+ cancers, but options for HER2 negative disease remain mostly palliative.

CONCLUSIONS

Our case highlights the need for suspecting this rare metastatic site, as early diagnosis and genetic characterization allow for exploring more treatment options including targeted therapies which may improve overall survival and quality of life.

INTRODUCTION

Leptomeningeal metastasis (LM) is an extremely rare complication of gastroesophageal (GE) cancer. Diagnosis is challenging due to frequently nonspecific clinical presentations, limited sensitivity of diagnostic testing, and potential overlap with neurologic immune-related adverse events (irAE). We describe a case of metastatic gastroesophageal cancer on immunotherapy presenting with LM masquerading as polyneuropathy.

CASE REPORT

A 74-year-old male with HER2+ GE junction cancer with peritoneal metastases diagnosed 6 months ago, on maintenance trastuzumab/pembrolizumab and with no previous history of cranial or spinal disease, presented with worsening ataxia, headache, and diplopia for one month with multiple negative outpatient MRIs. Examination showed left abducens nerve palsy, dysmetria and absent deep tendon reflexes in upper and lower extremities. CT head was unremarkable, and MRI showed non-specific mild enhancement of the right optic nerve, symmetrical lumbosacral nerve roots and cauda equina concerning for paraneoplastic versus immunotherapy-related polyneuropathy. He was started on empiric high-dose corticosteroids. PET-CT was negative for FDG-avid lesions. Cerebrospinal fluid (CSF) analysis revealed moderate pleocytosis with many large atypical cells, elevated protein (118 mg/dL) and LDH (28 IU/L). Immunohistochemistry was positive for CDX2, CA 19-9, CK7, and pankeratin, consistent with metastatic adenocarcinoma, negative for HER2 in contrast to the original tumor. He subsequently developed hydrocephalus requiring a ventriculoperitoneal shunt. He received ten fractions of whole brain irradiation before electing to pursue hospice care.

DISCUSSION

LM is an extremely rare complication of GE cancer with an incidence of <0.2% and carries a poor prognosis. Differentiation between LM and irAE in patients on immunotherapy can be challenging. Diagnosis relies mostly on CSF cytology, and lumbar puncture should not be delayed in patients with new neurologic symptoms. Treatment options are intrathecal chemotherapy, radiation and steroids. A recent phase II trial has shown promise for intrathecal trastuzumab in patients with HER2+ cancers, but options for HER2 negative disease remain mostly palliative.

CONCLUSIONS

Our case highlights the need for suspecting this rare metastatic site, as early diagnosis and genetic characterization allow for exploring more treatment options including targeted therapies which may improve overall survival and quality of life.

Janus kinase inhibitors (JAKi) are a novel class of oral, targeted small-molecule inhibitors that are increasingly used to treat several different autoimmune conditions. In terms of rheumatologic indications, the FDA first approved tofacitinib (TOF) for use in moderate to severe rheumatoid arthritis (RA) unresponsive to methotrexate therapy. Eleven years later, the indications for JAKi use have expanded to include ulcerative colitis, ankylosing spondylitis, and psoriatic arthritis (PsA), among other diseases. As with any new therapeutic mechanism, there are questions as to how JAKi should be incorporated into the treatment paradigm of PsA. In this article, we briefly review the efficacy and safety data of these agents and discuss our approach to their use in PsA.

Two JAKi are currently FDA approved for the treatment of PsA: tofacitinib (TOF) and upadacitinib (UPA). Other JAKi, such as filgotinib and peficitinib, are only approved outside the United States and will not be discussed here. 

TOF was originally studied in skin psoriasis (PsO) before 2 pivotal studies demonstrated efficacy in PsA. TOF or adalimumab (ADA) were compared with placebo in patients who had failed conventional synthetic disease-modifying antirheumatic drugs (DMARD).¹ ACR20 response was superior with TOF 5 mg twice daily (BID) (50%) and 10 mg BID (61%) vs placebo (33%), and it was comparable to ADA (52%), which was used in this study as an active comparator. The overall rate of adverse events was similar with both doses of TOF when compared with ADA; however, patients taking TOF had numerically more cases of cancer, serious infection, and herpes zoster. 

Another study evaluated TOF compared with placebo in patients with PsA who had an inadequate response to tumor necrosis factor inhibitor (TNFi) therapy.² The study showed an ACR20 response of 50% in patients taking TOF 5 mg BID and 47% in patients taking 10 mg BID, compared with 24% in those taking placebo. Patients who received the 10 mg TOF dose continuously had higher rates of adverse events compared to TOF 5 mg, placebo, and patients who crossed over from placebo to TOF at either dose. In the TOF groups, there were cases of serious infection and herpes zoster, as well as 2 patients with major adverse cardiovascular events (MACE). Following review of these data, the FDA approved only the 5 mg BID dose, and later an 11-mg daily extended-release formulation that was pharmacokinetically similar.

The efficacy for UPA in PsA was shown in 2 pivotal phase 3 trials. SELECT-PsA1 compared UPA at 2 doses, 15 mg and 30 mg daily, vs placebo and vs ADA in patients with biologic DMARD (bDMARD)-naïve PsA.³ This trial demonstrated superiority of UPA in the ACR20 response at both doses (71% and 79%, respectively) compared with placebo (36%). The 15-mg dose of UPA was comparable to ADA (65%), while the 30-mg dose achieved superiority compared to ADA. Secondary outcomes including skin activity, patient-reported symptoms, and inhibition of radiographic progression were also superior in UPA compared with placebo and similar or greater with UPA compared with ADA, depending on the specific outcome.⁴ SELECT-PsA2 compared UPA 15 mg, 30 mg, and placebo in patients with prior incomplete response or intolerance to a bDMARD.⁵ At week 12 of the study, patients taking UPA 15 mg and 30 mg had an ACR20 response of 57% and 64%, respectively, compared with placebo (24%). At week 24, minimal disease activity was achieved by 25% of patients taking UPA 15 mg and 29% of patients taking UPA 30 mg, which was superior to placebo (3%). 

Both studies found a significant increase in infections, including serious infections, at the 30-mg UPA dose compared with the placebo and adalimumab groups. Cytopenia and elevated creatine kinase (CK) level also occurred more frequently in the UPA 30-mg group. Rates of cancer were low overall and comparable between the patients treated with UPA and ADA. Given the higher incidence of adverse events with the 30-mg dose and the relatively similar efficacy, the sponsor elected to submit only the lower dose to the FDA for approval.

In the last few years, concerns for safety with JAKi use grew after the publication of data from the ORAL SURVEILLANCE trial, an FDA-mandated, post-approval safety study of TOF in RA. In this trial, patients with active RA over 50 years of age and with at least 1 additional cardiovascular risk factor were randomized to TOF at 1 of 2 doses, 5 mg or 10 mg BID, or a TNFi.⁶ This trial was designed as a noninferiority study, and TOF did not meet the noninferiority threshold compared to TNFi, with hazard ratios of 1.33 and 1.48 for MACE and malignancy, respectively. The results of this trial prompted the FDA to add a black box warning to the label for all JAKi, pointing out the risk of malignancy and MACE, as well as infection, mortality, and thrombosis. 

In the ORAL SURVEILLANCE trial, the increased risk of MACE and malignancy was primarily seen in the study patients with high risk for a cardiovascular event. To address the question of whether a similar risk profile exists when using JAKi to treat PsA, or whether this is a disease-specific process related to RA, a post hoc analysis of 3 PsA trials and 7 PsO trials of patients treated with TOF was conducted.⁷ The analysis found that patients with a history of atherosclerotic cardiovascular disease (ASCVD) or metabolic syndrome, or patients at high risk for ASCVD (score > 20%) had increased incidence rates of MACE compared with those with low risk scores for ASCVD. Interestingly, as in RA, increased incidence rates of malignancy were seen in patients with preexisting or at high risk for ASCVD.

While the FDA recommends JAKi use in patients who have failed or are inappropriate for treatment with a TNFi, we would consider the use of JAKi for first-line therapy in PsA on an individual basis. One advantage of JAKi is their efficacy across multiple PsA domains, including peripheral arthritis, axial disease, enthesitis, dactylitis, and skin disease (although the approved dose of TOF was not statistically effective for PsO in the pivotal trials). Based on this efficacy, we believe that patients with overlapping, multifaceted disease may benefit the most from these medications. Patient risk factors and comorbidities are a prominent consideration in our use of JAKi to ensure safety, as the risk for MACE and malignancy is informed partly by baseline cardiovascular status. In younger patients without cardiovascular risk factors, JAKi may be a strong candidate for first-line therapy, particularly in patients averse to subcutaneous or intravenous therapy. We do counsel all patients on the increased risk of infection, and we do recommend inactivated herpes zoster vaccination in previously unvaccinated patients planning to start JAKi therapy. 

On the horizon are the development of novel, oral agents targeting tyrosine kinase 2 (TYK2), which is a member of the JAK family of signaling proteins. In fact, the TYK2 inhibitor deucravacitinib was approved by the FDA in 2022 for the treatment of PsO. TYK2 inhibitors appear to have the advantage of a more selective mechanism of action, with fewer off-target effects. There were fewer adverse events in the deucravacitinib trials, which led to its prompt PsO authorization, and the FDA approval for the drug did not include the same black box warning that appears in the label for other JAKi.⁸ A phase 2 study showed early promise for the efficacy and safety of deucravacitinib in PsA.⁹ Further investigation will be needed to better understand the role of deucravacitinib and other TYK2 inhibitors being developed for the treatment of PsA. In the meantime, JAKi continue to be a prominent consideration for first-line PsA therapy in a carefully selected patient population. 

Janus kinase inhibitors (JAKi) are a novel class of oral, targeted small-molecule inhibitors that are increasingly used to treat several different autoimmune conditions. In terms of rheumatologic indications, the FDA first approved tofacitinib (TOF) for use in moderate to severe rheumatoid arthritis (RA) unresponsive to methotrexate therapy. Eleven years later, the indications for JAKi use have expanded to include ulcerative colitis, ankylosing spondylitis, and psoriatic arthritis (PsA), among other diseases. As with any new therapeutic mechanism, there are questions as to how JAKi should be incorporated into the treatment paradigm of PsA. In this article, we briefly review the efficacy and safety data of these agents and discuss our approach to their use in PsA.

Two JAKi are currently FDA approved for the treatment of PsA: tofacitinib (TOF) and upadacitinib (UPA). Other JAKi, such as filgotinib and peficitinib, are only approved outside the United States and will not be discussed here. 

TOF was originally studied in skin psoriasis (PsO) before 2 pivotal studies demonstrated efficacy in PsA. TOF or adalimumab (ADA) were compared with placebo in patients who had failed conventional synthetic disease-modifying antirheumatic drugs (DMARD).¹ ACR20 response was superior with TOF 5 mg twice daily (BID) (50%) and 10 mg BID (61%) vs placebo (33%), and it was comparable to ADA (52%), which was used in this study as an active comparator. The overall rate of adverse events was similar with both doses of TOF when compared with ADA; however, patients taking TOF had numerically more cases of cancer, serious infection, and herpes zoster. 

Another study evaluated TOF compared with placebo in patients with PsA who had an inadequate response to tumor necrosis factor inhibitor (TNFi) therapy.² The study showed an ACR20 response of 50% in patients taking TOF 5 mg BID and 47% in patients taking 10 mg BID, compared with 24% in those taking placebo. Patients who received the 10 mg TOF dose continuously had higher rates of adverse events compared to TOF 5 mg, placebo, and patients who crossed over from placebo to TOF at either dose. In the TOF groups, there were cases of serious infection and herpes zoster, as well as 2 patients with major adverse cardiovascular events (MACE). Following review of these data, the FDA approved only the 5 mg BID dose, and later an 11-mg daily extended-release formulation that was pharmacokinetically similar.

The efficacy for UPA in PsA was shown in 2 pivotal phase 3 trials. SELECT-PsA1 compared UPA at 2 doses, 15 mg and 30 mg daily, vs placebo and vs ADA in patients with biologic DMARD (bDMARD)-naïve PsA.³ This trial demonstrated superiority of UPA in the ACR20 response at both doses (71% and 79%, respectively) compared with placebo (36%). The 15-mg dose of UPA was comparable to ADA (65%), while the 30-mg dose achieved superiority compared to ADA. Secondary outcomes including skin activity, patient-reported symptoms, and inhibition of radiographic progression were also superior in UPA compared with placebo and similar or greater with UPA compared with ADA, depending on the specific outcome.⁴ SELECT-PsA2 compared UPA 15 mg, 30 mg, and placebo in patients with prior incomplete response or intolerance to a bDMARD.⁵ At week 12 of the study, patients taking UPA 15 mg and 30 mg had an ACR20 response of 57% and 64%, respectively, compared with placebo (24%). At week 24, minimal disease activity was achieved by 25% of patients taking UPA 15 mg and 29% of patients taking UPA 30 mg, which was superior to placebo (3%). 

Both studies found a significant increase in infections, including serious infections, at the 30-mg UPA dose compared with the placebo and adalimumab groups. Cytopenia and elevated creatine kinase (CK) level also occurred more frequently in the UPA 30-mg group. Rates of cancer were low overall and comparable between the patients treated with UPA and ADA. Given the higher incidence of adverse events with the 30-mg dose and the relatively similar efficacy, the sponsor elected to submit only the lower dose to the FDA for approval.

In the last few years, concerns for safety with JAKi use grew after the publication of data from the ORAL SURVEILLANCE trial, an FDA-mandated, post-approval safety study of TOF in RA. In this trial, patients with active RA over 50 years of age and with at least 1 additional cardiovascular risk factor were randomized to TOF at 1 of 2 doses, 5 mg or 10 mg BID, or a TNFi.⁶ This trial was designed as a noninferiority study, and TOF did not meet the noninferiority threshold compared to TNFi, with hazard ratios of 1.33 and 1.48 for MACE and malignancy, respectively. The results of this trial prompted the FDA to add a black box warning to the label for all JAKi, pointing out the risk of malignancy and MACE, as well as infection, mortality, and thrombosis. 

In the ORAL SURVEILLANCE trial, the increased risk of MACE and malignancy was primarily seen in the study patients with high risk for a cardiovascular event. To address the question of whether a similar risk profile exists when using JAKi to treat PsA, or whether this is a disease-specific process related to RA, a post hoc analysis of 3 PsA trials and 7 PsO trials of patients treated with TOF was conducted.⁷ The analysis found that patients with a history of atherosclerotic cardiovascular disease (ASCVD) or metabolic syndrome, or patients at high risk for ASCVD (score > 20%) had increased incidence rates of MACE compared with those with low risk scores for ASCVD. Interestingly, as in RA, increased incidence rates of malignancy were seen in patients with preexisting or at high risk for ASCVD.

While the FDA recommends JAKi use in patients who have failed or are inappropriate for treatment with a TNFi, we would consider the use of JAKi for first-line therapy in PsA on an individual basis. One advantage of JAKi is their efficacy across multiple PsA domains, including peripheral arthritis, axial disease, enthesitis, dactylitis, and skin disease (although the approved dose of TOF was not statistically effective for PsO in the pivotal trials). Based on this efficacy, we believe that patients with overlapping, multifaceted disease may benefit the most from these medications. Patient risk factors and comorbidities are a prominent consideration in our use of JAKi to ensure safety, as the risk for MACE and malignancy is informed partly by baseline cardiovascular status. In younger patients without cardiovascular risk factors, JAKi may be a strong candidate for first-line therapy, particularly in patients averse to subcutaneous or intravenous therapy. We do counsel all patients on the increased risk of infection, and we do recommend inactivated herpes zoster vaccination in previously unvaccinated patients planning to start JAKi therapy. 

On the horizon are the development of novel, oral agents targeting tyrosine kinase 2 (TYK2), which is a member of the JAK family of signaling proteins. In fact, the TYK2 inhibitor deucravacitinib was approved by the FDA in 2022 for the treatment of PsO. TYK2 inhibitors appear to have the advantage of a more selective mechanism of action, with fewer off-target effects. There were fewer adverse events in the deucravacitinib trials, which led to its prompt PsO authorization, and the FDA approval for the drug did not include the same black box warning that appears in the label for other JAKi.⁸ A phase 2 study showed early promise for the efficacy and safety of deucravacitinib in PsA.⁹ Further investigation will be needed to better understand the role of deucravacitinib and other TYK2 inhibitors being developed for the treatment of PsA. In the meantime, JAKi continue to be a prominent consideration for first-line PsA therapy in a carefully selected patient population. 

Janus kinase inhibitors (JAKi) are a novel class of oral, targeted small-molecule inhibitors that are increasingly used to treat several different autoimmune conditions. In terms of rheumatologic indications, the FDA first approved tofacitinib (TOF) for use in moderate to severe rheumatoid arthritis (RA) unresponsive to methotrexate therapy. Eleven years later, the indications for JAKi use have expanded to include ulcerative colitis, ankylosing spondylitis, and psoriatic arthritis (PsA), among other diseases. As with any new therapeutic mechanism, there are questions as to how JAKi should be incorporated into the treatment paradigm of PsA. In this article, we briefly review the efficacy and safety data of these agents and discuss our approach to their use in PsA.

Two JAKi are currently FDA approved for the treatment of PsA: tofacitinib (TOF) and upadacitinib (UPA). Other JAKi, such as filgotinib and peficitinib, are only approved outside the United States and will not be discussed here. 

TOF was originally studied in skin psoriasis (PsO) before 2 pivotal studies demonstrated efficacy in PsA. TOF or adalimumab (ADA) were compared with placebo in patients who had failed conventional synthetic disease-modifying antirheumatic drugs (DMARD).¹ ACR20 response was superior with TOF 5 mg twice daily (BID) (50%) and 10 mg BID (61%) vs placebo (33%), and it was comparable to ADA (52%), which was used in this study as an active comparator. The overall rate of adverse events was similar with both doses of TOF when compared with ADA; however, patients taking TOF had numerically more cases of cancer, serious infection, and herpes zoster. 

Another study evaluated TOF compared with placebo in patients with PsA who had an inadequate response to tumor necrosis factor inhibitor (TNFi) therapy.² The study showed an ACR20 response of 50% in patients taking TOF 5 mg BID and 47% in patients taking 10 mg BID, compared with 24% in those taking placebo. Patients who received the 10 mg TOF dose continuously had higher rates of adverse events compared to TOF 5 mg, placebo, and patients who crossed over from placebo to TOF at either dose. In the TOF groups, there were cases of serious infection and herpes zoster, as well as 2 patients with major adverse cardiovascular events (MACE). Following review of these data, the FDA approved only the 5 mg BID dose, and later an 11-mg daily extended-release formulation that was pharmacokinetically similar.

The efficacy for UPA in PsA was shown in 2 pivotal phase 3 trials. SELECT-PsA1 compared UPA at 2 doses, 15 mg and 30 mg daily, vs placebo and vs ADA in patients with biologic DMARD (bDMARD)-naïve PsA.³ This trial demonstrated superiority of UPA in the ACR20 response at both doses (71% and 79%, respectively) compared with placebo (36%). The 15-mg dose of UPA was comparable to ADA (65%), while the 30-mg dose achieved superiority compared to ADA. Secondary outcomes including skin activity, patient-reported symptoms, and inhibition of radiographic progression were also superior in UPA compared with placebo and similar or greater with UPA compared with ADA, depending on the specific outcome.⁴ SELECT-PsA2 compared UPA 15 mg, 30 mg, and placebo in patients with prior incomplete response or intolerance to a bDMARD.⁵ At week 12 of the study, patients taking UPA 15 mg and 30 mg had an ACR20 response of 57% and 64%, respectively, compared with placebo (24%). At week 24, minimal disease activity was achieved by 25% of patients taking UPA 15 mg and 29% of patients taking UPA 30 mg, which was superior to placebo (3%). 

Both studies found a significant increase in infections, including serious infections, at the 30-mg UPA dose compared with the placebo and adalimumab groups. Cytopenia and elevated creatine kinase (CK) level also occurred more frequently in the UPA 30-mg group. Rates of cancer were low overall and comparable between the patients treated with UPA and ADA. Given the higher incidence of adverse events with the 30-mg dose and the relatively similar efficacy, the sponsor elected to submit only the lower dose to the FDA for approval.

In the last few years, concerns for safety with JAKi use grew after the publication of data from the ORAL SURVEILLANCE trial, an FDA-mandated, post-approval safety study of TOF in RA. In this trial, patients with active RA over 50 years of age and with at least 1 additional cardiovascular risk factor were randomized to TOF at 1 of 2 doses, 5 mg or 10 mg BID, or a TNFi.⁶ This trial was designed as a noninferiority study, and TOF did not meet the noninferiority threshold compared to TNFi, with hazard ratios of 1.33 and 1.48 for MACE and malignancy, respectively. The results of this trial prompted the FDA to add a black box warning to the label for all JAKi, pointing out the risk of malignancy and MACE, as well as infection, mortality, and thrombosis. 

In the ORAL SURVEILLANCE trial, the increased risk of MACE and malignancy was primarily seen in the study patients with high risk for a cardiovascular event. To address the question of whether a similar risk profile exists when using JAKi to treat PsA, or whether this is a disease-specific process related to RA, a post hoc analysis of 3 PsA trials and 7 PsO trials of patients treated with TOF was conducted.⁷ The analysis found that patients with a history of atherosclerotic cardiovascular disease (ASCVD) or metabolic syndrome, or patients at high risk for ASCVD (score > 20%) had increased incidence rates of MACE compared with those with low risk scores for ASCVD. Interestingly, as in RA, increased incidence rates of malignancy were seen in patients with preexisting or at high risk for ASCVD.

While the FDA recommends JAKi use in patients who have failed or are inappropriate for treatment with a TNFi, we would consider the use of JAKi for first-line therapy in PsA on an individual basis. One advantage of JAKi is their efficacy across multiple PsA domains, including peripheral arthritis, axial disease, enthesitis, dactylitis, and skin disease (although the approved dose of TOF was not statistically effective for PsO in the pivotal trials). Based on this efficacy, we believe that patients with overlapping, multifaceted disease may benefit the most from these medications. Patient risk factors and comorbidities are a prominent consideration in our use of JAKi to ensure safety, as the risk for MACE and malignancy is informed partly by baseline cardiovascular status. In younger patients without cardiovascular risk factors, JAKi may be a strong candidate for first-line therapy, particularly in patients averse to subcutaneous or intravenous therapy. We do counsel all patients on the increased risk of infection, and we do recommend inactivated herpes zoster vaccination in previously unvaccinated patients planning to start JAKi therapy. 

On the horizon are the development of novel, oral agents targeting tyrosine kinase 2 (TYK2), which is a member of the JAK family of signaling proteins. In fact, the TYK2 inhibitor deucravacitinib was approved by the FDA in 2022 for the treatment of PsO. TYK2 inhibitors appear to have the advantage of a more selective mechanism of action, with fewer off-target effects. There were fewer adverse events in the deucravacitinib trials, which led to its prompt PsO authorization, and the FDA approval for the drug did not include the same black box warning that appears in the label for other JAKi.⁸ A phase 2 study showed early promise for the efficacy and safety of deucravacitinib in PsA.⁹ Further investigation will be needed to better understand the role of deucravacitinib and other TYK2 inhibitors being developed for the treatment of PsA. In the meantime, JAKi continue to be a prominent consideration for first-line PsA therapy in a carefully selected patient population. 

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1. The treatment of multiple myeloma has evolved significantly in recent years. What are some of the most important things you consider in the treatment of your newly diagnosed, transplant-ineligible patients?

We’ve seen great progress in the treatment of multiple myeloma over the last decade, and outcomes continue to improve for many patients.¹ Still, it is important to keep in mind that more than 34,000 patients will be diagnosed and more than 12,000 people will die from the disease this year.² We may have the greatest opportunity to impact the course of disease in the treatment of newly diagnosed patients due to the nature of this cancer:

• Multiple myeloma is characterized by relapse, and we know the length of remission generally decreases with each relapse and subsequent line of therapy.³
• Patients often become refractory to treatment over time.

When I meet with a patient who has been diagnosed with multiple myeloma, the first thing I consider is their eligibility for autologous stem cell transplant (ASCT). In my opinion, the introduction of ASCT is one of the biggest advancements in the last few decades, and we’ve found that ASCT followed by maintenance therapy with targeted tools improves progression-free survival (PFS).⁴

Unfortunately, many newly diagnosed patients are not eligible for ASCT–either because of comorbidities or other complexities related to the presentation of their disease.  

For patients who are transplant-ineligible (TIE), it is important to have treatment options that are proven effective in extending PFS and overall survival (OS), and capable of producing deep and durable responses.

2. What are the challenges associated with treating newly diagnosed patients who are not eligible for ASCT?

We still consider multiple myeloma to be an incurable disease but, in my opinion, the treatment of TIE patients is less challenging today than a decade ago due to the emergence of novel therapies. That said, TIE patients are typically older and present with more advanced disease and comorbidities, including diabetes or cardiovascular events.⁵ 

A retrospective analysis published in 2020 by Rafael Fonseca examined frontline treatment patterns and attrition rates by line of therapy among newly diagnosed multiple myeloma (NDMM) patients who are TIE. More than 22,000 patients were identified from three patient-level databases between 2000 and 2018 - the OPTUM Commercial Claims database, the OPTUM Electronic Medical Records database, and the Surveillance, Epidemiology, and End Results-Meidcare Linked database. Patients included had to have a multiple myeloma diagnosis on or after January 1, 2007. Results showed that attrition rates among newly diagnosed, TIE patients with multiple myeloma increase with each line of therapy, with the proportion of patients who receive a second line of therapy decreasing by 50 percent with each subsequent line.³ 

3. Can you provide more detail on the goals of therapy for newly diagnosed, transplant-ineligible patients?

When I discuss treatment goals with TIE patients, I feel it is important to emphasize managing side effects and achieving deep and durable responses. I have the benefit of being in an academic setting, where I regularly exchange information with my colleagues about what we’re learning from the clinical studies in which we participate. Choosing which treatment to administer is complex and involves other considerations. For example, if two regimens have comparable efficacy, I may recommend the regimen with a more established safety profile or more robust evidence so I can properly anticipate and manage toxicities in my patients. Overall survival is one of the most important endpoints I consider, in addition to depth of response and PFS. In recent years, we’ve seen increasing evidence pointing to the importance of  using a proven effective treatment in frontline patients that are ineligible for transplant. 

4. A key study in newly-diagnosed, transplant-ineligible multiple myeloma is the Phase 3 MAIA study. Can you share the key takeaways from this study and discuss how the results have shaped treatment for this patient population?

Of course. The MAIA study is a randomized Phase 3 study evaluating DARZALEX^® (daratumumab) intravenous injection in combination with lenalidomide and dexamethasone (D-Rd) compared with Rd in 737 adult patients with newly diagnosed, transplant-ineligible multiple myeloma. The median age of patients participating in the MAIA study was 73 (range 45-90), an important consideration since the median age for multiple myeloma diagnosis is approximately 66-70 years of age.⁶ The study evaluated PFS as the primary endpoint, and overall survival as a key secondary endpoint, and supported the FDA approval of DARZALEX^® in combination with lenalidomide and dexamethasone for adult patients with newly diagnosed, multiple myeloma who are ineligible for ASCT.

MAIA study design⁷

The baseline demographic and disease characteristics were similar between the 2 treatment groups. Forty-four percent of the patients were  ≥75 years of age. Fifty-two percent (52%) of patients were male, 92% White, 4% Black or African American, and 1% Asian. Three percent (3%) of patients reported an ethnicity of Hispanic or Latino. Thirty-four (34%) had an Eastern Cooperative Oncology Group (ECOG) performance score of 0, 50% had an ECOG performance score of 1, and 17% had an ECOG performance score of ≥2. Twenty-seven percent had International Staging System (ISS) Stage I, 43% had ISS Stage II, and 29% had ISS Stage III disease. 

Select Important Safety Information: 

CONTRAINDICATIONS

DARZALEX^® is contraindicated in patients with a history of severe hypersensitivity (eg, anaphylactic reactions) to daratumumab or any of the components of the formulation.

WARNINGS AND PRECAUTIONS
Infusion-Related Reactions: DARZALEX^® can cause severe and/or serious infusion-related reactions including anaphylactic reactions.
These reactions can be life-threatening, and fatal outcomes have been reported. Please scroll down to read Important Safety Information for DARZALEX^®. 

Primary findings from the study, which were published in 2019, showed an improvement in PFS in patients receiving D-Rd compared with those receiving Rd alone.⁷ The median PFS was not reached in the D-Rd arm and was reached at 31.9 months in the Rd arm (HR 0.56; 95% CI 0.43-0.73; P<0.0001).⁷ At a median of 30 months of follow-up, the data showed the clinical benefit of D-Rd therapy, with a 44% reduction in the risk of disease progression or death in patients receiving D-Rd compared with Rd alone.⁷ 

Progression-free survival in TIE NDMM after ~30 months of treatment with D-Rd^7,8

Additionally, 70.6% of patients (95% CI, 65.0-75.4) had no progressive disease with D-Rd treatment at median 30 months of follow-up, compared with 55.6% (95% CI, 49.5-61.3) of patients in the Rd group.⁷

In terms of depth of response, the percentage of patients with a complete response or better was 47.6% in patients receiving D-Rd compared with 24.9% in the Rd group.⁷

Overall response rate with D-Rd in TIE NDMM at ~30 months of follow-up⁸

An overview of the most frequent adverse events at 30-months of follow-up are provided below. The most frequent adverse reactions were reported in ≥20% of patients, with at least a 5% greater frequency in the D-Rd arm compared with Rd alone.⁸ 

Most frequent adverse events at ~30 months of follow-up with D-Rd in TIE NDMM⁸

Most frequent hematologic laboratory abnormalities with D-Rd in TIE NDMM at ~30 months⁸

Serious adverse reactions with a 2% greater incidence in the D-Rd arm compared with the Rd arm were pneumonia (D-Rd 15% vs Rd 8%), bronchitis (D-Rd 4% vs Rd 2%), and dehydration (D-Rd 2% vs Rd <1).
• Discontinuation rates due to any adverse event: 7% with D-Rd vs 16% with Rd
• Infusion-related reactions (IRRs) with D-Rd occurred in 41% of patients; 2% were Grade 3 and <1% were Grade 4
• IRRs of any grade or severity may require management by interruption, modification, and/or discontinuation of the infusion
• Most IRRs occurred during first infusion

5. Thanks for that overview. In addition to these results, The Lancet Oncology has published updated overall survival data from a 5-year follow-up on the MAIA study. Can you provide an overview of these data and insights on their potential for patients?  

The MAIA trial was an important study, and for me, the results were practice changing. We see that after a median of nearly 5 years of follow-up, D-Rd significantly improved OS in TIE NDMM patients who were treated to progression compared with Rd alone (66.3% vs. 53.1% [HR=0.68; 95% CI, 0.53-0.86; P=0.0013]).⁹ This equates to approximately a 32% reduction in death when DARZALEX^® was added to a two-drug regimen, which is a meaningful consideration when selecting the most appropriate regimens for my newly diagnosed, transplant-ineligible patients.⁹

Overall survival data at ~5 years with D-Rd compared to Rd alone in TIE NDMM⁹

Importantly, efficacy that resulted from longer treatment with D-Rd is also supported by approximately 5 years of safety evaluation. Below is information from a follow-up analysis of the MAIA study. This information is not included in the current Prescribing Information and has not been evaluated by the FDA. Treatment-emergent adverse events are reported as observed. These analyses have not been adjusted for multiple comparisons and no conclusions should be drawn. In what I’ve observed through published data and in my practice, longer treatment has not revealed new safety signals.

Most frequent treatment-emergent adverse events (any grade reported in ≥30% of patients and/or Grade 3/4 reported in ≥10% of patients) at ~5 years⁹

Select Important Safety Information: 

DARZALEX^® can cause severe and/or serious infusion-related reactions including anaphylactic reactions. These reactions can be life threatening, and fatal outcomes have been reported. In clinical trials (monotherapy and combination: N=2066), infusion-related reactions occurred in 37% of patients with the Week 1 (16 mg/kg) infusion, 2% with the Week 2 infusion, and cumulatively 6% with subsequent infusions. Less than 1% of patients had a Grade 3/4 infusion-related reaction at Week 2 or subsequent infusions. The median time to onset was 1.5 hours (range: 0 to 73 hours). Nearly all reactions occurred during infusion or within 4 hours of completing DARZALEX^®. Severe reactions have occurred, including bronchospasm, hypoxia, dyspnea, hypertension, tachycardia, headache, laryngeal edema, pulmonary edema, and ocular adverse reactions, including choroidal effusion, acute myopia, and acute angle closure glaucoma. Signs and symptoms may include respiratory symptoms, such as nasal congestion, cough, throat irritation, as well as chills, vomiting, and nausea. Less common signs and symptoms were wheezing, allergic rhinitis, pyrexia, chest discomfort, pruritus, hypotension and blurred vision. Please scroll down to see Important Safety Information for DARZALEX^®.

6. Does the availability of OS data influence your decisions on treatment selection in TIE NDMM?

Overall survival absolutely remains the gold standard and informs my practice. Prior to OS data being available, I will often look at other efficacy endpoints that are available sooner. In MAIA, I was encouraged by efficacy endpoints in earlier data, which were later confirmed by the latest data on OS.

7. The MAIA study shows that treating to disease progression or unacceptable toxicity is important. How does that impact your approach to treatment?

It's important to keep in mind that the MAIA trial was designed to evaluate treatment until progression or unacceptable toxicity. The results revealed a significant difference between the DR-d and Rd treatment arms, but results observed in this study are contingent on this treatment approach. From a clinical perspective, unless there is considerable toxicity, I advocate for treating with D-Rd to progression.

In the clinic, we also see that TIE patients who have higher frailty scores are more likely to discontinue treatment prior to progression.¹⁰ There can be other reasons too – such as a patient simply wanting to have a break from treatment. These conversations are not always easy, but it is important to have an honest dialogue with patients.

8. What can we learn from studies like the MAIA trial that included a wide range of patient populations including patients who are elderly, frail, or had high cytogenetic risk? 

Several patient subgroups were analyzed as part of the MAIA study. It is important to note that these subgroup analyses are not included in the Prescribing Information for DARZALEX^®. These analyses were not adjusted for multiple comparisons, and there are insufficient numbers of patients per subgroup to make definitive conclusions of efficacy among the subgroups.

As mentioned above, the MAIA study evaluated a wide range of patients (n=737). The baseline demographic and disease characteristics were similar between the D-Rd and Rd treatment groups and the median age was 73 (range: 45-90) years, with 44% of the patients ≥75 years of age.

In the various patient subgroups that were analyzed as part of the MAIA study, it was found that at ~3-years of follow-up the PFS numerically favored DRd compared with Rd alone in most subgroups (see table below).

Median progression-free survival by sub-population at ~3 year follow-up⁸

The MAIA trial also included patients who were frail and a post hoc analysis was conducted in this subgroup of patients. These analyses are not included in the Prescribing Information for DARZALEX^®. These analyses were conducted post hoc and there are insufficient numbers of patients per subgroup to make definitive conclusions of efficacy among the subgroups.

A frailty assessment was performed retrospectively using age, the Charlson Comorbidity Index (CCI) – which is calculated based on a retrospective review of the patient’s medical history to predict the 10-year mortality – and the baseline Eastern Cooperative Oncology Group (ECOG) performance status score, used to measure a patient’s level of functioning in terms of their ability to care for themselves, daily activity, and physical activity. The frailty scores were then added up to classify patients into fit (0), intermediate (1), or frail (≥2). Frailty status was further simplified into 2 categories: non-frail (0-1) and frail (≥2). The median age in the frail subgroup was 77 years (range: 57-80 years), with 88% of patients having ECOG performance score ≥1. CCI was calculated based on retrospective review of each patient’s medical history.¹²

The charts below illustrate the frailty scoring system with an overview of the patient population included in the 3-year post hoc analysis, PFS rate, and adverse events.

MAIA post hoc subgroup analysis by frailty status score¹²

The retrospective assessment of frailty score was a limitation of this study. Retrospective CCI calculations were based on reported medical history, which may contain missing data and result in underestimating or overestimating the number of patients in each frailty subgroup. The ECOG PS score parameter used for frailty score calculations in the study is more subjective, with susceptibility to intra- and inter-observer bias, compared with the ADL (activities of daily living) and IADL (instrumental activities of daily living) scales used in the IMWG scoring system. While the frailty scale used in the study is based on parameters that are routinely assessed in clinical practice for clinical use, the use of comprehensive frailty assessments that more accurately reflect biological or functional frailty will remain important for the further optimization of treatment strategies for frail patients. Patients with an ECOG PS score ≥3 and patients with comorbidities that may interfere with the study procedures were excluded from MAIA; the inclusion and exclusion criteria for the study limits the generalizability of these results to more frail patients seen in clinical practice.

Progression-free survival in a ~3-year subgroup analysis of frail patients following treatment with D-Rd in TIE NDMM¹²

Most frequent Grade 3/4 treatment-emergent adverse events (≥10%) in frail patients at ~3 year follow-up of MAIA trial¹²

Please see additional Important Safety Information for DARZALEX^® below.

IMPORTANT SAFETY INFORMATION

CONTRAINDICATIONS

DARZALEX^® is contraindicated in patients with a history of severe hypersensitivity (eg, anaphylactic reactions) to daratumumab or any of the components of the formulation.

WARNINGS AND PRECAUTIONS

Infusion-Related Reactions

DARZALEX^® can cause severe and/or serious infusion-related reactions including anaphylactic reactions. These reactions can be life‑threatening, and fatal outcomes have been reported. In clinical trials (monotherapy and combination: N=2066), infusion-related reactions occurred in 37% of patients with the Week 1 (16 mg/kg) infusion, 2% with the Week 2 infusion, and cumulatively 6% with subsequent infusions. Less than 1% of patients had a Grade 3/4 infusion-related reaction at Week 2 or subsequent infusions. The median time to onset was 1.5 hours (range: 0 to 73 hours). Nearly all reactions occurred during infusion or within 4 hours of completing DARZALEX^®. Severe reactions have occurred, including bronchospasm, hypoxia, dyspnea, hypertension, tachycardia, headache, laryngeal edema, pulmonary edema, and ocular adverse reactions, including choroidal effusion, acute myopia, and acute angle closure glaucoma. Signs and symptoms may include respiratory symptoms, such as nasal congestion, cough, throat irritation, as well as chills, vomiting, and nausea. Less common signs and symptoms were wheezing, allergic rhinitis, pyrexia, chest discomfort, pruritus, hypotension and blurred vision.

When DARZALEX^® dosing was interrupted in the setting of ASCT (CASSIOPEIA) for a median of 3.75 months (range: 2.4 to 6.9 months), upon re-initiation of DARZALEX^®, the incidence of infusion-related reactions was 11% for the first infusion following ASCT. Infusion-related reactions occurring at re-initiation of DARZALEX^® following ASCT were consistent in terms of symptoms and severity (Grade 3 or 4: <1%) with those reported in previous studies at Week 2 or subsequent infusions. In EQUULEUS, patients receiving combination treatment (n=97) were administered the first 16 mg/kg dose at Week 1 split over two days, ie, 8 mg/kg on Day 1 and Day 2, respectively. The incidence of any grade infusion-related reactions was 42%, with 36% of patients experiencing infusion-related reactions on Day 1 of Week 1, 4% on Day 2 of Week 1, and 8% with subsequent infusions.

Pre-medicate patients with antihistamines, antipyretics, and corticosteroids. Frequently monitor patients during the entire infusion. Interrupt DARZALEX^® infusion for reactions of any severity and institute medical management as needed. Permanently discontinue DARZALEX^® therapy if an anaphylactic reaction or life-threatening (Grade 4) reaction occurs and institute appropriate emergency care. For patients with Grade 1, 2, or 3 reactions, reduce the infusion rate when re-starting the infusion.

To reduce the risk of delayed infusion-related reactions, administer oral corticosteroids to all patients following DARZALEX^® infusions. Patients with a history of chronic obstructive pulmonary disease may require additional post-infusion medications to manage respiratory complications. Consider prescribing short- and long-acting bronchodilators and inhaled corticosteroids for patients with chronic obstructive pulmonary disease.

Ocular adverse reactions, including acute myopia and narrowing of the anterior chamber angle due to ciliochoroidal effusions with potential for increased intraocular pressure or glaucoma, have occurred with DARZALEX infusion. If ocular symptoms occur, interrupt DARZALEX infusion and seek immediate ophthalmologic evaluation prior to restarting DARZALEX.

Interference With Serological Testing

Daratumumab binds to CD38 on red blood cells (RBCs) and results in a positive indirect antiglobulin test (indirect Coombs test). Daratumumab-mediated positive indirect antiglobulin test may persist for up to 6 months after the last daratumumab infusion. Daratumumab bound to RBCs masks detection of antibodies to minor antigens in the patient’s serum. The determination of a patient’s ABO and Rh blood type is not impacted. Notify blood transfusion centers of this interference with serological testing and inform blood banks that a patient has received DARZALEX^®. Type and screen patients prior to starting DARZALEX^®.

Neutropenia and Thrombocytopenia

DARZALEX^® may increase neutropenia and thrombocytopenia induced by background therapy. Monitor complete blood cell counts periodically during treatment according to manufacturer’s prescribing information for background therapies. Monitor patients with neutropenia for signs of infection. Consider withholding DARZALEX^® until recovery of neutrophils or for recovery of platelets.

Interference With Determination of Complete Response

Daratumumab is a human immunoglobulin G (IgG) kappa monoclonal antibody that can be detected on both the serum protein electrophoresis (SPE) and immunofixation (IFE) assays used for the clinical monitoring of endogenous M-protein. This interference can impact the determination of complete response and of disease progression in some patients with IgG kappa myeloma protein.

Embryo-Fetal Toxicity

Based on the mechanism of action, DARZALEX^® can cause fetal harm when administered to a pregnant woman. DARZALEX^® may cause depletion of fetal immune cells and decreased bone density. Advise pregnant women of the potential risk to a fetus. Advise females with reproductive potential to use effective contraception during treatment with DARZALEX^® and for 3 months after the last dose.

The combination of DARZALEX^® with lenalidomide, pomalidomide, or thalidomide is contraindicated in pregnant women because lenalidomide, pomalidomide, and thalidomide may cause birth defects and death of the unborn child. Refer to the lenalidomide, pomalidomide, or thalidomide prescribing information on use during pregnancy.

ADVERSE REACTIONS

The most frequently reported adverse reactions (incidence ≥20%) were: upper respiratory infection, neutropenia, infusion‑related reactions, thrombocytopenia, diarrhea, constipation, anemia, peripheral sensory neuropathy, fatigue, peripheral edema, nausea, cough, pyrexia, dyspnea, and asthenia. The most common hematologic laboratory abnormalities (≥40%) with DARZALEX^® are: neutropenia, lymphopenia, thrombocytopenia, leukopenia, and anemia.

INDICATIONS

DARZALEX^® (daratumumab) is indicated for the treatment of adult patients with multiple myeloma:

• In combination with lenalidomide and dexamethasone in newly diagnosed patients who are ineligible for autologous stem cell transplant and in patients with relapsed or refractory multiple myeloma who have received at least one prior therapy
• In combination with bortezomib, melphalan, and prednisone in newly diagnosed patients who are ineligible for autologous stem cell transplant
• In combination with bortezomib, thalidomide, and dexamethasone in newly diagnosed patients who are eligible for autologous stem cell transplant
• In combination with bortezomib and dexamethasone in patients who have received at least one prior therapy
• In combination with carfilzomib and dexamethasone in patients with relapsed or refractory multiple myeloma who have received one to three prior lines of therapy
• In combination with pomalidomide and dexamethasone in patients who have received at least two prior therapies including lenalidomide and a proteasome inhibitor
• As monotherapy in patients who have received at least three prior lines of therapy including a proteasome inhibitor (PI) and an immunomodulatory agent or who are double-refractory to a PI and an immunomodulatory agent

Please click here to see the full Prescribing Information.

1. The treatment of multiple myeloma has evolved significantly in recent years. What are some of the most important things you consider in the treatment of your newly diagnosed, transplant-ineligible patients?

We’ve seen great progress in the treatment of multiple myeloma over the last decade, and outcomes continue to improve for many patients.¹ Still, it is important to keep in mind that more than 34,000 patients will be diagnosed and more than 12,000 people will die from the disease this year.² We may have the greatest opportunity to impact the course of disease in the treatment of newly diagnosed patients due to the nature of this cancer:

• Multiple myeloma is characterized by relapse, and we know the length of remission generally decreases with each relapse and subsequent line of therapy.³
• Patients often become refractory to treatment over time.

When I meet with a patient who has been diagnosed with multiple myeloma, the first thing I consider is their eligibility for autologous stem cell transplant (ASCT). In my opinion, the introduction of ASCT is one of the biggest advancements in the last few decades, and we’ve found that ASCT followed by maintenance therapy with targeted tools improves progression-free survival (PFS).⁴

Unfortunately, many newly diagnosed patients are not eligible for ASCT–either because of comorbidities or other complexities related to the presentation of their disease.  

For patients who are transplant-ineligible (TIE), it is important to have treatment options that are proven effective in extending PFS and overall survival (OS), and capable of producing deep and durable responses.

2. What are the challenges associated with treating newly diagnosed patients who are not eligible for ASCT?

We still consider multiple myeloma to be an incurable disease but, in my opinion, the treatment of TIE patients is less challenging today than a decade ago due to the emergence of novel therapies. That said, TIE patients are typically older and present with more advanced disease and comorbidities, including diabetes or cardiovascular events.⁵ 

A retrospective analysis published in 2020 by Rafael Fonseca examined frontline treatment patterns and attrition rates by line of therapy among newly diagnosed multiple myeloma (NDMM) patients who are TIE. More than 22,000 patients were identified from three patient-level databases between 2000 and 2018 - the OPTUM Commercial Claims database, the OPTUM Electronic Medical Records database, and the Surveillance, Epidemiology, and End Results-Meidcare Linked database. Patients included had to have a multiple myeloma diagnosis on or after January 1, 2007. Results showed that attrition rates among newly diagnosed, TIE patients with multiple myeloma increase with each line of therapy, with the proportion of patients who receive a second line of therapy decreasing by 50 percent with each subsequent line.³ 

3. Can you provide more detail on the goals of therapy for newly diagnosed, transplant-ineligible patients?

When I discuss treatment goals with TIE patients, I feel it is important to emphasize managing side effects and achieving deep and durable responses. I have the benefit of being in an academic setting, where I regularly exchange information with my colleagues about what we’re learning from the clinical studies in which we participate. Choosing which treatment to administer is complex and involves other considerations. For example, if two regimens have comparable efficacy, I may recommend the regimen with a more established safety profile or more robust evidence so I can properly anticipate and manage toxicities in my patients. Overall survival is one of the most important endpoints I consider, in addition to depth of response and PFS. In recent years, we’ve seen increasing evidence pointing to the importance of  using a proven effective treatment in frontline patients that are ineligible for transplant. 

4. A key study in newly-diagnosed, transplant-ineligible multiple myeloma is the Phase 3 MAIA study. Can you share the key takeaways from this study and discuss how the results have shaped treatment for this patient population?

Of course. The MAIA study is a randomized Phase 3 study evaluating DARZALEX^® (daratumumab) intravenous injection in combination with lenalidomide and dexamethasone (D-Rd) compared with Rd in 737 adult patients with newly diagnosed, transplant-ineligible multiple myeloma. The median age of patients participating in the MAIA study was 73 (range 45-90), an important consideration since the median age for multiple myeloma diagnosis is approximately 66-70 years of age.⁶ The study evaluated PFS as the primary endpoint, and overall survival as a key secondary endpoint, and supported the FDA approval of DARZALEX^® in combination with lenalidomide and dexamethasone for adult patients with newly diagnosed, multiple myeloma who are ineligible for ASCT.

MAIA study design⁷

The baseline demographic and disease characteristics were similar between the 2 treatment groups. Forty-four percent of the patients were  ≥75 years of age. Fifty-two percent (52%) of patients were male, 92% White, 4% Black or African American, and 1% Asian. Three percent (3%) of patients reported an ethnicity of Hispanic or Latino. Thirty-four (34%) had an Eastern Cooperative Oncology Group (ECOG) performance score of 0, 50% had an ECOG performance score of 1, and 17% had an ECOG performance score of ≥2. Twenty-seven percent had International Staging System (ISS) Stage I, 43% had ISS Stage II, and 29% had ISS Stage III disease. 

Select Important Safety Information: 

CONTRAINDICATIONS

DARZALEX^® is contraindicated in patients with a history of severe hypersensitivity (eg, anaphylactic reactions) to daratumumab or any of the components of the formulation.

WARNINGS AND PRECAUTIONS
Infusion-Related Reactions: DARZALEX^® can cause severe and/or serious infusion-related reactions including anaphylactic reactions.
These reactions can be life-threatening, and fatal outcomes have been reported. Please scroll down to read Important Safety Information for DARZALEX^®. 

Primary findings from the study, which were published in 2019, showed an improvement in PFS in patients receiving D-Rd compared with those receiving Rd alone.⁷ The median PFS was not reached in the D-Rd arm and was reached at 31.9 months in the Rd arm (HR 0.56; 95% CI 0.43-0.73; P<0.0001).⁷ At a median of 30 months of follow-up, the data showed the clinical benefit of D-Rd therapy, with a 44% reduction in the risk of disease progression or death in patients receiving D-Rd compared with Rd alone.⁷ 

Progression-free survival in TIE NDMM after ~30 months of treatment with D-Rd^7,8

Additionally, 70.6% of patients (95% CI, 65.0-75.4) had no progressive disease with D-Rd treatment at median 30 months of follow-up, compared with 55.6% (95% CI, 49.5-61.3) of patients in the Rd group.⁷

In terms of depth of response, the percentage of patients with a complete response or better was 47.6% in patients receiving D-Rd compared with 24.9% in the Rd group.⁷

Overall response rate with D-Rd in TIE NDMM at ~30 months of follow-up⁸

An overview of the most frequent adverse events at 30-months of follow-up are provided below. The most frequent adverse reactions were reported in ≥20% of patients, with at least a 5% greater frequency in the D-Rd arm compared with Rd alone.⁸ 

Most frequent adverse events at ~30 months of follow-up with D-Rd in TIE NDMM⁸

Most frequent hematologic laboratory abnormalities with D-Rd in TIE NDMM at ~30 months⁸

Serious adverse reactions with a 2% greater incidence in the D-Rd arm compared with the Rd arm were pneumonia (D-Rd 15% vs Rd 8%), bronchitis (D-Rd 4% vs Rd 2%), and dehydration (D-Rd 2% vs Rd <1).
• Discontinuation rates due to any adverse event: 7% with D-Rd vs 16% with Rd
• Infusion-related reactions (IRRs) with D-Rd occurred in 41% of patients; 2% were Grade 3 and <1% were Grade 4
• IRRs of any grade or severity may require management by interruption, modification, and/or discontinuation of the infusion
• Most IRRs occurred during first infusion

5. Thanks for that overview. In addition to these results, The Lancet Oncology has published updated overall survival data from a 5-year follow-up on the MAIA study. Can you provide an overview of these data and insights on their potential for patients?  

The MAIA trial was an important study, and for me, the results were practice changing. We see that after a median of nearly 5 years of follow-up, D-Rd significantly improved OS in TIE NDMM patients who were treated to progression compared with Rd alone (66.3% vs. 53.1% [HR=0.68; 95% CI, 0.53-0.86; P=0.0013]).⁹ This equates to approximately a 32% reduction in death when DARZALEX^® was added to a two-drug regimen, which is a meaningful consideration when selecting the most appropriate regimens for my newly diagnosed, transplant-ineligible patients.⁹

Overall survival data at ~5 years with D-Rd compared to Rd alone in TIE NDMM⁹

Importantly, efficacy that resulted from longer treatment with D-Rd is also supported by approximately 5 years of safety evaluation. Below is information from a follow-up analysis of the MAIA study. This information is not included in the current Prescribing Information and has not been evaluated by the FDA. Treatment-emergent adverse events are reported as observed. These analyses have not been adjusted for multiple comparisons and no conclusions should be drawn. In what I’ve observed through published data and in my practice, longer treatment has not revealed new safety signals.

Most frequent treatment-emergent adverse events (any grade reported in ≥30% of patients and/or Grade 3/4 reported in ≥10% of patients) at ~5 years⁹

Select Important Safety Information: 

DARZALEX^® can cause severe and/or serious infusion-related reactions including anaphylactic reactions. These reactions can be life threatening, and fatal outcomes have been reported. In clinical trials (monotherapy and combination: N=2066), infusion-related reactions occurred in 37% of patients with the Week 1 (16 mg/kg) infusion, 2% with the Week 2 infusion, and cumulatively 6% with subsequent infusions. Less than 1% of patients had a Grade 3/4 infusion-related reaction at Week 2 or subsequent infusions. The median time to onset was 1.5 hours (range: 0 to 73 hours). Nearly all reactions occurred during infusion or within 4 hours of completing DARZALEX^®. Severe reactions have occurred, including bronchospasm, hypoxia, dyspnea, hypertension, tachycardia, headache, laryngeal edema, pulmonary edema, and ocular adverse reactions, including choroidal effusion, acute myopia, and acute angle closure glaucoma. Signs and symptoms may include respiratory symptoms, such as nasal congestion, cough, throat irritation, as well as chills, vomiting, and nausea. Less common signs and symptoms were wheezing, allergic rhinitis, pyrexia, chest discomfort, pruritus, hypotension and blurred vision. Please scroll down to see Important Safety Information for DARZALEX^®.

6. Does the availability of OS data influence your decisions on treatment selection in TIE NDMM?

Overall survival absolutely remains the gold standard and informs my practice. Prior to OS data being available, I will often look at other efficacy endpoints that are available sooner. In MAIA, I was encouraged by efficacy endpoints in earlier data, which were later confirmed by the latest data on OS.

7. The MAIA study shows that treating to disease progression or unacceptable toxicity is important. How does that impact your approach to treatment?

It's important to keep in mind that the MAIA trial was designed to evaluate treatment until progression or unacceptable toxicity. The results revealed a significant difference between the DR-d and Rd treatment arms, but results observed in this study are contingent on this treatment approach. From a clinical perspective, unless there is considerable toxicity, I advocate for treating with D-Rd to progression.

In the clinic, we also see that TIE patients who have higher frailty scores are more likely to discontinue treatment prior to progression.¹⁰ There can be other reasons too – such as a patient simply wanting to have a break from treatment. These conversations are not always easy, but it is important to have an honest dialogue with patients.

8. What can we learn from studies like the MAIA trial that included a wide range of patient populations including patients who are elderly, frail, or had high cytogenetic risk? 

Several patient subgroups were analyzed as part of the MAIA study. It is important to note that these subgroup analyses are not included in the Prescribing Information for DARZALEX^®. These analyses were not adjusted for multiple comparisons, and there are insufficient numbers of patients per subgroup to make definitive conclusions of efficacy among the subgroups.

As mentioned above, the MAIA study evaluated a wide range of patients (n=737). The baseline demographic and disease characteristics were similar between the D-Rd and Rd treatment groups and the median age was 73 (range: 45-90) years, with 44% of the patients ≥75 years of age.

In the various patient subgroups that were analyzed as part of the MAIA study, it was found that at ~3-years of follow-up the PFS numerically favored DRd compared with Rd alone in most subgroups (see table below).

Median progression-free survival by sub-population at ~3 year follow-up⁸

The MAIA trial also included patients who were frail and a post hoc analysis was conducted in this subgroup of patients. These analyses are not included in the Prescribing Information for DARZALEX^®. These analyses were conducted post hoc and there are insufficient numbers of patients per subgroup to make definitive conclusions of efficacy among the subgroups.

A frailty assessment was performed retrospectively using age, the Charlson Comorbidity Index (CCI) – which is calculated based on a retrospective review of the patient’s medical history to predict the 10-year mortality – and the baseline Eastern Cooperative Oncology Group (ECOG) performance status score, used to measure a patient’s level of functioning in terms of their ability to care for themselves, daily activity, and physical activity. The frailty scores were then added up to classify patients into fit (0), intermediate (1), or frail (≥2). Frailty status was further simplified into 2 categories: non-frail (0-1) and frail (≥2). The median age in the frail subgroup was 77 years (range: 57-80 years), with 88% of patients having ECOG performance score ≥1. CCI was calculated based on retrospective review of each patient’s medical history.¹²

The charts below illustrate the frailty scoring system with an overview of the patient population included in the 3-year post hoc analysis, PFS rate, and adverse events.

MAIA post hoc subgroup analysis by frailty status score¹²

The retrospective assessment of frailty score was a limitation of this study. Retrospective CCI calculations were based on reported medical history, which may contain missing data and result in underestimating or overestimating the number of patients in each frailty subgroup. The ECOG PS score parameter used for frailty score calculations in the study is more subjective, with susceptibility to intra- and inter-observer bias, compared with the ADL (activities of daily living) and IADL (instrumental activities of daily living) scales used in the IMWG scoring system. While the frailty scale used in the study is based on parameters that are routinely assessed in clinical practice for clinical use, the use of comprehensive frailty assessments that more accurately reflect biological or functional frailty will remain important for the further optimization of treatment strategies for frail patients. Patients with an ECOG PS score ≥3 and patients with comorbidities that may interfere with the study procedures were excluded from MAIA; the inclusion and exclusion criteria for the study limits the generalizability of these results to more frail patients seen in clinical practice.

Progression-free survival in a ~3-year subgroup analysis of frail patients following treatment with D-Rd in TIE NDMM¹²

Most frequent Grade 3/4 treatment-emergent adverse events (≥10%) in frail patients at ~3 year follow-up of MAIA trial¹²

Please see additional Important Safety Information for DARZALEX^® below.

IMPORTANT SAFETY INFORMATION

CONTRAINDICATIONS

DARZALEX^® is contraindicated in patients with a history of severe hypersensitivity (eg, anaphylactic reactions) to daratumumab or any of the components of the formulation.

WARNINGS AND PRECAUTIONS

Infusion-Related Reactions

DARZALEX^® can cause severe and/or serious infusion-related reactions including anaphylactic reactions. These reactions can be life‑threatening, and fatal outcomes have been reported. In clinical trials (monotherapy and combination: N=2066), infusion-related reactions occurred in 37% of patients with the Week 1 (16 mg/kg) infusion, 2% with the Week 2 infusion, and cumulatively 6% with subsequent infusions. Less than 1% of patients had a Grade 3/4 infusion-related reaction at Week 2 or subsequent infusions. The median time to onset was 1.5 hours (range: 0 to 73 hours). Nearly all reactions occurred during infusion or within 4 hours of completing DARZALEX^®. Severe reactions have occurred, including bronchospasm, hypoxia, dyspnea, hypertension, tachycardia, headache, laryngeal edema, pulmonary edema, and ocular adverse reactions, including choroidal effusion, acute myopia, and acute angle closure glaucoma. Signs and symptoms may include respiratory symptoms, such as nasal congestion, cough, throat irritation, as well as chills, vomiting, and nausea. Less common signs and symptoms were wheezing, allergic rhinitis, pyrexia, chest discomfort, pruritus, hypotension and blurred vision.

When DARZALEX^® dosing was interrupted in the setting of ASCT (CASSIOPEIA) for a median of 3.75 months (range: 2.4 to 6.9 months), upon re-initiation of DARZALEX^®, the incidence of infusion-related reactions was 11% for the first infusion following ASCT. Infusion-related reactions occurring at re-initiation of DARZALEX^® following ASCT were consistent in terms of symptoms and severity (Grade 3 or 4: <1%) with those reported in previous studies at Week 2 or subsequent infusions. In EQUULEUS, patients receiving combination treatment (n=97) were administered the first 16 mg/kg dose at Week 1 split over two days, ie, 8 mg/kg on Day 1 and Day 2, respectively. The incidence of any grade infusion-related reactions was 42%, with 36% of patients experiencing infusion-related reactions on Day 1 of Week 1, 4% on Day 2 of Week 1, and 8% with subsequent infusions.

Pre-medicate patients with antihistamines, antipyretics, and corticosteroids. Frequently monitor patients during the entire infusion. Interrupt DARZALEX^® infusion for reactions of any severity and institute medical management as needed. Permanently discontinue DARZALEX^® therapy if an anaphylactic reaction or life-threatening (Grade 4) reaction occurs and institute appropriate emergency care. For patients with Grade 1, 2, or 3 reactions, reduce the infusion rate when re-starting the infusion.

To reduce the risk of delayed infusion-related reactions, administer oral corticosteroids to all patients following DARZALEX^® infusions. Patients with a history of chronic obstructive pulmonary disease may require additional post-infusion medications to manage respiratory complications. Consider prescribing short- and long-acting bronchodilators and inhaled corticosteroids for patients with chronic obstructive pulmonary disease.

Ocular adverse reactions, including acute myopia and narrowing of the anterior chamber angle due to ciliochoroidal effusions with potential for increased intraocular pressure or glaucoma, have occurred with DARZALEX infusion. If ocular symptoms occur, interrupt DARZALEX infusion and seek immediate ophthalmologic evaluation prior to restarting DARZALEX.

Interference With Serological Testing

Daratumumab binds to CD38 on red blood cells (RBCs) and results in a positive indirect antiglobulin test (indirect Coombs test). Daratumumab-mediated positive indirect antiglobulin test may persist for up to 6 months after the last daratumumab infusion. Daratumumab bound to RBCs masks detection of antibodies to minor antigens in the patient’s serum. The determination of a patient’s ABO and Rh blood type is not impacted. Notify blood transfusion centers of this interference with serological testing and inform blood banks that a patient has received DARZALEX^®. Type and screen patients prior to starting DARZALEX^®.

Neutropenia and Thrombocytopenia

DARZALEX^® may increase neutropenia and thrombocytopenia induced by background therapy. Monitor complete blood cell counts periodically during treatment according to manufacturer’s prescribing information for background therapies. Monitor patients with neutropenia for signs of infection. Consider withholding DARZALEX^® until recovery of neutrophils or for recovery of platelets.

Interference With Determination of Complete Response

Daratumumab is a human immunoglobulin G (IgG) kappa monoclonal antibody that can be detected on both the serum protein electrophoresis (SPE) and immunofixation (IFE) assays used for the clinical monitoring of endogenous M-protein. This interference can impact the determination of complete response and of disease progression in some patients with IgG kappa myeloma protein.

Embryo-Fetal Toxicity

Based on the mechanism of action, DARZALEX^® can cause fetal harm when administered to a pregnant woman. DARZALEX^® may cause depletion of fetal immune cells and decreased bone density. Advise pregnant women of the potential risk to a fetus. Advise females with reproductive potential to use effective contraception during treatment with DARZALEX^® and for 3 months after the last dose.

The combination of DARZALEX^® with lenalidomide, pomalidomide, or thalidomide is contraindicated in pregnant women because lenalidomide, pomalidomide, and thalidomide may cause birth defects and death of the unborn child. Refer to the lenalidomide, pomalidomide, or thalidomide prescribing information on use during pregnancy.

ADVERSE REACTIONS

The most frequently reported adverse reactions (incidence ≥20%) were: upper respiratory infection, neutropenia, infusion‑related reactions, thrombocytopenia, diarrhea, constipation, anemia, peripheral sensory neuropathy, fatigue, peripheral edema, nausea, cough, pyrexia, dyspnea, and asthenia. The most common hematologic laboratory abnormalities (≥40%) with DARZALEX^® are: neutropenia, lymphopenia, thrombocytopenia, leukopenia, and anemia.

INDICATIONS

DARZALEX^® (daratumumab) is indicated for the treatment of adult patients with multiple myeloma:

• In combination with lenalidomide and dexamethasone in newly diagnosed patients who are ineligible for autologous stem cell transplant and in patients with relapsed or refractory multiple myeloma who have received at least one prior therapy
• In combination with bortezomib, melphalan, and prednisone in newly diagnosed patients who are ineligible for autologous stem cell transplant
• In combination with bortezomib, thalidomide, and dexamethasone in newly diagnosed patients who are eligible for autologous stem cell transplant
• In combination with bortezomib and dexamethasone in patients who have received at least one prior therapy
• In combination with carfilzomib and dexamethasone in patients with relapsed or refractory multiple myeloma who have received one to three prior lines of therapy
• In combination with pomalidomide and dexamethasone in patients who have received at least two prior therapies including lenalidomide and a proteasome inhibitor
• As monotherapy in patients who have received at least three prior lines of therapy including a proteasome inhibitor (PI) and an immunomodulatory agent or who are double-refractory to a PI and an immunomodulatory agent

Please click here to see the full Prescribing Information.

1. The treatment of multiple myeloma has evolved significantly in recent years. What are some of the most important things you consider in the treatment of your newly diagnosed, transplant-ineligible patients?

We’ve seen great progress in the treatment of multiple myeloma over the last decade, and outcomes continue to improve for many patients.¹ Still, it is important to keep in mind that more than 34,000 patients will be diagnosed and more than 12,000 people will die from the disease this year.² We may have the greatest opportunity to impact the course of disease in the treatment of newly diagnosed patients due to the nature of this cancer:

• Multiple myeloma is characterized by relapse, and we know the length of remission generally decreases with each relapse and subsequent line of therapy.³
• Patients often become refractory to treatment over time.

When I meet with a patient who has been diagnosed with multiple myeloma, the first thing I consider is their eligibility for autologous stem cell transplant (ASCT). In my opinion, the introduction of ASCT is one of the biggest advancements in the last few decades, and we’ve found that ASCT followed by maintenance therapy with targeted tools improves progression-free survival (PFS).⁴

Unfortunately, many newly diagnosed patients are not eligible for ASCT–either because of comorbidities or other complexities related to the presentation of their disease.  

For patients who are transplant-ineligible (TIE), it is important to have treatment options that are proven effective in extending PFS and overall survival (OS), and capable of producing deep and durable responses.

2. What are the challenges associated with treating newly diagnosed patients who are not eligible for ASCT?

We still consider multiple myeloma to be an incurable disease but, in my opinion, the treatment of TIE patients is less challenging today than a decade ago due to the emergence of novel therapies. That said, TIE patients are typically older and present with more advanced disease and comorbidities, including diabetes or cardiovascular events.⁵ 

A retrospective analysis published in 2020 by Rafael Fonseca examined frontline treatment patterns and attrition rates by line of therapy among newly diagnosed multiple myeloma (NDMM) patients who are TIE. More than 22,000 patients were identified from three patient-level databases between 2000 and 2018 - the OPTUM Commercial Claims database, the OPTUM Electronic Medical Records database, and the Surveillance, Epidemiology, and End Results-Meidcare Linked database. Patients included had to have a multiple myeloma diagnosis on or after January 1, 2007. Results showed that attrition rates among newly diagnosed, TIE patients with multiple myeloma increase with each line of therapy, with the proportion of patients who receive a second line of therapy decreasing by 50 percent with each subsequent line.³ 

3. Can you provide more detail on the goals of therapy for newly diagnosed, transplant-ineligible patients?

When I discuss treatment goals with TIE patients, I feel it is important to emphasize managing side effects and achieving deep and durable responses. I have the benefit of being in an academic setting, where I regularly exchange information with my colleagues about what we’re learning from the clinical studies in which we participate. Choosing which treatment to administer is complex and involves other considerations. For example, if two regimens have comparable efficacy, I may recommend the regimen with a more established safety profile or more robust evidence so I can properly anticipate and manage toxicities in my patients. Overall survival is one of the most important endpoints I consider, in addition to depth of response and PFS. In recent years, we’ve seen increasing evidence pointing to the importance of  using a proven effective treatment in frontline patients that are ineligible for transplant. 

4. A key study in newly-diagnosed, transplant-ineligible multiple myeloma is the Phase 3 MAIA study. Can you share the key takeaways from this study and discuss how the results have shaped treatment for this patient population?

Of course. The MAIA study is a randomized Phase 3 study evaluating DARZALEX^® (daratumumab) intravenous injection in combination with lenalidomide and dexamethasone (D-Rd) compared with Rd in 737 adult patients with newly diagnosed, transplant-ineligible multiple myeloma. The median age of patients participating in the MAIA study was 73 (range 45-90), an important consideration since the median age for multiple myeloma diagnosis is approximately 66-70 years of age.⁶ The study evaluated PFS as the primary endpoint, and overall survival as a key secondary endpoint, and supported the FDA approval of DARZALEX^® in combination with lenalidomide and dexamethasone for adult patients with newly diagnosed, multiple myeloma who are ineligible for ASCT.

MAIA study design⁷

The baseline demographic and disease characteristics were similar between the 2 treatment groups. Forty-four percent of the patients were  ≥75 years of age. Fifty-two percent (52%) of patients were male, 92% White, 4% Black or African American, and 1% Asian. Three percent (3%) of patients reported an ethnicity of Hispanic or Latino. Thirty-four (34%) had an Eastern Cooperative Oncology Group (ECOG) performance score of 0, 50% had an ECOG performance score of 1, and 17% had an ECOG performance score of ≥2. Twenty-seven percent had International Staging System (ISS) Stage I, 43% had ISS Stage II, and 29% had ISS Stage III disease. 

Select Important Safety Information: 

CONTRAINDICATIONS

DARZALEX^® is contraindicated in patients with a history of severe hypersensitivity (eg, anaphylactic reactions) to daratumumab or any of the components of the formulation.

WARNINGS AND PRECAUTIONS
Infusion-Related Reactions: DARZALEX^® can cause severe and/or serious infusion-related reactions including anaphylactic reactions.
These reactions can be life-threatening, and fatal outcomes have been reported. Please scroll down to read Important Safety Information for DARZALEX^®. 

Primary findings from the study, which were published in 2019, showed an improvement in PFS in patients receiving D-Rd compared with those receiving Rd alone.⁷ The median PFS was not reached in the D-Rd arm and was reached at 31.9 months in the Rd arm (HR 0.56; 95% CI 0.43-0.73; P<0.0001).⁷ At a median of 30 months of follow-up, the data showed the clinical benefit of D-Rd therapy, with a 44% reduction in the risk of disease progression or death in patients receiving D-Rd compared with Rd alone.⁷ 

Progression-free survival in TIE NDMM after ~30 months of treatment with D-Rd^7,8

Additionally, 70.6% of patients (95% CI, 65.0-75.4) had no progressive disease with D-Rd treatment at median 30 months of follow-up, compared with 55.6% (95% CI, 49.5-61.3) of patients in the Rd group.⁷

In terms of depth of response, the percentage of patients with a complete response or better was 47.6% in patients receiving D-Rd compared with 24.9% in the Rd group.⁷

Overall response rate with D-Rd in TIE NDMM at ~30 months of follow-up⁸

An overview of the most frequent adverse events at 30-months of follow-up are provided below. The most frequent adverse reactions were reported in ≥20% of patients, with at least a 5% greater frequency in the D-Rd arm compared with Rd alone.⁸ 

Most frequent adverse events at ~30 months of follow-up with D-Rd in TIE NDMM⁸

Most frequent hematologic laboratory abnormalities with D-Rd in TIE NDMM at ~30 months⁸

Serious adverse reactions with a 2% greater incidence in the D-Rd arm compared with the Rd arm were pneumonia (D-Rd 15% vs Rd 8%), bronchitis (D-Rd 4% vs Rd 2%), and dehydration (D-Rd 2% vs Rd <1).
• Discontinuation rates due to any adverse event: 7% with D-Rd vs 16% with Rd
• Infusion-related reactions (IRRs) with D-Rd occurred in 41% of patients; 2% were Grade 3 and <1% were Grade 4
• IRRs of any grade or severity may require management by interruption, modification, and/or discontinuation of the infusion
• Most IRRs occurred during first infusion

5. Thanks for that overview. In addition to these results, The Lancet Oncology has published updated overall survival data from a 5-year follow-up on the MAIA study. Can you provide an overview of these data and insights on their potential for patients?  

The MAIA trial was an important study, and for me, the results were practice changing. We see that after a median of nearly 5 years of follow-up, D-Rd significantly improved OS in TIE NDMM patients who were treated to progression compared with Rd alone (66.3% vs. 53.1% [HR=0.68; 95% CI, 0.53-0.86; P=0.0013]).⁹ This equates to approximately a 32% reduction in death when DARZALEX^® was added to a two-drug regimen, which is a meaningful consideration when selecting the most appropriate regimens for my newly diagnosed, transplant-ineligible patients.⁹

Overall survival data at ~5 years with D-Rd compared to Rd alone in TIE NDMM⁹

Importantly, efficacy that resulted from longer treatment with D-Rd is also supported by approximately 5 years of safety evaluation. Below is information from a follow-up analysis of the MAIA study. This information is not included in the current Prescribing Information and has not been evaluated by the FDA. Treatment-emergent adverse events are reported as observed. These analyses have not been adjusted for multiple comparisons and no conclusions should be drawn. In what I’ve observed through published data and in my practice, longer treatment has not revealed new safety signals.

Most frequent treatment-emergent adverse events (any grade reported in ≥30% of patients and/or Grade 3/4 reported in ≥10% of patients) at ~5 years⁹

Select Important Safety Information: 

DARZALEX^® can cause severe and/or serious infusion-related reactions including anaphylactic reactions. These reactions can be life threatening, and fatal outcomes have been reported. In clinical trials (monotherapy and combination: N=2066), infusion-related reactions occurred in 37% of patients with the Week 1 (16 mg/kg) infusion, 2% with the Week 2 infusion, and cumulatively 6% with subsequent infusions. Less than 1% of patients had a Grade 3/4 infusion-related reaction at Week 2 or subsequent infusions. The median time to onset was 1.5 hours (range: 0 to 73 hours). Nearly all reactions occurred during infusion or within 4 hours of completing DARZALEX^®. Severe reactions have occurred, including bronchospasm, hypoxia, dyspnea, hypertension, tachycardia, headache, laryngeal edema, pulmonary edema, and ocular adverse reactions, including choroidal effusion, acute myopia, and acute angle closure glaucoma. Signs and symptoms may include respiratory symptoms, such as nasal congestion, cough, throat irritation, as well as chills, vomiting, and nausea. Less common signs and symptoms were wheezing, allergic rhinitis, pyrexia, chest discomfort, pruritus, hypotension and blurred vision. Please scroll down to see Important Safety Information for DARZALEX^®.

6. Does the availability of OS data influence your decisions on treatment selection in TIE NDMM?

Overall survival absolutely remains the gold standard and informs my practice. Prior to OS data being available, I will often look at other efficacy endpoints that are available sooner. In MAIA, I was encouraged by efficacy endpoints in earlier data, which were later confirmed by the latest data on OS.

7. The MAIA study shows that treating to disease progression or unacceptable toxicity is important. How does that impact your approach to treatment?

It's important to keep in mind that the MAIA trial was designed to evaluate treatment until progression or unacceptable toxicity. The results revealed a significant difference between the DR-d and Rd treatment arms, but results observed in this study are contingent on this treatment approach. From a clinical perspective, unless there is considerable toxicity, I advocate for treating with D-Rd to progression.

In the clinic, we also see that TIE patients who have higher frailty scores are more likely to discontinue treatment prior to progression.¹⁰ There can be other reasons too – such as a patient simply wanting to have a break from treatment. These conversations are not always easy, but it is important to have an honest dialogue with patients.

8. What can we learn from studies like the MAIA trial that included a wide range of patient populations including patients who are elderly, frail, or had high cytogenetic risk? 

Several patient subgroups were analyzed as part of the MAIA study. It is important to note that these subgroup analyses are not included in the Prescribing Information for DARZALEX^®. These analyses were not adjusted for multiple comparisons, and there are insufficient numbers of patients per subgroup to make definitive conclusions of efficacy among the subgroups.

As mentioned above, the MAIA study evaluated a wide range of patients (n=737). The baseline demographic and disease characteristics were similar between the D-Rd and Rd treatment groups and the median age was 73 (range: 45-90) years, with 44% of the patients ≥75 years of age.

In the various patient subgroups that were analyzed as part of the MAIA study, it was found that at ~3-years of follow-up the PFS numerically favored DRd compared with Rd alone in most subgroups (see table below).

Median progression-free survival by sub-population at ~3 year follow-up⁸

The MAIA trial also included patients who were frail and a post hoc analysis was conducted in this subgroup of patients. These analyses are not included in the Prescribing Information for DARZALEX^®. These analyses were conducted post hoc and there are insufficient numbers of patients per subgroup to make definitive conclusions of efficacy among the subgroups.

A frailty assessment was performed retrospectively using age, the Charlson Comorbidity Index (CCI) – which is calculated based on a retrospective review of the patient’s medical history to predict the 10-year mortality – and the baseline Eastern Cooperative Oncology Group (ECOG) performance status score, used to measure a patient’s level of functioning in terms of their ability to care for themselves, daily activity, and physical activity. The frailty scores were then added up to classify patients into fit (0), intermediate (1), or frail (≥2). Frailty status was further simplified into 2 categories: non-frail (0-1) and frail (≥2). The median age in the frail subgroup was 77 years (range: 57-80 years), with 88% of patients having ECOG performance score ≥1. CCI was calculated based on retrospective review of each patient’s medical history.¹²

The charts below illustrate the frailty scoring system with an overview of the patient population included in the 3-year post hoc analysis, PFS rate, and adverse events.

MAIA post hoc subgroup analysis by frailty status score¹²

The retrospective assessment of frailty score was a limitation of this study. Retrospective CCI calculations were based on reported medical history, which may contain missing data and result in underestimating or overestimating the number of patients in each frailty subgroup. The ECOG PS score parameter used for frailty score calculations in the study is more subjective, with susceptibility to intra- and inter-observer bias, compared with the ADL (activities of daily living) and IADL (instrumental activities of daily living) scales used in the IMWG scoring system. While the frailty scale used in the study is based on parameters that are routinely assessed in clinical practice for clinical use, the use of comprehensive frailty assessments that more accurately reflect biological or functional frailty will remain important for the further optimization of treatment strategies for frail patients. Patients with an ECOG PS score ≥3 and patients with comorbidities that may interfere with the study procedures were excluded from MAIA; the inclusion and exclusion criteria for the study limits the generalizability of these results to more frail patients seen in clinical practice.

Progression-free survival in a ~3-year subgroup analysis of frail patients following treatment with D-Rd in TIE NDMM¹²

Most frequent Grade 3/4 treatment-emergent adverse events (≥10%) in frail patients at ~3 year follow-up of MAIA trial¹²

Please see additional Important Safety Information for DARZALEX^® below.

IMPORTANT SAFETY INFORMATION

CONTRAINDICATIONS

DARZALEX^® is contraindicated in patients with a history of severe hypersensitivity (eg, anaphylactic reactions) to daratumumab or any of the components of the formulation.

WARNINGS AND PRECAUTIONS

Infusion-Related Reactions

DARZALEX^® can cause severe and/or serious infusion-related reactions including anaphylactic reactions. These reactions can be life‑threatening, and fatal outcomes have been reported. In clinical trials (monotherapy and combination: N=2066), infusion-related reactions occurred in 37% of patients with the Week 1 (16 mg/kg) infusion, 2% with the Week 2 infusion, and cumulatively 6% with subsequent infusions. Less than 1% of patients had a Grade 3/4 infusion-related reaction at Week 2 or subsequent infusions. The median time to onset was 1.5 hours (range: 0 to 73 hours). Nearly all reactions occurred during infusion or within 4 hours of completing DARZALEX^®. Severe reactions have occurred, including bronchospasm, hypoxia, dyspnea, hypertension, tachycardia, headache, laryngeal edema, pulmonary edema, and ocular adverse reactions, including choroidal effusion, acute myopia, and acute angle closure glaucoma. Signs and symptoms may include respiratory symptoms, such as nasal congestion, cough, throat irritation, as well as chills, vomiting, and nausea. Less common signs and symptoms were wheezing, allergic rhinitis, pyrexia, chest discomfort, pruritus, hypotension and blurred vision.

When DARZALEX^® dosing was interrupted in the setting of ASCT (CASSIOPEIA) for a median of 3.75 months (range: 2.4 to 6.9 months), upon re-initiation of DARZALEX^®, the incidence of infusion-related reactions was 11% for the first infusion following ASCT. Infusion-related reactions occurring at re-initiation of DARZALEX^® following ASCT were consistent in terms of symptoms and severity (Grade 3 or 4: <1%) with those reported in previous studies at Week 2 or subsequent infusions. In EQUULEUS, patients receiving combination treatment (n=97) were administered the first 16 mg/kg dose at Week 1 split over two days, ie, 8 mg/kg on Day 1 and Day 2, respectively. The incidence of any grade infusion-related reactions was 42%, with 36% of patients experiencing infusion-related reactions on Day 1 of Week 1, 4% on Day 2 of Week 1, and 8% with subsequent infusions.

Pre-medicate patients with antihistamines, antipyretics, and corticosteroids. Frequently monitor patients during the entire infusion. Interrupt DARZALEX^® infusion for reactions of any severity and institute medical management as needed. Permanently discontinue DARZALEX^® therapy if an anaphylactic reaction or life-threatening (Grade 4) reaction occurs and institute appropriate emergency care. For patients with Grade 1, 2, or 3 reactions, reduce the infusion rate when re-starting the infusion.

To reduce the risk of delayed infusion-related reactions, administer oral corticosteroids to all patients following DARZALEX^® infusions. Patients with a history of chronic obstructive pulmonary disease may require additional post-infusion medications to manage respiratory complications. Consider prescribing short- and long-acting bronchodilators and inhaled corticosteroids for patients with chronic obstructive pulmonary disease.

Ocular adverse reactions, including acute myopia and narrowing of the anterior chamber angle due to ciliochoroidal effusions with potential for increased intraocular pressure or glaucoma, have occurred with DARZALEX infusion. If ocular symptoms occur, interrupt DARZALEX infusion and seek immediate ophthalmologic evaluation prior to restarting DARZALEX.

Interference With Serological Testing

Daratumumab binds to CD38 on red blood cells (RBCs) and results in a positive indirect antiglobulin test (indirect Coombs test). Daratumumab-mediated positive indirect antiglobulin test may persist for up to 6 months after the last daratumumab infusion. Daratumumab bound to RBCs masks detection of antibodies to minor antigens in the patient’s serum. The determination of a patient’s ABO and Rh blood type is not impacted. Notify blood transfusion centers of this interference with serological testing and inform blood banks that a patient has received DARZALEX^®. Type and screen patients prior to starting DARZALEX^®.

Neutropenia and Thrombocytopenia

DARZALEX^® may increase neutropenia and thrombocytopenia induced by background therapy. Monitor complete blood cell counts periodically during treatment according to manufacturer’s prescribing information for background therapies. Monitor patients with neutropenia for signs of infection. Consider withholding DARZALEX^® until recovery of neutrophils or for recovery of platelets.

Interference With Determination of Complete Response

Daratumumab is a human immunoglobulin G (IgG) kappa monoclonal antibody that can be detected on both the serum protein electrophoresis (SPE) and immunofixation (IFE) assays used for the clinical monitoring of endogenous M-protein. This interference can impact the determination of complete response and of disease progression in some patients with IgG kappa myeloma protein.

Embryo-Fetal Toxicity

Based on the mechanism of action, DARZALEX^® can cause fetal harm when administered to a pregnant woman. DARZALEX^® may cause depletion of fetal immune cells and decreased bone density. Advise pregnant women of the potential risk to a fetus. Advise females with reproductive potential to use effective contraception during treatment with DARZALEX^® and for 3 months after the last dose.

The combination of DARZALEX^® with lenalidomide, pomalidomide, or thalidomide is contraindicated in pregnant women because lenalidomide, pomalidomide, and thalidomide may cause birth defects and death of the unborn child. Refer to the lenalidomide, pomalidomide, or thalidomide prescribing information on use during pregnancy.

ADVERSE REACTIONS

The most frequently reported adverse reactions (incidence ≥20%) were: upper respiratory infection, neutropenia, infusion‑related reactions, thrombocytopenia, diarrhea, constipation, anemia, peripheral sensory neuropathy, fatigue, peripheral edema, nausea, cough, pyrexia, dyspnea, and asthenia. The most common hematologic laboratory abnormalities (≥40%) with DARZALEX^® are: neutropenia, lymphopenia, thrombocytopenia, leukopenia, and anemia.

INDICATIONS

DARZALEX^® (daratumumab) is indicated for the treatment of adult patients with multiple myeloma:

• In combination with lenalidomide and dexamethasone in newly diagnosed patients who are ineligible for autologous stem cell transplant and in patients with relapsed or refractory multiple myeloma who have received at least one prior therapy
• In combination with bortezomib, melphalan, and prednisone in newly diagnosed patients who are ineligible for autologous stem cell transplant
• In combination with bortezomib, thalidomide, and dexamethasone in newly diagnosed patients who are eligible for autologous stem cell transplant
• In combination with bortezomib and dexamethasone in patients who have received at least one prior therapy
• In combination with carfilzomib and dexamethasone in patients with relapsed or refractory multiple myeloma who have received one to three prior lines of therapy
• In combination with pomalidomide and dexamethasone in patients who have received at least two prior therapies including lenalidomide and a proteasome inhibitor
• As monotherapy in patients who have received at least three prior lines of therapy including a proteasome inhibitor (PI) and an immunomodulatory agent or who are double-refractory to a PI and an immunomodulatory agent

Please click here to see the full Prescribing Information.