Clinical Edge Journal Scan

Key clinical point: A broad category of blood pressure (BP)-lowering medication classes and drugs effectively reduced headache frequency in patients with episodic migraine.

Major finding: Compared with placebo, headache days per month reduced significantly with alpha-blockers (P = .023), angiotensin II receptor blockers (P = .024), beta-blockers (P = .035), and calcium channel blockers (P = .025). Specific BP-lowering drugs, such as clonidine (P = .026), candesartan (P = .001), atenolol (P = .010), bisoprolol (P = .000), propranolol (P = .000), timolol (P = .000), nicardipine (P = .001), and verapamil (P = .016), also effectively reduced the number of headache days per month.

Study details: Findings are from a systematic review and meta-analysis of 50 studies including 4310 participants.

Disclosures: This study received no specific funding. LR Griffiths reported receiving migraine research funding from the Australian National Health and Medical Research Council. AS Zagami declared being an associate editor for Cephalalgia. A Rodgers declared being an inventor for George Health Enterprises. The other authors declared no conflicts of interest.

Source: Carcel C, Haghdoost F, et al. The effect of blood pressure lowering medications on the prevention of episodic migraine: A systematic review and meta-analysis. Cephalalgia. 2023 (Jun 23). Doi: 10.1177/03331024231183166

Key clinical point: A broad category of blood pressure (BP)-lowering medication classes and drugs effectively reduced headache frequency in patients with episodic migraine.

Major finding: Compared with placebo, headache days per month reduced significantly with alpha-blockers (P = .023), angiotensin II receptor blockers (P = .024), beta-blockers (P = .035), and calcium channel blockers (P = .025). Specific BP-lowering drugs, such as clonidine (P = .026), candesartan (P = .001), atenolol (P = .010), bisoprolol (P = .000), propranolol (P = .000), timolol (P = .000), nicardipine (P = .001), and verapamil (P = .016), also effectively reduced the number of headache days per month.

Study details: Findings are from a systematic review and meta-analysis of 50 studies including 4310 participants.

Disclosures: This study received no specific funding. LR Griffiths reported receiving migraine research funding from the Australian National Health and Medical Research Council. AS Zagami declared being an associate editor for Cephalalgia. A Rodgers declared being an inventor for George Health Enterprises. The other authors declared no conflicts of interest.

Source: Carcel C, Haghdoost F, et al. The effect of blood pressure lowering medications on the prevention of episodic migraine: A systematic review and meta-analysis. Cephalalgia. 2023 (Jun 23). Doi: 10.1177/03331024231183166

Key clinical point: A broad category of blood pressure (BP)-lowering medication classes and drugs effectively reduced headache frequency in patients with episodic migraine.

Major finding: Compared with placebo, headache days per month reduced significantly with alpha-blockers (P = .023), angiotensin II receptor blockers (P = .024), beta-blockers (P = .035), and calcium channel blockers (P = .025). Specific BP-lowering drugs, such as clonidine (P = .026), candesartan (P = .001), atenolol (P = .010), bisoprolol (P = .000), propranolol (P = .000), timolol (P = .000), nicardipine (P = .001), and verapamil (P = .016), also effectively reduced the number of headache days per month.

Study details: Findings are from a systematic review and meta-analysis of 50 studies including 4310 participants.

Disclosures: This study received no specific funding. LR Griffiths reported receiving migraine research funding from the Australian National Health and Medical Research Council. AS Zagami declared being an associate editor for Cephalalgia. A Rodgers declared being an inventor for George Health Enterprises. The other authors declared no conflicts of interest.

Source: Carcel C, Haghdoost F, et al. The effect of blood pressure lowering medications on the prevention of episodic migraine: A systematic review and meta-analysis. Cephalalgia. 2023 (Jun 23). Doi: 10.1177/03331024231183166

Key clinical point: Migraine increased the risk for premature ischemic stroke similarly among women and men aged ≤60 years; however, the effect of migraine on the risk for premature myocardial infarction (MI) and hemorrhagic stroke was greater only in women but not in men with migraine.

Major finding: Compared with those without migraine, women (adjusted HR [aHR] 1.21) and men (aHR 1.23; both P < .001) with migraine showed a similar increase in the risk for premature ischemic stroke. However, the risk for premature MI (aHR 1.22; 95% CI 1.14-1.31; P < .001) and hemorrhagic stroke (aHR 1.13; 95% CI 1.02-1.24; P = .014) was significantly higher in women with vs without migraine but not in men.

Study details: This nationwide population-based cohort study included 179,680 women and 40,757 men with migraine.

Disclosures: This study did not receive any specific funding. CH Fuglsang declared owning stock in Novo Nordisk, and M Schmidt declared being supported by the Novo Nordisk Foundation.

Source: Fuglsang CH et al. Migraine and risk of premature myocardial infarction and stroke among men and women: A Danish population-based cohort study. PLoS Med. 2023;20(6):e1004238 (Jun 13). Doi: 10.1371/journal.pmed.1004238

Key clinical point: Migraine increased the risk for premature ischemic stroke similarly among women and men aged ≤60 years; however, the effect of migraine on the risk for premature myocardial infarction (MI) and hemorrhagic stroke was greater only in women but not in men with migraine.

Major finding: Compared with those without migraine, women (adjusted HR [aHR] 1.21) and men (aHR 1.23; both P < .001) with migraine showed a similar increase in the risk for premature ischemic stroke. However, the risk for premature MI (aHR 1.22; 95% CI 1.14-1.31; P < .001) and hemorrhagic stroke (aHR 1.13; 95% CI 1.02-1.24; P = .014) was significantly higher in women with vs without migraine but not in men.

Study details: This nationwide population-based cohort study included 179,680 women and 40,757 men with migraine.

Disclosures: This study did not receive any specific funding. CH Fuglsang declared owning stock in Novo Nordisk, and M Schmidt declared being supported by the Novo Nordisk Foundation.

Source: Fuglsang CH et al. Migraine and risk of premature myocardial infarction and stroke among men and women: A Danish population-based cohort study. PLoS Med. 2023;20(6):e1004238 (Jun 13). Doi: 10.1371/journal.pmed.1004238

Key clinical point: Migraine increased the risk for premature ischemic stroke similarly among women and men aged ≤60 years; however, the effect of migraine on the risk for premature myocardial infarction (MI) and hemorrhagic stroke was greater only in women but not in men with migraine.

Major finding: Compared with those without migraine, women (adjusted HR [aHR] 1.21) and men (aHR 1.23; both P < .001) with migraine showed a similar increase in the risk for premature ischemic stroke. However, the risk for premature MI (aHR 1.22; 95% CI 1.14-1.31; P < .001) and hemorrhagic stroke (aHR 1.13; 95% CI 1.02-1.24; P = .014) was significantly higher in women with vs without migraine but not in men.

Study details: This nationwide population-based cohort study included 179,680 women and 40,757 men with migraine.

Disclosures: This study did not receive any specific funding. CH Fuglsang declared owning stock in Novo Nordisk, and M Schmidt declared being supported by the Novo Nordisk Foundation.

Source: Fuglsang CH et al. Migraine and risk of premature myocardial infarction and stroke among men and women: A Danish population-based cohort study. PLoS Med. 2023;20(6):e1004238 (Jun 13). Doi: 10.1371/journal.pmed.1004238

Calcitonin gene-related peptide (CGRP) antagonist medications have revolutionized migraine therapy since being introduced in 2018. The initial preventive trials for monoclonal antibodies (mAb) excluded older adults, with a cutoff in all studies at age 65 years. Long-term safety studies have not revealed signals for concern related to vascular or other adverse events. The study by Muñoz-Vendrell and colleagues investigated the efficacy of CGRP mAb in treatment-refractory older adults.

This was an observational retrospective study in participants older than 65 years that had previously used three or more prior migraine preventives unsuccessfully. The primary endpoints were reduction in monthly migraine days after 6 months of treatment and the presence of adverse effects. Secondary endpoints were reductions in headache and acute medication frequency as well as improvement in patient reported outcomes.

A total of 162 participants were followed at 18 different headache centers throughout Spain. All patients had at least 8 headache days per month and had been treated unsuccessfully with three prior medications for migraine prevention, one of which was botulinum toxin. The median age was 68 years, and over 80% had chronic migraine. The reduction in mean headache days was 10 days per month; 72% continued to use their CGRP mAb after using it for 6 months. Participants were compared relative to medication overuse but no significant differences were found between those who overused medication and others.

This study highlights the efficacy of CGRP medications in those outside of the initially studied population. Other preventive medications may be contraindicated in this population, but CGRP antagonists do appear to be safe and effective options for older adults.

Opiate medications are typically considered inappropriate as an acute treatment for migraine. Even infrequent use of opiate medications has been shown to be associated with worse migraine outcomes, specifically higher frequency and a higher likelihood to convert from episodic to chronic migraine. Van Welie and colleagues performed a cross-sectional questionnaire-based study assessing levels of opioid use in patients with migraine.

Participants were selected from the Leiden Headache Center and fit the diagnostic criteria of migraine. They were given an e-questionnaire to determine their use of these opiates: buprenorphine, fentanyl, hydromorphone, morphine, oxycodone, tapentadol, and tramadol (codeine was not included in this list). Patients were separately divided between chronic and episodic migraine groups. The primary outcome was assessing for current acute treatment of migraine with an opiate; secondary outcomes were association of chronicity of migraine and likelihood of medication overuse with opiate use.

Only approximately 1.8% of participants reported that they currently use an opiate for acute migraine treatment; 12.5% reported that they previously have used an opiate and 25.7% reported using an opiate for another pain condition. Tramadol was the most commonly used opiate medication, followed by oxycodone and morphine; 2.4% of patients reported that their opiate use was not prescribed by their doctor. Primary care doctors were the most common prescribers of the opiate medications; 16% of the time, patients were told that it was a preventive treatment for migraine. Opiate use was more frequent in patients with a diagnosis of chronic migraine, and the duration of use was greater.

Opiate medications remain a poor acute choice of treatment for migraine, and this study shows a correlation between higher opiate use and chronic migraine. There are many other acute medications now available for migraine, many of them migraine-specific treatments, such as triptans, gepants, and ditans. This research again shows that opiates should be avoided if at all possible for migraine.

Patients with medication overuse headache are more likely to be treatment-refractory, and the addition of acute medications often can be less effective if they remain on the overused medication. There has been a long-standing debate whether it is best to wean medications first or start a preventive initially when faced with medication overuse. The CGRP antagonists may be one of the better preventive options in this situation, and one mAb (fremenezumab) reported positive data in a small medication overuse trial. The study by Guerzoni and colleagues investigated the effectiveness of galcanezumab in chronic migraine with medication overuse.

This was a prospective trial conducted at the University Hospital of Modena. A total of 78 patients with a diagnosis of chronic migraine and medication overuse were enrolled for 15 months, with follow-up every 3 months. At each follow-up appointment, they completed a questionnaire asking them details about: mean migraine days per month, mean number of painkillers taken per month, mean days per month taking a painkiller, average migraine severity, and the Headache Impact Test (HIT-6) and Migraine Disability Assessment (MIDAS) questions. Patients were given the standard-dosing regimen of glacanezumab for migraine and were not blinded; this was an open-label study.

The mean migraine days per month were significantly reduced after 3, 6, 9, and 12 months. The amount of painkillers used per month and days of painkillers per month both reduced significantly as well. Migraine-related disability on HIT-6 and MIDAS were all reduced significantly as well. The most significant improvement long-term was noted in patients who improved the most during the initial 3 months of treatment.

The debate regarding the best treatment for patients with medication overuse will continue, but this study highlights the effectiveness of CGRP mAb use in this population. Patients were able to decrease the use of acute medications without a strict wean off of their previous medication. Ideally, a similar study should also be done for additional mAb and oral CGRP antagonists.

Calcitonin gene-related peptide (CGRP) antagonist medications have revolutionized migraine therapy since being introduced in 2018. The initial preventive trials for monoclonal antibodies (mAb) excluded older adults, with a cutoff in all studies at age 65 years. Long-term safety studies have not revealed signals for concern related to vascular or other adverse events. The study by Muñoz-Vendrell and colleagues investigated the efficacy of CGRP mAb in treatment-refractory older adults.

This was an observational retrospective study in participants older than 65 years that had previously used three or more prior migraine preventives unsuccessfully. The primary endpoints were reduction in monthly migraine days after 6 months of treatment and the presence of adverse effects. Secondary endpoints were reductions in headache and acute medication frequency as well as improvement in patient reported outcomes.

A total of 162 participants were followed at 18 different headache centers throughout Spain. All patients had at least 8 headache days per month and had been treated unsuccessfully with three prior medications for migraine prevention, one of which was botulinum toxin. The median age was 68 years, and over 80% had chronic migraine. The reduction in mean headache days was 10 days per month; 72% continued to use their CGRP mAb after using it for 6 months. Participants were compared relative to medication overuse but no significant differences were found between those who overused medication and others.

This study highlights the efficacy of CGRP medications in those outside of the initially studied population. Other preventive medications may be contraindicated in this population, but CGRP antagonists do appear to be safe and effective options for older adults.

Opiate medications are typically considered inappropriate as an acute treatment for migraine. Even infrequent use of opiate medications has been shown to be associated with worse migraine outcomes, specifically higher frequency and a higher likelihood to convert from episodic to chronic migraine. Van Welie and colleagues performed a cross-sectional questionnaire-based study assessing levels of opioid use in patients with migraine.

Participants were selected from the Leiden Headache Center and fit the diagnostic criteria of migraine. They were given an e-questionnaire to determine their use of these opiates: buprenorphine, fentanyl, hydromorphone, morphine, oxycodone, tapentadol, and tramadol (codeine was not included in this list). Patients were separately divided between chronic and episodic migraine groups. The primary outcome was assessing for current acute treatment of migraine with an opiate; secondary outcomes were association of chronicity of migraine and likelihood of medication overuse with opiate use.

Only approximately 1.8% of participants reported that they currently use an opiate for acute migraine treatment; 12.5% reported that they previously have used an opiate and 25.7% reported using an opiate for another pain condition. Tramadol was the most commonly used opiate medication, followed by oxycodone and morphine; 2.4% of patients reported that their opiate use was not prescribed by their doctor. Primary care doctors were the most common prescribers of the opiate medications; 16% of the time, patients were told that it was a preventive treatment for migraine. Opiate use was more frequent in patients with a diagnosis of chronic migraine, and the duration of use was greater.

Opiate medications remain a poor acute choice of treatment for migraine, and this study shows a correlation between higher opiate use and chronic migraine. There are many other acute medications now available for migraine, many of them migraine-specific treatments, such as triptans, gepants, and ditans. This research again shows that opiates should be avoided if at all possible for migraine.

Patients with medication overuse headache are more likely to be treatment-refractory, and the addition of acute medications often can be less effective if they remain on the overused medication. There has been a long-standing debate whether it is best to wean medications first or start a preventive initially when faced with medication overuse. The CGRP antagonists may be one of the better preventive options in this situation, and one mAb (fremenezumab) reported positive data in a small medication overuse trial. The study by Guerzoni and colleagues investigated the effectiveness of galcanezumab in chronic migraine with medication overuse.

This was a prospective trial conducted at the University Hospital of Modena. A total of 78 patients with a diagnosis of chronic migraine and medication overuse were enrolled for 15 months, with follow-up every 3 months. At each follow-up appointment, they completed a questionnaire asking them details about: mean migraine days per month, mean number of painkillers taken per month, mean days per month taking a painkiller, average migraine severity, and the Headache Impact Test (HIT-6) and Migraine Disability Assessment (MIDAS) questions. Patients were given the standard-dosing regimen of glacanezumab for migraine and were not blinded; this was an open-label study.

The mean migraine days per month were significantly reduced after 3, 6, 9, and 12 months. The amount of painkillers used per month and days of painkillers per month both reduced significantly as well. Migraine-related disability on HIT-6 and MIDAS were all reduced significantly as well. The most significant improvement long-term was noted in patients who improved the most during the initial 3 months of treatment.

The debate regarding the best treatment for patients with medication overuse will continue, but this study highlights the effectiveness of CGRP mAb use in this population. Patients were able to decrease the use of acute medications without a strict wean off of their previous medication. Ideally, a similar study should also be done for additional mAb and oral CGRP antagonists.

Calcitonin gene-related peptide (CGRP) antagonist medications have revolutionized migraine therapy since being introduced in 2018. The initial preventive trials for monoclonal antibodies (mAb) excluded older adults, with a cutoff in all studies at age 65 years. Long-term safety studies have not revealed signals for concern related to vascular or other adverse events. The study by Muñoz-Vendrell and colleagues investigated the efficacy of CGRP mAb in treatment-refractory older adults.

This was an observational retrospective study in participants older than 65 years that had previously used three or more prior migraine preventives unsuccessfully. The primary endpoints were reduction in monthly migraine days after 6 months of treatment and the presence of adverse effects. Secondary endpoints were reductions in headache and acute medication frequency as well as improvement in patient reported outcomes.

A total of 162 participants were followed at 18 different headache centers throughout Spain. All patients had at least 8 headache days per month and had been treated unsuccessfully with three prior medications for migraine prevention, one of which was botulinum toxin. The median age was 68 years, and over 80% had chronic migraine. The reduction in mean headache days was 10 days per month; 72% continued to use their CGRP mAb after using it for 6 months. Participants were compared relative to medication overuse but no significant differences were found between those who overused medication and others.

This study highlights the efficacy of CGRP medications in those outside of the initially studied population. Other preventive medications may be contraindicated in this population, but CGRP antagonists do appear to be safe and effective options for older adults.

Opiate medications are typically considered inappropriate as an acute treatment for migraine. Even infrequent use of opiate medications has been shown to be associated with worse migraine outcomes, specifically higher frequency and a higher likelihood to convert from episodic to chronic migraine. Van Welie and colleagues performed a cross-sectional questionnaire-based study assessing levels of opioid use in patients with migraine.

Participants were selected from the Leiden Headache Center and fit the diagnostic criteria of migraine. They were given an e-questionnaire to determine their use of these opiates: buprenorphine, fentanyl, hydromorphone, morphine, oxycodone, tapentadol, and tramadol (codeine was not included in this list). Patients were separately divided between chronic and episodic migraine groups. The primary outcome was assessing for current acute treatment of migraine with an opiate; secondary outcomes were association of chronicity of migraine and likelihood of medication overuse with opiate use.

Only approximately 1.8% of participants reported that they currently use an opiate for acute migraine treatment; 12.5% reported that they previously have used an opiate and 25.7% reported using an opiate for another pain condition. Tramadol was the most commonly used opiate medication, followed by oxycodone and morphine; 2.4% of patients reported that their opiate use was not prescribed by their doctor. Primary care doctors were the most common prescribers of the opiate medications; 16% of the time, patients were told that it was a preventive treatment for migraine. Opiate use was more frequent in patients with a diagnosis of chronic migraine, and the duration of use was greater.

Opiate medications remain a poor acute choice of treatment for migraine, and this study shows a correlation between higher opiate use and chronic migraine. There are many other acute medications now available for migraine, many of them migraine-specific treatments, such as triptans, gepants, and ditans. This research again shows that opiates should be avoided if at all possible for migraine.

Patients with medication overuse headache are more likely to be treatment-refractory, and the addition of acute medications often can be less effective if they remain on the overused medication. There has been a long-standing debate whether it is best to wean medications first or start a preventive initially when faced with medication overuse. The CGRP antagonists may be one of the better preventive options in this situation, and one mAb (fremenezumab) reported positive data in a small medication overuse trial. The study by Guerzoni and colleagues investigated the effectiveness of galcanezumab in chronic migraine with medication overuse.

This was a prospective trial conducted at the University Hospital of Modena. A total of 78 patients with a diagnosis of chronic migraine and medication overuse were enrolled for 15 months, with follow-up every 3 months. At each follow-up appointment, they completed a questionnaire asking them details about: mean migraine days per month, mean number of painkillers taken per month, mean days per month taking a painkiller, average migraine severity, and the Headache Impact Test (HIT-6) and Migraine Disability Assessment (MIDAS) questions. Patients were given the standard-dosing regimen of glacanezumab for migraine and were not blinded; this was an open-label study.

The mean migraine days per month were significantly reduced after 3, 6, 9, and 12 months. The amount of painkillers used per month and days of painkillers per month both reduced significantly as well. Migraine-related disability on HIT-6 and MIDAS were all reduced significantly as well. The most significant improvement long-term was noted in patients who improved the most during the initial 3 months of treatment.

The debate regarding the best treatment for patients with medication overuse will continue, but this study highlights the effectiveness of CGRP mAb use in this population. Patients were able to decrease the use of acute medications without a strict wean off of their previous medication. Ideally, a similar study should also be done for additional mAb and oral CGRP antagonists.

Mantle cell lymphoma (MCL) is a rare and often heterogenous subtype of non-Hodgkin lymphoma (NHL). Though patients can experience prolonged remissions after frontline therapy, most patients ultimately relapse. Treatment of relapsed/refractory disease can be challenging, but there have recently been a growing number of therapeutic options in this setting. Covalent Bruton tyrosine kinase (BTK) inhibitors, for example, have demonstrated activity in patients with MCL and are approved by the US Food and Drug Administration (FDA) for relapsed/refractory disease. Chimeric antigen receptor (CAR) T-cell therapy is also an effective option for relapsed/refractory disease, though this is typically available only at select centers and is associated with toxicities, such as cytokine release syndrome and neurologic toxicity.

Recently, a novel BTK inhibitor, pirtobrutinib, has also been studied across NHL, including MCL (Wang et al) Pirtobrutinib is a selective, noncovalent BTK inhibitor with the ability to bind both the C481S-mutant and wild-type BTK. The multicenter, phase 1/2 BRUIN study included 90 patients with MCL who were previously treated with a covalent BTK inhibitor. Patients in the phase 1 portion of the study were treated with oral pirtobrutinib at a dose of 25-300 mg once daily, and patients in the phase 2 study were treated at the recommended dose of 200 mg once daily. The overall response rate was 57.8% (95% CI 46.9%-68.1%), with the complete response rate being 20.0%. At a median follow-up of 12 months, the median duration of response was 21.6 (95% CI 7.5 to not reached) months. Treatment-related adverse events that were grade 3 or higher were not frequent, with neutropenia (8.5%) being the most common. Of note, grade 3 or higher hemorrhage and atrial fibrillation, which can be seen with BTK inhibitors, were rare, occurring in 3.7% and 1.2% of patients, respectively. Based on the results of this study, pirtobrutinib has been approved by the FDA for patients with relapsed/refractory MCL after at least two prior lines of therapy, including a BTK inhibitor. This is an appealing oral option for patients with relapsed disease.

Options for patients with relapsed/refractory large B-cell lymphoma (LBCL) have also significantly increased in recent years. One of the most important advances in this disease has been the use of anti-CD19 CAR T-cell therapy. There are currently three FDA-approved options for patients with relapsed/refractory LBCL who have received at least two prior lines of therapy.^1-3 More recently, axicabtagene ciloleucel (axi-cel) and lisocabtagene maraleucel (liso-cel) have also been approved for the second line based on the results of the ZUMA-7 and TRANSFORM studies, respectively.^4,5

Longer follow-up of the ZUMA-7 trial continues to confirm the advantage of axi-cel over standard-care therapy for patients with primary refractory or early relapse of disease, now with evidence of an overall survival advantage (Westin et al). The ZUMA-7 trial included 359 adults with LBCL (refractory to or relapsed within 12 months of first-line treatment) who were randomly assigned to receive axi-cel (n = 180) or standard care (n = 179). At a median follow-up of 47.2 mo, patients receiving axi-cel vs standard care had a significantly longer median overall survival (not reached vs 31.1 mo; hazard ratio [HR] 0.73; P = .03) and an absolute improvement in overall survival (8.6 percentage points at 4 years). No new treatment-related deaths were reported since the primary event-free survival analysis. These data confirm that early use of axi-cel is preferred over standard-care therapy with high-dose chemotherapy and autologous stem cell transplantation.

Another important study that was recently published looked at the role of mental health on outcomes in patients with diffuse large B-cell lymphoma (DLBCL) (Kuczmarski et al). Though it is known that mental health disorders can decrease the quality of life of patients with cancer, there is limited information on the survival implications of these issues. A recent retrospective cohort study analyzed the data of 13,244 patients aged 67 years or older with DLBCL from the Surveillance, Epidemiology, and End Results (SEER)–Medicare registry, of which, 2094 patients had depression, anxiety, or both at the time of their DLBCL diagnosis. At a median follow-up of 2.0 years, patients with depression, anxiety, or both vs without any mental disorder had significantly lower 5-year overall survival rates (27.0% vs 37.4%; HR 1.37; 95% CI 1.29-1.44). They also found that those patients with preexisting depression vs without any mental disorder have the worst survival (23.4% vs 38.0%; HR 1.37; P < .0001). Though the mechanism accounting for decreased survival is not clear, the authors postulate that mental health disorders may lead to delays or interruptions in lymphoma-directed therapy. They also note the potential for increased barriers to care in patients with mental health disorders, which may result in nonadherence in this patient population. Regardless, these results highlight the importance of mental health screening and interventions in patients with DLBCL.

Additional References

1. Neelapu SS, Locke FL, Bartlett NL, et al. Axicabtagene ciloleucel CAR T-Cell therapy in refractory large B-cell lymphoma. N Engl J Med. 2017;377:2531-2544. doi: 10.1056/NEJMoa1707447
    
2. Schuster SJ, Bishop MR, Tam CS, et al; JULIET Investigators. Tisagenlecleucel in adult relapsed or refractory diffuse large B-cell lymphoma. N Engl J Med. 2019;380:45-56. doi: 10.1056/NEJMoa1804980
    
3. Abramson JS, Palomba ML, Gordon LI, et al. Lisocabtagene maraleucel for patients with relapsed or refractory large B-cell lymphomas (TRANSCEND NHL 001): A multicentre seamless design study. Lancet. 2020;396:839-852. doi: 10.1016/S0140-6736(20)31366-0
    
4. Locke FL, Miklos DB, Jacobson CA, et al; All ZUMA-7 Investigators and Contributing Kite Members. Axicabtagene ciloleucel as second-line therapy for large B-cell lymphoma. N Engl J Med. 2022;386:640-654. doi: 10.1056/NEJMoa2116133
5. Kamdar M, Solomon SR, Arnason J, et al; TRANSFORM Investigators. Lisocabtagene maraleucel versus standard of care with salvage chemotherapy followed by autologous stem cell transplantation as second-line treatment in patients with relapsed or refractory large B-cell lymphoma (TRANSFORM): Results from an interim analysis of an open-label, randomised, phase 3 trial. Lancet. 2022;399:2294-2308. doi: 10.1016/S0140-6736(22)00662-6

Mantle cell lymphoma (MCL) is a rare and often heterogenous subtype of non-Hodgkin lymphoma (NHL). Though patients can experience prolonged remissions after frontline therapy, most patients ultimately relapse. Treatment of relapsed/refractory disease can be challenging, but there have recently been a growing number of therapeutic options in this setting. Covalent Bruton tyrosine kinase (BTK) inhibitors, for example, have demonstrated activity in patients with MCL and are approved by the US Food and Drug Administration (FDA) for relapsed/refractory disease. Chimeric antigen receptor (CAR) T-cell therapy is also an effective option for relapsed/refractory disease, though this is typically available only at select centers and is associated with toxicities, such as cytokine release syndrome and neurologic toxicity.

Recently, a novel BTK inhibitor, pirtobrutinib, has also been studied across NHL, including MCL (Wang et al) Pirtobrutinib is a selective, noncovalent BTK inhibitor with the ability to bind both the C481S-mutant and wild-type BTK. The multicenter, phase 1/2 BRUIN study included 90 patients with MCL who were previously treated with a covalent BTK inhibitor. Patients in the phase 1 portion of the study were treated with oral pirtobrutinib at a dose of 25-300 mg once daily, and patients in the phase 2 study were treated at the recommended dose of 200 mg once daily. The overall response rate was 57.8% (95% CI 46.9%-68.1%), with the complete response rate being 20.0%. At a median follow-up of 12 months, the median duration of response was 21.6 (95% CI 7.5 to not reached) months. Treatment-related adverse events that were grade 3 or higher were not frequent, with neutropenia (8.5%) being the most common. Of note, grade 3 or higher hemorrhage and atrial fibrillation, which can be seen with BTK inhibitors, were rare, occurring in 3.7% and 1.2% of patients, respectively. Based on the results of this study, pirtobrutinib has been approved by the FDA for patients with relapsed/refractory MCL after at least two prior lines of therapy, including a BTK inhibitor. This is an appealing oral option for patients with relapsed disease.

Options for patients with relapsed/refractory large B-cell lymphoma (LBCL) have also significantly increased in recent years. One of the most important advances in this disease has been the use of anti-CD19 CAR T-cell therapy. There are currently three FDA-approved options for patients with relapsed/refractory LBCL who have received at least two prior lines of therapy.^1-3 More recently, axicabtagene ciloleucel (axi-cel) and lisocabtagene maraleucel (liso-cel) have also been approved for the second line based on the results of the ZUMA-7 and TRANSFORM studies, respectively.^4,5

Longer follow-up of the ZUMA-7 trial continues to confirm the advantage of axi-cel over standard-care therapy for patients with primary refractory or early relapse of disease, now with evidence of an overall survival advantage (Westin et al). The ZUMA-7 trial included 359 adults with LBCL (refractory to or relapsed within 12 months of first-line treatment) who were randomly assigned to receive axi-cel (n = 180) or standard care (n = 179). At a median follow-up of 47.2 mo, patients receiving axi-cel vs standard care had a significantly longer median overall survival (not reached vs 31.1 mo; hazard ratio [HR] 0.73; P = .03) and an absolute improvement in overall survival (8.6 percentage points at 4 years). No new treatment-related deaths were reported since the primary event-free survival analysis. These data confirm that early use of axi-cel is preferred over standard-care therapy with high-dose chemotherapy and autologous stem cell transplantation.

Another important study that was recently published looked at the role of mental health on outcomes in patients with diffuse large B-cell lymphoma (DLBCL) (Kuczmarski et al). Though it is known that mental health disorders can decrease the quality of life of patients with cancer, there is limited information on the survival implications of these issues. A recent retrospective cohort study analyzed the data of 13,244 patients aged 67 years or older with DLBCL from the Surveillance, Epidemiology, and End Results (SEER)–Medicare registry, of which, 2094 patients had depression, anxiety, or both at the time of their DLBCL diagnosis. At a median follow-up of 2.0 years, patients with depression, anxiety, or both vs without any mental disorder had significantly lower 5-year overall survival rates (27.0% vs 37.4%; HR 1.37; 95% CI 1.29-1.44). They also found that those patients with preexisting depression vs without any mental disorder have the worst survival (23.4% vs 38.0%; HR 1.37; P < .0001). Though the mechanism accounting for decreased survival is not clear, the authors postulate that mental health disorders may lead to delays or interruptions in lymphoma-directed therapy. They also note the potential for increased barriers to care in patients with mental health disorders, which may result in nonadherence in this patient population. Regardless, these results highlight the importance of mental health screening and interventions in patients with DLBCL.

Additional References

1. Neelapu SS, Locke FL, Bartlett NL, et al. Axicabtagene ciloleucel CAR T-Cell therapy in refractory large B-cell lymphoma. N Engl J Med. 2017;377:2531-2544. doi: 10.1056/NEJMoa1707447
    
2. Schuster SJ, Bishop MR, Tam CS, et al; JULIET Investigators. Tisagenlecleucel in adult relapsed or refractory diffuse large B-cell lymphoma. N Engl J Med. 2019;380:45-56. doi: 10.1056/NEJMoa1804980
    
3. Abramson JS, Palomba ML, Gordon LI, et al. Lisocabtagene maraleucel for patients with relapsed or refractory large B-cell lymphomas (TRANSCEND NHL 001): A multicentre seamless design study. Lancet. 2020;396:839-852. doi: 10.1016/S0140-6736(20)31366-0
    
4. Locke FL, Miklos DB, Jacobson CA, et al; All ZUMA-7 Investigators and Contributing Kite Members. Axicabtagene ciloleucel as second-line therapy for large B-cell lymphoma. N Engl J Med. 2022;386:640-654. doi: 10.1056/NEJMoa2116133
5. Kamdar M, Solomon SR, Arnason J, et al; TRANSFORM Investigators. Lisocabtagene maraleucel versus standard of care with salvage chemotherapy followed by autologous stem cell transplantation as second-line treatment in patients with relapsed or refractory large B-cell lymphoma (TRANSFORM): Results from an interim analysis of an open-label, randomised, phase 3 trial. Lancet. 2022;399:2294-2308. doi: 10.1016/S0140-6736(22)00662-6

Mantle cell lymphoma (MCL) is a rare and often heterogenous subtype of non-Hodgkin lymphoma (NHL). Though patients can experience prolonged remissions after frontline therapy, most patients ultimately relapse. Treatment of relapsed/refractory disease can be challenging, but there have recently been a growing number of therapeutic options in this setting. Covalent Bruton tyrosine kinase (BTK) inhibitors, for example, have demonstrated activity in patients with MCL and are approved by the US Food and Drug Administration (FDA) for relapsed/refractory disease. Chimeric antigen receptor (CAR) T-cell therapy is also an effective option for relapsed/refractory disease, though this is typically available only at select centers and is associated with toxicities, such as cytokine release syndrome and neurologic toxicity.

Recently, a novel BTK inhibitor, pirtobrutinib, has also been studied across NHL, including MCL (Wang et al) Pirtobrutinib is a selective, noncovalent BTK inhibitor with the ability to bind both the C481S-mutant and wild-type BTK. The multicenter, phase 1/2 BRUIN study included 90 patients with MCL who were previously treated with a covalent BTK inhibitor. Patients in the phase 1 portion of the study were treated with oral pirtobrutinib at a dose of 25-300 mg once daily, and patients in the phase 2 study were treated at the recommended dose of 200 mg once daily. The overall response rate was 57.8% (95% CI 46.9%-68.1%), with the complete response rate being 20.0%. At a median follow-up of 12 months, the median duration of response was 21.6 (95% CI 7.5 to not reached) months. Treatment-related adverse events that were grade 3 or higher were not frequent, with neutropenia (8.5%) being the most common. Of note, grade 3 or higher hemorrhage and atrial fibrillation, which can be seen with BTK inhibitors, were rare, occurring in 3.7% and 1.2% of patients, respectively. Based on the results of this study, pirtobrutinib has been approved by the FDA for patients with relapsed/refractory MCL after at least two prior lines of therapy, including a BTK inhibitor. This is an appealing oral option for patients with relapsed disease.

Options for patients with relapsed/refractory large B-cell lymphoma (LBCL) have also significantly increased in recent years. One of the most important advances in this disease has been the use of anti-CD19 CAR T-cell therapy. There are currently three FDA-approved options for patients with relapsed/refractory LBCL who have received at least two prior lines of therapy.^1-3 More recently, axicabtagene ciloleucel (axi-cel) and lisocabtagene maraleucel (liso-cel) have also been approved for the second line based on the results of the ZUMA-7 and TRANSFORM studies, respectively.^4,5

Longer follow-up of the ZUMA-7 trial continues to confirm the advantage of axi-cel over standard-care therapy for patients with primary refractory or early relapse of disease, now with evidence of an overall survival advantage (Westin et al). The ZUMA-7 trial included 359 adults with LBCL (refractory to or relapsed within 12 months of first-line treatment) who were randomly assigned to receive axi-cel (n = 180) or standard care (n = 179). At a median follow-up of 47.2 mo, patients receiving axi-cel vs standard care had a significantly longer median overall survival (not reached vs 31.1 mo; hazard ratio [HR] 0.73; P = .03) and an absolute improvement in overall survival (8.6 percentage points at 4 years). No new treatment-related deaths were reported since the primary event-free survival analysis. These data confirm that early use of axi-cel is preferred over standard-care therapy with high-dose chemotherapy and autologous stem cell transplantation.

Another important study that was recently published looked at the role of mental health on outcomes in patients with diffuse large B-cell lymphoma (DLBCL) (Kuczmarski et al). Though it is known that mental health disorders can decrease the quality of life of patients with cancer, there is limited information on the survival implications of these issues. A recent retrospective cohort study analyzed the data of 13,244 patients aged 67 years or older with DLBCL from the Surveillance, Epidemiology, and End Results (SEER)–Medicare registry, of which, 2094 patients had depression, anxiety, or both at the time of their DLBCL diagnosis. At a median follow-up of 2.0 years, patients with depression, anxiety, or both vs without any mental disorder had significantly lower 5-year overall survival rates (27.0% vs 37.4%; HR 1.37; 95% CI 1.29-1.44). They also found that those patients with preexisting depression vs without any mental disorder have the worst survival (23.4% vs 38.0%; HR 1.37; P < .0001). Though the mechanism accounting for decreased survival is not clear, the authors postulate that mental health disorders may lead to delays or interruptions in lymphoma-directed therapy. They also note the potential for increased barriers to care in patients with mental health disorders, which may result in nonadherence in this patient population. Regardless, these results highlight the importance of mental health screening and interventions in patients with DLBCL.

Additional References

1. Neelapu SS, Locke FL, Bartlett NL, et al. Axicabtagene ciloleucel CAR T-Cell therapy in refractory large B-cell lymphoma. N Engl J Med. 2017;377:2531-2544. doi: 10.1056/NEJMoa1707447
    
2. Schuster SJ, Bishop MR, Tam CS, et al; JULIET Investigators. Tisagenlecleucel in adult relapsed or refractory diffuse large B-cell lymphoma. N Engl J Med. 2019;380:45-56. doi: 10.1056/NEJMoa1804980
    
3. Abramson JS, Palomba ML, Gordon LI, et al. Lisocabtagene maraleucel for patients with relapsed or refractory large B-cell lymphomas (TRANSCEND NHL 001): A multicentre seamless design study. Lancet. 2020;396:839-852. doi: 10.1016/S0140-6736(20)31366-0
    
4. Locke FL, Miklos DB, Jacobson CA, et al; All ZUMA-7 Investigators and Contributing Kite Members. Axicabtagene ciloleucel as second-line therapy for large B-cell lymphoma. N Engl J Med. 2022;386:640-654. doi: 10.1056/NEJMoa2116133
5. Kamdar M, Solomon SR, Arnason J, et al; TRANSFORM Investigators. Lisocabtagene maraleucel versus standard of care with salvage chemotherapy followed by autologous stem cell transplantation as second-line treatment in patients with relapsed or refractory large B-cell lymphoma (TRANSFORM): Results from an interim analysis of an open-label, randomised, phase 3 trial. Lancet. 2022;399:2294-2308. doi: 10.1016/S0140-6736(22)00662-6

Despite multiple existing conventional synthetic disease-modifying antirheumatic drug (csDMARD) and biologic DMARD (bDMARD) options, many patients with rheumatoid arthritis (RA) do not respond adequately to treatment. In an exciting development, a recent phase 2 study by Tuttle and colleagues examined a novel treatment approach in RA: stimulation of the programmed cell death protein 1 (PD-1) inhibitor pathway. PD-1 is a checkpoint inhibitor receptor whose activation reflects T-cell activation and may play a role in synovitis and extra-articular inflammation. Blocking PD-1 in cancer therapy has been associated with an increase in inflammatory arthritis. In this 12-week study, RA disease activity was analyzed in patients randomly assigned to two different monthly intravenous doses of peresolimab or placebo. Of note, a large majority of participants were seropositive for rheumatoid factor (RF) or cyclic citrullinated peptide (CCP). Patients receiving the 700-mg dose of peresolimab had a better American College of Rheumatology (ACR) 20 response than did those receiving placebo (71% vs 42%), but not a better ACR50 or ACR70 response; the 300-mg dose was not better than placebo. Although reported adverse events were similar in all three groups, with a short timeframe it would be difficult to address concerns about cancer risk. Though this novel treatment is exciting, a larger and longer-term trial is necessary to address this concern as well as potentially tease out risk factors (including age or other immunosuppression) in this susceptible group.

Two other studies examined use of a much older csDMARD therapy, hydroxychloroquine (HCQ), in Brazilian patients with RA. Bredemeier and colleagues looked at the effects of HCQ on adverse events as well as the persistence of bDMARD/targeted synthetic DMARD (tsDMARD) therapy in over 1300 patients with RA. Using the BiobadaBrasil registry of patients starting their first bDMARD or Janus kinase (JAK) inhibitor, they looked at effects of combination therapy with HCQ during the treatment course of up to six bDMARD or JAK inhibitors. At baseline, patients prescribed antimalarial therapy had shorter RA duration and began treatment earlier, perhaps due to patient or physician preferences regarding starting "milder" antimalarial medication earlier or due to use of "triple therapy" with methotrexate and sulfasalazine. Of interest, patients receiving antimalarial therapy had a lower incidence of adverse events, especially serious infections, but no effect on cardiovascular events was seen despite HCQ's perceived beneficial effects on thrombotic risk and cholesterol profile. Patients receiving HCQ were also more likely to persist in their course of bDMARD or JAK inhibitor therapy, though the effect size seems relatively small. As the focus in this study was on adverse effects, the authors' analysis of the effects on antimalarials on the persistence of therapy was not detailed.

Lin and colleagues also looked at the effects of HCQ in patients with older-onset RA with respect to mortality risk. Using data from the electronic health records of a hospital in Taiwan, mortality-associated risk factors were evaluated in 980 patients with RA diagnosed at >60 years. Male sex, current smoking status, and cancer status were all associated with mortality, whereas HCQ use was associated with reduced mortality (hazard ratio 0.30). In contrast to the registry study mentioned above, patients receiving HCQ had a lower risk for cardiovascular events, hyperlipidemia, diabetes, and chronic kidney disease. Interaction with cancer was less clear due to lower number of patients. Of interest, use of cyclosporine, leflunomide, and a bDMARD was associated with higher mortality risk. The source and true relevance of the potential risk reduction in this study is not clear because of the lack of prospective data, but combined with the information above, this study suggests that the benefits of HCQ use should not be discounted in patients with RA.

Despite multiple existing conventional synthetic disease-modifying antirheumatic drug (csDMARD) and biologic DMARD (bDMARD) options, many patients with rheumatoid arthritis (RA) do not respond adequately to treatment. In an exciting development, a recent phase 2 study by Tuttle and colleagues examined a novel treatment approach in RA: stimulation of the programmed cell death protein 1 (PD-1) inhibitor pathway. PD-1 is a checkpoint inhibitor receptor whose activation reflects T-cell activation and may play a role in synovitis and extra-articular inflammation. Blocking PD-1 in cancer therapy has been associated with an increase in inflammatory arthritis. In this 12-week study, RA disease activity was analyzed in patients randomly assigned to two different monthly intravenous doses of peresolimab or placebo. Of note, a large majority of participants were seropositive for rheumatoid factor (RF) or cyclic citrullinated peptide (CCP). Patients receiving the 700-mg dose of peresolimab had a better American College of Rheumatology (ACR) 20 response than did those receiving placebo (71% vs 42%), but not a better ACR50 or ACR70 response; the 300-mg dose was not better than placebo. Although reported adverse events were similar in all three groups, with a short timeframe it would be difficult to address concerns about cancer risk. Though this novel treatment is exciting, a larger and longer-term trial is necessary to address this concern as well as potentially tease out risk factors (including age or other immunosuppression) in this susceptible group.

Two other studies examined use of a much older csDMARD therapy, hydroxychloroquine (HCQ), in Brazilian patients with RA. Bredemeier and colleagues looked at the effects of HCQ on adverse events as well as the persistence of bDMARD/targeted synthetic DMARD (tsDMARD) therapy in over 1300 patients with RA. Using the BiobadaBrasil registry of patients starting their first bDMARD or Janus kinase (JAK) inhibitor, they looked at effects of combination therapy with HCQ during the treatment course of up to six bDMARD or JAK inhibitors. At baseline, patients prescribed antimalarial therapy had shorter RA duration and began treatment earlier, perhaps due to patient or physician preferences regarding starting "milder" antimalarial medication earlier or due to use of "triple therapy" with methotrexate and sulfasalazine. Of interest, patients receiving antimalarial therapy had a lower incidence of adverse events, especially serious infections, but no effect on cardiovascular events was seen despite HCQ's perceived beneficial effects on thrombotic risk and cholesterol profile. Patients receiving HCQ were also more likely to persist in their course of bDMARD or JAK inhibitor therapy, though the effect size seems relatively small. As the focus in this study was on adverse effects, the authors' analysis of the effects on antimalarials on the persistence of therapy was not detailed.

Lin and colleagues also looked at the effects of HCQ in patients with older-onset RA with respect to mortality risk. Using data from the electronic health records of a hospital in Taiwan, mortality-associated risk factors were evaluated in 980 patients with RA diagnosed at >60 years. Male sex, current smoking status, and cancer status were all associated with mortality, whereas HCQ use was associated with reduced mortality (hazard ratio 0.30). In contrast to the registry study mentioned above, patients receiving HCQ had a lower risk for cardiovascular events, hyperlipidemia, diabetes, and chronic kidney disease. Interaction with cancer was less clear due to lower number of patients. Of interest, use of cyclosporine, leflunomide, and a bDMARD was associated with higher mortality risk. The source and true relevance of the potential risk reduction in this study is not clear because of the lack of prospective data, but combined with the information above, this study suggests that the benefits of HCQ use should not be discounted in patients with RA.

Despite multiple existing conventional synthetic disease-modifying antirheumatic drug (csDMARD) and biologic DMARD (bDMARD) options, many patients with rheumatoid arthritis (RA) do not respond adequately to treatment. In an exciting development, a recent phase 2 study by Tuttle and colleagues examined a novel treatment approach in RA: stimulation of the programmed cell death protein 1 (PD-1) inhibitor pathway. PD-1 is a checkpoint inhibitor receptor whose activation reflects T-cell activation and may play a role in synovitis and extra-articular inflammation. Blocking PD-1 in cancer therapy has been associated with an increase in inflammatory arthritis. In this 12-week study, RA disease activity was analyzed in patients randomly assigned to two different monthly intravenous doses of peresolimab or placebo. Of note, a large majority of participants were seropositive for rheumatoid factor (RF) or cyclic citrullinated peptide (CCP). Patients receiving the 700-mg dose of peresolimab had a better American College of Rheumatology (ACR) 20 response than did those receiving placebo (71% vs 42%), but not a better ACR50 or ACR70 response; the 300-mg dose was not better than placebo. Although reported adverse events were similar in all three groups, with a short timeframe it would be difficult to address concerns about cancer risk. Though this novel treatment is exciting, a larger and longer-term trial is necessary to address this concern as well as potentially tease out risk factors (including age or other immunosuppression) in this susceptible group.

Two other studies examined use of a much older csDMARD therapy, hydroxychloroquine (HCQ), in Brazilian patients with RA. Bredemeier and colleagues looked at the effects of HCQ on adverse events as well as the persistence of bDMARD/targeted synthetic DMARD (tsDMARD) therapy in over 1300 patients with RA. Using the BiobadaBrasil registry of patients starting their first bDMARD or Janus kinase (JAK) inhibitor, they looked at effects of combination therapy with HCQ during the treatment course of up to six bDMARD or JAK inhibitors. At baseline, patients prescribed antimalarial therapy had shorter RA duration and began treatment earlier, perhaps due to patient or physician preferences regarding starting "milder" antimalarial medication earlier or due to use of "triple therapy" with methotrexate and sulfasalazine. Of interest, patients receiving antimalarial therapy had a lower incidence of adverse events, especially serious infections, but no effect on cardiovascular events was seen despite HCQ's perceived beneficial effects on thrombotic risk and cholesterol profile. Patients receiving HCQ were also more likely to persist in their course of bDMARD or JAK inhibitor therapy, though the effect size seems relatively small. As the focus in this study was on adverse effects, the authors' analysis of the effects on antimalarials on the persistence of therapy was not detailed.

Lin and colleagues also looked at the effects of HCQ in patients with older-onset RA with respect to mortality risk. Using data from the electronic health records of a hospital in Taiwan, mortality-associated risk factors were evaluated in 980 patients with RA diagnosed at >60 years. Male sex, current smoking status, and cancer status were all associated with mortality, whereas HCQ use was associated with reduced mortality (hazard ratio 0.30). In contrast to the registry study mentioned above, patients receiving HCQ had a lower risk for cardiovascular events, hyperlipidemia, diabetes, and chronic kidney disease. Interaction with cancer was less clear due to lower number of patients. Of interest, use of cyclosporine, leflunomide, and a bDMARD was associated with higher mortality risk. The source and true relevance of the potential risk reduction in this study is not clear because of the lack of prospective data, but combined with the information above, this study suggests that the benefits of HCQ use should not be discounted in patients with RA.

After a median follow-up of 21.6 mo, the dalpiciclib group demonstrated a significantly longer median progression-free survival (PFS) compared with the placebo group (30.6 mo vs 18.2 mo; stratified hazard ratio [HR] 0.51; 95% CI 0.38-0.69; P < .0001). Overall, the dalpiciclib group demonstrated a manageable safety profile, although a higher percentage of grade 3/4 adverse events was noted with dalpiciclib than with placebo (90% vs 12%), as expected. Overall survival data for this CDK4/6 inhibitor are yet to come. These results suggest that dalpiciclib in combination with endocrine therapy is an alternative treatment for this group of patients, especially in countries where the traditionally approved CDK4/6 inhibitors (palbociclib, ribociclib, and abemaciclib) are not available.

The optimal sequencing of endocrine therapy (ET) after progression on CDK4/6 inhibitor–based therapy remains a challenge. In the phase 2 MAINTAIN trial, 119 patients (all of whom had HR+/HER2- metastatic breast cancer and who progressed on ET and CDK4/6 inhibitors) were randomly assigned to receive a different ET (fulvestrant or exemestane) from the previous ET they had received plus either the CDK4/6 inhibitor ribociclib or placebo. In the study by Kalinksky and colleagues, at a median follow-up of 18.2 mo, a significant improvement in PFS was observed in the switched ET-plus-ribociclib group compared with the switched ET-plus-placebo group (HR 0.57; P = .006). The phase 2 MAINTAIN trial is the first randomized trial to show the benefit of a CDK4/6 inhibitor after progression on another CDK4/6 inhibitor. It is important to note that the majority of patients in the MAINTAIN study previously received palbociclib in the first-line setting, which in recent studies has been demonstrated to be inferior to other CDK4/6 inhibitors. Therefore, it is important to confirm whether this will hold true upon progression from ribociclib or abemaciclib in the first-line setting. In addition, more data are needed to compare this approach with other ET treatment options, such as phosphoinositide 3-kinases inhibitors and oral selective estrogen receptor degraders.

There are several options for adjuvant radiation therapy for early-stage breast cancer. A meta-analysis of 14 randomized controlled trials and six comparative observational studies assessed the efficacy of whole breast irradiation (WBI) compared with partial breast irradiation (PBI) in 17,234 adults with early-stage breast cancer. Results of this meta-analysis showed that PBI was not significantly different from WBI, with similar rates of ipsilateral breast recurrence  at 5 years (relative risk [RR] 1.34; 95% CI 0.83-2.18) and 10 years (RR 1.29; 95% CI 0.87-1.91), although patients undergoing PBI reported fewer acute adverse events  compared with patients undergoing WBI (incidence rate ratio [IRR] 0.53; 95% CI 0.31-0.92) and acute grade ≥2 adverse events (IRR 0.21; 95% CI 0.07-0.62). These findings support using PBI as the adjuvant radiotherapy modality for select patients with favorable-risk early-stage breast cancer.

Another meta-analysis looked at assessing the survival benefit of adding CDK4/6 inhibitors to standard ET in older patients with advanced breast cancer. The study included 10 trials with 1985 older patients with advanced ER+ breast cancer who received ET with or without CDK4/6 inhibitors. The findings showed that adding CDK4/6 inhibitors to ET (letrozole or fulvestrant) significantly reduced the mortality risk by 21% (HR 0.79; 95% CI 0.69-0.91) and progression risk by 41% (HR 0.59; 95% CI 0.51-0.69) in older patients (age ≥ 65 years) with advanced breast cancer. Grade 3-4 neutropenia and diarrhea were similar in older patients. This study supports the use of CDK4/6 inhibitors as a reasonable treatment modality for older patients. More studies dedicated to the geriatric population are needed to help elaborate on the efficacy and tolerability of such agents in this population.

The phase 3 National Surgical Adjuvant Breast and Bowel Project B-42 (NSABP B-42) trial evaluated the role of extended letrozole therapy in postmenopausal breast cancer patients who were disease-free after 5 years of aromatase inhibitor–based therapy. The study included 3966 postmenopausal women with stage I-IIIA HR+ breast cancer who were randomly assigned to receive letrozole or placebo for 5 more years. After a median follow-up of 10.3 years, letrozole significantly improved disease-free survival (10-year absolute benefit 3.4%; HR 0.85; P = .01) compared with placebo, although there were no differences noted in overall survival between the groups (HR 0.97, P = .74). Furthermore, letrozole significantly reduced the breast cancer–free interval (HR 0.75, ,P = .003) and distant recurrence (HR 0.72, P = .01). There were no notable differences in toxicity, particularly rates of osteoporotic fractures and arterial thrombotic events, between the groups. Extended therapy with aromatase inhibitors beyond 5 years can be considered for select patients with early-stage breast cancer. Careful consideration of risks and benefits is needed to make these recommendations. 

After a median follow-up of 21.6 mo, the dalpiciclib group demonstrated a significantly longer median progression-free survival (PFS) compared with the placebo group (30.6 mo vs 18.2 mo; stratified hazard ratio [HR] 0.51; 95% CI 0.38-0.69; P < .0001). Overall, the dalpiciclib group demonstrated a manageable safety profile, although a higher percentage of grade 3/4 adverse events was noted with dalpiciclib than with placebo (90% vs 12%), as expected. Overall survival data for this CDK4/6 inhibitor are yet to come. These results suggest that dalpiciclib in combination with endocrine therapy is an alternative treatment for this group of patients, especially in countries where the traditionally approved CDK4/6 inhibitors (palbociclib, ribociclib, and abemaciclib) are not available.

The optimal sequencing of endocrine therapy (ET) after progression on CDK4/6 inhibitor–based therapy remains a challenge. In the phase 2 MAINTAIN trial, 119 patients (all of whom had HR+/HER2- metastatic breast cancer and who progressed on ET and CDK4/6 inhibitors) were randomly assigned to receive a different ET (fulvestrant or exemestane) from the previous ET they had received plus either the CDK4/6 inhibitor ribociclib or placebo. In the study by Kalinksky and colleagues, at a median follow-up of 18.2 mo, a significant improvement in PFS was observed in the switched ET-plus-ribociclib group compared with the switched ET-plus-placebo group (HR 0.57; P = .006). The phase 2 MAINTAIN trial is the first randomized trial to show the benefit of a CDK4/6 inhibitor after progression on another CDK4/6 inhibitor. It is important to note that the majority of patients in the MAINTAIN study previously received palbociclib in the first-line setting, which in recent studies has been demonstrated to be inferior to other CDK4/6 inhibitors. Therefore, it is important to confirm whether this will hold true upon progression from ribociclib or abemaciclib in the first-line setting. In addition, more data are needed to compare this approach with other ET treatment options, such as phosphoinositide 3-kinases inhibitors and oral selective estrogen receptor degraders.

There are several options for adjuvant radiation therapy for early-stage breast cancer. A meta-analysis of 14 randomized controlled trials and six comparative observational studies assessed the efficacy of whole breast irradiation (WBI) compared with partial breast irradiation (PBI) in 17,234 adults with early-stage breast cancer. Results of this meta-analysis showed that PBI was not significantly different from WBI, with similar rates of ipsilateral breast recurrence  at 5 years (relative risk [RR] 1.34; 95% CI 0.83-2.18) and 10 years (RR 1.29; 95% CI 0.87-1.91), although patients undergoing PBI reported fewer acute adverse events  compared with patients undergoing WBI (incidence rate ratio [IRR] 0.53; 95% CI 0.31-0.92) and acute grade ≥2 adverse events (IRR 0.21; 95% CI 0.07-0.62). These findings support using PBI as the adjuvant radiotherapy modality for select patients with favorable-risk early-stage breast cancer.

Another meta-analysis looked at assessing the survival benefit of adding CDK4/6 inhibitors to standard ET in older patients with advanced breast cancer. The study included 10 trials with 1985 older patients with advanced ER+ breast cancer who received ET with or without CDK4/6 inhibitors. The findings showed that adding CDK4/6 inhibitors to ET (letrozole or fulvestrant) significantly reduced the mortality risk by 21% (HR 0.79; 95% CI 0.69-0.91) and progression risk by 41% (HR 0.59; 95% CI 0.51-0.69) in older patients (age ≥ 65 years) with advanced breast cancer. Grade 3-4 neutropenia and diarrhea were similar in older patients. This study supports the use of CDK4/6 inhibitors as a reasonable treatment modality for older patients. More studies dedicated to the geriatric population are needed to help elaborate on the efficacy and tolerability of such agents in this population.

The phase 3 National Surgical Adjuvant Breast and Bowel Project B-42 (NSABP B-42) trial evaluated the role of extended letrozole therapy in postmenopausal breast cancer patients who were disease-free after 5 years of aromatase inhibitor–based therapy. The study included 3966 postmenopausal women with stage I-IIIA HR+ breast cancer who were randomly assigned to receive letrozole or placebo for 5 more years. After a median follow-up of 10.3 years, letrozole significantly improved disease-free survival (10-year absolute benefit 3.4%; HR 0.85; P = .01) compared with placebo, although there were no differences noted in overall survival between the groups (HR 0.97, P = .74). Furthermore, letrozole significantly reduced the breast cancer–free interval (HR 0.75, ,P = .003) and distant recurrence (HR 0.72, P = .01). There were no notable differences in toxicity, particularly rates of osteoporotic fractures and arterial thrombotic events, between the groups. Extended therapy with aromatase inhibitors beyond 5 years can be considered for select patients with early-stage breast cancer. Careful consideration of risks and benefits is needed to make these recommendations. 

After a median follow-up of 21.6 mo, the dalpiciclib group demonstrated a significantly longer median progression-free survival (PFS) compared with the placebo group (30.6 mo vs 18.2 mo; stratified hazard ratio [HR] 0.51; 95% CI 0.38-0.69; P < .0001). Overall, the dalpiciclib group demonstrated a manageable safety profile, although a higher percentage of grade 3/4 adverse events was noted with dalpiciclib than with placebo (90% vs 12%), as expected. Overall survival data for this CDK4/6 inhibitor are yet to come. These results suggest that dalpiciclib in combination with endocrine therapy is an alternative treatment for this group of patients, especially in countries where the traditionally approved CDK4/6 inhibitors (palbociclib, ribociclib, and abemaciclib) are not available.

The optimal sequencing of endocrine therapy (ET) after progression on CDK4/6 inhibitor–based therapy remains a challenge. In the phase 2 MAINTAIN trial, 119 patients (all of whom had HR+/HER2- metastatic breast cancer and who progressed on ET and CDK4/6 inhibitors) were randomly assigned to receive a different ET (fulvestrant or exemestane) from the previous ET they had received plus either the CDK4/6 inhibitor ribociclib or placebo. In the study by Kalinksky and colleagues, at a median follow-up of 18.2 mo, a significant improvement in PFS was observed in the switched ET-plus-ribociclib group compared with the switched ET-plus-placebo group (HR 0.57; P = .006). The phase 2 MAINTAIN trial is the first randomized trial to show the benefit of a CDK4/6 inhibitor after progression on another CDK4/6 inhibitor. It is important to note that the majority of patients in the MAINTAIN study previously received palbociclib in the first-line setting, which in recent studies has been demonstrated to be inferior to other CDK4/6 inhibitors. Therefore, it is important to confirm whether this will hold true upon progression from ribociclib or abemaciclib in the first-line setting. In addition, more data are needed to compare this approach with other ET treatment options, such as phosphoinositide 3-kinases inhibitors and oral selective estrogen receptor degraders.

There are several options for adjuvant radiation therapy for early-stage breast cancer. A meta-analysis of 14 randomized controlled trials and six comparative observational studies assessed the efficacy of whole breast irradiation (WBI) compared with partial breast irradiation (PBI) in 17,234 adults with early-stage breast cancer. Results of this meta-analysis showed that PBI was not significantly different from WBI, with similar rates of ipsilateral breast recurrence  at 5 years (relative risk [RR] 1.34; 95% CI 0.83-2.18) and 10 years (RR 1.29; 95% CI 0.87-1.91), although patients undergoing PBI reported fewer acute adverse events  compared with patients undergoing WBI (incidence rate ratio [IRR] 0.53; 95% CI 0.31-0.92) and acute grade ≥2 adverse events (IRR 0.21; 95% CI 0.07-0.62). These findings support using PBI as the adjuvant radiotherapy modality for select patients with favorable-risk early-stage breast cancer.

Another meta-analysis looked at assessing the survival benefit of adding CDK4/6 inhibitors to standard ET in older patients with advanced breast cancer. The study included 10 trials with 1985 older patients with advanced ER+ breast cancer who received ET with or without CDK4/6 inhibitors. The findings showed that adding CDK4/6 inhibitors to ET (letrozole or fulvestrant) significantly reduced the mortality risk by 21% (HR 0.79; 95% CI 0.69-0.91) and progression risk by 41% (HR 0.59; 95% CI 0.51-0.69) in older patients (age ≥ 65 years) with advanced breast cancer. Grade 3-4 neutropenia and diarrhea were similar in older patients. This study supports the use of CDK4/6 inhibitors as a reasonable treatment modality for older patients. More studies dedicated to the geriatric population are needed to help elaborate on the efficacy and tolerability of such agents in this population.

The phase 3 National Surgical Adjuvant Breast and Bowel Project B-42 (NSABP B-42) trial evaluated the role of extended letrozole therapy in postmenopausal breast cancer patients who were disease-free after 5 years of aromatase inhibitor–based therapy. The study included 3966 postmenopausal women with stage I-IIIA HR+ breast cancer who were randomly assigned to receive letrozole or placebo for 5 more years. After a median follow-up of 10.3 years, letrozole significantly improved disease-free survival (10-year absolute benefit 3.4%; HR 0.85; P = .01) compared with placebo, although there were no differences noted in overall survival between the groups (HR 0.97, P = .74). Furthermore, letrozole significantly reduced the breast cancer–free interval (HR 0.75, ,P = .003) and distant recurrence (HR 0.72, P = .01). There were no notable differences in toxicity, particularly rates of osteoporotic fractures and arterial thrombotic events, between the groups. Extended therapy with aromatase inhibitors beyond 5 years can be considered for select patients with early-stage breast cancer. Careful consideration of risks and benefits is needed to make these recommendations. 

Despite using methotrexate (MTX) in the management of psoriasis and PsA for more than 50 years, there is paucity of data on its effectiveness in PsA. It is also largely assumed that MTX is more effective for rheumatoid arthritis (RA) than for PsA. To evaluate MTX effectiveness vis-à-vis RA, Lindström and colleagues conducted an observational study with disease-modifying antirheumatic drug (DMARD)–naive patients with newly diagnosed PsA (n = 3642) who initiated MTX and matched comparator patients with RA (n = 3642) from national Swedish registers. At 6 months, although both groups of patients had improvement in pain, global health, and remission, the rates were higher in RA compared with PsA. Overall, 71% of patients with PsA and 76% of patients with RA were still taking MTX 2 years after initiating MTX. The time to starting another DMARD was shorter in RA compared with PsA. Thus, in early PsA, MTX treatment seems to provide significant benefits. However, the improvements are less impressive than they are for RA.

Biologic agents are generally safe and effective in the treatment of PsA. However, there are limited data on the safety and effectiveness in older and younger populations with PsA. Gossec and colleagues conducted a post hoc analysis of the PsABio trial that included patients with PsA who received ustekinumab, an interleukin 12/23 inhibitor, and were subgrouped into those < 60 years (n = 336) and ≥ 60 years (n = 103). At 6 months, a numerically higher proportion of patients < 60 years achieved clinical Disease Activity Index for Psoriatic Arthritis low disease activity compared with those ≥ 60 years. The proportions of patients reporting at least one (32.7% vs 40.9%) or serious (5.3% vs 9.6%) adverse events were numerically higher in the older population. However, treatment persistence was numerically higher in the older subgroup. These differences were not clinically meaningful; thus, ustekinumab may be safely used in older populations.

There are also limited data on the effectiveness of biologics in patients with juvenile PsA (jPsA). To address this, Correll and colleagues evaluated the safety and effectiveness of etanercept, an anti–tumor necrosis factor agent, in patients with jPsA using data from the Childhood Arthritis and Rheumatology Research Alliance Registry. In 226 patients, the overall incidence of adverse events of special interest and serious adverse events were low and included three cases of uveitis (incidence rate [IR]/100 person-years 0.55; 95% CI 0.18-1.69), one of neuropathy (IR/100 person-years 0.18; 95% CI 0.03-1.29), and one of cancer (IR/100 person-years 0.13; 95% CI 0.02-0.90). The ACR provisional criteria for inactive disease were achieved by 51.9% and 43.8% of patients at 6 and 12 months. Thus, etanercept is safe and effective in jPsA.

Despite using methotrexate (MTX) in the management of psoriasis and PsA for more than 50 years, there is paucity of data on its effectiveness in PsA. It is also largely assumed that MTX is more effective for rheumatoid arthritis (RA) than for PsA. To evaluate MTX effectiveness vis-à-vis RA, Lindström and colleagues conducted an observational study with disease-modifying antirheumatic drug (DMARD)–naive patients with newly diagnosed PsA (n = 3642) who initiated MTX and matched comparator patients with RA (n = 3642) from national Swedish registers. At 6 months, although both groups of patients had improvement in pain, global health, and remission, the rates were higher in RA compared with PsA. Overall, 71% of patients with PsA and 76% of patients with RA were still taking MTX 2 years after initiating MTX. The time to starting another DMARD was shorter in RA compared with PsA. Thus, in early PsA, MTX treatment seems to provide significant benefits. However, the improvements are less impressive than they are for RA.

Biologic agents are generally safe and effective in the treatment of PsA. However, there are limited data on the safety and effectiveness in older and younger populations with PsA. Gossec and colleagues conducted a post hoc analysis of the PsABio trial that included patients with PsA who received ustekinumab, an interleukin 12/23 inhibitor, and were subgrouped into those < 60 years (n = 336) and ≥ 60 years (n = 103). At 6 months, a numerically higher proportion of patients < 60 years achieved clinical Disease Activity Index for Psoriatic Arthritis low disease activity compared with those ≥ 60 years. The proportions of patients reporting at least one (32.7% vs 40.9%) or serious (5.3% vs 9.6%) adverse events were numerically higher in the older population. However, treatment persistence was numerically higher in the older subgroup. These differences were not clinically meaningful; thus, ustekinumab may be safely used in older populations.

There are also limited data on the effectiveness of biologics in patients with juvenile PsA (jPsA). To address this, Correll and colleagues evaluated the safety and effectiveness of etanercept, an anti–tumor necrosis factor agent, in patients with jPsA using data from the Childhood Arthritis and Rheumatology Research Alliance Registry. In 226 patients, the overall incidence of adverse events of special interest and serious adverse events were low and included three cases of uveitis (incidence rate [IR]/100 person-years 0.55; 95% CI 0.18-1.69), one of neuropathy (IR/100 person-years 0.18; 95% CI 0.03-1.29), and one of cancer (IR/100 person-years 0.13; 95% CI 0.02-0.90). The ACR provisional criteria for inactive disease were achieved by 51.9% and 43.8% of patients at 6 and 12 months. Thus, etanercept is safe and effective in jPsA.

Despite using methotrexate (MTX) in the management of psoriasis and PsA for more than 50 years, there is paucity of data on its effectiveness in PsA. It is also largely assumed that MTX is more effective for rheumatoid arthritis (RA) than for PsA. To evaluate MTX effectiveness vis-à-vis RA, Lindström and colleagues conducted an observational study with disease-modifying antirheumatic drug (DMARD)–naive patients with newly diagnosed PsA (n = 3642) who initiated MTX and matched comparator patients with RA (n = 3642) from national Swedish registers. At 6 months, although both groups of patients had improvement in pain, global health, and remission, the rates were higher in RA compared with PsA. Overall, 71% of patients with PsA and 76% of patients with RA were still taking MTX 2 years after initiating MTX. The time to starting another DMARD was shorter in RA compared with PsA. Thus, in early PsA, MTX treatment seems to provide significant benefits. However, the improvements are less impressive than they are for RA.

Biologic agents are generally safe and effective in the treatment of PsA. However, there are limited data on the safety and effectiveness in older and younger populations with PsA. Gossec and colleagues conducted a post hoc analysis of the PsABio trial that included patients with PsA who received ustekinumab, an interleukin 12/23 inhibitor, and were subgrouped into those < 60 years (n = 336) and ≥ 60 years (n = 103). At 6 months, a numerically higher proportion of patients < 60 years achieved clinical Disease Activity Index for Psoriatic Arthritis low disease activity compared with those ≥ 60 years. The proportions of patients reporting at least one (32.7% vs 40.9%) or serious (5.3% vs 9.6%) adverse events were numerically higher in the older population. However, treatment persistence was numerically higher in the older subgroup. These differences were not clinically meaningful; thus, ustekinumab may be safely used in older populations.

There are also limited data on the effectiveness of biologics in patients with juvenile PsA (jPsA). To address this, Correll and colleagues evaluated the safety and effectiveness of etanercept, an anti–tumor necrosis factor agent, in patients with jPsA using data from the Childhood Arthritis and Rheumatology Research Alliance Registry. In 226 patients, the overall incidence of adverse events of special interest and serious adverse events were low and included three cases of uveitis (incidence rate [IR]/100 person-years 0.55; 95% CI 0.18-1.69), one of neuropathy (IR/100 person-years 0.18; 95% CI 0.03-1.29), and one of cancer (IR/100 person-years 0.13; 95% CI 0.02-0.90). The ACR provisional criteria for inactive disease were achieved by 51.9% and 43.8% of patients at 6 and 12 months. Thus, etanercept is safe and effective in jPsA.

Despite using methotrexate (MTX) in the management of psoriasis and PsA for more than 50 years, there is paucity of data on its effectiveness in PsA. It is also largely assumed that MTX is more effective for rheumatoid arthritis (RA) than for PsA. To evaluate MTX effectiveness vis-à-vis RA, Lindström and colleagues conducted an observational study with disease-modifying antirheumatic drug (DMARD)–naive patients with newly diagnosed PsA (n = 3642) who initiated MTX and matched comparator patients with RA (n = 3642) from national Swedish registers. At 6 months, although both groups of patients had improvement in pain, global health, and remission, the rates were higher in RA compared with PsA. Overall, 71% of patients with PsA and 76% of patients with RA were still taking MTX 2 years after initiating MTX. The time to starting another DMARD was shorter in RA compared with PsA. Thus, in early PsA, MTX treatment seems to provide significant benefits. However, the improvements are less impressive than they are for RA.

Biologic agents are generally safe and effective in the treatment of PsA. However, there are limited data on the safety and effectiveness in older and younger populations with PsA. Gossec and colleagues conducted a post hoc analysis of the PsABio trial that included patients with PsA who received ustekinumab, an interleukin 12/23 inhibitor, and were subgrouped into those < 60 years (n = 336) and ≥ 60 years (n = 103). At 6 months, a numerically higher proportion of patients < 60 years achieved clinical Disease Activity Index for Psoriatic Arthritis low disease activity compared with those ≥ 60 years. The proportions of patients reporting at least one (32.7% vs 40.9%) or serious (5.3% vs 9.6%) adverse events were numerically higher in the older population. However, treatment persistence was numerically higher in the older subgroup. These differences were not clinically meaningful; thus, ustekinumab may be safely used in older populations.

There are also limited data on the effectiveness of biologics in patients with juvenile PsA (jPsA). To address this, Correll and colleagues evaluated the safety and effectiveness of etanercept, an anti–tumor necrosis factor agent, in patients with jPsA using data from the Childhood Arthritis and Rheumatology Research Alliance Registry. In 226 patients, the overall incidence of adverse events of special interest and serious adverse events were low and included three cases of uveitis (incidence rate [IR]/100 person-years 0.55; 95% CI 0.18-1.69), one of neuropathy (IR/100 person-years 0.18; 95% CI 0.03-1.29), and one of cancer (IR/100 person-years 0.13; 95% CI 0.02-0.90). The ACR provisional criteria for inactive disease were achieved by 51.9% and 43.8% of patients at 6 and 12 months. Thus, etanercept is safe and effective in jPsA.

Despite using methotrexate (MTX) in the management of psoriasis and PsA for more than 50 years, there is paucity of data on its effectiveness in PsA. It is also largely assumed that MTX is more effective for rheumatoid arthritis (RA) than for PsA. To evaluate MTX effectiveness vis-à-vis RA, Lindström and colleagues conducted an observational study with disease-modifying antirheumatic drug (DMARD)–naive patients with newly diagnosed PsA (n = 3642) who initiated MTX and matched comparator patients with RA (n = 3642) from national Swedish registers. At 6 months, although both groups of patients had improvement in pain, global health, and remission, the rates were higher in RA compared with PsA. Overall, 71% of patients with PsA and 76% of patients with RA were still taking MTX 2 years after initiating MTX. The time to starting another DMARD was shorter in RA compared with PsA. Thus, in early PsA, MTX treatment seems to provide significant benefits. However, the improvements are less impressive than they are for RA.

Biologic agents are generally safe and effective in the treatment of PsA. However, there are limited data on the safety and effectiveness in older and younger populations with PsA. Gossec and colleagues conducted a post hoc analysis of the PsABio trial that included patients with PsA who received ustekinumab, an interleukin 12/23 inhibitor, and were subgrouped into those < 60 years (n = 336) and ≥ 60 years (n = 103). At 6 months, a numerically higher proportion of patients < 60 years achieved clinical Disease Activity Index for Psoriatic Arthritis low disease activity compared with those ≥ 60 years. The proportions of patients reporting at least one (32.7% vs 40.9%) or serious (5.3% vs 9.6%) adverse events were numerically higher in the older population. However, treatment persistence was numerically higher in the older subgroup. These differences were not clinically meaningful; thus, ustekinumab may be safely used in older populations.

There are also limited data on the effectiveness of biologics in patients with juvenile PsA (jPsA). To address this, Correll and colleagues evaluated the safety and effectiveness of etanercept, an anti–tumor necrosis factor agent, in patients with jPsA using data from the Childhood Arthritis and Rheumatology Research Alliance Registry. In 226 patients, the overall incidence of adverse events of special interest and serious adverse events were low and included three cases of uveitis (incidence rate [IR]/100 person-years 0.55; 95% CI 0.18-1.69), one of neuropathy (IR/100 person-years 0.18; 95% CI 0.03-1.29), and one of cancer (IR/100 person-years 0.13; 95% CI 0.02-0.90). The ACR provisional criteria for inactive disease were achieved by 51.9% and 43.8% of patients at 6 and 12 months. Thus, etanercept is safe and effective in jPsA.

Despite using methotrexate (MTX) in the management of psoriasis and PsA for more than 50 years, there is paucity of data on its effectiveness in PsA. It is also largely assumed that MTX is more effective for rheumatoid arthritis (RA) than for PsA. To evaluate MTX effectiveness vis-à-vis RA, Lindström and colleagues conducted an observational study with disease-modifying antirheumatic drug (DMARD)–naive patients with newly diagnosed PsA (n = 3642) who initiated MTX and matched comparator patients with RA (n = 3642) from national Swedish registers. At 6 months, although both groups of patients had improvement in pain, global health, and remission, the rates were higher in RA compared with PsA. Overall, 71% of patients with PsA and 76% of patients with RA were still taking MTX 2 years after initiating MTX. The time to starting another DMARD was shorter in RA compared with PsA. Thus, in early PsA, MTX treatment seems to provide significant benefits. However, the improvements are less impressive than they are for RA.

Biologic agents are generally safe and effective in the treatment of PsA. However, there are limited data on the safety and effectiveness in older and younger populations with PsA. Gossec and colleagues conducted a post hoc analysis of the PsABio trial that included patients with PsA who received ustekinumab, an interleukin 12/23 inhibitor, and were subgrouped into those < 60 years (n = 336) and ≥ 60 years (n = 103). At 6 months, a numerically higher proportion of patients < 60 years achieved clinical Disease Activity Index for Psoriatic Arthritis low disease activity compared with those ≥ 60 years. The proportions of patients reporting at least one (32.7% vs 40.9%) or serious (5.3% vs 9.6%) adverse events were numerically higher in the older population. However, treatment persistence was numerically higher in the older subgroup. These differences were not clinically meaningful; thus, ustekinumab may be safely used in older populations.

There are also limited data on the effectiveness of biologics in patients with juvenile PsA (jPsA). To address this, Correll and colleagues evaluated the safety and effectiveness of etanercept, an anti–tumor necrosis factor agent, in patients with jPsA using data from the Childhood Arthritis and Rheumatology Research Alliance Registry. In 226 patients, the overall incidence of adverse events of special interest and serious adverse events were low and included three cases of uveitis (incidence rate [IR]/100 person-years 0.55; 95% CI 0.18-1.69), one of neuropathy (IR/100 person-years 0.18; 95% CI 0.03-1.29), and one of cancer (IR/100 person-years 0.13; 95% CI 0.02-0.90). The ACR provisional criteria for inactive disease were achieved by 51.9% and 43.8% of patients at 6 and 12 months. Thus, etanercept is safe and effective in jPsA.

The neoadjuvant setting provides a favorable environment to study de-escalation approaches as treatment response (via pathologic complete response [pCR] assessment) can be used as a surrogate marker for outcome. Studies have shown the effect of HER2-enriched subtype and high ERBB2 expression on pCR rates after receipt of a chemotherapy-free, dual HER2-targeted regimen.² The prospective, multicenter, neoadjuvant phase 2 WSG-TP-II trial randomly assigned 207 patients with HR+/HER2+ early breast cancer to 12 weeks of endocrine therapy (ET)–trastuzumab-pertuzumab vs paclitaxel-trastuzumab-pertuzumab. The pCR rate was inferior in the ET arm compared with the paclitaxel arm (23.7% vs 56.4%; odds ratio 0.24; 95% CI 0.12-0.46; P < .001). In addition, an immunohistochemistry ERBB2 score of 3 or higher and ERBB2-enriched subtype were predictors of higher pCR rates in both arms (Gluz et al). This study not only supports a deescalated chemotherapy neoadjuvant strategy of paclitaxel + dual HER2 blockade but also suggests that a portion of patients may potentially be spared chemotherapy with very good results. The role of biomarkers is integral to patient selection for these approaches, and the evaluation of response in real-time will allow for the tailoring of therapy to achieve the best outcome.

Systemic staging for locally advanced breast cancer (LABC) is important for informing prognosis as well as aiding in development of an appropriate treatment plan for patients. The PETABC study included 369 patients with LABC (TNM stage III or IIB [T3N0]) with random assignment to ¹⁸F-labeled fluorodeoxyglucose PET-CT or conventional staging (bone scan, CT of chest/abdomen/pelvis), and was designed to assess the rate of upstaging with each imaging modality and effect on treatment (Dayes et al). In the PET-CT group, 23% (N = 43) of patients were upstaged to stage IV compared with 11% (N = 21) in the conventional-staging group (absolute difference 12.3%; 95% CI 3.9-19.9; P = .002). Fewer patients in the PET-CT group received combined modality treatment vs those patients in the conventional staging group (81% vs 89.2%; P = .03). These results support the consideration of PET-CT as a staging tool for LABC, and this is reflected in various clinical guidelines. Furthermore, the evolving role of other imaging techniques such as ¹⁸F-fluoroestradiol (18F-FES) PET-CT in detection of metastatic lesions related to estrogen receptor–positive breast cancer³ will continue to advance the field of imaging.

Additional References

1. Rugo HS, Lerebours F, Ciruelos E, et al. Alpelisib plus fulvestrant in PIK3CA-mutated, hormone receptor-positive advanced breast cancer after a CDK4/6 inhibitor (BYLieve): One cohort of a phase 2, multicentre, open-label, non-comparative study. Lancet Oncol. 2021;22:489-498. doi: 10.1016/S1470-2045(21)00034-6. Erratum in: Lancet Oncol. 2021;22(5):e184. doi: 10.1016/S1470-2045(21)00194-7
2. Prat A, Pascual T, De Angelis C, et al. HER2-enriched subtype and ERBB2 expression in HER2-positive breast cancer treated with dual HER2 blockade. J Natl Cancer Inst. 2020;112:46-54. doi: 10.1093/jnci/djz042
3. Ulaner GA, Jhaveri K, Chandarlapaty S, et al. Head-to-head evaluation of ¹⁸F-FES and ¹⁸F-FDG PET/CT in metastatic invasive lobular breast cancer. J Nucl Med. 2021;62:326-331. doi: 10.2967/jnumed.120.247882

The neoadjuvant setting provides a favorable environment to study de-escalation approaches as treatment response (via pathologic complete response [pCR] assessment) can be used as a surrogate marker for outcome. Studies have shown the effect of HER2-enriched subtype and high ERBB2 expression on pCR rates after receipt of a chemotherapy-free, dual HER2-targeted regimen.² The prospective, multicenter, neoadjuvant phase 2 WSG-TP-II trial randomly assigned 207 patients with HR+/HER2+ early breast cancer to 12 weeks of endocrine therapy (ET)–trastuzumab-pertuzumab vs paclitaxel-trastuzumab-pertuzumab. The pCR rate was inferior in the ET arm compared with the paclitaxel arm (23.7% vs 56.4%; odds ratio 0.24; 95% CI 0.12-0.46; P < .001). In addition, an immunohistochemistry ERBB2 score of 3 or higher and ERBB2-enriched subtype were predictors of higher pCR rates in both arms (Gluz et al). This study not only supports a deescalated chemotherapy neoadjuvant strategy of paclitaxel + dual HER2 blockade but also suggests that a portion of patients may potentially be spared chemotherapy with very good results. The role of biomarkers is integral to patient selection for these approaches, and the evaluation of response in real-time will allow for the tailoring of therapy to achieve the best outcome.

Systemic staging for locally advanced breast cancer (LABC) is important for informing prognosis as well as aiding in development of an appropriate treatment plan for patients. The PETABC study included 369 patients with LABC (TNM stage III or IIB [T3N0]) with random assignment to ¹⁸F-labeled fluorodeoxyglucose PET-CT or conventional staging (bone scan, CT of chest/abdomen/pelvis), and was designed to assess the rate of upstaging with each imaging modality and effect on treatment (Dayes et al). In the PET-CT group, 23% (N = 43) of patients were upstaged to stage IV compared with 11% (N = 21) in the conventional-staging group (absolute difference 12.3%; 95% CI 3.9-19.9; P = .002). Fewer patients in the PET-CT group received combined modality treatment vs those patients in the conventional staging group (81% vs 89.2%; P = .03). These results support the consideration of PET-CT as a staging tool for LABC, and this is reflected in various clinical guidelines. Furthermore, the evolving role of other imaging techniques such as ¹⁸F-fluoroestradiol (18F-FES) PET-CT in detection of metastatic lesions related to estrogen receptor–positive breast cancer³ will continue to advance the field of imaging.

Additional References

1. Rugo HS, Lerebours F, Ciruelos E, et al. Alpelisib plus fulvestrant in PIK3CA-mutated, hormone receptor-positive advanced breast cancer after a CDK4/6 inhibitor (BYLieve): One cohort of a phase 2, multicentre, open-label, non-comparative study. Lancet Oncol. 2021;22:489-498. doi: 10.1016/S1470-2045(21)00034-6. Erratum in: Lancet Oncol. 2021;22(5):e184. doi: 10.1016/S1470-2045(21)00194-7
2. Prat A, Pascual T, De Angelis C, et al. HER2-enriched subtype and ERBB2 expression in HER2-positive breast cancer treated with dual HER2 blockade. J Natl Cancer Inst. 2020;112:46-54. doi: 10.1093/jnci/djz042
3. Ulaner GA, Jhaveri K, Chandarlapaty S, et al. Head-to-head evaluation of ¹⁸F-FES and ¹⁸F-FDG PET/CT in metastatic invasive lobular breast cancer. J Nucl Med. 2021;62:326-331. doi: 10.2967/jnumed.120.247882

The neoadjuvant setting provides a favorable environment to study de-escalation approaches as treatment response (via pathologic complete response [pCR] assessment) can be used as a surrogate marker for outcome. Studies have shown the effect of HER2-enriched subtype and high ERBB2 expression on pCR rates after receipt of a chemotherapy-free, dual HER2-targeted regimen.² The prospective, multicenter, neoadjuvant phase 2 WSG-TP-II trial randomly assigned 207 patients with HR+/HER2+ early breast cancer to 12 weeks of endocrine therapy (ET)–trastuzumab-pertuzumab vs paclitaxel-trastuzumab-pertuzumab. The pCR rate was inferior in the ET arm compared with the paclitaxel arm (23.7% vs 56.4%; odds ratio 0.24; 95% CI 0.12-0.46; P < .001). In addition, an immunohistochemistry ERBB2 score of 3 or higher and ERBB2-enriched subtype were predictors of higher pCR rates in both arms (Gluz et al). This study not only supports a deescalated chemotherapy neoadjuvant strategy of paclitaxel + dual HER2 blockade but also suggests that a portion of patients may potentially be spared chemotherapy with very good results. The role of biomarkers is integral to patient selection for these approaches, and the evaluation of response in real-time will allow for the tailoring of therapy to achieve the best outcome.

Systemic staging for locally advanced breast cancer (LABC) is important for informing prognosis as well as aiding in development of an appropriate treatment plan for patients. The PETABC study included 369 patients with LABC (TNM stage III or IIB [T3N0]) with random assignment to ¹⁸F-labeled fluorodeoxyglucose PET-CT or conventional staging (bone scan, CT of chest/abdomen/pelvis), and was designed to assess the rate of upstaging with each imaging modality and effect on treatment (Dayes et al). In the PET-CT group, 23% (N = 43) of patients were upstaged to stage IV compared with 11% (N = 21) in the conventional-staging group (absolute difference 12.3%; 95% CI 3.9-19.9; P = .002). Fewer patients in the PET-CT group received combined modality treatment vs those patients in the conventional staging group (81% vs 89.2%; P = .03). These results support the consideration of PET-CT as a staging tool for LABC, and this is reflected in various clinical guidelines. Furthermore, the evolving role of other imaging techniques such as ¹⁸F-fluoroestradiol (18F-FES) PET-CT in detection of metastatic lesions related to estrogen receptor–positive breast cancer³ will continue to advance the field of imaging.

Additional References

1. Rugo HS, Lerebours F, Ciruelos E, et al. Alpelisib plus fulvestrant in PIK3CA-mutated, hormone receptor-positive advanced breast cancer after a CDK4/6 inhibitor (BYLieve): One cohort of a phase 2, multicentre, open-label, non-comparative study. Lancet Oncol. 2021;22:489-498. doi: 10.1016/S1470-2045(21)00034-6. Erratum in: Lancet Oncol. 2021;22(5):e184. doi: 10.1016/S1470-2045(21)00194-7
2. Prat A, Pascual T, De Angelis C, et al. HER2-enriched subtype and ERBB2 expression in HER2-positive breast cancer treated with dual HER2 blockade. J Natl Cancer Inst. 2020;112:46-54. doi: 10.1093/jnci/djz042
3. Ulaner GA, Jhaveri K, Chandarlapaty S, et al. Head-to-head evaluation of ¹⁸F-FES and ¹⁸F-FDG PET/CT in metastatic invasive lobular breast cancer. J Nucl Med. 2021;62:326-331. doi: 10.2967/jnumed.120.247882

Silverberg and colleagues described a very well-designed, vehicle-controlled, randomized 8-week study of a topical formulation of a purified strain of Nitrosomonas eutropha, an ammonia-oxidizing bacterium. In theory, this bacterium may reduce Staphylococcus aureus. The study compared two concentrations of the bacterium vs vehicle delivered as a spray twice per day. Study participants were adults with AD affecting 10%-40% of body surface area.

The study found "meaningful" improvements in itch and objective signs of disease, with clear separation between both doses of the bacterial spray compared with vehicle. At week 4, about 23% of participants treated with the bacterium were clear or almost clear (with a 2-point improvement) compared with 12% in the vehicle group (for comparison, in a phase 2 study comparing topical ruxolitinib with 0.1% triamcinolone cream, there was a 25% clear or almost clear rate [with 2-point improvement] in the triamcinolone-treated individuals).

Though an "all-natural" bacterial approach to managing AD may be appealing to some, it sounded like magic to me. But this well-done study makes it seem like the bacterial approach could be more promising than I had thought. This study also reported about twice as many adverse events (including gastrointestinal issues) with the bacterium-treated participants compared with those who received vehicle, adding to my belief that the bacterial product has efficacy. Whether any other topical will be more effective and safer than is topical triamcinolone remains to be seen. I'm still pessimistic about topicals because of patients' poor adherence to topical treatment, but perhaps an easy-to-use spray that isn't associated with patients' fear of "steroids" will be helpful.

Chen and colleagues. They analyzed data on hundreds of thousands of patients with and without AD. Adults with AD had a "significantly increased risk" of developing venous thromboembolism compared with adults without AD. The huge sample size of their study seems compelling. That huge sample size allows detection of effects so small that they may be clinically insignificant.

They report that patients with AD had a venous thromboembolism at a rate of 1.05/1000 patients-years; the rate was 0.82 for patients without AD. From that, we can calculate that there would be an additional 23 patients with venous thromboembolism for every 100,000 patient-years or about one more venous thromboembolism in the AD group in every 4000 patient-years. Though the finding was statistically significant, I don't think it is clinically meaningful.

The authors correctly conclude that "vascular examination and consultation with the emergency department, cardiologists, or pulmonologists are indicated for patients with AD who present with relevant symptoms (eg, unexplained dyspnea, chest tightness, and limb swelling)." But it is probably also true that vascular examination and consultation with the emergency department, cardiologists, or pulmonologists are indicated for patients without AD who present with those symptoms. I think the authors might have been on solid ground if they had concluded that there was a statistically significant but clinically insignificant increased risk for venous thromboembolism in patients with AD.

Eichenfeld and colleagues examined the use of topical crisaborole once per day as a maintenance treatment for patients with mild to moderate AD. The study compared patients given topical crisaborole with those randomly assigned to vehicle. The active treatment was effective because topical crisaborole treated patients had longer times to the first flare following treatment and fewer flares over the 1 year of treatment. The differences were not huge, but I think they were clinically meaningful. I'm guessing that the topical crisaborole maintenance treatment would have been even more effective had it been used regularly. The study did not, as far as I could tell, assess how well the treatment was used.

An interesting aspect of this study is that it began with nearly 500 participants who started on twice daily topical crisaborole. The 270 patients who responded to the treatment (achieving clear or almost clear with at least a 2-point improvement) were enrolled in the 1-year maintenance phase. Thus, the participants in the maintenance phase were preselected for patients who respond to topical crisaborole. We don't know why they were responders (I, of course, expect it is because they selected for patients who are better than others are at using a topical treatment), but it may be best not to try to generalize these results and assume this form of maintenance treatment would work equally well in a population who achieve initial success with an oral therapy regimen (for example, a quick course of oral prednisone).

Dupilumab was a revolutionary treatment for AD. I didn't think that I'd ever see a more effective treatment. It's so safe too! It has been a first-line treatment for AD since its introduction. Now, we also have oral Janus kinase inhibitor options. Blauvelt and colleagues examined what happens when patients who have been on dupilumab are switched to a high dose (30 mg/d) of upadacitinib (the standard starting dose of upadacitinib is 15 mg/d). Though dupilumab is very effective, upadacitinib is more so. After 4 weeks of switching to upadacitinib, nearly half the patients were completely clear of AD compared with only 16.0% after 24 weeks of dupilumab! The authors point out, optimistically, that "No new safety risks were observed." Though there were no cancers, gastrointestinal perforations, major adverse cardiovascular events, or venous thromboembolic events, there were cases of eczema herpeticum and zoster in patients treated with upadacitinib. Having upadacitinib available for patients who fail dupilumab is a clear benefit; the role of upadacitinib before dupilumab seems less clear.

Patients doing great on dupilumab for AD may be wondering: Do I still need to take it every 2 weeks? Spekhorst and colleagues may have the answer. They describe the response to tapering dupilumab in patients who had been on the drug for at least 1 year with well-controlled disease for at least 6 months. Patients in the study then continued dupilumab with the longest possible dosing interval while maintaining control of their AD.

Generally, patients maintained good control of their AD, with only a small increase in mean disease severity and in concomitant use of topical steroids. For the patients who attempted prolongation, 83% successfully continued dupilumab treatment with a prolonged interval. Not at all surprisingly, the authors calculated that prolonging the interval between dosing led to large savings in cost.

One of the nice features of dupilumab treatment is that loss of response over time seems unusual. Perhaps there is a low propensity for forming antidrug antibodies when dupilumab is used in the standard every 2-week dosing regimen. I don't know whether antidrug antibodies would be more likely with the intermittent dosing regimen. But now that we have other good systemic treatment options for AD, losing dupilumab efficacy would not be as critical a problem as it used to be. I also want to point out that patients' adherence to injection treatment, though better than adherence to topicals, is far from perfect. It's likely that many patients have already been prolonging the interval between taking their treatments. If you want to know, just ask them. The way I like to phrase the question is: "Are you keeping the extra injectors you've accumulated refrigerated like you are supposed to?"

Silverberg and colleagues described a very well-designed, vehicle-controlled, randomized 8-week study of a topical formulation of a purified strain of Nitrosomonas eutropha, an ammonia-oxidizing bacterium. In theory, this bacterium may reduce Staphylococcus aureus. The study compared two concentrations of the bacterium vs vehicle delivered as a spray twice per day. Study participants were adults with AD affecting 10%-40% of body surface area.

The study found "meaningful" improvements in itch and objective signs of disease, with clear separation between both doses of the bacterial spray compared with vehicle. At week 4, about 23% of participants treated with the bacterium were clear or almost clear (with a 2-point improvement) compared with 12% in the vehicle group (for comparison, in a phase 2 study comparing topical ruxolitinib with 0.1% triamcinolone cream, there was a 25% clear or almost clear rate [with 2-point improvement] in the triamcinolone-treated individuals).

Though an "all-natural" bacterial approach to managing AD may be appealing to some, it sounded like magic to me. But this well-done study makes it seem like the bacterial approach could be more promising than I had thought. This study also reported about twice as many adverse events (including gastrointestinal issues) with the bacterium-treated participants compared with those who received vehicle, adding to my belief that the bacterial product has efficacy. Whether any other topical will be more effective and safer than is topical triamcinolone remains to be seen. I'm still pessimistic about topicals because of patients' poor adherence to topical treatment, but perhaps an easy-to-use spray that isn't associated with patients' fear of "steroids" will be helpful.

Chen and colleagues. They analyzed data on hundreds of thousands of patients with and without AD. Adults with AD had a "significantly increased risk" of developing venous thromboembolism compared with adults without AD. The huge sample size of their study seems compelling. That huge sample size allows detection of effects so small that they may be clinically insignificant.

They report that patients with AD had a venous thromboembolism at a rate of 1.05/1000 patients-years; the rate was 0.82 for patients without AD. From that, we can calculate that there would be an additional 23 patients with venous thromboembolism for every 100,000 patient-years or about one more venous thromboembolism in the AD group in every 4000 patient-years. Though the finding was statistically significant, I don't think it is clinically meaningful.

The authors correctly conclude that "vascular examination and consultation with the emergency department, cardiologists, or pulmonologists are indicated for patients with AD who present with relevant symptoms (eg, unexplained dyspnea, chest tightness, and limb swelling)." But it is probably also true that vascular examination and consultation with the emergency department, cardiologists, or pulmonologists are indicated for patients without AD who present with those symptoms. I think the authors might have been on solid ground if they had concluded that there was a statistically significant but clinically insignificant increased risk for venous thromboembolism in patients with AD.

Eichenfeld and colleagues examined the use of topical crisaborole once per day as a maintenance treatment for patients with mild to moderate AD. The study compared patients given topical crisaborole with those randomly assigned to vehicle. The active treatment was effective because topical crisaborole treated patients had longer times to the first flare following treatment and fewer flares over the 1 year of treatment. The differences were not huge, but I think they were clinically meaningful. I'm guessing that the topical crisaborole maintenance treatment would have been even more effective had it been used regularly. The study did not, as far as I could tell, assess how well the treatment was used.

An interesting aspect of this study is that it began with nearly 500 participants who started on twice daily topical crisaborole. The 270 patients who responded to the treatment (achieving clear or almost clear with at least a 2-point improvement) were enrolled in the 1-year maintenance phase. Thus, the participants in the maintenance phase were preselected for patients who respond to topical crisaborole. We don't know why they were responders (I, of course, expect it is because they selected for patients who are better than others are at using a topical treatment), but it may be best not to try to generalize these results and assume this form of maintenance treatment would work equally well in a population who achieve initial success with an oral therapy regimen (for example, a quick course of oral prednisone).

Dupilumab was a revolutionary treatment for AD. I didn't think that I'd ever see a more effective treatment. It's so safe too! It has been a first-line treatment for AD since its introduction. Now, we also have oral Janus kinase inhibitor options. Blauvelt and colleagues examined what happens when patients who have been on dupilumab are switched to a high dose (30 mg/d) of upadacitinib (the standard starting dose of upadacitinib is 15 mg/d). Though dupilumab is very effective, upadacitinib is more so. After 4 weeks of switching to upadacitinib, nearly half the patients were completely clear of AD compared with only 16.0% after 24 weeks of dupilumab! The authors point out, optimistically, that "No new safety risks were observed." Though there were no cancers, gastrointestinal perforations, major adverse cardiovascular events, or venous thromboembolic events, there were cases of eczema herpeticum and zoster in patients treated with upadacitinib. Having upadacitinib available for patients who fail dupilumab is a clear benefit; the role of upadacitinib before dupilumab seems less clear.

Patients doing great on dupilumab for AD may be wondering: Do I still need to take it every 2 weeks? Spekhorst and colleagues may have the answer. They describe the response to tapering dupilumab in patients who had been on the drug for at least 1 year with well-controlled disease for at least 6 months. Patients in the study then continued dupilumab with the longest possible dosing interval while maintaining control of their AD.

Generally, patients maintained good control of their AD, with only a small increase in mean disease severity and in concomitant use of topical steroids. For the patients who attempted prolongation, 83% successfully continued dupilumab treatment with a prolonged interval. Not at all surprisingly, the authors calculated that prolonging the interval between dosing led to large savings in cost.

One of the nice features of dupilumab treatment is that loss of response over time seems unusual. Perhaps there is a low propensity for forming antidrug antibodies when dupilumab is used in the standard every 2-week dosing regimen. I don't know whether antidrug antibodies would be more likely with the intermittent dosing regimen. But now that we have other good systemic treatment options for AD, losing dupilumab efficacy would not be as critical a problem as it used to be. I also want to point out that patients' adherence to injection treatment, though better than adherence to topicals, is far from perfect. It's likely that many patients have already been prolonging the interval between taking their treatments. If you want to know, just ask them. The way I like to phrase the question is: "Are you keeping the extra injectors you've accumulated refrigerated like you are supposed to?"

Silverberg and colleagues described a very well-designed, vehicle-controlled, randomized 8-week study of a topical formulation of a purified strain of Nitrosomonas eutropha, an ammonia-oxidizing bacterium. In theory, this bacterium may reduce Staphylococcus aureus. The study compared two concentrations of the bacterium vs vehicle delivered as a spray twice per day. Study participants were adults with AD affecting 10%-40% of body surface area.

The study found "meaningful" improvements in itch and objective signs of disease, with clear separation between both doses of the bacterial spray compared with vehicle. At week 4, about 23% of participants treated with the bacterium were clear or almost clear (with a 2-point improvement) compared with 12% in the vehicle group (for comparison, in a phase 2 study comparing topical ruxolitinib with 0.1% triamcinolone cream, there was a 25% clear or almost clear rate [with 2-point improvement] in the triamcinolone-treated individuals).

Though an "all-natural" bacterial approach to managing AD may be appealing to some, it sounded like magic to me. But this well-done study makes it seem like the bacterial approach could be more promising than I had thought. This study also reported about twice as many adverse events (including gastrointestinal issues) with the bacterium-treated participants compared with those who received vehicle, adding to my belief that the bacterial product has efficacy. Whether any other topical will be more effective and safer than is topical triamcinolone remains to be seen. I'm still pessimistic about topicals because of patients' poor adherence to topical treatment, but perhaps an easy-to-use spray that isn't associated with patients' fear of "steroids" will be helpful.

Chen and colleagues. They analyzed data on hundreds of thousands of patients with and without AD. Adults with AD had a "significantly increased risk" of developing venous thromboembolism compared with adults without AD. The huge sample size of their study seems compelling. That huge sample size allows detection of effects so small that they may be clinically insignificant.

They report that patients with AD had a venous thromboembolism at a rate of 1.05/1000 patients-years; the rate was 0.82 for patients without AD. From that, we can calculate that there would be an additional 23 patients with venous thromboembolism for every 100,000 patient-years or about one more venous thromboembolism in the AD group in every 4000 patient-years. Though the finding was statistically significant, I don't think it is clinically meaningful.

The authors correctly conclude that "vascular examination and consultation with the emergency department, cardiologists, or pulmonologists are indicated for patients with AD who present with relevant symptoms (eg, unexplained dyspnea, chest tightness, and limb swelling)." But it is probably also true that vascular examination and consultation with the emergency department, cardiologists, or pulmonologists are indicated for patients without AD who present with those symptoms. I think the authors might have been on solid ground if they had concluded that there was a statistically significant but clinically insignificant increased risk for venous thromboembolism in patients with AD.

Eichenfeld and colleagues examined the use of topical crisaborole once per day as a maintenance treatment for patients with mild to moderate AD. The study compared patients given topical crisaborole with those randomly assigned to vehicle. The active treatment was effective because topical crisaborole treated patients had longer times to the first flare following treatment and fewer flares over the 1 year of treatment. The differences were not huge, but I think they were clinically meaningful. I'm guessing that the topical crisaborole maintenance treatment would have been even more effective had it been used regularly. The study did not, as far as I could tell, assess how well the treatment was used.

An interesting aspect of this study is that it began with nearly 500 participants who started on twice daily topical crisaborole. The 270 patients who responded to the treatment (achieving clear or almost clear with at least a 2-point improvement) were enrolled in the 1-year maintenance phase. Thus, the participants in the maintenance phase were preselected for patients who respond to topical crisaborole. We don't know why they were responders (I, of course, expect it is because they selected for patients who are better than others are at using a topical treatment), but it may be best not to try to generalize these results and assume this form of maintenance treatment would work equally well in a population who achieve initial success with an oral therapy regimen (for example, a quick course of oral prednisone).

Dupilumab was a revolutionary treatment for AD. I didn't think that I'd ever see a more effective treatment. It's so safe too! It has been a first-line treatment for AD since its introduction. Now, we also have oral Janus kinase inhibitor options. Blauvelt and colleagues examined what happens when patients who have been on dupilumab are switched to a high dose (30 mg/d) of upadacitinib (the standard starting dose of upadacitinib is 15 mg/d). Though dupilumab is very effective, upadacitinib is more so. After 4 weeks of switching to upadacitinib, nearly half the patients were completely clear of AD compared with only 16.0% after 24 weeks of dupilumab! The authors point out, optimistically, that "No new safety risks were observed." Though there were no cancers, gastrointestinal perforations, major adverse cardiovascular events, or venous thromboembolic events, there were cases of eczema herpeticum and zoster in patients treated with upadacitinib. Having upadacitinib available for patients who fail dupilumab is a clear benefit; the role of upadacitinib before dupilumab seems less clear.

Patients doing great on dupilumab for AD may be wondering: Do I still need to take it every 2 weeks? Spekhorst and colleagues may have the answer. They describe the response to tapering dupilumab in patients who had been on the drug for at least 1 year with well-controlled disease for at least 6 months. Patients in the study then continued dupilumab with the longest possible dosing interval while maintaining control of their AD.

Generally, patients maintained good control of their AD, with only a small increase in mean disease severity and in concomitant use of topical steroids. For the patients who attempted prolongation, 83% successfully continued dupilumab treatment with a prolonged interval. Not at all surprisingly, the authors calculated that prolonging the interval between dosing led to large savings in cost.

One of the nice features of dupilumab treatment is that loss of response over time seems unusual. Perhaps there is a low propensity for forming antidrug antibodies when dupilumab is used in the standard every 2-week dosing regimen. I don't know whether antidrug antibodies would be more likely with the intermittent dosing regimen. But now that we have other good systemic treatment options for AD, losing dupilumab efficacy would not be as critical a problem as it used to be. I also want to point out that patients' adherence to injection treatment, though better than adherence to topicals, is far from perfect. It's likely that many patients have already been prolonging the interval between taking their treatments. If you want to know, just ask them. The way I like to phrase the question is: "Are you keeping the extra injectors you've accumulated refrigerated like you are supposed to?"